IPI Summer 2022

Page 1

Volume 14 Issue 2

Peer Reviewed

Annex 1 Implementation of the Final Draft Applying Advanced Powder Testing to Tackle the Toughest Formulation Challenges Achieving Faster Investigational New Drug Timelines with a Robust Cell Line Development Strategy Shared Care Strengthening Self-management Support for Chronic Patients

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

DIRECTOR: Mark A. Barker BUSINESS DEVELOPMENT: Michael Hossain michael@senglobalcoms.com EDITORIAL: Virginia Toteva virginia@senglobalcoms.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Akash Shama accounts@senglobal.com RESEARCH & CIRCULATION: Jessica Chapman jessica@senglobalcoms.com COVER IMAGE: iStockphoto © PUBLISHED BY: Senglobal Ltd. Unit 5.02, E1 Studios, 7 Whitechapel Road, E1 1DU, United Kingdom Tel: +44 (0) 2045417569 Email: info@senglobalcoms.com www.international-pharma.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Autumn 2022. ISSN No.International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2022 Senglobal Ltd./Volume 14 Issue 2 – Summer – 2022


08 PDA Europe Annex 1 Workshop The Pharmaceutical world and those involved with the manufacture of sterile products, is anxiously looking out for the publication of the final approved revision of EudraLex Annex 1 “Manufacture of Sterile Products. Organisations must prepare themselves based on the text of Draft Revision 12 that was published in February 2020. In support of preparation, PDA organised several workshops using the publicised Revision 12 as a reference point. The 2022 PDA Annex 1 Workshop held on 16 & 17 May in Dublin was the second of a series of four and the first one on European soil. Delegates had the opportunity to discuss their interpretation, challenges and possible solutions with peers from the industry. Patrick Nieuwenhuizen, Director Senior Consultant at PharmaLex, summarises the main takeaways from this forum. 10 Annex 1-Implementation of the Final Draft Annex 1 “Manufacture of Sterile Medicinal Products” was first published in 1971 and forms part of EudraLex Volume 4 [1], that interprets the basic principles of GMP as detailed in European Directive 2003/94/ EEC [2]. Annex 1 provides guidance on the minimum controls that are required to protect sterile medicinal products during manufacturing. Patrick Nieuwenhuizen, Director Senior Consultant at PharmaLex gives a brief overview of the new Annex 1. The overall message for manufacturers of sterile products is to ensure the systems and processes are in place to demonstrate sustainable control of the entire process and associated facilities, therewith ensuring product safety and ultimately protection of the patient. 14 Latest Developments in IP Strategies for Pharmaceuticals The strategies used to create and maintain strong-pharmaceutical patent portfolios must evolve with developments in the pharmaceutical space. These developments include not just scientific advancements but also requirements and practices of regulatory bodies, such as the United States Food and Drug Administration (FDA). This article by Sara A. Leiman, Jordan Gringauz, Stacy Lewis, and Amanda K. Murphy at Finnegan addresses innovative prosecution strategies and usable considerations that may facilitate a better agreement between pharmaceutical patent practice and FDA policy. 18 Pharma’s Time to Jointly Redefine Healthcare is Now The challenge of ensuring healthcare sustainability, the rise in more targeted treatments, and a shift in emphasis to preventative interventions, not to mention the importance of patient centricity in determining healthcare decisions, are creating a perfect storm for the transformation of healthcare systems and pharma’s role within them. Here, Gérard Klop of Vintura Consultancy explores how pharma’s new role will evolve in an increasingly value-based healthcare scenario. The challenges companies will encounter as they reinvent themselves and the cultural and organisational changes that will be required. 20 The New Age in Strategic Outsourcing Lies in the Mature Portfolio Companies must safeguard their mature portfolios while continuously innovating and developing new products. But in-house resources are stretched and often lack the broader knowledge needed to ensure best practices for ongoing maintenance activities. As a result, traditional models of outsourcing – the low-cost, “lift and shift” approach of the past – are giving way to a more nuanced, strategic approach. One that leverages external expertise globally and delivers more efficient methods for supporting the product lifecycle. Dr. Constanze Burkhardt, Vice President, Head of Program Management at Pharmalex, explores why outsourcing the mature portfolio has become an industry priority. INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

Contents 24 Pathway for Marketing Authorization Approval of Medical Device in US The process of developing a revolutionary medical device from the proof-of-concept stage to the marketing stage is expensive and complicated. The creation of a new product is a costly and timeconsuming endeavour. Demonstrating the safety and efficacy of the technology is just as crucial as the innovation itself. Deeksha K S, et all at JSS College of Pharmacy, discusses why these requirements can assist you to update your development operations and create a product that fulfils the regulatory standards of a safe and effective product for its intended application. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 32 Applying Advanced Powder Testing to Tackle the Toughest Formulation Challenges The application of high throughput screening techniques and computational chemistry has resulted in a marked shift in drug candidates with identified therapeutic potential, increasing the prevalence of BCS Class II and IV compounds. Faced with a growing need to effectively develop these drugs, formulators are becoming increasingly reliant on more complex and sophisticated strategies. The intensifying requirement to effectively formulate Class II and IV drugs increases the need to optimise analytical strategies. Jamie Clayton at Freeman Technology considers the value of powder rheometry within this context, focusing on its ability to support innovative product development. 38 Option 1 - Pressure’s on: How Roller Compaction is Helping Pharma’s Formulators Achieve Better Poorly Soluble API Delivery Advances in combinatorial chemistry and high-throughput screening continue to introduce poorly water-soluble active ingredient (API) chemistries into pharmaceutical development. For more than 25 years, high-throughput chemistries and techniques have driven a dramatic increase in the number of poorly water-soluble drug candidates in development. Anshul Gupte at Metrics Contract Services discusses how pharmacologists are now better able to successfully synthesize more potential candidate compounds and efficiently optimize drugreceptor binding to achieve better selectivity. 40 Crystallisation Development – A Quality by Design Approach using Modelling Nearly all synthetic steps in industrial chemical manufacturing end with a crystallisation. This is because it is almost always the most efficient method to purify and isolate the material. While most chemists are proficient at coming up with a basic procedure, when it comes down to the fine details, often crystallisation is seen as a mysterious process and subject to factors beyond our control. Various quality issues may be important for the product: purity, residual solvents, filtration speed, polymorph, crystal habit, particle size distribution. Steve Winter at Solitek explains how an in-depth understanding of the crystallisation process will help keep these issues under control. CLINICAL & MEDICAL RESEARCH 42 Achieving faster Investigational New Drug timelines with a robust cell line development strategy Technological advances in drug manufacturing equipment and process optimisation play a significant role in increasing the speed of the clinic of critical biologic drugs. Although implementing new technologies and strategies can shorten drug development and manufacturing timelines, there is still one consistently time-consuming area: cell line development. Even with well-established automated platforms, 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

it typically takes three months to complete cell line development (CLD) while working towards an Investigative New Drug (IND) filing. In this article, Youlim Kim at Samsung Biologics America explores the challenges associated with CLD and offers an expert look into the tactics contract development and manufacturing organisations (CDMOs) can employ to shorten commercial timelines. 44 COVID-19 and Sepsis Co-infection: The Impact of Advanced Detection and Diagnosis Sepsis is characterised as life-threatening and fast-progressing organ dysfunction caused by a dysregulated host response to infection. Sepsis shares several clinical manifestations with COVID-19, making diagnosis challenging. SARS-CoV-2 co-infection, where an individual may be infected with the virus and one or more additional pathogens concomitantly, leads to both innate and adaptive immune responses, which in some cases of severe disease, can become dysfunctional and cause significant lung and systemic pathology. Philip Perry at Bruker Daltonics GmbH & Co. explains why it is vitally important to rapidly detect co-infection in COVID-19 patients and accurately identify causative pathogens to deliver effective treatment. TECHNOLOGY 46 Transforming The Status Quo Through Digitalisation and AI For all the extraordinary innovations made in the field of medical science, in many ways we are still working in the dark. Take renal transplants. When it comes to selecting kidneys for transplantation, the status quo is an unsatisfactory compromise based largely on a hopeful assumption as to the health of the donated organ – primarily based on the age of the donor – with very little empirical evidence. If the status quo can be improved, in this one field out of many, there are priceless potential benefits to patients and healthcare systems everywhere. Simon Tilley at SAS, discuss the collaborative partnership between SAS & The University of Cambridge for identifying ways in which the process of selecting kidneys for transplantation could be better delivered through AI-augmented interpretation of renal biopsies. 48 The Importance of User Insights in Digital Product Design Gathering user insights should be a key part of any medical device development. Understanding your user’s context of use, behaviours and views can allow you to design a solution that meets actual user needs. The use of technologies, such as smart phones, social networks, and internet applications, is not only changing the way we communicate, but also providing innovative ways for us to monitor our health and well-being and giving us greater access to information. Charlotte Harris at Team Consulting explains that these advancements are leading to a convergence of people, information, technology, and connectivity to improve health care and health outcomes. MANUFACTURING 52 Does Remote Pharma GMP Auditing Have a Future? The two years since COVID struck, have seen virtual auditing checks and inspections take the place of on-site visits. Some auditors believe that the tools and adapted services they have developed during the pandemic might offer a permanent solution, but deeper analysis shows that clients have misgivings about this scenario. Two years on from the first wave of COVID and following a new survey that was conducted in February 2022, Alasdair Leckie at Rephine, looks at clients’ auditing preferences. 54 New Manufacturing Technology Platforms for Biosimilars Innovation in process and bioreactor technology, better understanding Summer 2022 Volume 14 Issue 2

KLINGE TEMPERATURE CONTROL The Biopharma Cold Chain Sourcebook (a leading resource to the pharmaceutical industry) recently reported: “Recent Good Distribution Practice (GDP) guidelines, to which the industry is gradually adopting, require control of even room-temperature product, which is essentially everything that is not refrigerated or frozen. With each passing year, the oversight of pharmaceutical and biologics shipping is getting tighter.” Klinge Corporation has been safely transporting and storing pharmaceuticals for over 30 years. Protect your product with our qualified refrigerated and deep freezer containers.

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Contents of cell lines, advances in analytical methods and equipment, continuous processing, single-use technologies, has accelerated, de-risked and lowered the cost for biosimilar development. Regulators are similarly clearing the path for biosimilar developers to enter the market. Biosimilar developers and CDMOs operating in the space that have invested in the appropriate technologies and have the expertise in handling other biologics have an immediate, inherent advantage over reference molecule owners. Gerrit Hagens at BioXpress Therapeutics and Simon Keen at Abzena’s Scientific Leadership Group, explains that, as more biosimilar products clear the final commercial hurdle, it becomes vital that manufacturers maintain focus on quickly and efficiently moving through development and stripping costs from their processes wherever possible.

Earl at Owen Mumford Ltd discusses the benefits of supported patient self-care and self-administration.

58 Big Strides in Small Batch Aseptic Processing Growing demand for small-batch processing, poses new challenges for the life sciences sector. Adapting to variances while maintaining quality, efficiency and adherence to aseptic processing requirements are more complex than ever. Advanced Aseptic Processing (AAP) systems, enabled by robotics and other advanced technologies, offer inventive solutions. Mathias Konne at Stäubli Corporation discusses the prime example of the aseptic small batch filling and closing machine from Automated Systems of Tacoma (AST).


60 Making a Case for a Fixed Dose Combination Drug Strategy Over the past two decades, pharma’s acute focus on the patient has driven great innovation and investment in ways to deliver active pharmaceutical ingredients (APIs) in finished drug products. Every aspect of the dose and formulation, colour and size, taste and texture, controlled release, and dosing frequency, can have an impact on therapeutic performance Oral administration is the most convenient method of drug administration for patients due to the ease and flexibility of dosing. Rob Pratt and Dáire O'Donnell at Pfizer explains why this makes it the route preferred by health care providers and drug developers. PACKAGING 62 Tackling Pharma’s Shadow Market: Getting ‘Smarter’ in the Fight Against Fake Pharmaceuticals If you were to ask a member of the public “what is the world’s most counterfeited product?”, it’s highly likely they’ll say designer handbags or watches. But, in fact, the world’s largest fraud market is pharmaceuticals – and by a large margin. The larger the industry supplying a consumer product, the more likely it is that criminals will try and exploit it. And with counterfeit and falsified medicine, the profits can be huge. But so too can the risks to public health and the industry’s reputation. Rich Quelch at Origin explains why this risk is growing, accelerated by the disruption of the COVID-19 pandemic, complex global supply chains, widening access to healthcare in emerging economies and the rise of pharmaceutical e-commerce.

70 The Benefits of Patient Centricity in Clinical Trials: How it Can Support Clinical Operations and Study Adherence Patient centricity in clinical operations and study adherence is growing in popularity. A patient-centric approach means that the needs of patients are placed at the forefront of all decisions and actions within healthcare organisations. This includes all aspects of care, from research and development of new treatments to delivery of care. Patient centricity can be summed up by the phrase "the patient comes first." Karen Ooms at Quanticate explains the many benefits to implementing a patient-centric approach in clinical trials. Listening to Healthcare Professionals and Patients Through Co-creation Working in partnership with patients and healthcare professionals is becoming a core part of the design of patient education. But how should pharmaceutical companies balance the needs of multiple different stakeholders? Alex Merckx at Cognitant explains how listening and discussion can deliver successful co-creation. Financial Barriers to Participation: The Missing Piece of the Patient Centric Jigsaw The patient-centricity revolution has seen the industry pour resources into ensuring clinical trials place the needs of participants front and centre of drug development plans. Collecting insights to inform study design, for example, is a tried and tested method of increasing recruitment and retention rates – but that work is wasted if financial barriers render participation unfeasible. Caroline Jackson of mdgroup speaks about modern automated payment systems that combine technology and the human touch. 76

LOGISTICS & SUPPLY CHAIN MANAGEMENT 78 Maintaining Integrity of the Pharma Cold Chain Two years since the start of the Covid-19 pandemic, the social and economic implications are still being felt on a global scale. The pandemic has impacted practically every phase of our lives, and it also greatly influenced the cold chain logistics industry bringing new challenges and requirements. This challenge is predicted only to get bigger as mRNA vaccine technology is applied to tackling other diseases – from cancer and flu to malaria and HIV. It’s a technology that’s revolutionising the pharmaceutical sector and ushering in a new era of vaccinology. Muge Suner at Thermo King identifies a clear sign that ultra-cold temporary storage, as well as 15–25°C and 2–8°C temperature ranges will, be a common need for pharmaceutical transport and logistics in the future.

HEALTH OUTCOMES 66 Shared Care: Strengthening Self-management Support for Chronic Patients In recent years, converging healthcare trends have been creating more empowered patients. Before the pandemic, patients could already monitor their own condition through connected devices such as glucose monitors for diabetes. Self-administration of injectable medication had become more prevalent; the development of biologics for subcutaneous administration coincided with the need to treat rising cases of chronic diseases, and an ageing population presenting comorbidities. Michael 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2022 Volume 14 Issue 2

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Editor's Letter The manufacture of sterile medicinal products covers a wide range of product types, (sterile active substance through to finished dosage form), batch sizes (single unit to multiple units), processes (from highly automated systems to manual processes), primary packaging materials and technologies (e.g., biotechnology, classical small molecule manufacturing and closed systems). This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product. The intent of the Annex is to provide guidance for sterile medicinal products. However, some of the principles and guidance, such as contamination control strategy, room qualification, classification, monitoring, and gowning, may be used to support the manufacture of other products that are not intended to be sterile (such as certain liquids, creams, ointments and low bioburden biological intermediates) but where the control of microbial, particulate and pyrogen contamination, to reduce it as far as possible, is considered important. The Pharmaceutical world and those involved with the manufacture of sterile products, is anxiously looking out for the publication of the final approved revision of EudraLex Annex 1 “Manufacture of Sterile Products. Organisations must prepare themselves based on the text of Draft Revision 12 that was published in February 2020. In support of preparation, PDA organised several workshops using the publicised Revision 12 as a reference point. The 2022 PDA Annex 1 Workshop held on 16 & 17 May in Dublin was the second of a series of four and the first one on European soil. Delegates had the opportunity to discuss their interpretation, challenges, and possible solutions with peers from the industry. Patrick Nieuwenhuizen, Director Senior Consultant at PharmaLex, summarises the main takeaways from this forum.

In the Drug Development Section, we have a very important article by Steve Winter of Solitek on Crystallisation Development. Nearly all synthetic steps in industrial chemical manufacturing end with a crystallisation. This is because it is almost always the most efficient method to purify and isolate the material. While most chemists are proficient at coming up with a basic procedure, when it comes down to the fine details, often crystallisation is seen as a mysterious process and subject to factors beyond our control.

Rob Pratt and Dáire O'Donnell of Pfizer, makes a Case for a Fixed Dose Combination Drug Strategy. Over the past two decades, pharma’s acute focus on the patient has driven great innovation and investment in ways to deliver active pharmaceutical ingredients (APIs) in finished drug products. Every aspect of the dose and formulation, colour and size, taste and texture, controlled release, and dosing frequency, can have an impact on therapeutic performance Oral administration is the most convenient method of drug administration for patients due to the ease and flexibility of dosing.

The Manufacturing Section begins with trying to ascertain if Remote Pharma GMP Auditing Have a Future? Alasdair Leckie at Rephine, looks at clients’ auditing preferences.

I hope you all enjoy this issue of IPI and look forward to meeting you all with the Autumn edition. Lucy Robertshaw, CEO LucyJRobertshaw

Welcome to the Summer Issue of IPI. From this issue onwards we will feature a new section titled – Health Outcomes. Health outcomes are defined as those events occurring because of an intervention. These may be measured clinically (physical examination, laboratory testing, imaging), self-reported, or observed (such as gait or movement fluctuations seen by a healthcare provider or caregiver). Some health outcomes require complex assessments to determine if they are present or absent. Health outcomes form the denominator of the value equation, generally understood to be the health outcomes achieved that matter to patients relative to the cost of achieving those outcomes. It is a complicated and vast area and requires the input of clinicians and patients, who will need to work together, possibly on a global scale, to agree and develop health outcomes measures. Michael Earl at Owen Mumford, in the article titled “Shared Care: Strengthening Selfmanagement Support for Chronic Patients In recent years” (Page 66) discusses the benefits of

supported patient self-care and self-administration. Karen Ooms at Quanticate explains the many benefits to implementing a patientcentric approach in clinical trials. (Page 70) & Caroline Jackson of mdgroup within her article “Financial Barriers to Participation: The Missing Piece of the Patient Centric Jigsaw” (Page 76), explains the modern automated payment systems that combine technology and the human touch. The IPI Journal, your first choice for indepth, peer reviewed, knowledge bank for the pharma industry is partnering with multiple exhibitions and conferences this year. The likes of Connect in Pharma (14th–15th September in Geneva), CPHI/ICSE (1st–3rd November in Frankfurt), ELRIG (4th–5th October in London), Festival of Biologics (2nd–4th November in Basel) & many more. I hope to meet some of you at these events. I hope you enjoy this edition of IPI & my team and I look forward to bringing you more innovative and though provoking articles in the future issues. Virginia Toteva, Editorial Manager – IPI

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

Georg Mathis Founder and Managing Director, Appletree AG

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Deborah A. Komlos, Principal Content Writer, Clarivate

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

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

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

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

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB T S Jaishankar, Managing Director, QUEST Life Sciences Summer 2022 Volume 14 Issue 2




Regulatory & Marketplace

PDA Europe Annex 1 Workshop Patrick Nieuwenhuizen Summarises the Key Take Aways from the Event The Pharmaceutical world, in particular those involved with the manufacture of sterile products, is anxiously looking out for the publication of the final approved revision of EudraLex Annex 1 “Manufacture of Sterile Products”. The latest information received is that this is expected during the Summer – which could be somewhere between June and September. Organisations have to prepare themselves based on the text of Draft Revision 12 that was published in February 2020. In support of preparation, PDA organised a number of workshops using the publicised Revision 12 as a reference point. The 2022 PDA Annex 1 Workshop held on 16 & 17 May in Dublin was the second of a series of four and the first one on European soil. The Workshop was characterised by a mix of presentations based on specific Draft Annex 1 topics combined with interactive workshops whereby the participants had the opportunity to ask the Panel of Experts about the presented subject but, above all, delegates had the opportunity to discuss their interpretation, challenges and possible solutions with peers from the industry. Based on the feedback received, the event was a great success. From these discussions the following 6 Key Takeaways could be distilled. Implementation period In the run up to the final publication there is already much debate about the allowed implementation period. The industry requested an implementation period of 12 months for standard topics, with an extended implementation period up to 36 months for more complex matters that would require facility or process updates. It was re-emphasised by (ex) regulatory representation that the Draft Annex 1 is based on what regulators already have seen in the industry as a practice and is, in essence, not new. The new Revision puts more emphasis on these practices and it is 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

now important for the industry to formalise these practices in a presentable format. As such, during a 2021 discussion meeting between EU member states, a standard implementation period of 6 months was proposed and a 24-month period for more sophisticated and intricate changes such as automated loading / unloading systems for lyophilisation or implementation of PUPSIT. As the Draft Text is already out for discussion and consultation for quite some time, organisations know what is coming. Where a company believes it will not be fully compliant within the timeframes agreed, a GAP analysis with a clear and realistic remediation program is expected to be in place and demonstrated adherence to the plan will be key. Pre-Use Post Sterilisation Integrity Testing (PUPSIT) A robustly discussed topic concerning the benefit, or more, the risks related to the expected implementation of PUPSIT. It is expected that it will remain the norm in the EU and outside. According to the regulators, PUPSIT will increase the level of aseptic assurance of the final product, and, consequently, patient safety. In addition to the aforementioned reasoning, it also makes sense from a business perspective according to the same regulators, as it prevents the rejection of products as a result of failing filter. There can be situations where PUPSIT can be omitted, but these have to be rigorously scientifically justified with supporting data. The use of pre-assembled and pre-sterilised Single Use Systems is not deemed a reason in itself and PUPSIT will still be an expectation in these scenarios The PDA performed masking test studies and published a Points to Consider for implementation of PUPSIT. Quality Risk Management (QRM) It is made clear from the Scope of the Draft Annex 1 that QRM applies to the document in its entirety and not only to specific paragraphs. QRM is to be used pro-actively based on a scientific approach, whereby data are expected to be seen to support QRM.

Risk Experts often work with an extremely in-depth Risk Assessment tool which is not necessarily always required. Select the most appropriate tool based on system knowledge, how complex it is and the criticality of the system. Risk Assessments are about having meaningful assessments that are data driven and scientifically sound, not about the number of Risk Assessments completed to come to a justification. A common pitfall is when the endpoint of a Risk Assessment is predetermined and people involved work their way to this assumed or desired endpoint. Good Risk Management requires an experienced Risk Facilitator guiding the process with a multi-disciplinary team. For small organisations this can be a challenge. Contamination Control Strategy (CCS) Although not entirely new within the regulations, the Draft Annex 1 makes it clear that organisations are expected to have a Contamination Control Strategy (CCS) implemented across the facility defining all critical control points present with an assessment of their effectiveness. The CCS should evaluate the end-to-end process in a holistic manner to prevent contamination and is risk-based. Hence CCS and QRM go hand-in-hand. Often companies have scattered disjointed information that does not consider both CCS and QRM holistically. The CCS brings all this information together with pointers to the relevant documents for the details. The general consensus is that the CCS should be a roadmap-like document and not a tick box exercise. It must drive continuous improvement and; therefore, requires periodic re-evaluation. The Draft Annex 1 summarises 16 elements to consider at a minimum as part of the CCS and it requires a multidisciplinary team with in-depth technical knowledge. The ownership of the CCS is a point of debate and the availability of resources and getting a team together to create the Risk Assessment and CCS is often seen as the most difficult task. The PDA will publish a Technical Report for development of a CCS in pharmaceutical manufacturing shortly which will provide guidance as to how to establish such a CCS in an effective manner. Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace

Direct & Indirect Product Contact Surfaces/ HPV Decontamination The Draft Annex 1 clearly describes that direct and indirect contact parts are expected to be sterilised. For existing configurations this can be a challenge as parts such as stopper bowls and tracks can be difficult to remove from their setting, sterilise and then reassemble. In some situations the size of equipment prevents removal from the enclosure or can poses a Health & Safety risk. Another consideration is how the sterilised parts are handled after sterilisation and reassembly as it is of paramount importance that the equipment is not compromised during transport and installation. The selected method of sterilisation is an important factor to account for. EU Regulators do not view Hydrogen Peroxide Vapour (HPV) as a sterilisation process, although the target is 6-log reduction of a highly resistant microbial spore. There is ambiguity among regulators between the EU and US as the FDA refers to HPV sterilisation and need to be aware of this. While HPV decontamination is the method of choice for isolator technology, it is not deemed suitable for sterilisation of direct and indirect product contact parts. wwww.international-pharma.com

Qualification and Training Despite all technology available, the human factor cannot be eliminated. Personnel with the right level of skillsets and attitude are of paramount importance for a robust and reliable sterile manufacturing process. For this reason, training and qualification of personnel is one of the most critical aspects for a company but also one of the most challenging. How can knowledge transfer be measured and when does one know if training is effective? There is general agreement that there should be a greater focus on personnel qualifications whereby the “why to do” is at least as important as the how. A good Training Program is about education of personnel. It is about the investment in resources and the likelihood of success is directly related to the investment the company is willing to make to develop effective training programmes for its personnel. Concepts like virtual training allow operators to become familiar with aseptic working environments. It gives them an opportunity to safely gain experience of working in a critical area without being directly thrown in the deep end.

February 2020 and organisations were able to familiarise and prepare themselves with the new text there are still many points for discussion. The final text is expected to be published before the end of the Summer and despite regulators indicating that the final text will not deviate too much from what is currently published and guidance as given in the new Annex 1 is what they already have seen in the industry, companies still have many questions relating to the interpretation and implementation of many aspects of the new Annex. For both regulators and the industry it will be important to understand and align expectations. As such, a joint Regulator/ Industry Workshop was suggested and although the idea is welcomed by both parties no concrete plans have been made.

Summary Although the Draft Annex 1 was published in

Director Senior Consultant at PharmaLex

Patrick Nieuwenhuizen


Regulatory & Marketplace

Annex 1-Implementation of the Final Draft

Annex 1 “Manufacture of Sterile Medicinal Products” was first published in 1971 and forms part of EudraLex Volume 41 that interprets the basic principles of GMP as detailed in European Directive 2003/94/ EEC.2 Annex 1 provides guidance on the minimum controls that are required to protect sterile medicinal products during manufacturing. All manufacturers that provide medicinal products to the European market must comply with these requirements to minimise the risk of microbial, particulate and pyrogen contamination in the final product. Since its first publication, Annex 1 has been revised several times with the latest update published in 2008. However, the document has never been subject to a full revision. A Working Group with representatives from a wide range of global countries, including representation from internationally recognised bodies, WHO and PIC/S, collaborated on a major revision and a long-awaited draft was published for public consultation in December 2017. With an overwhelming response to this first revision of over 6200 lines of comments received by the Working Group, an updated draft guidance was issued in February 2020 for a second targeted consultation. While the Pharmaceutical world is awaiting further development at the time of writing this article, the latest information received is that the final version is with the European Commission for final approval and is likely to be released in the near future. A full revision of the current Annex 1 was much desired since the Pharmaceutical Industry has evolved at a very fast pace over the last decade particularly, with the development and emergence of new technologies and many new products such as personalised medicines onto the Pharmaceutical Market. In addition, Regulatory Bodies have observed poor investigation practices, a lack of true root cause analysis and inadequate identification of effective CAPA during inspections. 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Revision of Annex 1 was crucial to reinforce the existing EU requirements and to keep up with advanced technologies such as the use of barrier technology. The new revision was required to reflect new insights and expectations in cleanroom, equipment and utility design as well the deployment of new rapid microbiological methods. The changing pharmaceutical landscape made this revision necessary. The current version of Annex 1 documents the current EU guidance on 16 pages. However, the new draft spans 52 pages and contains 11 sections. The first subtle but important change is in the Title as it now reads: “Manufacture of Sterile Products” where the word “Medicinal” is omitted compared to the current title. This subtle change indicates the broadening of the scope of the document beyond medicinal products. On review, it also becomes clear that Regulatory Bodies will expect that certain elements are also applied to manufacturers of non-sterile products as in the Scope of the document it is described that some of the principles and guidance “may be used to support the manufacture of other products that are not intended to be sterile”. While not mandatory, Manufacturers can expect that regulatory bodies will also look at the aspects of the new revision of Annex 1 that could apply and expect a justification or rationale where certain aspects are not adopted. Also, a discussion point may be the topic of how a Manufacturer has implemented aspects of Annex 1 into their non-sterile manufacturing process. A central point in the new Annex 1 is the application Quality Risk Management (QRM) a in a pro-active manner. The concept of QRM within the Pharmaceutical Industry is not new. The FDA presented the initiative of risk-based approaches as far back as 2002 in their meeting “Pharmaceutical Quality for the 21st Century: a risk-based approach”.3 In 2005 the International Conference of Harmonisation (ICH) introduced ICH Q9 “Quality Risk Management” The various documents available describe the aspects to take into account when integrating Quality in the whole chain of the pharmaceutical process including prospective identification of potential risks, with the purpose to

enhance process understanding and support patient safety. While the principles of QRM are not specific to sterile products, their application is at the centre of the new Annex 1. The document emphasises the expectation that the manufacturing process and associated activities, equipment and facilities are managed proactively using QRM principles to identify potential risks to quality, based on scientific knowledge and data. The new Annex 1 does not refer to QRM in specific paragraphs but expects that the principles are applied to the entirety of the document. The document also indicates the importance of using the right Risk Assessment tools for Root Cause Analysis and effective CAPA implementation. Rationales and justifications are expected to be in place for the practices deployed and there should be documentation regarding why practices employed are adequate for guaranteeing product, and therefore patient, safety. Quality Risk Management should also be employed to evaluate an acceptable level of residual risk and it is expected that this evaluation is always kept current through ongoing review and re-assessment of process risk. It requires employees with adequate knowledge and expertise of QRM to undertake Risk Assessments, as well Subject Matter Experts with in-depth knowledge in their field of expertise to provide the objective input as required. Next to the explicit introduction of QRM principles, another key aspect new to the Annex 1 is the requirement for Manufacturers to implement a Contamination Control Strategy (CCS). The new Annex 1 provides the principles and guidance regarding the elements that should be accounted for in the CCS. The correct application of QRM principles is essential to obtain a meaningful document that is of added value to a company. Typically, organisations have a scattered collection of documents that individually describe some aspects of Contamination Control and these elements are assessed on an individual basis. Often there is not a single document in place holistically describes all measures in place, their interdependencies and overall evaluation of effectiveness. The new Annex 1 now requires a holistic CCS document to Summer 2022 Volume 14 Issue 2


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Regulatory & Marketplace

be in place that assesses the efficacy of the sum of all controls and monitoring measures employed within the Organisation’s facilities, utilities and processes with the purpose of minimizing the risk of microbial, particulate and pyrogen contamination in the final product. It is expected that the CCS is actively updated to drive continuous improvement regarding Contamination Control. How successful a CCS is, depends on how well the individual elements that are assessed work together to reduce the risk for contamination. In addition to QRM and Risk Assessments, under all circumstances, good knowledge of an organisation’s own process is paramount and requires a multi-disciplinary team. Crossfunctional expertise allows science-based assessments to be made regarding potential contamination risks to the product and allows the organisation to focus on the key areas in the CCS and also provides rationale for implementation of control or detection measures. In the paragraph addressing Production and Specific Technologies it states that the finished product should be terminally sterilised using a validated and controlled sterilisation process. This is in alignment with the 2019 Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container.4 Where 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

terminal sterilisation or bioburden reduction steps like heat treatments are not possible for products in their final container, it is expressed that solutions or liquids must be sterilised by filtration followed by aseptic processing. The new Annex 1 sums up several requirements an organisation must comply with when it comes to sterile filtration and the characteristics of the selected filter. Compatibility of the filter material with the product, bacterial retention studies and the much-debated requirement for PreUse Post Sterilisation Integrity Testing – or PUPSIT are described among other topics. It is recognised in the document that PUPSIT may not always be possible and examples where this derogation apply are included. In such cases, an alternative approach may be taken by the Manufacturer, provided that the alternative approach is justified by a thorough supporting Risk Assessment. This section gives guidance to the Manufacturer on points to consider in the Risk Assessment in addition to the requirement for implementation of appropriate controls to reduce the risk of microbial contamination of the product. The new Annex 1 provides additional guidance for consideration the topic of premises and cleanroom design, all with the intention of maintaining control

of contamination and separation of non-essential processes from critical production steps. There are specifics included for the design of airlocks and expectations for how these are operated. The recommendation for consideration of separate changing rooms for entering and leaving the cleanroom area remains unchanged but now includes more specific text as it applies to Grade B cleanrooms or where the Organisation’s CCS indicates a high-risk for cross contamination. The new Annex 1 also has included the specific desire for separate personnel and material airlocks. This can be a particular challenge for existing or “aging facilities” with legacy systems and process flows. While not mandated, the use of Restricted Access Barrier Systems (RABS) or Isolators are to be considered with the purpose of minimising the risk of contamination as a result of direct operator intervention. A specific section in Annex 1 is dedicated to describing the expectations for barrier technology, including minimum background requirements, glove integrity testing and decontamination / disinfection of the system. When a Manufacturer does not avail of barrier technology, the alternative approached is to be justified and supported using Quality Risk Management principles. Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace More specifics are given about cleanroom and clean air equipment qualification and a summary of the expected test requirements is provided, which are subject to the relevant cleanroom design. While the maximum time intervals allowed for cleanroom requalification remain unchanged, there is an expectation that the minimum test requirements as summarised are also performed after completion of remedial actions due to an out-of-compliance situation in the cleanroom or air handling system. An important part of a facility’s Contamination Control Program is its disinfection program. Similar to cleanroom requirements, additional guidance is provided regarding the expectations for cleaning and disinfection of cleanrooms. A distinction between cleaning and disinfection has been made with emphasis on the removal of surface contamination which must be performed in order for the disinfection process to be effective. The applied cleaning program must be capable of removing disinfectant residues. While the 2008 revision of Annex 1 expressed the need to use more than one type of disinfectant, the new Annex 1 added the requirement for periodic use of a sporicidal agent. Besides cleanroom disinfection the new Annex 1 also provides clarified guidance for the transfer of materials and between areas of different grades, including specific instances where microbiological monitoring is recommended. The current Annex 1 included the requirement that Environmental Monitoring (EM) must be performed in accordance with the principles of QRM. In the new revision additional information is provided for Risk Assessments to be completed to establish the EM program and which elements to include. It is expected that these Risk Assessments are reviewed on a regular basis to confirm the effectiveness of the EM program. The limits for microbial contamination have not changed with the exception of Grade A limits, as these have been changed from <1 CFU to “no growth”. This is a clear reflection that no micro-organisms are expected to be recovered from a Grade A environment. For non-viable particles there is now the expectation that Companies establish their in-operation limits for 5.0µm particles based on a Risk Assessment and historical data. The use of historical data trends is also expected for setting viable and nonviable EM limits of other graded areas in such a way that adverse trends can be detected early. Evaluation of EM data trends wwww.international-pharma.com

are an important aspect, which includes the identification and trending of the identity of micro-organisms recovered in cleanrooms. These trends must be reviewed periodically and where required; actions must be taken for remediation. The process for EM data trending and definition of remediation actions is to be described in a procedure. Closely related to EM sampling is Personnel Monitoring (PM). Both EM and PM are expected to be incorporated in the overall aseptic manufacturing process based on risk and completed at regular intervals. Besides monitoring of personnel after involvement in critical interventions, there is now also the requirement for sampling of personnel upon each exit of the Grade B cleanroom. Note that there is now a dedicated section entitled ‘Personnel’ that prescribes that only the minimum number of personnel should be present in a cleanroom and a maximum number of operators is to be determined, documented and validated. The use of rapid or automated monitoring systems is encouraged in the new Annex 1 to expedite detection of microbial contamination, i.e. increase detectability or reduce time of detection. When availing of such technology, the alternative method must demonstrate at least equivalency to the conventional methodology through validation. In Summary, the new Annex 1 contains more information compared to the current revision and covers more aspects and expectations for sterile manufacturing. The general guidance document tries to strike a balance between providing guidance information and setting expectation without being too prescriptive and being unnecessarily restrictive. It is not known what the exact text of the final version will be, but it is not expected to deviate too far from the draft version that was published in February 2020. While this article is only a brief overview and cannot cover all the aspects of the new Annex 1, the overall message for manufacturers of sterile products is to ensure the systems and processes are in place to demonstrate sustainable control of the entire process and associated facilities, therewith ensuring product safety and ultimately protection of the patient. Manufacturers should familiarise themselves with the content and consider the potential impact to their organisation

with a remediation plan in place where required. REFERENCES 1.

2. 3.


EudraLex Volume 4 Good Manufacturing (GMP) Guidelines. Accessed through: https:// ec.europa.eu/health/medicinal-products/ eudralex/eudralex-volume-4_en Commission Directive 2003/94/EC (2003). Accessed through: https://eur-lex.europa.eu/ legal-content/EN/TXT/?uri=CELEX:32003L0094 FDA (2004) Pharmaceutical Quality for the 21st Century: a risk-based approach – Final Report. Accessed through https://www.fda. gov/media/77391/download EMA (2019) Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container. Accessed through: https://www.ema.europa.eu/en/ documents/scientific-guideline/guidelinesterilisation-medicinal-product-activesubstance-excipient-primary-container_en.pdf

Patrick Nieuwenhuizen Director Senior Consultant at Pharmalex

Quality professional with a Microbiology & Sterile Manufacturing background with over 25 years’ experience in the Pharmaceutical Industry. Worked for several global Pharmaceutical and Biotechnology companies across a variety of platforms including Biologics, Sterile Fill Finish and Solid Oral Dose. Involved with several site and laboratory expansion projects from construction design through to method transfer and operational readiness, and has provided Quality, Sterility Assurance and Microbiology oversight where relevant during these projects. In addition to site responsibilities, involved in several corporate initiatives such as Sterility Assurance Council and the roll-out of corporate standard programs that required collaboration and communication across multiple diverse sites for the improvement and maintenance of organizational quality standards. Next to that acting as a lead auditor and have been involved with audits facing several competent authority inspections including but not limited to the HPRA, FDA, ANVISA, Chinese FDA and Canadian Health Authority inspections. Acted as risk facilitator for Quality Risk Management programs and have gained significant experience with problemsolving and management of complex investigations.


Regulatory & Marketplace

Latest Developments in IP Strategies for Pharmaceuticals The strategies used to create and maintain strong pharmaceutical patent portfolios must evolve with developments in the pharmaceutical space. These developments include not just scientific advancements but also requirements and practices of regulatory bodies, such as the United States Food and Drug Administration (FDA). This article addresses innovative prosecution strategies and useful considerations that may facilitate better agreement between pharmaceutical patent practice and FDA policy. Means-Plus-Function Claiming Rooted in the principle that bioequivalent products need not undergo duplicative testing to get to market, US regulatory law offers two routes to accelerated FDA approval that rely, at least in part, on studies conducted by an earlier innovator. One route is the abbreviated new drug application (ANDA) pathway (for small molecule drugs) or abbreviated biologics license application (aBLA) pathway (for biologics). The other is the 505(b)(2) pathway. The ANDA and aBLA pathways typically require that the applicant use the same active agent(s) in their product as used in the innovator’s product, while the 505(b)(2) pathway permits more variation, including in dosage form or regimen, route of administration, or even new active ingredients. However, these pathways also highlight a mismatch between US regulatory law and patent law. For example, the level of equivalence appropriate for accelerated US regulatory review, particularly under 505(2) (b), is often broader than the scope of an innovator’s patent claims as assessed under literal infringement. Moreover, the doctrine of equivalents can be greatly restricted by, for example, prosecution history estoppel, increasing the likelihood of design-arounds that significantly reduce an innovator’s patent exclusivity. Means-plus-function claims, under 35 U.S.C. § 112(f), may better harmonise patent prosecution strategy with FDA practice. These claims define an element, 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in a combination claim, by its function instead of its structure. Importantly, meansplus-function claims guarantee a scope of equivalence that is independent from the scope provided under the doctrine of equivalents and is not subject to the same prosecution history-based estoppels as the doctrine of equivalents. Instead, meansplus-function claims cover equivalents to “the corresponding structure, material, or acts described in the specification.”2 There are two basic types of means-plusfunction claims in the pharmaceutical space. The first type recites (a) a structure-defined composition, and (b) a means for achieving a desirable outcome. In pharmaceutical inventions, such a claim commonly recites a specified active agent and a “means” for improving delivery, stability, or bioavailability of the active agent. In other words, the “means” is typically a functionlimited pharmaceutically acceptable excipient. Examples of this type of claim appear below:

This first type of means-plus-function claim may prove valuable against an ANDA or aBLA applicant, who would necessarily use the same active agent claimed by the innovator but might seek approval for an alternative formulation compared to the innovator’s product and formulation claims. While a showing of bioequivalence is required for ANDA or aBLA approval, it might not suffice for a finding of infringement under the doctrine of equivalents. By contrast, infringement of a “means” term, which includes statutory functional equivalents, may be evidenced by the same showing of bioequivalence required by the FDA. Thus, a means-plus-function claim may provide an innovator with more comprehensive protection of their invention by bridging the gap between FDA practice and patent law. The second type of means-plus-function claim may prove valuable against a 505(b) (2) applicant or a competing innovator. As exemplified below, the second type of means-plus-function claim is characterised

U.S. Patent No.

Means-plus-Function Claim (First Type)


13. A pharmaceutical composition, comprising (a) a compound of which is 4-5{-[bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyric acid dodecyl ester having the chemical structure:

or a pharmaceutically acceptable salt thereof, and (b) a means for increasing the circulation time of the compound in an aqueous environment. 10,413,611

1. A pharmaceutical composition comprising: (a) at least one poloxamer selected from poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407, or a mixture thereof; and (b) means for keeping the pharmaceutical composition in liquid phase up to a temperature of about 40° C. in vitro, wherein the pharmaceutical composition is for use in submucosal lift of gastrointestinal mucosal lesions in a patient undergoing a gastrointestinal endoscopic procedure.


20. A pharmaceutical composition, comprising at least one core which is surrounded by at least one osmotic subcoat, at least one control-releasing coat which surrounds the at least one osmotic subcoat, wherein the at least one core comprises bupropion hydrobromide and at least one excipient, wherein the at least one osmotic subcoat comprises at least one osmotic agent and at least one osmotic deposition vehicle, and a means for releasing the bupropion hydrobromide from the composition. Summer 2022 Volume 14 Issue 2



Regulatory & Marketplace by (a) a means term that describes the function of an active agent, and (b) a second component (e.g., an excipient). In Ex parte Gleave,3 the Patent Trial and Appeal Board (PTAB) reversed an examiner’s rejection of such a means-plus-function claim, which ultimately granted as claim 9 in US Patent No. 8,722,872:

means-plus-function claims, such patents could attract challenges in post grant proceedings and/or litigation. We, therefore, recommend pursuing such claims in patent applications that clearly define the scope of the means term in the specification, such as through a definition, a detailed description of embodiments, or a table linking the

U.S. Patent No.

Means-plus-Function Claim (Second Type)


9. A pharmaceutical composition comprising a (a) means for reducing the amount of active hsp27 in cancerous cells and (b) a pharmaceutically acceptable carrier.

The PTAB found that the means-plusfunction claims were proper and summarised the scope of the recited “means” term based on support in the specification: We agree with Appellants that the structures disclosed in the Specification as having the function recited in the claims are limited to (a) the specific antisense oligonucleotides in Example 1, (b) the specific RNAi molecules of Example 5, and (c) equivalents thereof, that are effective in reducing the amount of hsp27 in cancerous cells.4 Again, “equivalents,” as used in this context, include statutory functional equivalents, and do not implicate the stricter standards of the doctrine of equivalents. Therefore, a “means” term that characterises an active agent may enhance patent protection against design-arounds that exchange the innovator’s drug with an alternative having equivalent therapeutic properties. By encompassing statutory equivalents of the claimed subject matter, means-plusfunction claims can prevent competitors from designing around an invention by making a change to a drug composition or combination that is not expressly recited in an innovator’s claims but would still qualify for accelerated approval under current FDA practice. As such, meansplus-function claims can be a powerful tool when drafting pharmaceutical claims to encompass broader claim scope and thus more fully protect an inventor’s rights and provide greater protection against infringement. We note, however, that pharmaceutical patents containing means-plus-function claims have rarely been considered by the PTAB or the courts. Thus, while it may be possible to obtain a patent containing 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

means term to its intended scope. This approach may provide patent owners with greater confidence surrounding the scope and enablement of their means-plusfunction claims. We also note that means-plus-function claims may be interpreted differently, if allowed at all, outside of the US. Certain jurisdictions disfavour claim terms defined by function rather than structure, even with strong support in the specification as to the scope of those terms. Moreover, patent laws guiding the interpretation of equivalents to a claimed feature can differ significantly across jurisdictions and can be inconsistently applied. Thus, the protective scope of means-plus-function claims outside of the US will likely vary by country and court.

Claiming the Label (“Sanofi v. Watson” Claiming) As alluded to above, the ANDA pathway allows a generic company to rely on an innovator company’s studies to obtain FDA approval for their generic product, thus potentially accelerating its entry into the market. Similarly, through the aBLA pathway, a biosimilar company may rely on innovator data to accelerate FDA approval of its biosimilar product. With limited exceptions, the generic or biosimilar drug must carry the same label information provided in the label for the innovator’s drug.5 While the FDA does allow a generic or biosimilar label to differ from an innovator’s label by omitting a feature protected by patent exclusivity, the innovator can use strategic patent claiming to limit the applicability of this exception. The 2017 Federal Circuit decision in Sanofi v. Watson6 illustrates that an innovator can use patent claims that closely correspond to their drug label language to provide extended protection against generic or biosimilar products. As summarised in the Sanofi decision, Sanofi claimed certain Phase III clinical trial results of its drug Multaq® (dronedarone) in its US Patent No. 8,410,167. The Multaq® label included the same clinical trial results recited in the ’167 patent claims, both explicitly and by reference to the underlying Phase III study. The similarities in Sanofi’s claim and label language are depicted in the table below:

US Patent No. 8,410,167, Claim 1

Multaq® Label

1. A method of decreasing a risk of cardiovascular hospitalisation in a patient, said method comprising administering to said patient an effective amount of dronedarone or a pharmaceutically acceptable salt thereof, twice a day with a morning and an evening meal, wherein said patient does not have severe heart failure, (i) wherein severe heart failure is indicated by: a) NYHA Class IV heart failure or b) hospitalisation for heart failure within the last month; and (ii) wherein said patient has a history of, or current, paroxysmal or persistent non-permanent atrial fibrillation or flutter; and (iii) wherein the patient has at least one cardiovascular risk factor selected from the group consisting of:

INDICATIONS AND USAGE MULTAQ is an antiarrhythmic drug indicated to reduce the risk of cardiovascular hospitalisation in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted (1,14).

i. ii. iii. iv. v. vi.

an age greater than or equal to 75; hypertension; diabetes; a history of cerebral stroke or of systemic embolism; a left atrial diameter greater than or equal to 50 mm; and a left ventricular ejection fraction less than 40%.

DOSAGE AND ADMINISTRATION One tablet of 400 mg twice a day with morning and evening meals (2)… CONTRAINDICATIONS Class IV heart failure or symptomatic heart failure with a recent decompensation (Boxed Warning, 4) …

Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace Defendants, Watson Laboratories Inc. and Sandoz Inc., filed ANDAs with the FDA, requesting approval to market generic versions of Multaq®. In compliance with FDA policy, Watson and Sandoz proposed essentially copying the Multaq® label for their generic drug label, including relying on the same clinical study data and information described and referenced in the Multaq® label. The Federal Circuit found that the defendants’ generic label provided sufficient basis for a finding of “intentional encouragement of infringing use and, therefore, of inducement” to infringe the ’167 patent claims.7

design-arounds. These techniques, which align pharmaceutical claim strategy with FDA policy, have enormous potential to more robustly protect an inventor’s rights and provide greater protection against infringement. REFERENCES 1.

This decision reveals that, by “claiming the label,” an innovator can leverage their knowledge of FDA procedure to force generic or biosimilar companies into induced infringement, and thus into a choice between early market entry and freedom to operate.8 A caveat to this strategy is the prior art effect of published clinical trial protocols and data. Therefore, patent teams should coordinate early and frequently with regulatory teams to ensure that innovators file their patent applications before any upcoming clinical trial disclosures, or at least within the grace period permitted under US law. We also caution that this strategy may not find similar success outside of the US. In certain jurisdictions, local patent laws may prohibit features like dosages, dosing regimens, and patient subpopulations from carrying patentable weight. And other jurisdictions may not permit medical treatment or use claims under any circumstances. Further, grace periods outside of the US tend to be less generous, if they exist at all, making coordination of these patent application filings and clinical trial disclosures a greater challenge. Thus, it may not be feasible to draft claims that track drug label language in all jurisdictions.9 Conclusion The claim strategies discussed herein provide pharmaceutical inventors with additional tools to achieve meaningful patent protection for their inventions in the US. By drafting claims to track the FDA-approved label via “Sanofi v. Watson” claiming, pharmaceutical patent owners can improve their chances of establishing induced infringement. And by pursuing means-plus-function claims, pharmaceutical patent owners may be able to more fully protect against obvious wwww.international-pharma.com


3. 4. 5. 6. 7. 8.


Amanda K. Murphy is a partner at Finnegan, Henderson, Farabow, Garrett & Dunner, LLP (“Finnegan”), Sara A. Leiman is an associate at Finnegan, Jordan Gringauz is an associate at Finnegan, and Stacy Lewis is a member of the New York bar and is a law clerk with Finnegan. The authors also thank Victoria Randall, Ph.D., an associate at Finnegan and chartered UK and European patent attorney, for her valuable input on the article. These materials have been prepared solely for educational and entertainment purposes to contribute to the understanding of U.S. intellectual property law. These materials reflect only the personal views of the authors and are not individualised legal advice. It is understood that each case is fact specific, and that the appropriate solution in any case will vary. Therefore, these materials may or may not be relevant to any particular situation. Thus, the authors and Finnegan (including Finnegan Europe LLP, and Fei Han Foreign Legal Affairs Law Firm) cannot be bound either philosophically or as representatives of their various present and future clients to the comments expressed in these materials. The presentation of these materials does not establish any form of attorney-client relationship with these authors. While every attempt was made to ensure that these materials are accurate, errors or omissions may be contained therein, for which any liability is disclaimed. The statutory language reads: “An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.” 35 U.S.C. § 112(f). Appeal 2012-004973 (P.T.A.B. Jan. 22, 2014). Id. at *7. See, e.g., 21 U.S.C. 355(j)(2)(C); 21 CFR 314.93; 21 CFR 314.94(a)(8)(iv). Sanofi v. Watson Lab’ys Inc., 875 F.3d 636 (Fed. Cir. 2017). Id. at 646. This claim approach, also used in Sanofi’s US Patent No. 10,300,065, not only provided Sanofi with additional protective scope of Multaq® and its use, but also extended Sanofi’s patent exclusivity 10 years beyond the term of their composition-of-matter patent. Thus, a potential added benefit of “claiming the label” is to increase the duration of an innovator’s patent exclusivity. For further guidance on whether “claiming the label” may be feasible in jurisdictions beyond

the US, see Patent Subject Matter Eligibility: A Global Guide (Paul W. Browning et al. eds., 2021), and consult local counsel.

Sara Leiman Sara Leiman, Ph.D. is an associate at Finnegan located in the Boston office. She focuses on prosecution and strategic counseling on U.S. and foreign patent portfolios and handles intellectual property matters related to biological and pharmaceutical areas.

Jordan Gringauz Jordan Gringauz is an associate at Finnegan located in the Washington, DC office. He focuses on all areas of patent law, including litigation, client counseling, and prosecution. His technical experience includes pharmaceuticals and biologics.

Stacy Lewis Stacy Lewis is a law clerk at Finnegan and called to the Bar in New York. She focuses on research and writing, particularly in the life sciences. She is the coordinating editor of the books Global Patent Litigation: How and Where to Win and Design Patent Law, as well as the coursebook Chemical Patent Practice. Stacy sits on the AIPLA Quarterly Journal and IPO Law Journal editorial boards.

Amanda Murphy1 Amanda Murphy, Ph.D. is a partner at Finnegan located in the London office. She focuses her practice on strategic client counseling, portfolio management, and patent prosecution for a range of clients, including small startup companies, research foundations, and large biotechnology and pharmaceutical companies.


Regulatory & Marketplace

Pharma’s Time to Jointly Redefine Healthcare is Now

The challenge of ensuring healthcare sustainability, the rise in more targeted treatments, and a shift in emphasis to preventative interventions – not to mention the importance of patient centricity in determining healthcare decisions – are creating a perfect storm for the transformation of healthcare systems and of pharma’s role within them. Here, Gérard Klop of Vintura explores how pharma’s new role will evolve in an increasingly value-based healthcare scenario, the challenges companies will encounter as they reinvent themselves, and the cultural and organisational changes that will be required. For more than 15 years, experts have been sounding the death knell for traditional models of healthcare delivery, emphasising the rising importance of patient outcomes and measurable value. With large and growing ageing populations and increased instances of comorbidities, all stakeholders need to plan care and treatments in smarter ways, taking a more holistic approach to patient care. It is the only way healthcare systems will be able to cope with overwhelming demand. The pharma industry – experiencing its own identity crisis as blockbuster revenue streams give way to more expensive niche therapies – has a big opportunity here, to reposition its role and activities so that these contribute more directly to a future in which the ecosystem functions more seamlessly as one, and where outcomes and value can be measured appropriately. Becoming more deeply embedded in the delivery and monitoring of patient outcomes, which is warranted with advanced therapies, offers an opportunity for pharma companies to reposition themselves as trusted healthcare partners. In this scenario they can leverage their deep disease and therapeutic insights, play a role in transforming healthcare and thereby enhance their reputation. But how can companies position themselves optimally for such a future? 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

First: Acceptance As more advanced, personalised and targeted therapeutics become the strategic focus, pharma companies need to be able to justify the high prices of those treatments through closer real-world monitoring of their impact on patients and their wider value to the healthcare ecosystem (e.g. in more efficient use of resources and reduced dependency on healthcare personnel long term). This requires that pharma’s relationship with patients extends beyond a single or series of indirect transaction(s), assuming a more of an active – and even innovative role – in the patient pathway and healthcare system. Leading pharma companies have acknowledged the shift to value-based and value-managed healthcare and have already started to initiate and nurture new types of partnership with hospitals and physicians, sowing the seeds for a more collaborative, embedded and value-based role. Preparing for a Marathon, Not a Sprint While these early steps are encouraging, they also suggest that some pharma organisations may be looking for shortcuts in a journey which is going to take time and require a lot more high-level planning. Certainly, a shift away from each ‘function’ or set of stakeholders in the healthcare ecosystem operating from its own agenda is an important step forward. Yet for pharma to really assume a role as a trusted partner, it must first identify and hone what it is bringing to the table, beyond access to products and therapies. The same teams cannot simply approach healthcare providers with a different PowerPoint presentation and expect to reset the terms of the engagement. Rather there must be long-term engagement at different levels in the healthcare system, from physician up to national authorities, to reposition the pharma role and shape the readiness of healthcare ecosystems for upcoming innovation. Identifying Pharma’s Added Value Compared to physicians who are delivering care in the here and now, pharma companies

are ahead of the curve in their scientific knowledge and have deep research and valuable clinical development-based insights they can share. And because they understand how more targeted therapies work optimally, pharma companies have an opportunity to help shape the evolution of the healthcare system and the way that it contracts and budgets for treatments. As proficient collators and analysers of data, meanwhile, pharma could help to transform the monitoring and reporting of outcomes, by providing advice on shared access to appropriate IT infrastructure and making it easier for clinicians to capture data more routinely and consistently, towards greater transparency and more continuous measurement of value. In most cases this will also require shaping of data standardisation, data disclosure and privacy laws at a national level. Sustainable Partnerships Go Right to the Top While it might be tempting to send ‘advisors’ into individual hospitals to establish individual projects linked to a particular treatment, a tactical approach risks driving up costs without achieving a critical mass and, more crucially, without driving an overarching strategy. Although it can yield new insights and client access in the short term, ultimately it leads to projects that do not add up to a bigger strategy or a redefined role for pharma. Meaningful transformation will require conscious top team/CxO-level reflection on the kind of role pharma companies want to play in the future, which in turn will be informed by their primary areas of longterm therapeutic focus. It is only by aligning any next decisions and steps accordingly, and building therapeutic leadership and a differentiated company brand, that pharma companies will be able to justify the status of ‘trusted partners’ to physicians and reduce their exposure to patent expiry/ revenue loss. Looking Beyond Sales for Success Inevitably there will be consequences from pharma’s repositioning. As well as adopting a different mind-set, the shift from selling Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace

Innovation in Action – What Does Good Look Like? Last year a large pharma company entered into a world-first agreement with the NHS to enable broad and rapid access to first-in-class cholesterol-lowering medicine across England. Rather than negotiate with individual hospitals, it gained a nationwide agreement through its ability to demonstrate the impact of treating adults with a history of certain cardiovascular events such as heart attack or stroke who record persistently high cholesterol (despite diet and treatment with maximally tolerated statins). By helping healthcare providers to segment and profile patients, through enriched data and advanced analytics, pharma has an opportunity to influence the way care is delivered. Knowing when to continue with treatment at the end of life has always been a delicate area for physicians who are guided largely by protocol. Drawing on value-based healthcare principles, one pharma company was able to extend the decision process to incorporate the patient perspective by developing a questionnaire based on patient preferences that clinician could use collaboratively. Although this approach could potentially undermine pharma sales, the company took the long-term view, thinking beyond product performance to its social/ethical responsibility to patients, building trust and brand equity. So intent was one medtech company on maximising the impact of its treatment for diabetes that it made the strategic decision to acquire an associated care provider network, allowing it to influence and monitor the use of its product for the ultimate impact and benefit for patients. Although this approach allowed the company to leapfrog the process of negotiating and building trust with healthcare providers as separate entities, considerations when taking this path would usually need to include legal boundaries between product sales and care provision operations, to avoid ethical grey areas.


products to becoming more intrinsically involved in patient care pathways and outcomes requires that pharma companies develop new ways of measuring their own strategic progress – rather than continuing to rely on new and repeat product sales and short-term gains in market share. Greater involvement in the care pathway, for example, will afford pharma teams a chance to capture new insights into the impact of their therapies, helping to justify their higher cost. Working more closely with care providers will also help to create fertile ground for the given therapeutic area (say, CAR T-cell therapy) and the way that associated and innovative care is delivered. If care at home would improve the experience for patients, and reduce the burden on hospitals, there will need to be dialogue and negotiation between care providers and payers. These are the kinds of conversations drug sales reps are not equipped to have at the present time. So, companies must factor in adjustments to their core capabilities. Horses for Courses: Segmenting Product Portfolios The reinvention of pharma will be gradual. It makes sense then to segment portfolios so that, while traditional sales models prevail for established products, companies can concentrate on shaping the environment and forging sustainable and strategic healthcare partnerships ahead of the launch of more advanced, targeted and personalised therapies. Here, progress is likely to cascade down through three stages. First, via a ‘Traditional +’ model, the company can prepare market access, introducing the new therapy and its value story. Then they can pave the way for associated care to be delivered in partnership with healthcare providers, facilitating the adoption of innovation. Finally, to maximise long-term sustainability and the potential for future portfolios, companies should be looking to shape the healthcare system itself, taking an integrated view of how care is delivered and budgeted for, and measuring the broader impact of new therapies (e.g. on the healthcare burden, as well as patient outcomes – including quality of life). Emerging long-term strategies must start with the current product pipeline and any therapeutic areas of importance. These will help define the new role each company

could play in a more integrated healthcare ecosystem, and the implications for its business metrics and people/capabilities going forward. However, daunting the required transformation might seem now, there is much to play for in terms of a trusted partner role in bringing therapeutic expertise to the market; new company brand equity; an enduring role with reduced dependence on patents for revenues; a more strategically targeted and optimised R&D engine; and an enriched reputation (and with that a different seat at the table). As pharma becomes more embedded in care pathways, the scope grows too to close the loop and feed patient data and requests back to R&D, further boosting a therapy’s value and innovation over time and making treatments more sustainable.

Gérard Klop Gérard Klop is a partner at Vintura, which provides strategy consultancy to pharma and healthcare providers embracing transformation. Vintura, based in the Netherlands, Germany, France and the UK, is a recognised expert in value-based and value-managed healthcare (VBHC and VMHC). Email: gklop@vintura.com Web: www.vintura.com


Regulatory & Marketplace

The New Age in Strategic Outsourcing Lies in the Mature Portfolio Companies must safeguard their mature portfolios while continuously innovating and developing new products. But inhouse resources are stretched and often lack the broader knowledge needed to ensure best practice for ongoing maintenance activities. As a result, traditional models of outsourcing – the low-cost, “lift and shift” approach of the past – are giving way to a more nuanced, strategic approach, one that leverages external expertise globally and delivers more efficient methods for supporting the product lifecycle. Dr. Constanze Burkhardt, Vice President, Head of Program Management, explores why outsourcing the mature portfolio has become an industry priority. Mature products are integral to a pharmaceutical company’s financial bottom line and to its reputation. Consider one of the best-known products on the market, Aspirin, which established Bayer as a leader in pain relief and stroke prevention. Companies build a reputation in a particular therapeutic category (Novo Nordisk and Lilly in diabetes, Genentech in oncology, AbbVie in rheumatoid arthritis, GSK in vaccines) and strive to protect their mature portfolio, while continuously innovating. Yet mature products require ongoing maintenance activities, such as pharmacovigilance, maintaining regulatory dossiers and labels, and conducting ongoing benefitrisk analyses in order to maintain licenses. Drug companies must comply with fastevolving regulatory requirements to avoid critical actions from the healthcare authorities and the enormous cost this implies, both financially and to a company’s reputation. Adding to this complexity is the fact that regulatory authorities across different countries and regions often have divergent expectations – even within the EU, despite strong and ongoing efforts by the European Medicines Agency to harmonise processes.

trend in outsourcing, where companies seek to outsource the maintenance and strategic management of their mature product portfolios.

companies began seeking partners that could provide specialised domain expertise in key geographic regions and local knowledge in countries where they didn’t have presence.

A New Era in Outsourcing Pharmaceutical outsourcing has changed significantly since its early days 40 years ago when companies began turning to external partners to reduce their costs and enhance their flexibility. What started out as a “lift and shift” model, with transactional outsourcing to low-cost, offshore locations, has changed over the years. In recent years,

Increasingly, there has been a need for a more nuanced approach to outsourcing, where expertise and regulatory intelligence are combined with efficiency and cost containment. Equally, companies have sought to find new ways to strengthen their pipelines and develop more efficient methods to support the product lifecycle. This has led companies to build relationship-

These challenges, combined with the need to keep internal resources focused on product innovation, are leading to a new 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace based models to manage their established, marketed products in a more strategic way through partners that offer a tailored, blended model of in-country, near-shore, and offshore resources. Importantly, there is also an emphasis on partners that not only have demonstrated expertise in global regulatory requirements but have also adopted innovative, best-practice approaches. To make the most out of this more strategic outsourcing approach, pharmaceutical companies need to assess their existing operating models for the maintenance of their mature products and consider how they might benefit from an integrated safety, quality, and regulatory model available through trusted third-party partners that can provide tailored services where required. There is more to a tailored approach than delivering integrated services. At its best, a partnership is about a trusted relationship that brings regulatory intelligence and insights, as well as ongoing back-up, stability and security for all processes. This end-to-end relationship is only made possible when trust is built between all parties involved. It’s not enough, however, just to have that central expertise. Rather, any mature product portfolio strategy must also provide local support through teams of compliance experts, particularly for routine functions. Aside from the obvious cost benefits that outsourcing provides, removing the burden of maintaining compliance for established products enables companies to focus on innovations and other strategic business. As importantly, it also provides ready access to a large pool of external industry expertise and knowledge, which may be limited in-house. Moreover, this expertise brings together best practice and knowledge gained from working across many different companies – large and small – in multiple markets, which in turn leads to greater innovation and efficiency. Strategic and Tailored There should never be a one-size-fits-all approach to strategic outsourcing, since success is about far more than short-term cost savings. To determine the right outsourcing approach, companies should first consider their geographic markets – both current and intended – to determine whether they have the necessary resources to manage mature products in those regions. Even if there are teams in place in those markets, do they have capacity to manage mature products as well wwww.international-pharma.com

as support new launches or does it make more sense to leverage the local expertise that a partner can provide as part of a tailored outsourcing model? This also applies at a global level, where companies often have resource constraints and need to focus on products under development. Having an external global strategist oversee maintenance of the mature portfolio allows internal employees to focus their attention on new developments. Companies need to decide where best to focus internal resources and whether having in-house teams spend their time maintaining mature products makes strategic sense. Managing established products can be even more challenging given the varied organisational structures that many companies are working with. A company with 100 or more operating companies or affiliates worldwide needs to understand the structural constraints facing many of those affiliates, many of which will have tiny offices and perhaps only one full-time staff member to manage all regulatory activities. To allow these affiliates to focus on core activities – including helping to launch innovative new products to market – pharmaceutical companies should consider tailored models that introduce greater efficiencies to lift the burden local affiliates face. A flexible and strategic approach will also be important when managing new technical requirements from the health authorities.

There are any number of different operating models – from headquarters being responsible for determining technology and processes and coordinating regional efforts; to a collaborative approach between headquarters and the affiliates; to a model where affiliates hold responsibility for maintaining products in their region. Irrespective of the model, however, local teams may struggle with the workload demands of managing mature products or they may lack the expertise to navigate complex safety and quality requirements. Technology and process limitations also represent a challenge for affiliate offices; for example, while automation is increasingly being leveraged to streamline many repetitive processes, affiliates may not have the technology or expertise needed. Global strategic outsourcing of the mature portfolio can alleviate those issues, ensuring local requirements are met and allowing the overall organisation to take advantage of digital and other innovations to improve the product maintenance process. Cross-functional Collaboration By outsourcing the maintenance and strategic management of mature portfolios, pharmaceutical companies can achieve better collaboration across cross-functional teams and elevate the organisation so there is better coordination and further optimisation of business processes. One way this is achieved is through models that are built around task rather than function, which facilitates collaboration across functions, INTERNATIONAL PHARMACEUTICAL INDUSTRY 21

Regulatory & Marketplace locations and regions, enabling companies to pivot faster as priorities change and evolve. The ability to be agile and innovative is important when preparing for changing regulatory requirements. As an example, the EMA is moving away from documents and toward data and digital systems. What that means is that, going forward, when submitting variations to a marketed product, companies will need to ensure the product datasets in the SPOR database (substance, product, organisation and referential) are correct and complete. Such changes will require operational agility to ensure quality and compliance requirements are met to safeguard products on the market; it will require knowledge of the shifting regulatory environment; and it will require digital know-how. The challenge is exacerbated where companies have a decentralised approach to portfolio maintenance. Here there is a very real risk of disparate functions and teams managing their activities in an uncoordinated manner, resulting in fragmented data and documentation at different locations. Having partners that bring specialised expertise and a blended, tailored model, lets companies take advantage of new and emerging technologies, better manage regulatory information, adapt to evolving global regulations, mitigate risk at the local and global level and respond quickly to data and documentation requirements. Such a model ensures information is centrally available and managed by the outsourcing partner, which is better able to adapt to new ways of working regionally and globally to meet changing regulatory requirements. From the 1980s to 2022 As has been observed, the trend that began more than 40 years ago amid efforts to cut spiralling development and regulatory costs has evolved into a highly specialised field, where outsourcing partners have gained extensive knowledge and process expertise. So, while cost savings and flexibility remain factors for outsourcing, the bigger focus is on knowledge wealth. Today’s more strategic outsourcing models allow companies to tap into a network of specialists and gain efficiencies that wouldn’t be possible inhouse, given the outdated and inefficient processes most pharma companies have acquired over the years. 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Through strategic and tailored outsourcing of the mature portfolio, companies can modernize their processes and safeguard compliance and quality while staying ahead in a rapidly evolving regulation landscape. A further advantage is the ability to leverage organisational information across the regulatory, safety and quality continuum to achieve productivity gains and a more holistic view of the portfolio. The new wave of outsourcing also leads to a more coordinated multi-functional approach to portfolio maintenance, which helps to overcome a common challenge of fragmented data and documentation at different locations. Furthermore, outsourcing allows companies to take advantage of technology advances, such as automation, without the need to invest in infrastructure or deal with quality management testing and validation. This new wave of outsourcing, when carefully planned and prepared, can bring huge advantages to organisations, allowing them to improve processes and remain compliant while allowing in-house teams to focus on innovation and value-added activities. Across the board, this more tailored, strategic approach gives companies access to innovative perspective and more efficient ways of managing regulatory activities.

Dr. Constanze Burkhardt Dr. Constanze Burkhardt is known for her innovative, solution-oriented approach to global program management strategies. With over 15 years experience in the pharmaceutical and biotech industry, she has an extensive track record and experience with building strong team environments in a matrix management setting, with high commitment to the drug development and LCM process. She is applying her analytical and conceptual thinking ability, international working experience and expertise in Program Management to build integrated Global E-2-E Delivery platforms, Outsourcing solutions, and Strategic Consultancy. Dr. Constanze Burkhardt is currently leading the Global Program Management department responsible for delivering large Global programs to clients. She and her team are driving operational excellence by implementing strategic program platforms designed to optimise efficiency and product compliance from drug development through commercialisation to product maintenance.

Summer 2022 Volume 14 Issue 2

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Regulatory & Marketplace

Pathway for Marketing Authorisation Approval of Medical Device in US The process of developing a revolutionary medical device from the proofof-concept stage to the marketing stage is expensive and complicated. The creation of a new product is a costly and time-consuming endeavour. Demonstrating the safety and efficacy of the technology is just as crucial as the innovation itself. These requirements can assist you update your development operations and create a product that fulfils the regulatory standards of your targeted authority, i.e., a safe and effective product for its intended application. Although information on the regulatory requirements (e.g., laws, guidance documents, international standards) for the creation of healthcare products is readily available, navigating the regulatory system is not easy, and it becomes even more complicated when working with various countries. To assist healthcare product developers who are entrepreneurs or regulators. The major objective is to facilitate the knowledge of the regulatory framework that controls medical devices and to ensure compliance with regulatory frameworks. It is possible to make use of it as a launching point for the development of your device. The purpose of the guidance is not to serve as a collection of regulations; rather, it focuses on discussing the underlying ideas and principles involved in regulatory affairs. It lays out a plan of action for entrepreneurs to follow. Key words: Marketing Authorisation Approval, Medical Devices, Regulatory Information Management, Food Drug Administration, Navigation, Guidance’s, Entrepreneurs, Healthcare Products. The process of producing an innovative healthcare product (a drug, a biologic, or a medical device) from the proof-ofconcept stage (idea to demonstrate) to the commercialisation stage is expensive and complex. It needs a substantial investment of time and effort in research and development over many years.1 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In order to reduce the amount of time and money spent on bringing products to market, product development processes ought to be carried out in accordance with the pertinent regulatory standards. By adhering to these requirements, you may be able to speed up the development operations and produce a product that satisfies the regulatory standards of your target authority(s), which means that the product will be of high quality and will be both safe and effective for the use to which it is put.2 The drug regulatory bodies are being set up in different countries all over the world. The regulatory body makes sure that a drug meets all of the rules and laws that apply to it. In every country, there is a regulatory body that enforces the rules and regulations and sets guidelines for how drugs are made, licenced, registered, sold, and labelled. The regulatory body also makes sure that the rules and regulations are being followed.3 In order to assure the safety, efficacy, and quality of pharmaceuticals, as well as the accuracy and appropriateness of drug information available to the general public, regulatory authorities and organisations are responsible for effective drug regulation.4 In order to have access to information regarding drugs, one must first gain an understanding of the locations on regulatory websites where the regulated material, such as acts, regulations, and guidance, is kept. After that, in order to acquire the correct information, one needs to be aware of the correct information that is stored on particular regulatory websites. To gain access to this, you will need to follow a "navigation pathway" that has been established by a particular agency in order to get regulatory approval. To commercialise a product, we must first submit an application to the appropriate regulatory agency, which then ensures that the product is both safe and effective for people all over the world. As a result, we require a specific navigation method for specific applications or pharmaceutical items.5 It is quite simple to implement a comprehensive regulatory information management (RIM) solution, which can be used to a wide range of difficult situations. Regulatory agencies becoming

more safety conscious and demanding more data, regulatory information management (RIM) which leads to increase in demand of navigation pathway. Global regulatory authorities and organisations face a number of significant challenges, the most significant of which are: ensuring the safety, quality, and efficacy of medicines and medical devices; harmonising legal procedures related to drug development; and monitoring and ensuring compliance with statutory obligations.6 Discussion: United States • The United States is a founding member of numerous international organisations, including the United Nations, the World Bank, the International Monetary Fund, and the Organization of American States (OAS). •

The US is either the third or fourth largest country in terms of total area, and it has the third-highest population.

• •

Capital: Washington D.C. Area: 3.8 million square miles (9.8 million km2) Population: 325 million people National language: English Currency: American Dollar (1 dollar = 64 Indian Rupee) The US is a highly developed country which is provided in Table 1 It has the largest economy in the world when measured by nominal GDP and the second largest economy when measured by PPP (Public-Private Partnerships). 7

• • • •

Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace Parameteres


Regulatory factsheet




Medical device

Primary language(s)




Type of application


Total healthcare spending

$3 trillion

Lifecycle phase


Healthcare expenditures total (% of GDP)


Regulatory department

Department of Helath and Human Services

Healtcare expenditures per capita

$9403 (USD)

Regulatory agency

US Food & Drugs administration (FDA) Medical device

Expenditures on healthcare

Regulatory classification Government: 48% Private: 52%


Size of medical device market (USD)

$147.7 billion (USD)

Regulations: Code of Federal Regulation


US dollar ($)

Table 1: General Information about USA7

1. 2.

3. 4. 5. 6.


IDE Regulations set down in accordance with 21 CFR 812 are referred to as IDE. The sponsor's research application has been approved by the IRB (and FDA for major risk devices) and all conditions under 21 CFR 812 have been met with an approved IDE. Guidance documents required for the IDE provided in Table 3. An IDE application must be submitted by the sponsor of a major risk device study to the FDA. Discussion about the regulatory process about Medical Device as provided in Table 2. Submission and the navigation pathway required for the Medical Device according to the IDE guidance documents has provided in the Figure 1 & Figure 2. A 510K is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR 807.92((a)(3)) that is not subject to PMA, Exemptions and the waivers has to be followed by the applicant as mentioned in the Table 4. Person who wants to market in the U.S., as to follow the guidance documents which is provided in the Table 5 a class I, II and III devices intended for human use, for which a Premarket Approval (PMA)



CFR Part

Application Type


21 CFR 812

Investigational Device Exemptions


21 CFR 56

Institutional Review Boards

21 CFR 58

Good Laboratory Practice for Nonclinical Laboratory Studies


is not required, must submit a 510(k) to FDA unless the device is exempt from 510(k) requirements of the Federal Food, Drug and Cosmetics Act. Navigation and the submission pathway which is required for the 510k approval has to be followed by the applicant is mentioned below in the Figure 3 & Figure 4.


Table 2: Regulatory Factsheet about Medical Device in US8

Sl. Title No.



Guidance for Sponsors, Investigators, and Institutional Review Boards – Questions and Answers on Informed Consent Elements 21 CFR 50.25(c)

http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/ UCM291085.pdf


Centre for Devices and Radiological Health's Investigational Device Exemption (IDE) Refuse to Accept Policy

http://www.fda.gov/ downloads/MedicalDevices/ DeviceRegulationandGuidance/ GuidanceDocuments/UCM081312.pdf


Continued Access to Investigational Devices During PMA Preparation and Review July 15, 1996 (Blue Book Memo)

http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/ GuidanceDocuments/ucm080260.htm


Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies – Guidance for Industry and Food and Drug Administration Staff

http://www.fda.gov/ downloads/MedicalDevices/ DeviceRegulationandGuidance/ GuidanceDocuments/UCM279103.pdf


FDA Decisions for Investigational Device Exemption Clinical Investigations - Guidance for Sponsors, Clinical Investigators, Institutional Review Boards, and Food and Drug Administration Staff

http://www.fda.gov/ downloads/MedicalDevices/ DeviceRegulationandGuidance/ GuidanceDocuments/UCM279107.pdf


Regulatory & Marketplace 9.

Figure 1: Submission Pathway for IDE9

Regulatory factsheet Product

Medical device



Type of application


Fees: MDUFA III Fee page lists 510(k) fees.

Regulatory department

Department of Helath and Human Services

Regulatory agency

US Food & Drugs administration (FDA)

Regulatory classification

Medical device

Exemptions and waivers:

Premarket Approval (PMA): It is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. PMA is the most stringent type of device marketing application required by FDA is provided in the Table 6. The applicant must receive FDA approval of its PMA application prior to marketing the device. PMA approval is based on a determination by FDA that the PMA contains sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). 10. Title 21 Code of Federal Regulations (CFR) Part 814 governs premarket approval. The PMA application procedure necessitates a copy of the relevant federal regulation code as been provided in Table 7. 11. Submission & Navigation pathway which is required for the Premarket approval in US as been provided in the Figure 5 & 6.


Exemption or Waiver

Third-party 510(k)

Exempt from any FDA fee; however, the third-party does charge a fee for its review

Any application for a device intended solely for paediatric use

Exempt from user fee. Please note that changing the intended use from paediatric use to adult use requires the submission of a new 510(k). The new 510(k) is subject to the 510(k)-review fee at the time of submission

Any application from a State or Federal Government entity

Exempt from any fee unless the device is to be distributed commercially Table 4: Key Resources10

Sl. No. Title



Guidance for Industry and FDA Staff: Bundling Multiple Devices or Multiple Indications in a Single Submission

http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/ ucm089731.htm


Guidance for Industry and Food and Drug Administration Staff – User Fees and Refunds for Premarket Notification Submissions (510(k)s)

http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/ ucm345277.ht

Table 5: USFDA 510K Guidance Documents11

12. Post Approval Changes (PAC) FDA must be notified of any changes to a product, manufacturing process, quality controls, equipment facilities, or the employees responsible for them: A supplement requiring approval prior to distribution •

Figure 3: Submission Pathway for 510k approval12 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A supplement at least 30 days prior to distribution of the product made using the change, all the documents related to changes has to be followed the guidelines which is given from the FDA is provided in Table 8. Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace

Figure 4: USFDA 510K Navigation Pathway13


Medical device



Type of application

PMA Approval

Lifecycle phase


Regulatory department

Department of Helath and Human Services

Regulatory agency

US Food & Drugs administration (FDA)

Regulatory classification

Medical device

Table 6: Regulatory Factsheet of PMA14


CFR Part

Application Type


21 CFR 814

Premarket Approval of Medical Devices


21 CFR 54

Financial Disclosure by Clinical Investigators


21 CFR 201



21 CFR 820

Quality System Regulation Table 7: US Code of Federal Regulations14

Figure 5: Submission Pathway for Premarket Approval14 wwww.international-pharma.com


Regulatory & Marketplace •

On the basis of its potential to affect the biological product's identity, strength, quality and purity as they may relate to the product's safety or effectiveness, an annual report may be required. Changes which is required during the post approval changes in FDA is mentioned below in Figure 7.

Pharmaceutical Quality related issues has to be followed a particular Submission and Navigation Pathway is provided below in Figure 8 & Figure 9. Applications for FDA approval to market a new drug in USA as to be followed a particular code of federal regulations is mentioned below in Figure 10. Resource

Figure 6: USFDA PMA Navigation Pathway15

Regulatory factsheet Product

Drugs, Biologics & Medical Devices



Lifecycle phase


Regulatory department

Department of Helath and Human Services

Regulatory agency

US Food & Drugs administration (FDA)

Regulatory classification

Drugs, Biologics & Medical Devices

Reporting Category

List of Changes

Type of Changes

Supplement Application

Major Change

Prior Approval Supplement

Moderate Change

Change Being Affected in 30 days/

Minor Change

Annual Report

• • • • • • • •

Figure 7: Types of Changes in Post Approval Changes16

Component and Composition Manufacturing Sites Manufacturing Process Specifications Container closure system Labelling Miscellaneous Changes and Multiple related Changes

Sl. No. Guidance

Issued Date


SUPAC: Manufacturing Equipment Addendum



SUPAC-IR: Immediate-release Solid Oral Dosage Forms: Scale-UP and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation



SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-UP and Post-approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation



SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Post-approval Changes: Chemistry, Manufacturing and Controls, In Vitro Release Testing, and In Vivo Bioequivalence Documentation



Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace

Figure 8: Submission Pathway for Pharmaceutical Quality16

Figure 9: USFDA PAC Navigation Pathway15

Figure 10: USFDA 21 CFR Part 31415 wwww.international-pharma.com


Regulatory & Marketplace Determine the classification of your device by searching the FDA classification database using relevant search terms, or by identifying another device with the same intended use and technology. Pay special attention to the three letters. Product code and seven-digit Regulation Number associated with the predicate devices you identify. If the classification cannot be determined, use 513(q) process to request classification from the FDA



Some Class 1 devices are exempt from most QSR requirements, with expectations. *

• •


been prepared based on the guidelines issued by the USFDA Collation of compliance requirements for navigation pathway. Hence, US regulatory authority has their own regulation and guidelines for navigation pathway for the drug improvements and for the patient’s safety.

Implement Quality Management System (QMS) which meets FDA Quality System regulation (Q5R) found in 21 CFR Part 820.

Acknowledgment We extended our thanks to JSS Academy of Higher Education and Research, Mysuru

Innovative Class II, and all Class III, devices will likely require clinical studies. Get “Pre-Submission (Pre-Sub)” feedback from the FDA.

Conflict of Interest There are no conflicts of interest. It has been mentioned by authors.

If clinical studies will be required, apply for an Investigational Device Exemption (IDE). Develop clinical trail protocol and conduct studies. **Non-significant risk studies may be performed with IRB approval.

Authors Contribution All the authors are contributed in preparing the manuscript and designing the information pertaining to the article.

Prepare and submit 510(k) Premarket Notification application. Pay fee.

Prepare** and submit Premarket Approval (PMA) application. Pay fee.

FDA conducts facility inspections of manufacturer and all major suppliers involved in the design and production of your device. All parties must be compliant with FDA QSR.

FDA issues 510(k) clearance letter: posts online. No certificate issued.

FDA issues PMA approval letter: posts online. No certificate issued.

At this time, you must be in full compliance with QSR1. The FDA will not inspect Class I or II device manufacturers for compliance prior to device registration but does conduct random inspections and can issue a Form 483 for non-compliance.

If you have no local presence in the US, appoint an FDA US Agent representative as a local point of contact with the FDA

List your device and register your company using FURLS system on the FDA website in accordance with 21 CFR Part 807; Pay fees for Establishment Registration and Listing which must be renewed each year.




4. 5.


You are now able to sell your device in the US. Your company and device registration status will be listed on the FDA website. Your authorisation does on expire as long as no changes are made to the device design, intended use, etc. Figure 11: Registration Procedure for Medical Device in US16

Registration procedure has to be followed by the applicant for the manufacturing of medical device in USA according to the classes which is classified is provided below in the Figure 11. Requirements related to the Medical Device regulatory pathway has to be 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

followed according to the guidelines and is mentioned in Table 9. Conclusion • •

To understand the regulatory pathway for Medical device in US A detailed Factsheet & checklist has




Ashfaq A: 2018, March| Understanding the 5 Phases of Medical Device Development | Greenlight Guru Available from: https://www. greenlight.guru/blog/5-phases-of-medicaldevice-development S Sridhar, V Balamuralidhara, Comparative Study of Medical Device Vigilance in Canada, USA, Australia. International Journal of Pharmaceutical Quality Assurance; vol 10 (3) 2019: 32-40. Geetanjali, Pranab T: 2012| Pharmaceutical Regulatory Agencies and Organizations around the World: Scope and Challenges in Drug Development | PharmaTutor Available from: https://www.pharmatutor.org/articles/ pharmaceutical-regulatory-agenciesand-organizations-around-world-scopechallenges-in-drug-development S. S. Tarun Nag, V. Balamuralidhara. Innovation in medical device at glance; Drug Invention Today | Vol 13 • Issue 2 • 2020 Tarun K R, Naveen K R: 2017| Significance Of Pharmaceutical Regulatory Bodies - A Review | PharmaTutor. Available from: https://www. pharmatutor.org/articles/significance-ofpharmaceutical-regulatory-bodies-a-review Shilpi Khattri, Balamuralidhara V, T. M. Pramod Kumar: 2013| Clinical Investigation of Medical Device: Promoting Convergence. Journal for Clinical Studies| Available from: https://www. researchgate.net/publication/284431227_ Clinical_Investigation_of_Medical_Device_ Promoting_Convergence Ramya Shree Gangadhar, Balamuralidhara V, Rajeshwari S R Biocompatibility of Medical Device: A Review Journal of Evolution of Medical and Dental Science 2021;10(36): 31523158 Lee Ventola C, 2011, Oct| Direct-to-Consumer Pharmaceutical Advertising: Therapeutic or Toxic? Pharm Ther; 36(10):669. Available from: /pmc/articles/PMC3278148/ Chandan B V, Balamuralidhara V, Gowrav M Summer 2022 Volume 14 Issue 2

Regulatory & Marketplace Device classification in the United States

Class I

How long you should expect to wait after submission until approval is granted

1 month

Class II

Class III 13.

6–9 months

18–30 months 14.

Validity period for device registrations

Does not expire

Registration renewal should be started this far in advance

Not applicable

Complexity of the registration process for this classification

Simple Complex 2

Overall cost of gaining regulatory approval

Does not expire

Does not expire 15.

Not applicable

Not applicable 16.

Low 1


Simple Complex 4


High 3

Simple Complex 5


High 5

Table 9: Requirements for medical device registration in the US16




P, Vishakharaju Motupalli Applications of Medical Devices in Healthcare Industry Journal of Evolution of Medical and Dental Science 2021;10(38): 3419-3423 Balamuralidhara V, Prasannakumar P Bhat, Suhas S, Tarun Nags S Joshi Clinical Trials in Medical devices: Risk Management (Review) Journal for Clinical Studies 2021; 13(3): 24-27 Zaletel M, Kralj M, Magajne M, Doupi P. Methodological Guidelines and Recommendations for Efficient and Rationale Governance of Patient Registries. Vol. 25, European Journal of Public Health. 2015. Amar S, Balamuralidhara V, T M Pramod Kumar Manufacturing and Designing of Implantable 3d- Printed Medical Devices: An Overview of

Dr. Balamuralidhara V

Deeksha K S obtained Master of Pharmaceutical Regulatory Affairs degree from Rajiv Gandhi University, Bangalore. Currently pursuing as a Research Scholar in Pharmaceutical Regulatory Affairs department in JSS College of Pharmacy, Mysuru, JSS Academy of Higher Education and Research, Mysuru-570015, Karnataka, India

Dr. Balamuralidhara V received his PhD from the Department of Pharmaceutics at JSS University and PG Diploma in Intellectual Property Rights Law (IPRL) from the National Law School of India University, Bangalore. He has more than 18 years of experience in academia and has published more than 200 Publications in national and international journals and filed 4 patents. Currently working as Associate Professor in the Department of Pharmaceutics at JSS College of Pharmacy, Mysuru, JSS Academy of Higher Education and Research, Mysuru-570015, Karnataka, India.

Email: deekshaksjss@gmail.com

Email: baligowda@jssuni.edu.in

Deeksha KS

Thoyajaksha V


Regulatory Challenges Research Journal of Pharmaceutical and Technology, 2021;14(3): 1785-1790 Kaushik Devaraju., Balamuralidhara V, T M Pramod Kumar, Sidharth Malhotra. Medical Device Regulation – Recent Developments and Challenges in India. Journal of Global Trends in Pharmaceutical Sciences: 2019; 10(3): 6466 – 6478. Balamuralidhara V, Kavya Reddy., Sanhita Singha Roy., M.P. Venkatesh., Clinical Evaluation and Post-marketing Surveillance of Medical Devices in the USA; Journal for Clinical Studies, Volume 12 Issue 4: 26-28 Jan B P et.al., 2007: Review of US Medical Device Regulation: Journal of Medical Device: Available from:https://www.researchgate. net/publication/262376262_Review_of_US_ Medical_Device_Regulation Gail A, Van Norman M D, 2016: Drugs and Devices: Comparison of European and US Approval Processes: Journal of the American college of Cardiology: Available from: https:// www.sciencedirect.com/science/article/pii/ S2452302X16300638

Thanush D

Research Student, Pharmaceutical Regulatory Affairs, JSS College of Pharmacy, Mysuru, JSS Academy of Higher Education and Research, Mysuru-570015, Karnataka, India

Research Student, Pharmaceutical Regulatory Affairs, JSS College of Pharmacy, Mysuru, JSS Academy of Higher Education and Research, Mysuru-570015, Karnataka, India

Email: v1thoya2911@gmail.com

Email: thanushdinesh080@gmail.com


Drug Discovery, Development & Delivery

Applying Advanced Powder Testing to Tackle the Toughest Formulation Challenges The application of high throughput screening techniques and computational chemistry has resulted in a marked shift in the nature of drug candidates with identified therapeutic potential, increasing the prevalance of BCS Class II and IV compounds.1,2 Estimates suggest that Class II drugs currently account for around 30% of marketed drugs but between 50 and 60% of drugs in the development pipeline.1 Class II drugs have low solubility and high permeability while Class IV combine poor solubility with poor permeability. Both present a demanding formulation challenge with bioavailability potentially limited by the difficulties of solvation, and for Class IV drugs, by the difficulty and variability of in vivo absorption. Faced with a growing need to effectively develop these drugs formulators are becoming increasingly reliant on more complex and sophisticated strategies. Here we consider the value of powder rheometry within this context focusing on its ability to support innovative product development. By sensitively capturing critical aspects of powder behaviour, multi-faceted powder characterisation with a powder rheometer can help formulators to knowledgably manipulate formulation and excipient properties to achieve desirable performance. Experimental studies by researchers at the School of Pharmacy, Sungkyunkwan University3 and Bernal Institute, University of Limerick, Ireland4 provide practical illustrations of industrial relevance and application in the development of gastroretentive (GR) tablets and amorphous solids dispersions (ASD) respectively. A Changing Landscape for Formulation As the number of Class II and Class IV drug candidates increases, formulation science and practice are advancing to address the specific issues that each present. Class II candidates exhibit good permeability once in solution, so formulation necessarily focuses on improving dissolution rate or increasing solubility. Salt formation, size reduction and the use of surfactants all have potential to 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

increase the rate of drug dissolution while functional excipients such as cyclodextrins, lipid-based drug delivery systems and formulation as an ASD are proven strategies for boosting solubility.5 Boosting dissolution rate or solubility is also vital for Class IV drugs, but poor permeability brings additional issues. Class IV drugs may exhibit erratic absorption, significant intra- and inter-patient variability, pronounced fed state dependence, and narrow absorption windows.6,7 Previously listed formulation strategies remain relevant for these drugs, notably lipid delivery systems and solid dispersions, but formulation is especially demanding. While the chemistry of Class II and IV drug formulations is critical, physical properties may be equally vital with respect to product commercialisation. For example, formulation as an ASD, one of the most popular ways of improving solubility, can give rise to poor flowability, a potential barrier to high manufacturing efficiency.4 Engineered oral solid dosage forms such as GR tablets may be advantageous for Class II and IV drugs with a narrow absorption window or poor solubility/stability lower in the gastrointestinal tract but are exacting with respect to excipient choice and stable product manufacture. As formulation becomes increasingly focused on these more demanding drug candidates the need for more informative physical characterisation techniques intensifies. Exploring the Value of Multi-faceted Powder Characterisation Bulk powder property measurements,

notably flowability, support the development of formulations with robust processability that deliver consistent product quality. For example, in tablet manufacture, powder flow properties impact the consistency of diefilling and have been securely correlated with critical quality attributes such as tablet hardness.8,9 Day-to-day poor flowability can trigger unscheduled process interruptions and reduce throughput. Traditional techniques for assessing powder flowability include angle of repose, tapped density methods (Hausner ratio (HR) and Carr’s Index (CI)) and flow through an orifice. However, these are limited with respect to: •

Sensitivity: imprecisely defined methodologies, variations in equipment design and a high degree of operator dependence mean that many traditional techniques suffer from poor repeatability and a lack of sensitivity. Relevance: by defining flowability with just a single number, traditional techniques fail to capture the effect of variables such as consolidation, aeration, fluidisation, applied shear rate and temperature.

Dynamic powder testing is a modern technique that involves generating values of flow energy from measurements of the axial and rotational forces acting on a precision-engineered blade as it rotates through a powder sample (see figure 1).10 High sensitivity and the ability to test powders under conditions that simulate the process environment set dynamic testing apart from other methods and

Figure 1: Dynamic testing quantifies powder flow behaviour with high sensitivity and allows manipulation of the test environment to simulate different processes Summer 2022 Volume 14 Issue 2

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Drug Discovery, Development & Delivery make it a uniquely valuable tool for those applying cutting edge formulation strategies. Powders can be tested in a consolidated, moderate stress, aerated or fluidised state to rigorously assess flow behaviour under all the conditions associated with manufacture of a complex oral solid dosage form. The impact of flow additives and other excipients designed to improved processability and performance can be precisely and robustly assessed. Furthermore, the instrumentation used for dynamic powder testing enables shear and bulk property measurements. Shear cell analysis generates the properties required for hopper design and troubleshooting, and more generally quantifies the ease with which a consolidated powder transitions from the static to dynamic state. Bulk powder properties – compressibility, permeability, and bulk density – quantify response to compression, resistance to air flow, and particle packing efficiency, respectively. Both shear and bulk property measurement therefore have much to contribute to the optimization of formulations properties for tableting processes.8 Applied in combination dynamic, shear and bulk property measurements deliver multi-faceted powder characterisation, providing comprehensive insight into a formulation to support, for example, excipient choice and processing route. The following examples illustrate the value of multi-faceted powder characterisation when formulating Class II and IV drugs. Case Study: Developing a Bilayer Floating Tablet for a Class IV Drug with Poor Oral Bioavailability Rebamipide (RBM), a BCS Class IV drug, is prescribed for the treatment of gastric and duodenal ulcers and other gastric disorders. Due to low oral bioavailability maintaining a therapeutic effect relies on relatively high frequency dosing making the drug an ideal candidate for sustained release formulation. Researchers at Sungkyunkwan University working on the development of GR tablets therefore selected RBM as a model drug for the development of a floating tablet with discrete GR and drug release layers.3 This bilayer structure makes it possible to independently optimise GR and drug release characteristics. Developing a GR layer that combined the strength needed to withstand gastric action with buoyancy was a critical step. Hydrophobic rather than hydrophilic 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

polymers were screened for this task, a novel approach. The performance of the preferred hydrophobic polymer – Kollidon® SR was then compared with analogues formulated with polyethylene oxide (PEO) 7M, a hydrophilic alternative. A sublimating agent, camphor, was added to introduce porosity, and by extension buoyancy. Such agents have potential to increase blend cohesivity making successful formulation reliant on understanding how best to manipulate compression force and sublimating agent concentration to produce strong, buoyant tablets with acceptable flow properties. Two techniques were particularly helpful in navigating these issues: mercury porosimetry and multi-faceted powder characterisation.

comparable average porosity and density but the Kollidon® SR formulation has much smaller pores. This difference is attributable to the morphology of Kollidon® SR particles which are smaller, less dense, and more regularly shaped than PEO 7M analogues. Figure 2 shows mercury porosimetry data for Kollidon® SR samples quantifying the impact of camphor concentration and compression pressure on porosity. In the absence of camphor, pore size distribution is narrower. Blends containing 20% camphor produce an appreciable population of larger pores regardless of compression force. However, increasing compression force shifts pore size distribution to finer values for both the 0 and 20% camphor blends.

Table 1: Kollidon® SR and PEO 7M samples incorporating 20% camphor and compressed at 1 ton have comparable total porosity though the Kollidon® SR sample has much finer pores

Figure 2: Total porosity of the GR layer can be increased by reducing compression force or increasing camphor content (left); the inclusion of camphor broadens pore size distribution (right)

Table 2: Flow property data for GR blends incorporating 20% camphor

Table 1 summarises porosity characteristics measured by mercury porosimetry for Kollidon® SR and polyethylene oxide (PEO) 7M samples containing 20% camphor, 1 ton compression force. The two blends deliver

The only two formulations that successfully produced floating bilayer tablets were those with the highest total porosity, the 20% camphor formulation subject to a 0.75ton compression force Summer 2022 Volume 14 Issue 2

Drug Discovery, Development & Delivery and the 0% camphor blend compressed at 0.5ton. Tablets produced with higher levels of camphor or at low compression lacked viable hardness. A 20% camphor concentration was subsequently identified as optimal, taking into account all the data. Optimised candidate GR blends were assessed using traditional techniques (Angle of Repose and CI) and by measuring dynamic and bulk powder properties using standard testing protocols10 (see Table 2). Both blends contain magnesium stearate and Aerosil® R972 to improve flow properties and tableting performance. Traditional methods provide minimal statistically relevant differentiation between the samples making them of limited value for this application. In contrast, dynamic and bulk property values provide more robust differentiation and much greater insight. Basic Flowability Energy (BFE) values are measured during a downward traverse of the powder rheometer blade that pushes the powder down against the confining base of the test vessel. The resulting values reflect flow behaviour under forcing conditions, such as in the feed frame of a tablet press. BFE values for Kollidon® SR are much lower than for PEO 7M suggesting superior performance in this type of unit operation. Specific Energy (SE) values are measured on an upward traverse of the blade and are more relevant to gravitational powder flow. These results similarly highlight the better flowability of the Kollidon® SR and the greater cohesivity of the PEO 7M blend. Flow Rate Index (FRI) is determined by measuring BFE as a function of blade tip speed (FRI = BFE at 10 mm/s / BFE at 100 mm/s.). Generally, more cohesive powders have a greater tendency to entrain and trap air and therefore show greater sensitivity to flow rate. The lower Conditioned Bulk Density (CBD) of the PEO 7M blend suggests higher air content and less efficient packing providing a rationale for the higher FRI value of this sample. Both FRI and CBD provide further evidence of the greater cohesivity of the PEO blend which is therefore likely to be more sensitive to changes in processing rate. Taken together the dynamic and bulk properties indicate that the Kollidon® SR blend is likely to exhibit superior performance at every stage of the tableting process. Differences in morphology help to rationalise this superior performance. Though finer in size Kollidon particles wwww.international-pharma.com

have a smooth, regular morphology more conducive to flow and efficient packing. Case Study: Optimising the Processability of an ASD of a Class II Drug Itraconazole (ITZ), a Class II drug, is a broad spectrum anti-fungal medication that can be formulated as an ASD to improve solubility, and by extension bioavailability. Researchers at the Bernal Institute, University of Limerick, Ireland produced ternary ASDs of ITZ using two polymer excipients: Soluplus® and hypromellose phthalate to determine how spray dried (SD) samples compared with analogues made by hot melt extrusion (HME); HME samples were subjected to a final ball milling (BM) step for 1 min. The aim of the study was to assess any potential to optimise ASD processability via choice of processing route. Dynamic, shear and bulk powder properties were all measured to support this objective.10 Figure 3 shows powder stability and variable flow rate data for the SD and the HME + BM ASDs. SI quantifies how flow

properties change with repeat testing and is mathematically defined as the ratio of BFEtest7 to BFEtest1. SI values close to 1, (0.96 +/- 0.06 for the HME + BM ASD and 1.24 +/- 0.26 for the SD ASD) are indicative of relatively stable behaviour. The SD ASD has a lower BFE than the HME + BM ASD, but also exhibits significantly higher FRI, 3.73 +/-0.35 c.f. 1.40 +/- 0.02, indicating greater cohesivity. From a practical perspective the difference in FRI between the two ASD samples suggests that they would respond differently to changes in flow/ shear rate during processing. This finding is particularly relevant for unit operations such as blending and feeding, where performance has been shown to correlate directly with FRI.11 In aeration testing (see figure 4) BFE measurement protocols are applied as air flows upwards through the sample at a defined velocity. Aeration Ratio (AR) directly quantifies a powder’s response to air and is mathematically defined as flow energy10 mm/s/BFE. The SD ASD has an AR in the

Figure 3: BFE, stability and variable flow rate data capture clear differences between the SD and HME + BM ASDs.*

Figure 4: In aeration testing the non-cohesive HME + BM is sample significantly impacted by aeration, in contrast the SD ASD sample is largely unaffected.* *Please note both Figure 3 and Figure 4 include other data sets measured in the study that are not directly relevant to this discussion. INTERNATIONAL PHARMACEUTICAL INDUSTRY 35

Drug Discovery, Development & Delivery range 1.73–2.02 suggesting it is relatively insensitive to aeration, a trait associated with more cohesive powders. Strong interparticulate forces inhibit the passage of air around individual particles, preventing the lubricating and fluidising effects that reduce flow energy. In contrast the HME + BM sample has an AR of between 45.9 and 58.2. Aeration has a strong effect on this much less cohesive powder. Once again, the observed difference between the ASDs has implications for pharmaceutical processing notably for unit operations such as Würster coating, a fluidised bed microencapsulation process, and pneumatic conveying. Figure 5/Table 3 shows shear properties for the two ASDs. Flow Function (FF) values for the SD and HME + BM ASDs classify them as cohesive and free-flowing, respectively, though repeatability is markedly lower for the less cohesive powder, a widely recognised issue with all shear cell testers.

discharge. However, it is worth noting that the measured shear stress values are actually quite similar for these materials. The derivation of shear cell parameters involves a process of mathematical extrapolation that can magnify the impact of measurement errors particularly for less cohesive materials. Other more relevant methodologies may therefore provide much clearer differentiation. Table 4 shows density metrics for the ASDs and raw materials including ‘Conditioned’ Bulk Density (CBD) values as measured with the powder rheometer. Conditioning involves gentle agitation of the powder bed using the blade of the instrument and leaves samples in a consistent, homogeneous, loosely packed state. It is a precursor to all measurements and helps to ensure excellent repeatability. In contrast, ‘measured’ bulk density (MBD) values were determined by simply pouring

Figure 5/Table 3: Shear testing provides further evidence of the greater cohesivity of the SD ASD

Table 4: Density metrics provide further evidence of the greater cohesivity of ASD SD and illustrate the benefit of conditioning with respect to repeatable bulk density measurement

Unconfined Yield Strength (UYS) and Cohesion values similarly rank the ASDs with respect to cohesivity, since higher UYS values are generally associated with more cohesive powders. The higher Angle of Internal Friction (AIF) of the HSM + BM ASD sample suggests it will also be more sensitive to increasing levels of consolidation. More generally, the shear cell data provide more evidence that the ASDs are likely to exhibit different behaviour, notably in packaging, shipping and hopper 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

samples directly from storage into a preweighed graduated cylinder. Tapped density values were measured and used with both MBD and CBD to generate values of HR and CI. CBD values exhibit excellent repeatability. The CBD of the SD ASD is much lower than that of the HME + BM ASD, a result consistent with higher cohesivity. Strong inter-particulate forces of cohesion support the development of structure in the bed and

the associated entrainment of air, thereby reducing bulk density. MBD and CBD are broadly consistent though MBD values are appreciably lower suggesting that the conditioning step may be associated with deaeration and particle rearrangement into a more efficiently packed state. HR and CI provide no or minimal differentiation between the two ASDs, depending on whether they are calculated using CBD or MBD. At best they classify the HME + BM sample as cohesive and the SD sample as very cohesive. These results therefore highlight both the potential for variability in density measurements and the limitations of tapped density methods when it comes to reliably and sensitively differentiating powders. Taken together the dynamic, shear, and bulk properties (CBD) provide a robust process-relevant assessment of the two ASDs, clearly identifying HME + BM as the preferred production route with respect to processability. The cohesivity and poor flowability of SD can be rationalised with reference to its particle morphology, to smaller particle size and more complex shape. Measuring bulk powder properties translates these morphological differences into process relevant insight and allows formulators to determine how steps taken to improve bioavailability might impact manufacturability. In Conclusion The intensifying requirement to effectively formulate Class II and IV drugs increases the need to optimise analytical strategies. Multi-faceted powder characterisation via the measurement of dynamic, shear and bulk powder properties supports the formulation of drug products with better processability, and by extension, more consistent performance. The example data presented here illustrates this approach and its superiority to other powder testing techniques. REFERENCES 1. 2. 3. 4.

M. Sherry Ku “Use of the Biopharmacutical Classification System in Early Drug Development” AAPS J 10(1) (2008) 208–212 R. Ghadi and N. Dand “BCS Class IV drugs: highly notorious candidates for formulation development” J Control Release 248 (2017) 71-95 T. T. Nguyen et al, ‘Development of novel bilayer tablet based on hydrophobic polymers’ Int J of Pharmaceutics, 574 (2020) M. Davis, C. Potter and G. Walker, ‘Downstream processing of a ternary amorphous solid dispersion: The impacts of spraying drying and hot melt extrusion on powder flow, Summer 2022 Volume 14 Issue 2

Drug Discovery, Development & Delivery to download at: http://www.freemantech. co.uk/literature/white%20papers/Using_ powder_characterisation_methods_to_assess_ blending_behaviour.pdf

Jamie Clayton





compression and dissolution’ International J of Pharmaceutics, 544 (2018) 242–253 D. P . Elder “Effective Formulation Development Strategies for Poorly Soluble Active Pharmaceutical Ingredients” American Pharmaceutical Review October 1st 2010. R. Ghadi and N. Dand “BCS Class IV drugs: Highly notorious candidates for formulation development” J Control Release, 2017 Feb 28;248:71-95. M. Markovic et al. “BCS Class IV Oral Drugs and Absorption Windows: Regional-Dependent Intestinal Permeability of Furosemide” Pharmaceutics 2020 Dec; 12(12): 1175 J. Clayton “Reviewing Current Practice in




Powder Testing” Org. Process Res. Dev. 2015, 19, 1, 102–109 T. Freeman “In Pursuit of Wet Granulation Optimization.” Pharmaceutical Manufacturing 2014. Available to view at: http://www. pharmamanufacturing.com/articles/2014/inpursuit-of-wet-granulation-optimization/ R. Freeman ‘Measuring the flow properties of consolidated, conditioned and aerated powders — A comparative study using a powder rheometer and a rotational shear cell.’ Powder Technology, 174 25-33 (2007) T. Freeman and B. Armstrong ‘Using powder characterisation methods to assess blending behaviour’ Whitepaper available

Jamie Clayton is Operations Director at powder characterisation company Freeman Technology, based at the company’s headquarters in Tewkesbury, UK. He graduated from University of Sheffield with a degree in Control Engineering and is responsible for overall management of company activities, including the R&D, production, sales and customer support teams. During his time with the company, Jamie has worked as a mentor with several academic groups and is an active member of ASTM F42. Jamie is also a regular contributor to conferences and workshops on the topic of powder rheology and works closely with clients on the application of the company’s technology.


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Control valves

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Drug Discovery, Development & Delivery

Option 1 – Pressure’s On: How Roller Compaction is Helping Pharma’s Formulators Achieve Better Poorly Soluble API Delivery Advances in combinatorial chemistry and high-throughput screening continue to introduce poorly water-soluble active ingredient (API) chemistries into pharmaceutical development. For more than 25 years, high-throughput chemistries and techniques have driven a dramatic increase in the number of poorly watersoluble drug candidates in development. Because these methodologies have become so well-understood, pharmacologists are now better able to successfully synthesize more potential candidate compounds and efficiently optimise drug-receptor binding to achieve better selectivity. Approximately 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble.1 Issues associated with poor solubility can lead to low bioavailability and result in suboptimal drug delivery. For those reasons and more, the majority of new drug development failures have been attributed to poor water solubility. Although the risk remains that APIs can fail in development because bioavailability issues can’t be overcome, pharma and its contract partners have become extremely good at applying enabling technologies that in final dose form overcome the pharmacokinetic conflicts of even the “poorest” poorly soluble API chemistries. Amorphous Forms and Solid Dispersions Required Stable crystal drugs chemistries often present solubilisation issues due to high lattice energy. Typically, to achieve desired endpoints more hydrophobic domains are ‘bolted’ to the molecular scaffold which can increase molecular weight and hydrophobicity. Both of these attributes contribute to reduced aqueous solubility.1 Pharma’s experience has proven disordered amorphous solid dispersion (ASD) particle forms offer distinct advantages over crystal forms relative to solubility. Hence, changing the solid-state characteristics of the API can help render the molecule more water-soluble. The advent of new techniques 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to improve stability of amorphous forms will continue to support the challenges of formulating and processing poorly soluble chemistries into successful commercial products ready to meet patient needs more effectively. Enabling Technologies Granulation, the technique of particle enlargement by agglomeration, is recognised as one of the best ways to manage the pharmacokinetic dynamics of poorly soluble APIs and formulate them for use in OSDs1. During the process, small, fine or coarse particles are converted into larger agglomerates otherwise known as granules. This transforms fine powders into freeflowing, dust-free granules that are easy to compress into tablets or fill into capsules precisely. Generally, the granulation step occurs after initial dry mixing of the necessary powder ingredients and API so that a homogeneous distribution of each ingredient throughout the mixture is accomplished. Because most particles encountered in OSD formulations are in the range of 0.2 to4.0 mm, they are generally produced in an intermediary size (ranging from 0.2 to 0.5 mm) first, ready to be either packed as a finished dose form or be mixed with other excipients before tablet compaction or capsule filling. Wet versus dry granulation? It’s up to the chemistry Granulation can be divided into two ‘types’: wet granulation that utilises a liquid in the process and dry granulation which does not. Selection requires thorough knowledge of physicochemical properties of the drug, excipients involved, required flow and release properties, to name just a few of the critical aspects of the drug substance.2 Dry granulation is the go-to manufacturing process for ASD-enabled poorly soluble APIs and intermediates for two primary reasons: 1.

Process avoids the addition of water, important in maintaining the amorphous form of the API formed via enabling technologies


Provides densification needed for the enabled intermediate where the drug load in the intermediate can typically range between 10–50%

The inherently poor flow properties of most small molecule APIs, the worsening of flow associated with particle size reduction techniques such as micronisation or nanonisation and the low drug loads associated with HPAPIs make granulation almost necessary for facile downstream processing of oral solid dosage forms. Granulation’s “enabling” technologies include roller compaction, spray drying, supercritical fluid, low/high shear mixing, fluid bed granulation, extrusion/spheronisation. However well understood, granulation presents many challenges due to quality requirements associated with content uniformity and physicochemical properties. These include granule size, bulk density, porosity, hardness, moisture, compressibility, as well as with physical and chemical stability of the drug. Roller Compaction to the Rescue Dry granulation agglomerates powder ingredients without the use of liquid binders or water. When granulated, the crystalline chemistries of poorly soluble APIs become more soluble and bioavailable. However, when the granules are exposed to water, it can cause them to recrystallise and reverse the solubility gains from granulating the ASDs in the first place. Roller compaction is one method of producing granulates without moisture because it uses pressure to minimise the space between individual particles. In essence it’s a densification process that has proven to be extremely effective at managing the inherent properties of the “brick dust” powders poorly soluble APIs often present to manufacturers and formulators. As opposed to wet granulation, dry granulation via roller compaction is a truly continuous-flow process that offers manufacturers various economies and advantages operationally. Dry granulation systems require lower capital investment in facilities or equipment. This, together with much lower maintenance Summer 2022 Volume 14 Issue 2

Drug Discovery, Development & Delivery processing associated with the use of less energy, labour and time. Roller compaction being a continuous process makes scale-up that much easier and a function solely of time. The ability to automate the process with recipes also adds to the efficiency of scale-up. Central to the process is the machine. Central to the capabilities of the machine are pharma’s equipment suppliers. Ostensibly modular, current systems in service offer great utility in delivering the process efficiently. Functionally, today’s roller compactors can be calibrated with precision to assure the formulation’s ingredients achieve required properties. Equipment suppliers have also seen continuous operational improvements and innovation to overcome the tough granulation challenges poorly soluble compounds present. However, from the first “mile” of ribbon to the last, delivering the stable, compliant validatable process developers need to assure critical quality attributes is up to the operators – not to mention the formulation and analytical teams assigned to the program. However, these capabilities are accessed, in-house or with external manufacturing partners, the more experience with dry granulation and roller compaction the more likely all stakeholders will yield better results for all stakeholders, especially patients. requirements results in drastically reduced lifecycle costs. Currently, the throughput of common dry granulation systems can reach approximately 400kg/h. Benefits of Roller Compaction Compared to wet granulation and other dry granulation methods, roller compaction offers advantages that make it more suitable for use in pharmaceutical production applications, such as: •

Primarily addresses the poor flowability of powders and other issues, such as dustiness, low bulk density and propensity for segregation. Better suitability for heat and moisturesensitive compounds in ASD forms. Dry granulation allows for granulation without liquids, so it is ideal for APIs that are degraded by the presence of moisture or heat. Since no liquids are added, there is no need for a drying stage, which is ideal, especially for the processing of materials with low melting or thermal degradation points.


Greater process accuracy. Compared to slugging, roller compacted ingredients deliver more consistent powder flow, which results in more consistent compaction results. Easier scalability. For roller compaction operations, both pilot and commercial product batches can occur on the same machine, making it simple to expand production without additional machinery investment. Lower operational costs. Since the roller compaction process eliminates the need for material wetting and drying stages, operational costs are reduced compared to wet granulation operations.

Quality Depends on Equipment, Supplier and the People Applying it Roller compaction offers a straightforward, seamlessly scalable granulation technique to increase particle size while also improving blend uniformity of low dose APIs. Dry granulation has supplanted wet granulation techniques for the overall efficiency in


https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4629443/ https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4401168/

Anshul Gupte Anshul is responsible for technical and scientific oversight of client projects. He works across various functional teams in RFP considerations and scope of work development, proposal delivery, client and prospective client meetings, and contributes to the company's thought leadership agenda. Anshul holds a Bachelor of Pharmacy from the RGPV University, Bhopal, India, a Master of Science in Pharmaceutical Sciences from Temple University, and a Doctorate in Pharmaceutical Sciences from the University of Kentucky. He holds the RAC credential.


Drug Discovery, Development & Delivery

Crystallisation Development – A Quality by Design Approach using Modelling Nearly all synthetic steps in industrial chemical manufacturing end with a crystallisation. This is because it is almost always the most efficient method to purify and isolate the material. While most chemists are proficient at coming up with a basic procedure, when it comes down to the fine details, often crystallisation is seen as a mysterious process and subject to factors beyond our control. Various quality issues may be important for the product: purity, residual solvents, filtration speed, polymorph, crystal habit, particle size distribution. An in-depth understanding of the crystallisation process will help keep these issues under control. Basic Concepts A crystallisation consists mainly of two fundamental processes: crystal growth and nucleation. Other processes such as attrition and agglomeration may also play a role, and should be considered, but first we need to understand growth and nucleation. These two processes occur throughout the crystallisation with rates that depend on many factors including supersaturation, crystal surface area, collision rate, viscosity and temperature. Several of these factors are changing throughout the crystallisation and therefore, the relative rates of growth and nucleation that determine the final particle size distribution, are also variable along the process profile. The fundamental driving force for crystallisation is supersaturation. In simple terms this is how far away the solution concentration is from the thermodynamic equilibrium, or solubility. Thermodynamics Since the solubility is the reference point to determine supersaturation, this is the starting point. The solubility of the product changes during the course of the process, providing the driving force for the crystallisation: supersaturation. Therefore, we need to know the solubility at all times. For a simple, cooled, classical crystallisation this could be provided by a solubility curve. In other systems the solvent may be changing by anti-solvent addition and 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

a solubility model that takes into account both temperature and composition is more appropriate. The solubility model is an essential map to help us navigate through the process. A typical model that gives solubility (C) as a function of temperature (T) and antisolvent fraction (X1) might be based on a modified van’t Hoff equation, as shown in Equation 1, where A, B, C and D constants are to be determined from experimental data.

Equation 1

Kinetics The kinetics of crystallisation, that is the rates of growth and nucleation, depend on supersaturation and the relative rates of these two processes will define the particle size distribution (PSD). The solubility model is our essential process map, but to evaluate effects on PSD we also need to model the supersaturation. This problem becomes complex due to continuously changing solubility, particle size distribution and supersaturation throughout the crystallisation. However, despite the seemingly impossible challenge of these calculations, valuable information can be gained by making some simplifying approximations. Supersaturation Modelling Firstly, the growth kinetics (KG) can be estimated by performing experiments in

which the nucleation is effectively turned off at low supersaturation. This allows us to generate a supersaturation model based solely on crystal growth. A simple crystal growth equation is shown below, Equation 2, where Mt and VS represent crystal mass and volume at time t, and CLC* is the supersaturation. C*, the solubility, is calculated using the model described earlier in Equation 1.

Equation 2

In Figure 1 are shown experimentally determined solution concentration values (dark blue dots), together with the temperature profile (light blue line), solubility curve (green), and simulated growth kinetics according to the above equation for three different growth rates, slow (orange), fast (red) and intermediate (purple). We should remember that, due to the approximations, this model is erroneous, but despite this, it can still be extremely useful. An example is shown (Figure 2), in which the supersaturation model shows the effects of seeding temperature and ageing time. The model allows us to perform a virtual DoE on our computer, exploring many different seeding and temperature profiles in very little time. This is important because, unlike in a real DoE, we can simulate

Figure 1: Effect of Crystal Growth Coefficient (KG) on Crystallisation Kinetics Summer 2022 Volume 14 Issue 2

Drug Discovery, Development & Delivery many intermediate values that would be impractical to explore experimentally. Solubility, and therefore crystallisation kinetics, are often extremely sensitive to temperature and the optimum values could be missed by experimenting with a range that is too wide. The interpretation of this approximation can give insights into PSD. Because nucleation has a higher dependence on supersaturation than growth, the process with higher maximum in supersaturation will give smaller particles. In the following example we see that depending on the kinetics of crystal growth, different process factors are significant for control of supersaturation, and therefore PSD. Knowing the crystal growth kinetics could help simplify an experimental DoE by reducing the number of factors to be considered. Using the model and virtual DoE method, we are able to explore the effect of seeding temperature at many levels, and different ageing regimes (15 and 60 minutes in the following example). In Figure 3 we see the effect on supersaturation with time for the different scenarios. Interestingly the

simulation that gave lowest supersaturation is not one that was seeded at higher temperature. Seeding at lower temperature, 56°C and ageing for 60 minutes results in a lower maximum in the supersaturation curve. A subsequent confirmatory experimental DoE confirmed that larger particle sizes were obtained by seeding at lower temperature, in agreement with the supersaturation model. A clue to the explanation lies in the initial gradient of the curve after seeding. When seeding at lower temperature the initial supersaturation is higher, which results in more precipitation during the ageing process, when compared with an experiment seeded at higher temperature. The largest value of supersaturation occurs during the cooling ramp, but if more crystal density is already present at this moment, the growth rate is higher and the resulting jump in supersaturation is lowered. This result is probably not obvious at first sight, and is due to the changing crystal mass and kinetics throughout the crystallisation process. It is an example of using simulation tools to bring understanding to our process, and underpinning the concept of Quality

by Design, in a way that, perhaps, a purely statistical approach could not. Particle Size Distribution Modelling We would love to be able to model how the PSD changes with process profile and, perhaps more importantly, on scale-up. This becomes challenging, requiring models for solubility, growth and nucleation kinetics (and possibly attrition and agglomeration) together with a population balance model and correlation to the type of distribution used by the analytical method (e.g. spherical equivalent diameter). Again, we would initially opt for a more simple, practical approach. As part of the crystallisation process optimisation, chemical engineering parameters (e.g. power/unit mass, shear, Reynolds number, tip speed) for different reactor designs, agitation and scale can be calculated. For processes involving reactive crystallisations (e.g. salt formation) or dominated by antisolvent addition, the meso-mixing time may also be influential. Some targeted lab experiments based on these calculations can help identify potential factors and reduce risk on scale-up. Conclusion To paraphrase the famous statistician George Box, all models are wrong, but some models are useful. We believe modelling is extremely valuable for crystallisation development and these models add to the knowledge base that is the foundation for Quality by Design. We recommend a practical approach using a mixture of simple semi-empirical models and targeted experimentation.

Figure 2: Effects on Maximum Supersaturation from Virtual DoE


R. McKeown, Using Dynochem to Inform Experimental Design, 2011 S. Winter, Barcelona Crystallization Workshop, 2019

Steve Winter Steve Winter has over 20 years’ experience in the pharmaceuticals and fine chemicals industry, with a large proportion of his time dedicated to solid form and crystallisation. Much of his research has been dedicated to developing and transferring processes to production and troubleshooting historical processes. Figure 3: Effect of Seeding Temperature and Ageing Time on Supersaturation wwww.international-pharma.com


Clinical and Medical Research

Achieving Faster Investigational New Drug Timelines with a Robust Cell Line Development Strategy Technological advances in drug manufacturing equipment and process optimisation play a significant role in increasing speed to clinic of critical biologic drugs. Although implementing new technologies and strategies can shorten drug development and manufacturing timelines, there is still one area that is consistently time-consuming: cell line development. Even with wellestablished automated platforms, it typically takes three months to complete cell line development (CLD) while working towards an Investigative New Drug (IND) filing. In this article, Youlim Kim, a Lead Scientist at Samsung Biologics, explores the challenges associated with CLD and offers an expert look into the tactics contract development and manufacturing organisations (CDMOs) can employ to shorten commercial timelines while preserving quality and yield. The Growing CLD Market Consistent growth in the antibody therapy market has been largely driven by the rising demand for monoclonal antibodies (mAbs), bispecific antibodies, recombinant proteins, and vaccines. However, development of these therapies targeting a vast array of therapeutic areas, including oncological, autoimmune, and infectious diseases can be complex and challenging, particularly CLD. Producing stable cell lines and avoiding inherent contamination risks in upstream and downstream development are common areas where difficulties can arise. Subsequently, developers of antibody therapies looked to those with experience and expertise in offering CLD services for support. As a result, the market for CLD services has grown at a double-digit compound annual growth rate (CAGR) and is expected to reach $1.7 billion by 2028.1 Technological advancements in cell line engineering and screening techniques are also factors that are set to fuel this growth. A Drive for Faster CLD Despite the increasingly advancing capabilities 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of biopharma’s CDMO partners, CLD remains to be an area with both technical and operational challenges. Currently, best practices will often rely on processes that are manual, laborious, and time-consuming. One example of this is the use of selection markers for gene integration that require thousands of clones to be extensively screened. For biopharma’s CDMO partners, embracing technical innovation and achieving operational excellence will be the key to shortening the typical 3-month timeline taken to complete CLD when filing IND applications. By optimising protein expression platforms and developing cell lines that can accommodate an accelerated approach, patients will receive essential therapies faster. A Robust CLD Program is Key to Acceleration When striving to achieve faster CLD processes, it is important to develop a robust CLD program that aims to not only shorten timelines but to maintain yield, stability, and product quality. It must also ensure that regulatory compliance is upheld. Identifying the fastest processes capable of achieving IND approval while providing high product quality requires an appreciation of the balance needed between speed and quality. The program should optimise CLD, increasing the specific productivities of often difficult-to-express proteins while improving titer, cell growth, and cell viability for commercialisation. When building a CLD program, developers should consider introducing new screening technologies, optimising cell culture conditions, and developing new cell lines to maximise CLD output and achieve accelerated timelines. Start by Choosing the Right Cell Line Developing a robust CDL program relies on selection of the best expression host system for protein product expression. There are many different types of expression host system that can be used when developing and manufacturing biologics, including mammalian, bacterial, or fungal cells. However, mammalian cells provide unique characteristics to the molecule that

often cannot be achieved by lower-level organisms like bacteria and fungi: •

Protein folding and assembly Folding and assembly of human proteins like mAbs into the right conformation is more likely to be achieved by mammalian cells, which will have cellular components and enzymes that more closely resemble the native host.2

Bond formation The disulfide bonds of antibodies must be formed in oxidizing conditions. In gram-negative bacterial expression systems like Escherichia coli, the reducing conditions of the cytoplasmic compartment will result in the formation of non-functional protein aggregates.2

Glycosylation As glycans attached to mAbs impact their pharmacokinetics, efficacy, and safety, correct glycosylation of the molecule is of utmost importance.2 However, this post-translational modification (PTM) cannot be achieved by prokaryotic cells, including bacteria.

If the expression system chosen cannot properly fold and assemble the protein, form the bonds needed or conduct essential PTMs, there will be no viable product. Consequently, the potential for success in CLD and complex biologic production when using unicellular organisms is often not as high relative to mammalian cell line platforms. As a result, reliable mammalian cell lines, like Chinese Hamster Ovary (CHO) are often the ideal cell system to produce a variety of therapeutic proteins. An Ideal Expression system: CHO Cell Lines CHO cell lines are commonly used in the production of mAbs and bispecific antibodies, as they can not only express proteins with the correct quaternary structure but have many other advantages: •

Relatively easy culturing As CHO cells can grow well as suspension cultures and have a high tolerance to a range of culture conditions, including pH, Summer 2022 Volume 14 Issue 2

Clinical and Medical Research pressure, and temperature. This allows improvement of safety and stability profiles as growth conditions can easily be adapted. •

Ideal for scalable manufacturing The ability of CHO cells to grow as suspension cultures means that they are ideal for scalable manufacturing, avoiding the contamination risks and laborious manual processes that can be associated with adherent cell cultures.

High productivity By optimising and engineering CHO cell lines, developers and manufacturers can achieve a high yield of high-quality recombinant proteins.

Similar pharmaceutical activity and biocompatibility As CHO cell lines are capable of proper PTM, including glycosylation, that is similar to those in humans, they are able to produce biosimilar human products with biocompatibility and comparable pharmaceutical activity. Widely available engineering tools The CHO cell line is well-characterised and has been widely understood for many years. As a result, there are many tools for CHO cell line engineering that are commercially available. Well-recognised by the FDA As CHO cell lines have been used to produce around 50 biotherapeutics already approved in the U.S and EU, the FDA is very familiar with these expression systems.

Optimising CLD further with CHO Building a CLD program around the use of an expression system like CHO will clearly provide many advantages. Optimising CLD further to produce a highly developed cell line is the key to forming a robust CLD program that balances high quality with accelerated speed. There are many different techniques that could be employed to shorten CLD timelines and improve efficiency: •

Use proprietary CHO cell lines Many CDMOs have developed and engineered their own proprietary CHO cell lines to further optimise their CLD. With this approach, manufacturingready cell lines offering high growth rate, yield, and productivity can be generated.


Optimise upstream processes By optimising upstream processes, including cell culture processes for large-scale production, developers and manufacturers of antibody therapeutics can start CLD and production from a position of strength. Optimisation should be carried out with the aim of achieving high specific production rate for qualified protein expression and secretion. Using customised cell culture media and preparation of the molecule and formulation for commercial manufacturing can further strengthen this starting position. Consider improving facilities, capacity, and technologies Implementing advanced analytical technologies and high-throughput tools can also help to shorten CLD timelines. For example, high-throughput affinity capture technologies can accelerate cell isolation, screening, and selection with automation. Using single-cell printing techniques for cell sorting, or advanced artificial and machine learning can also be used to increase production speed.

Outsourcing to Further Strengthen Development Programs Increasingly, the best-performing development programs are those that outsource CLD to strong partners with experience and expertise with similar molecules. This is because working with a single, end-to-end CDMO partner can alleviate or eliminate the disconnect between different stages of CLD. Partnering with specialists can improve CLD programs by: • •

Providing access to innovative and efficient CLD platforms to maximise process and quality outcomes Bringing cost efficiencies with new ways to manage and curtail costs that do not compromise product quality or patient safety Alleviating internal resources and allowing developers to focus on core competencies

Always Keep IND Goals in mind As each phase of CLD will have differing and sometimes competing priorities, it is important to always come back to the larger IND and BLA development goals throughout optimisation. From the onset of CLD program development, all aspects of the product lifecycle must be considered to identify areas for optimisation early

and determine areas where time could be saved. Building a robust CLD program with IND and BLA goals in mind can offer developers key elements that will allow them to start future programs more effectively, regardless of strategy or partner. The collaboration of key project stakeholders involved in development of the program will help to build a thorough understanding of the characteristics of the model as well as the program needs. The development of well-defined communication and issue-resolving protocols can also be achieved more easily with a robust CLD program in place, allowing for real-time project transparency. Drug programs are also more likely to meet challenging end goals and criteria with a program emphasizing transparency and enabling critical data to be accessible and sharable. Key lessons Balancing high quality and accelerated timelines in CLD is the key to achieving faster IND and relies on the careful optimisation of all areas in the process. It is important to not focus too heavily on one aspect or analytical area when building a robust CLD program. With expertise across all fields, leading CLD service providers are well-placed to optimise processes holistically and pave a faster and more efficient path to IND filing. REFERENCES 1.


www.prnewswire.com/news-releases/global-1-7billion-cell-line-development-services-markets2020-2028---advanced-technologies-forscreening-cell-line-engineering-and-bioprocessing-301154707.html Frenzel A, Hust M, Schirrmann T. Expression of recombinant antibodies. Front Immunol. 2013;4:217. Published 2013 Jul 29.

Youlim Kim Youlim Kim has more than 10 years of cell line development experience. She joined Samsung Biologics in 2017 as a Lead Scientist of the CLD group. Prior to joining Samsung Biologics, she worked on in-house/customer cell line platform development, vector construction, and cell culture manufacturing at Bi-nex and CHA University. She earned her M.S at Korea University for Molecular genetics.


Clinical and Medical Research

COVID-19 and Sepsis Co-infection: The Impact of Advanced Detection and Diagnosis Sepsis is characterised as life-threatening and fast-progressing organ dysfunction caused by a dysregulated host response to infection. Sepsis shares several clinical manifestations with COVID-19 including fever, laboured/rapid breathing, and increased heart rate,1 making diagnosis challenging. SARS-CoV-2 co-infection, where an individual may be infected with the virus and one or more additional pathogens concomitantly, leads to both innate and adaptive immune responses which, in some cases of severe disease, can become dysfunctional and cause significant lung and systemic pathology.2 This lung damage and dysregulated immune response in severe COVID-19 pneumonia puts these patients at an increased risk of secondary infection with bacteria, fungi, or other viruses. In addition, individuals with pre-existing conditions could be more susceptible to severe COVID-19 disease if infected. Rapid diagnosis is critical to identifying and diagnosing such infections and determining the correct course of treatment as quickly as possible. However, as COVID-19 has a variety of clinical manifestations, it may be challenging to distinguish co-infections which share clinical features, such as sepsis. It is vitally important to rapidly detect co-infection in COVID-19 patients and accurately identify causative pathogens to deliver effective treatment. Challenges in Patient Diagnosis and Treatment There are several factors that can complicate patient diagnosis and treatment in the case of co-infection. Secondary infection could be more easily missed and go undiagnosed in the face of SARS-CoV-2 primary infection, especially if symptoms overlap. Diligent testing of COVID-19 patients for other infectious diseases is therefore vital. Importantly, patients with severe COVID-19 disease in intensive care units (ICU) are at increased risk of nosocomial infection and should be carefully monitored. Rapid 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

treatment decisions are needed, particularly in the case of multi-drug-resistant (MDR) microorganisms. Although the reported incidence of bacterial, fungal, and viral co-infections in hospitalised COVID-19 patients is relatively low,3 when present they may cause severe diseases with poorer outcomes. For example, many studies have reported a higher incidence of secondary infections in patients admitted to ICU,4,5 and those diagnosed with secondary infections had lower discharge rates and higher mortality rates than those without secondary infection.6 Researchers are still looking to determine whether this outcome is a function of longer ICU stay, concomitantly administered medications (e.g., antibiotics, immunomodulators), the immunocompromising effects of severe COVID-19 itself, or other factors.7 Sepsis The high prevalence and poor recognition of sepsis make it a considerable burden to public healthcare systems worldwide. The repercussions associated with longer bed stays and prolonged antimicrobial treatment impact both patient wellbeing and the cost to hospitals. Treatment with broad-spectrum antibiotics is the first step in tackling sepsis. Although these drugs can help bring the infection under control, without knowing the identity of the microorganism and providing targeted antimicrobials, the severity of sepsis can rapidly increase. Bloodstream infections have been reported to represent approximately 20% of ICU-acquired cases of sepsis and septic shock,8 and a growing body of research demonstrates the increased risk of secondary infection in hospitalised patients with severe COVID-19, particularly ventilated ICU patients.9 Most SARS-CoV-2–infected patients admitted to ICU show a dysregulated host response characterised by hyperinflammation, alterations in coagulation, and dysregulation in the immune response that contributes to multiple organ failure – common clinical features to sepsis. There are two mechanisms to consider when evaluating the incidence of sepsis

in COVID-19 ICU patients. Firstly, many patients with severe COVID-19 meet the Third International Consensus Definitions for Sepsis (Sepsis-3), which define sepsis as “a life-threatening condition that arises when the body’s response to infection damages the host’s own tissues”.10 Therefore, SARS-CoV-2 viral infection is likely the most common cause of sepsis. Secondly and perhaps most easily overlooked, coinfection with bacteria, fungi, or another virus could lead to bloodstream infection and sepsis. One multi-centre study reported the increased risk of ICU bloodstream infection for COVID-19 over non-COVID-19 critically ill patients after 7 days of ICU stay, which was associated with the use of IL-1 or IL-6 receptor antagonists in critically ill COVID-19 patients.11 Coagulase-negative Staphylococci were the most prevalent microorganisms identified in COVID-19 patients with ICU bloodstream infections. While the source of infection in the majority of cases was unknown, catheter and pulmonary routes were the most frequently reported known sources. There is a clinical need to better understand the relationship of molecular mechanisms dysregulated or mediated by SARS-CoV-2 that can lead to sepsis, the risk factors for co-infection in COVID-19 patients that can lead to hospital-acquired bacterial or fungal sepsis, and how COVID-19-related sepsis impacts morbidity and mortality. The mortality rate of patients with septic shock who receive inappropriate antimicrobials has been reported at approximately 90%, whereas those who received appropriate antibiotics had a fivefold mortality rate reduction.12 If this is translated into the current COVID-19 setting, clinicians stand to drastically improve outcomes by rapidly providing targeted antimicrobial treatment to COVID-19 patients with sepsis. The threat of MDR among gram-negative and gram-positive pathogens has increased worldwide over recent years, impacting both hospital and community acquired infections. The COVID-19 pandemic presents a risk to Summer 2022 Volume 14 Issue 2

Clinical and Medical Research antimicrobial stewardship as many patients hospitalised with severe disease are given antibiotics as empiric treatment, despite no bacterial infection being identified. This, plus the greater risk of ICU patients developing serious secondary infections and sepsis, accelerates the emergence of AMR pathogens. Identifying and Diagnosing Co-infections Appropriate and timely clinical decisions depend on rapid and accurate identification of the causative pathogen in sepsis cases. Although culture-based methods remain the ‘gold standard’, molecular assays are increasingly used as faster alternatives.8 Multiplex PCR tests applied on positive blood culture (PBC) have been shown to decrease the time to an optimised antibiotic regimen (spectrum narrowing or broadening or even cessation when a contaminant was identified) but neither the mortality nor the length of stay.13 However, such methods are limited by the number of PCR probes and require expertise and strong collaboration between microbiologists and clinicians. Matrix assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS) is a user-friendly and reliable solution that can be used to identify microorganisms directly from PBC and is capable of rapid phenotypic resistance detection. Looking Ahead Sepsis is the result of the body’s immune response damaging tissues and organs when attempting to fight an infection, with potentially devastating consequences. When appropriate treatment is given quickly, patients can make a full recovery, but poor recognition of symptoms and delays in identifying the causative pathogen can lead to life-changing morbidity and often mortality. Studies have shown that for every hour appropriate treatment is delayed, the chance of survival decreases by 7.6%.14 The scientific community is responding to the ongoing threat of COVID-19 by learning as much as possible about how the disease spreads, how it affects people and communities, the long-term impact on the body after infection, and the incidence of concomitant infection with other pathogens. Microbiologists, epidemiologists, virologists, and pathologists have generated vast bodies of research investigating the structure of SARS-CoV-2, its mechanism of infection, the COVID-19 disease pathway and how it affects individuals differently, studying the longwwww.international-pharma.com

term effects of COVID-19 and, more recently, studying and tracking mutations that could lead to new viral variants. In addition, more research is unfolding to better understand the challenges of diagnosing and managing co-infections like sepsis. However, research remains in the early stages and there is not yet a clear picture of how co-infection impacts clinical outcomes or if existing infections predispose individuals to poorer COVID-19 resilience. Rapidly identifying secondary pathogens and diagnosing such co-infections is vital to determining the correct course of treatment and improving patient outcomes. Microbial detection and identification tools, are not only contributing to research discoveries, but allow clinical microbiologists to make fast and well-informed treatment decisions that, for critically ill COVID-19 patients, can make the difference between life or death. For more information visit https://www. bruker.com/en/products-and-solutions/ microbiology-and-diagnostics/customerinformation-covid-19.html


7. 8.









4. 5.

DHMOSH - Public Health Unit, "COVID-19: Differential Diagnosis and Co-infections", 23 June 2020. [Online]. Available: https://www. un.org/sites/un2.un.org/files/coronavirus_ guidancecoinfections.pdf. [Accessed 07 April 2021]. M. Z. Tay, C. M. Poh, L. Rénia et al., "The trinity of COVID-19: Immunity, inflammation and intervention", Nat Rev Immunol, vol. 20, pp. 363374, 2020. T. M. Rawson, R. C. Wilson and A. Holmes, "Understanding the role of bacterial and fungal infection in COVID-19", Clinical Microbiology and Infection, vol. 27, pp. 9-11, 2021. M. Ripa, L. Galli, A. Poli et al., "Secondary infections in patients hospitalized with COVID-19: incidence and predictive factors", vol. 27, no. 3, 2021. T. Bardi, V. Pintado, M. Gomez-Rojo et al., "Nosocomial infections associated to COVID-19 in the intensive care unit: clinical characteristics and outcome", Eur J Clin Microbiol Infect Dis, vol. 40, pp. 495-502, 2021.


H. Zhang, Y. Zhang, J. Wu et al., "Risks and features of secondary infections in severe and critical ill COVID-19 patients", Emerging Microbes & Infections, vol. 9, no. 1, pp. 1958-1964, 2020. T. Glück, Secondary Infections in Patients with Severe COVID-10, NEJM Journal Watch, March 2021 J. Timsit, E. Ruppé, F. Barbier et al., "Bloodstream infections in critically ill patients: an expert statement", Intensive Care Med , vol. 46, pp. 266-284, 2020. K. K. Søgaard, V. Baettig, M. Osthoff et al., "Community-acquired and hospital-acquired respiratory tract infection and bloodstream infection in patients hospitalized with COVID-19 pneumonia", Journal of Intensive Care, vol. 9, no. 10, 2021. SM. Singer, C. S. Deutschman, C. W. Seymour et al., "The third international consensus definitions for sepsis and septic shock (sepsis-3)", JAMA, vol. 315, pp. 801-810, 2016. N. Buetti, S. Ruckly, E. de Montmollin et al., "COVID 19 increased the risk of ICU acquired bloodstream infections: a case–cohort study from the multicentric OUTCOMEREA network", Intensive Care Med, vol. 47, pp. 180-187,2021. A. O. Coz Yataco and S. Q. Simpson, "Coronavirus Disease 2019 Sepsis: A nudge towards antibiotic stewardship", Chest, vol. 158, no. 5, pp. 1833-1834, 2020. R. Banerjee, C. B. Teng, S. M. Ihde and et al., "Randomized trial of rapid multiplex polymerase chain reaction- based blood culture identification and susceptibility testing", Clin Infect Dis, vol. 61, pp. 1071-1080, 2015. Kumar A et al. "Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock", Critical care medicine 2006 34:1589-1596.

Philip Perry Philip Perry is Vice President of Marketing and Product Management at Bruker Microbiology and Diagnostics and works together with colleagues, customers and clinical partners to provide solutions for complex diagnostic problems.



Transforming the Status Quo Through Digitalisation and AI For all of the extraordinary innovations made in the field of medical science, in many ways we are still working in the dark. Take renal transplants. When it comes to selecting kidneys for transplantation, the status quo is an unsatisfactory compromise based largely on a hopeful assumption as to the health of the donated organ – primarily based on the age of the donor – with very little empirical evidence. Were a more rigorous and forensic means of assessing the health of a kidney available on a wider scale the benefits would be immense. Not only would doctors benefit from far greater levels of information, patients in vital need of a donated kidney would have a much greater chance of survival as well as improved quality of life-reducing the need for severe, lifesaving or merely life-prolonging treatment. Healthcare services could operate at a far greater level of efficiency and success, both in terms of the outcomes and survival rates for their patients, and the cost and time needed to achieve those outcomes. If the status quo can be improved, even transformed, in this one field out of many, there are incalculable potential benefits to patients and healthcare systems everywhere. Changing the Status Quo To that end, in May 2021 SAS UK & Ireland and The University of Cambridge completed a successful collaborative partnership. The starting objective: identifying ways in which the process of selecting kidneys for transplantation could be better delivered through AI-augmented interpretation of renal biopsies. Beyond that, the partnership, backed up by the University's Office for Translational Research (OTR), was charged with adumbrating the potential for a first-of-its-kind digital histopathology service, fit for purpose on a national scale. 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The benefits of this collaboration could go well beyond this crucial field of study. Towards a future envisaged by Professor Gavin Pettigrew, Reader in Experimental and Clinical Transplantation at the University of Cambridge, when the "state of the art computational neural network technology" we have jointly developed is "widely adopted, even beyond the UK". This potentially transformative step forward is just one example out of hundreds where data, digitalisation, and AI might enlighten murky fields of study. Our Guiding Principle; Our Motivation as Professionals If we can help to advance data-driven research and medical practice in the most intelligent way possible, the insights we can yield will enable us to see more clearly and further. In turn we will enable medical scientists and physicians to think smarter, and to act faster, to save lives and improve lives; •

We can radically improve and streamline clinical trials, saving pharmaceutical companies enormous outlays in cost and time each year.

patients down to the most minute metabolomic or proteomic detail, as well as looking at the wider contextual factors that might affect a particular patient's suitability for a therapeutic or medicinal course. •

We can peer through the darkness, see further and more clearly, into the nebulae of as yet intangible factors and variables, from a patient's social identity or psychological wellbeing, to their life experience.

All of these things are now within our reach. We are at a fulcrum point in the development of biomedical science, parallel to major breakthrough moments in history. The Next Micrographia? In 1665 Robert Hooke published Micrographia, one of the most important scientific papers ever written. In it, Hooke illustrated for the first time, to the wonder of his contemporaries, the extraordinary, minute details of the natural world his endeavours with the microscope had revealed.

We can enable pharmaceutical companies to fail faster, so that trials can be wound up sooner rather than later.

Yet those astonishing minutia had always been there. "The things themselves as they appear" as Hooke wrote, had been waiting to be glimpsed for the very first time, when the technology became available.

We can furnish physicians with unprecedented levels of data from those trials, backed up by powerful feature extraction tools to deliver clinical-grade insights.

It is no exaggeration to say that data and AI, harnessed effectively, could prove as transformative as the microscope in our understanding of the minute details of biology and medical science.

By augmenting the level of data and intelligence at physicians' disposal we can enable a generational transformation in the therapeutic journey, leading to greatly improved patient outcomes.

We can provide doctors and nurses with levels of insight and wisdom far beyond their own experience, by aggregating the insight and analysis that huge volumes of data can provide.

Through our efforts we are uncovering microscopic details of a different kind: trillions of bits and bytes of digital data streamed in real time that, through the prism of meaningful measures and intelligent analytics, become far greater than the sum of their parts.

We can provide for a far deeper understanding of differentials between

Think of the transformative effect such powerful data could have on, say, our understanding of pre-eclampsia. There are many awful risks to mother and child that could be mitigated with greater understanding of what is going on within the womb, thereby avoiding the terrible dilemma Summer 2022 Volume 14 Issue 2

Technology Such powerful data and AI empower doctors by augmenting the information on which they can make clinical decisions. But for this to happen requires a degree of state-level observation of populations that many, including myself, have concerns over. What is the right balance between government-led monitoring and civilian liberties? Should individuals be forced to hand over data, and submit to mass observation, for the sake of the wider population? When the next pandemic comes, should we go immediately back to the tracking systems and enforced lockdowns that have caused so much emotional strain and political discord? There are no easy answers to these questions. forced on physicians and mothers over when it is safe to deliver a baby. Think of how much more effectively we could treat type 2 diabetes with data so powerful it can uncover new levels of information about where a patient is on their own disease pathway. And think of what we have all been through over the past two years. The fear, the anxiety, and the great loss of life that we have endured globally. If the Covid Pandemic has Proven Anything, it is the Power of Data-Driven Healthcare Without good data-gathering we would have been attempting to tackle the pandemic half-blind. Without data we could not have known where and when a new variant was emerging; we would not have been able to track infection rates, death rates, immunity levels, or uptake of vaccinations. With even better data than was available when Covid-19 struck, we could have done all these things more effectively, more efficiently, and saved many more lives. When, rather than if, there is another pandemic, we must go into it with both eyes open. The data and analytics tools that were developed and implemented during the pandemic need to be ready to be deployed immediately, anywhere in the world. Of course, what we are talking about here raises many questions. wwww.international-pharma.com

Nobody wants to allow an Orwellian state to develop as the price of freedom from a virus. And those in the pharmaceutical industry should be acutely aware, more than most, that well-intentioned and benevolent means can easily be subverted to further sinister ends. With power comes responsibility, and we must all be aware of how we handle both sides of this equation. We are working towards a future when clinical decisions are never taken without the absolute best possible information (or close to it). In the process we must not forget the less tangible factors to be considered, that go beyond the clinical. Inevitably during the pandemic healthcare providers and governments focused their efforts on immediate clinical needs, and the binary choices between life and death, hospitalisation and isolation, freedom and restriction. What was perhaps unavoidable was the immense toll all of this was taking on the psychological wellbeing of people caught in the middle. We know that lockdowns severely exacerbated a number of mental health and related problems: drug and alcohol addiction, anxiety, domestic violence and abuse, loneliness. But do we really know how much damage has been done? The true, painful consequences of the traumatic experiences of the past two years might take years to resolve, and could leave many, especially young people,

with debilitating long-term mental health struggles. But we can still analyse the emerging data to significantly improve our understanding of some of these wider impacts. The Real Power of Data When we think of the sort of data that we and others are developing, we must never think that its uses are purely clinical, or that health can be reduced to digital binaries. Data and analytics could and should be applied more to the more abstract variables of psychology, identity, social worth, and emotional wellbeing. If we neglect this aspect of its use, we will be overlooking areas of huge potential progress in medicine. In any case, whether it is in the treatment of conditions with purely physical red flags such as pre-eclampsia, or procedures such as a kidney transplant, or whether it is in furthering our understanding of mental health, data has a vital role to play. The profound potential of the technology we and other data and analytics leaders are developing is already being realised by organisations such as the OTR at Cambridge. With greater collaboration between academics, governments, NGOs, the global pharmaceutical industry, and healthcare providers around the world, the possibilities become almost endless.

Simon Tilley Simon Tilley, Global Lead for Healthcare and Life Science, SAS, has worked in software companies exclusively supporting the entire value chain of the pharmaceutical industry – from discovery to commercialisation through drug development and manufacturing. He has worked across all aspects of software companies – from R&D to sales & marketing through to systems design and delivery. Simon has worked extensively across Europe, the USA and Asia. He has a well-rounded and practical understanding of delivering real value to businesses using a wide range of software technologies.



The Importance of User Insights in Digital Product Design

Gathering user insights should be a key part of any medical device development. Understanding your user’s context of use, behaviours and views can allow you to design a solution that meets actual user needs. As society continues to weave digital devices and solutions into every aspect of our lives, it is essential that we understand what our user’s will expect from our digital products and how they will fit into their existing routines, in order to provide the best user experience possible. What are the benefits of digital products in medical? As highlighted by the FDA,1 digital technologies are providing a multitude of innovative ways to help people monitor their health and wellbeing. From medical apps to cloud connected devices, digital health technologies can help users better adhere to their therapies, understand their condition(s), make more informed decisions and manage their health overall away from a clinic setting. For health care providers and other stakeholders, digital products offer a wealth of user data to help track the efficacy of their therapies, understand user behaviours, reduce inefficiencies and provide a more personalised solution for the patient. Clearly, there are many benefits to digital products, but in order for these to be fully realised, the essential step is ensuring your product both adds value to its users and motivates and engages them to use it. This is where gathering detailed user insights both before and during your digital product development can be invaluable.

Without understanding patients’ preferences and needs, it is impossible to create valuable solutions that will offer the best user experience for them. In any medical device development, the user should be included from the very start to identify unmet needs and challenges, even before any design ideas hit the paper. Due to the complex nature of healthcare and MedTech, there can often be a blurred line between the users, end users and decision makers. For example, in the case of a telemedicine app, the end users may be the patients and/or their caregivers. However, the patients’ doctors may also have input, as will insurance providers who may have the final decision on whether to implement the solution. By considering all the various stakeholders around a digital product, we can maximise the chances of success. When we undertake user insights research to inform our digital product design, we are attempting to understand the bigger picture and consider not just how a user physically uses the product, but also to think about how this new digital product will fit into the way they manage their health and their life in general, including any other products (digital or otherwise) they may be using. Failing to consider the bigger picture can result in you missing vital things that will really make a difference to the patient and what will ultimately lead to a more successful digital product.

Which Resource Techniques Can We Use? User insights research, or User Experience (UX) research, is different from traditional market research techniques, in that rather than consulting large groups of people in search of the truth, the number of participants tends to be smaller. The aim here is to uncover rich insights to drive and inform the design of our digital solution. Whereas traditional market research will typically provide statements of fact such as ‘37 out of 100 people said they did not own a mobile phone’, user insights research provides detail, context and a richer understanding of the challenges people are facing. It immerses us as medical device developers more deeply in the patient’s world, highlighting specific challenges and opportunities that we can address in our designs. The objectives of our research are to gather rich insights and a deep understanding of: • • • • •

Context of use What it’s like to live with a condition Unmet needs, behaviours and motivations Challenges and opportunities for digital innovation The real value and benefit of digital features and functionality

By shifting our focus away from just the task in hand to also encompass the bigger

Why Should You Gather User Insights? Although the goal of most healthcare products and services is the improvement of patient outcomes, the most common mistake a digital health company can do is forgetting their users. According to statistics, most digital health start-ups do not survive long, despite having sufficient users and investor funding. Forbes suggests that 98% of digital health startups face severe challenges, and many are already viewed as dead.2 A key cause of this failure is not taking into account the needs of patients, caregivers and healthcare professionals.3 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2022 Volume 14 Issue 2

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Technology picture we can begin to fully understand where our new digital solution can really add value.

the results can also help a moderator to prepare a tailored follow up interview with the patient.

There are several research techniques we can employ to carry out this user research. These include the more commonly known focus groups and in-depth interviews, alongside cultural probes, observations in context and online communities.

Observations in Context While remote interviews and tasks can get us so far, there’s nothing quite as impactful as seeing someone’s context of use and behaviours first hand. These observations can take many forms, from visiting patients in their homes to observing procedures in clinics. The aim here is to understand the workflow, or ‘day in the life’, to identify where an intervention could be useful. The observation typically covers the process, purpose, people, products, and places involved around the management of their condition. These approaches are typically more costly and involve time and travel, however they can provide rich, first-hand insights, which a patient may have neglected or forgotten to say in interview. Such insights can help a design team to work out, where digital health applications, such as dose reminders, might be useful in a patient’s day-to-day life.

In-depth Interviews Whether face to face or remote, in-depth interviews involve exploratory conversations conducted one-on-one with individuals. They are typically 30–90 minute discussions with the participant to explore and understand the challenges they face in managing their health, what they perceive their behaviours and motivations to be, as well as where digital health could add value. It’s worth noting that it can however be challenging to gain other contextual information from just a conversation. Focus Groups Focus groups also involve exploratory conversations, however this time with multiple participants at the same time, typically four to eight. They also offer a valuable way of determining where digital health might add value, as well as different participant’s digital literacy levels and attitudes to digital health solutions. While this can allow for group tasks and dynamic discussions, with participants building on each other’s experiences, it’s important to be wary of ‘group think’, whereby some participants influence others. Cultural Probes The aim of cultural probes is to provide users with activity workbooks and pre-interview tasks, designed to capture insights into: 1) the context in which a digital solution might be used and 2) the emotional aspects of managing a medical condition. This might include photos of where and how they administer their therapies, as well as any other products they are using to manage their health (digital or otherwise) and what their experience is with those. We can also ask participants to create a model of what it's like to live with the medical condition or undertake other tasks which help us understand the factors affecting their behaviour, their personality type and how they may respond to different behavioural 'nudges'. Cultural probes tend to provide a much deeper understanding of the emotional side of managing a condition, helping to immerse you in their world. While this requires more time and effort to prepare, 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Online Communities In addition to individual interviews and observations, online communities can provide a valuable snapshot across a period of time. These platforms encourage users to carry out set tasks in their own time, uploading photos, videos and written entries over a longer period, with the flexibility for participants to engage individually or chat with each other in a 'forum-style' setting. This remote approach allows researchers to explore participants' experiences over a few days or weeks, and can be used for gathering context of use information, uncovering unmet needs and challenges and gathering rich, emotional insights. It does not however, allow for direct observation meaning we are limited to what the user chooses to share with us.

How to Analyse User Insights Once you’ve captured your user insights, you need to then turn your findings into meaningful insights. User journey mapping and personas are strategic UX research tools that can help provide an in-depth understanding of who your users are, what they need, and every touch point they will have with your product. These tools can be used to then identify pain points and opportunities for digital innovation across all your user’s touch points. These exercises can also be critical for immersing your digital design teams in the world of the target users, allowing them to gain empathy for their challenges and ultimately create a more successful digital solution to address their needs. Personas User personas are archetypical users whose goals and characteristics represent the needs of a larger group of users. The descriptions include behaviour patterns, goals, skills, attitudes, motivations and background information, as well as the environment in which a persona operates. They also often include a few fictional personal details to make the persona a more realistic character, such as quotes from real users, as well as context-specific details. Personas can provide a constant reminder for the design team about who the digital solution is intended for, putting the user at the heart of the subsequent product development. User Journey Mapping A user journey map is a very in-depth and detailed process that explores a user’s journey and the touchpoints and interactions they have along the way. This could be from their first symptoms, through to an initial diagnosis, treatment, therapy and follow up. Exploring each stage is an effective way

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Technology to form the basis of research conversations. It can also be used to identify pain points and opportunities for innovation, which you may not have been aware of. The end result is a visual and holistic view of what you need to know and think about with your digital solution, from all angles, and from the viewpoint of different stakeholders. Translating Insights into Design Challenges Analysis and coding of our user insights can lead us to solution agnostic problem statements around which to innovate with our digital solution. Key themes can be drawn from this research, based on multiple real-use scenarios and experiences. These themes can then be translated into specific design challenges. To further steer the subsequent innovation activities, it can be helpful to prioritise the design challenges to understand which are essential to be addressed with the digital solution and which will have negative impacts for the product if not addressed, as well as which are more of a nice to have. This can be amalgamated in a table, as shown in Figure 2.

including the packaging, device, app, web portal and anything else. Moderators can also gain an understanding of how the solution fits into the user’s environment, as well as their digital literacy levels and how easily they interact with the product features, workflows and UI designs. Eye Tracking In this case, eye tracking glasses or software are used to track and show where, and how long someone is looking at different aspects of the UI. This technology offers a valuable way of understanding what draws a user’s focus and how they read and scan text, which can be especially useful on larger screens or web pages. Whilst eye tracking has some limitations as it is only assessing one element of the digital product ecosystem – it can provide valuable feedback on the implementation of your UI – a very important part of your solution. 5 Second Test Another great tool for assessing the implementation of your UI, is the 5 second

page, who they think it is intended for and which elements they can recall after. Conclusion Digital health technologies can have real benefit for both the health and care system, as well as the patient, caregiver and health care professional. For your product to be successful, it is crucial to put the user at the centre of your digital health solution. User insights offer a valuable way to immerse medical device developers and their digital design teams in the world of all their potential users, helping them to understand their specific needs, challenges, motivations and behaviours, and lead to a digital health solution that adds real value. For this process to be successful, it is essential to continuously test early solutions with your users and use their feedback to evolve your ideas. This will lead to a digital health solution that is well implemented with good UI design and flow – ultimately leading to a more successful product. REFERENCES 1. 2.


https://www.fda.gov/medical-devices/digitalhealth-center-excellence/what-digital-health https://www.forbes.com/sites/davechase/ 2016/05/18/why-98-of-digital-health-startupsare-zombies-and-what-they-can-do-aboutit/?sh=112120e050eb https://medicalfuturist.com/10-reasons-whydigital-health-start-ups-go-bust/

Figure 2

Designing, Testing and Optimising Your Solution Once you have identified your design challenges, implementation is key. How your digital ecosystem, UI design and workflows are implemented, will determine the success of your solution. As well as gathering initial user insights, it is equally important to then continue to test your digital solution with real users throughout the prototype and design stages. The following are some key research techniques used to gather feedback on digital health solutions from your users. Contextual Research Contextual research at this stage of the process, involves exploratory testing of prototype digital health products with users in their context of use. Such research provides valuable insights into the user’s reactions to the full digital health ecosystem, wwww.international-pharma.com

test. Five second tests are a method of user research that help you measure your user’s impressions and what they take away within the first five seconds of viewing your design. This technique is often used to test whether web pages are effectively communicating their intended message. This is as five seconds is considered long enough for a good design to communicate its primary message. There is a growing trend for website visitors to open many sites at once, resulting in the user giving much less attention to each page. Effective design and messaging is therefore key to holding a user's attention within the first five seconds, something which can also apply to a digital health solution. It's therefore important to ensure the design is effective and impactful during the user's initial engagement. When conducting this research, the aim is to determine if a user immediately understands the purpose of a

Charlotte Harris Charlotte is Head of Front-End Innovation at Team Consulting. She is an experienced project manager and facilitator, guiding clients through both difficult strategic decisions and encouraging creative thinking through the facilitation of innovation workshops. She has a wealth of experience in contextual/ design research and many innovation tools under her belt to help navigate through the fuzzy front end of product development. 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 in clinical, research, start-up, and consultancy environments.



Does Remote Pharma GMP Auditing have a Future?

The two years since COVID struck have seen virtual auditing checks and inspections take the place of on-site visits. Some auditors believe that the tools and adapted services they have developed during the pandemic might offer a permanent solution, but deeper analysis shows that clients have misgivings about this scenario. Two years on from the first wave of COVID, and following a new survey that was conducted in February 2022, Alasdair Leckie, Operations Director at Rephine, takes a look at clients’ auditing preferences. Before the onset of COVID-19, neither pharma regulators nor suppliers would ever have countenanced the idea of remote audits to verify the manufacturing and distribution standards of supply-chain partners. But fast-forward and two years of lockdowns, social distancing and travel restrictions have disrupted the former status quo. Regulators such as the European Medicines Agency (EMA) adapted their requirements to ensure that inspections could still take place, rather than having to be curtailed. As well as allowing a grace period, so that marketing authorisation holders did not fall foul of compliance requirements if they failed to maintain a maximum threeyear auditing cycle (in Europe), the authorities made provision for virtual assessments to be conducted online.

present a hazard, breaching compliance. In a live remote session with a video link, these transgressions could be missed if cameras are not directed into every corner. The View from the Coal Face In February 2022 Rephine conducted international research among pharma clients and senior auditors to get a better view of how the pharma industry has adapted its auditing activities and to gauge companies’ priorities for a post-pandemic future. Of the 30 or so people we polled, just over half were in the quality function of pharma companies, with the balance comprising professional auditors, and around twothirds of responses were from Europe, the remainder primarily from Asia – particularly India. For both respondent groups (clients and auditors), the greatest challenge with remote auditing has proved to be the lack of a site tour, which leaves auditees in control of what is shown. This gives much less scope for auditors to spontaneously go off plan and explore behind closed doors. As a consequence, auditors cited the restricted scope for real-life face-to-face interaction, and the ability to apply their softer skills (eg that sixth sense that something warrants further investigation) as major challenges with remote audits. Clients agreed that this limitation presented a concern, but worried more about technology-based issues such as a loss of connection potentially preventing or interrupting remote inspections.

But remote auditing was only ever intended to be a temporary measure and although they offer appealing convenience for pharma brands and industry regulators alike, the prospect of standardising on remote audits in the longer term appears to be untenable.

Lack of Trust in Remote Audits Our survey clearly reveals that pharma clients do not trust remote auditing as a permanent solution, with two-thirds saying they would not accept a remote-only audit in order to qualify a new API supplier. Auditors responded in a similar fashion.

Remote inspections simply cannot go into sufficient detail compared to onsite audits, meaning there is a risk that something important might be overlooked. That could be something as seemingly innocuous as a cracked floor – which could

By the same logic, almost two-thirds of client company QA respondents said they would not be comfortable going more than two years before re-auditing, following a remote inspection: a fifth said they would want to redo the audit within a year. (Two-


thirds of auditors said they would look to re-audit within a year following a remoteonly inspection.) For services like packaging (particularly secondary packaging), remote audits felt more tolerable for pharma clients, but for suppliers of active ingredients or finished products, indefinite reliance on virtual inspections was unthinkable. The vast majority agreed or strongly agreed that remote/virtual audits were a good temporary solution during the pandemic, but a sizeable proportion of client QA respondents felt that remote auditing could even require additional resources, compared with an in-person inspection. Might Hybrid Solutions be Acceptable? A hybrid approach to supplier auditing, however, meets with more approval, with two-thirds of audit clients happy with concept. Under such an approach, routine aspects such as sharing and completing documentation could be done remotely but on-site inspections would still take place physically. A third said they would favour a return to 100 per cent in-person audits. Only 1 client expressed a preference for persisting with remote audits across both the documentation element and physical inspections. Open responses in the survey suggested that the long-term value of remote auditing would be for occasional use only and in the context of a long-term, trusted relationship, and where standard operating procedures had been shared ahead of time. For auditors, it was felt that any decisions about continued use of remote audits would need to be risk based and would depend heavily on the willingness of auditees to cooperate, for instance in making the right documents and people available to maximise results. Where client respondents had themselves played host to remote audits during the pandemic, three-quarters favoured a hybrid approach in future, whereby a day on site could be combined with a day providing documentation remotely. In Favour of Third Parties The idea of working with an independent Summer 2022 Volume 14 Issue 2


third-party auditor to generate a single, comprehensive report that could be shared with multiple customers, rather than allowing multiple auditors on site over 1-3 years met with the approval of almost all respondents. It was through conducting this kind of activity, with strict observance of social

distancing, testing and PPE use, that our own auditors were able to continue conducting on-site audits throughout the pandemic. Although numbers of physical audits halved during 2020 in favour of increased remote activity (and the sharpest reduction in activity was really only during that first global lockdown from March-May of 2020), by 2021 highly accredited auditors located on the ground in target markets were largely back on site – with 82 per cent of inspections conducted in person and just 11 per cent done virtually (compared to a ratio of 72 per cent on-site/28 per cent remote audits in 2020).

normality. In other countries with dense populations and still-high infection rates, the situation over the coming months is more uncertain. The key to maintaining high standards of supplier compliance will depend on continued, tailored vigilance, with a return on-site re-audits as soon as is practicable.

Ultimately, however, whatever the perceived convenience of at-distance documentation sharing and virtual inspections, there is no substitute for the real thing and remote activity should only ever be seen as a support activity to the main event.

Alasdair Leckie is Operations Director at Rephine, a firm of deeply experienced GMP auditors which proactively helps pharmaceutical companies around the world with their supply-chain quality assurance. Alasdair has been with Rephine for nine years and has a Bachelor’s Degree in Chinese and Economics from SOAS, University of London.

We do not know what the next phase of the pandemic will bring. Where there are high rates of vaccination and reduced hospitalisations, regions are already seeing a tentative return to some form of

Alasdair Leckie

Email: al@rephine.com Web: www.rephine.com

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New Manufacturing Technology Platforms for Biosimilars One of the main drivers for the pipeline growth in biosimilars is the number of originator blockbuster molecules coming off patent – 17 blockbuster molecules with annual peak sales worth $60 billion have or will lose exclusivity between 2020 and 2025. Global sales topped $15 billion in 2020, representing a compound annual growth rate (CAGR) of 56% since 2015. According to McKinsey’s biosimilars market model, double-digit growth is set to continue with the market anticipated to double in size by 2025.1 There have also been several biosimilars approved, entering the market and gaining major market share – since the FDA approved Zarxio in 2015, a further 32 biosimilars have entered the US market2 with Herceptin and Humira being the subject of most competition. An executive order from the Biden administration,3 in combination with plans from the Department of Health and Human Services (HHS),4 have made it clear that biosimilars are seen as a means to increase competition and reduce costs. There are also many developing countries and emerging economies that can't afford the originators – a high quality biosimilar, with the same efficacy and quality aspects, could open up entirely new markets. Concurrently, advances in biosimilar development and biologics manufacturing have created the potential for companies to reduce the comparative production cost of drugs and to put these out to the market at significantly lower prices. The sector then is poised for significant growth over the next ten years. Here, Dr. Gerrit Hagens Director at BioXpress and Simon Keen, Vice President Cell Line Development at Abzena, explore the technologies that will enable and drive this growth. Upstream Process Development One of the technological advantages that biosimilar developers have compared to originators are the advances seen in enhanced cell line productivity and 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

upstream process development. Titers for example have increased tenfold in the last 10 years, and the move away from older adherent cell lines into suspension has allowed developers to grow larger cell culture volumes more efficiently and cost effectively. As originators come off patent, they're ‘stuck’ using dated, less efficient systems. The development of more productive cell lines and processes offers developers the option to use these to manufacture biosimilars. The overarching impact is that cost of goods comes down, helping to reduce the financial risk associated with development and production. In addition, the cost of clinical trials and capital spending on research and development are reduced, through streamlined regulatory pathways. This drives down the overall costs associated with approving and manufacturing biosimilar molecules which permits a lower market price than the originator. Single Use and Agile Manufacturing There has been a simultaneous advancement in the innovation and adoption of single use technologies. Many biosimilar molecules will be manufactured at lower scales because these products are expected to have smaller market demands than originator drugs, as several biosimilars are expected to share each market as is the case. The Humira ‘patent cliff’ in the US for example will see at least six FDAapproved biosimilars enter the market in 2023.5 Many producers in the biosimilar space are smaller innovators, some of them virtual, who may lack the capabilities to manufacture their product at any volume.

at a CAGR of 19.36% from 2021 to 2028.6 This technology is a key enabler, allowing manufacturers to flexibly handle small batch volumes and multiple biosimilars. Current SUBs are offering improved changeover times as well as better containment performance. Initiatives to enhance stirring mechanism precision, integrate process analytical technologies as well as key advances in disposable technology are all paying operational dividends. Because of their improved reliability and performance 2,000L SUBs are fast becoming the default bioreactor technology for small-scale biologics manufacturing. Continuous Processing The industry is also on the cusp of introducing continuous biologics processing to further improve the batch quality and production efficiency of biosimilars. For example, continuous processing reactors for cell culture perfusion are beginning to enter the commercial manufacturing environment. The technique incorporates a cell retention device and continuous media exchange, while the product of interest, spent media and waste are continuously removed. This allows the process to reach and sustain higher cell densities and viabilities, while increasing productivity over longer periods of time. Long term, continuous perfusion compares favourably against shorter applications, such as High Productivity Harvest, that focus on intensifying fed-batch processes, as it provides reduced batch-to-batch variability. Continuous perfusion technologies may also be used to intensify the seed train with reduced steps and faster overall time to production.

This requirement for lower volume capabilities and the rise in virtual companies, is invariably pushing manufacturing to contract partners (CDMOs). CDMOs in turn are using single use technologies to give them the flexibility and adaptability to take on multiple projects at a time so they can be much more cost effective.

When biosimilar developers effectively implement these technologies, they can further decrease CoGs and reduce timelines, while keeping productivity and quality extremely high. Innovation here will continue to control costs which supports competitive product pricing and other very tangible and marketable differentiators.

One area of significant progress has been the adoption of single-use bioreactors (SUBs) – a market which is projected to grow

De-risking Development Most pharmaceutical and biotech developers are now looking to control every aspect Summer 2022 Volume 14 Issue 2


of their process from start to finish. To support better process control in biosimilar development it is vital that developers characterise the reference molecules in every detail. Exceptional analytical capabilities are required to achieve the desired outcome – which is to be able to generate the data required to identify and match the critical quality attributes (CQAs) between biosimilar and originator. This needs to be tracked throughout development and subsequent manufacture of the biosimilar. The resulting data allows for a more thorough analytical understanding of a product which de-risks development. In combination with lower processing costs, accelerated timelines and a lower compliance burden, resulting from taking advantage of advanced process technologies, incentives for pharma to pursue biosimilar development are becoming increasingly persuasive. Sensing the Most Critical Aspects of the Process As analytical technologies have become increasingly sensitive, what the industry wwww.international-pharma.com

has come to learn is that manufacturing and characterising the cell line has become the most important part of the process during the development of biosimilars. When the analytical capabilities of chromatography and mass spectrometry are aligned with cell line and process development, it can generate accurate data early in development. Equipped with precise analytical capabilities developers are achieving the appropriate product quality right from the beginning of cell line development which reduces the amount of work required downstream. Studies show that glycosylation is a key factor in biosimilarity. As well as modulating mechanism of action through Fc-mediated effector functions, glycosylation may also impact a product’s safety and efficacy. For these reasons, regulatory guidelines recommend an analysis of Fc functions in detail, including binding to Fc receptors and Fc-mediated cytotoxicity such as antibodydependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Recent advances in innovative techniques such as ex vivo T-cell assays7 and MHCassociated peptide proteomics (MAPPs)8 have become powerful tools for assessing immunogenic potential and demonstrating similar safety profiles between originator and biosimilar molecules when it comes to their immunogenic profiles. Analytics and Regulatory Innovation The industry is also pushing for regulatory innovation with one area of note being in removing the need for clinical efficacy studies where it is justifiable. In 2021, the UK’s Medicines and Healthcare Regulatory Authority (MHRA), dropped the requirement for biosimilars to pass through comparative efficacy trials in most cases. The guidance ‘encourages a stepwise approach to development of biosimilar products, with emphasis on the comprehensive physicochemical and biological comparability studies, functional (in vitro) analysis and a confirmatory clinical PK (pharmacokinetic)’.9 The World Health Organization (WHO) is also consulting on whether regulators should remove these requirements. This could significantly reduce the costs and time of biosimilar development INTERNATIONAL PHARMACEUTICAL INDUSTRY 55


Gerrit Hagens

but does raise questions around regulatory robustness – the MHRA made it clear that its decision to removing the requirement was a means of attracting biosimilar manufacturers to the UK. The decision has a secondary effect of highlighting the importance of robust physicochemical and biological characterisation of the product and pharmacokinetic (PK) studies which remain essential. Quality, safety and efficacy remain the most important metrics against which manufacturers are judged and assuring this with comprehensive analytics and data is essential. Packages showing high biosimilarity are key to convincing authorities that smaller clinical studies are sufficient. It’s another area where there has been notable progress as the analytical techniques used to demonstrate a clear structural and functional links between biosimilars and their originator molecules have advanced significantly. Analytical techniques in biologics are becoming more routine – the equipment is also becoming higher throughput, smaller and less expensive. Importantly, there has been a broad acceptance and increasing use of advanced in-process analytical testing, which gives manufacturers better control and invariably lowers failure rates and other poor batch outcomes. Summary Innovation in process and bioreactor technology – better understanding of cell lines, advances in analytical methods and equipment, continuous processing, singleuse technologies – has accelerated, derisked and lowered the cost for biosimilar development. Regulators are similarly clearing the path for biosimilar developers to enter the market. 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

As a result, biosimilar developers and CDMOs operating in the space that have invested in the appropriate technologies and have the expertise in handling other biologics have an immediate, inherent advantage over reference molecule owners. But as more biosimilar products clear the final commercial hurdle, it becomes vital that manufacturers maintain focus on quickly and efficiently moving through development and stripping costs from their processes wherever possible – especially where they will be competing against the originator and multiple other biosimilars. Getting a product to market first and making it more affordable for patients in comparison to the originator and competing biosimilars will define a product’s commercial success. REFERENCES 1. 2. 3.

4. 5.


7. 8. 9.

https://www.mckinsey.com/industries/lifesciences/our-insights/an-inflection-point-forbiosimilars https://www.fda.gov/drugs/biosimilars/ biosimilar-product-information https://www.whitehouse.gov/briefing-room/ presidential-actions/2021/07/09/executiveorder-on-promoting-competition-in-theamerican-economy/ https://aspe.hhs.gov/reports/comprehensiveplan-addressing-high-drug-prices https://www.healio.com/news/rheumatology/ 20210617/market-gears-up-for-biosimilarboom-in-2023-as-humira-exclusivity-drawsto-a-close https://www.globenewswire.com/newsrelease/2021/11/24/2340673/0/en/SingleUse-Bioreactors-Market-size-worth-11-60332-Million-Globally-by-2028-at-19-36-CAGRVerified-Market-Research.html https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7338774/ https://www.frontiersin.org/articles/10.3389/ fimmu.2020.00698/full https://www.gov.uk/government/consultations/ mhra-draft-guidance-on-the-licensing-ofbiosimilar-products

Gerrit Hagens is director at BioXpress Therapeutics and Professor at the University of Applied Sciences HESSO, Sion, Switzerland. Gerrit Hagens gained a strong manufacturing process development experience during more than 20 years in the industry. Before joining BioXpress where he leads biosimilar development projects, he was member of Serono’s core team managing the Neurology Business Unit bringing Rebif for treating multiple sclerosis to a blockbuster status. He then took over executive roles at ExcellGene and RiboVax as COO and President and helped developing manufacturing processes for biologics. Gerrit has a PhD in molecular biology from the University of Berne and an MBA from the University of Lausanne and co-founded several start-ups in the biotech arena.

Simon Keen Simon Keen has over 25 years of experience in molecular biology and cell line development in the biotechnology industry. His career began with him working on antibody humanisation technologies at the Medical Research Council (MRC) antibody engineering group, before moving to work for multiple small and mid-size biotech companies in the Cambridge UK ecosystem. Simon has developed a deep expertise in different production systems for vaccine, antibody and fusion protein therapies. Having spent the last 15 years at Abzena, Simon has helped to develop mammalian cell line development technologies suitable for the manufacture of biological drugs and is now VP of Cell Line Development. He sits on Abzena’s Scientific Leadership Group, working with clients to shape projects to meet the demands of preclinical and clinical development for their drug candidates, to guide them through to regulatory submission.

Summer 2022 Volume 14 Issue 2


Discovering new pharma automation solutions Robots for Life Sterile or standard environments, high-end or routine tasks, Stäubli robots deliver clean, consistent performance ensuring the highest levels of product hygiene, safety, flexibility and productivity. Benefit from our know-how and discover the new automation possibilities of intelligent and safe robot technology. Stäubli – Experts in Man and Machine www.staubli.com


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Application Note

Big Strides in Small Batch Aseptic Processing

Growing demand for small batch processing poses new challenges for the life sciences sector. Adapting to variances while maintaining quality, efficiency and adherence to aseptic processing requirements is more complex than ever. Advanced Aseptic Processing (AAP) systems, enabled by robotics and other advanced technologies, offer inventive solutions. The GENiSYS® R aseptic small batch filling and closing machine from Automated Systems of Tacoma (AST) is a prime example. AST is a U.S.-based pharmaceutical machine manufacturer specialising in advanced aseptic filling equipment and packaging machines, and a pioneer in the use of robotics in the fill/finish industry. Its relationship with Stäubli goes back more than two decades. In 2010 AST chose Stäubli to develop a multi-format robotic filling machine – the first ever capable of processing different types of container formats on a single machine. The GENiSYS® R, launched in 2018, represents another noteworthy innovation. This flexible modular system automates aseptic filling and closing of ready-touse vials, syringes and cartridges in strict accordance with CGMP requirements. It can be integrated with isolator-barrier or RABS technologies to maintain required aseptic conditions in tightly controlled ISO 7 and ISO 5 environments. The GENiSYS® R is optimised for small batch filling, with a focus on dosing precision and high yield, and uses robotics to achieve 100% in-process control (IPC). This makes it ideal for clinical and commercial applications in drug manufacturing, compounding, cell and gene therapy development, personalised medicine, cytotoxic drug processing and other areas.

used to create 21 CFR Part 11-compliant batch reports. The combination of modular design and advanced robotics allow the GENiSYS® R to be configured to meet different process requirements and containers without the cost or extra time associated with customisation. Operators can program recipes specific to container formats and drug products, as well as precise robot movements and pump settings, using the intuitive human-machine interface (HMI), ASTView®. This can include fine-tuning needle fill depth and speed to prevent bubbling, or exact positioning in a given space to mitigate air disturbance, for example – with minimal downtime during changes. The system’s modular design also provides flexibility with regard to the degree of automation desired: Bag and tub opening can be manual, semi-automated, or fully automated, while filling and vial sealing are always fully automated. The Role of Stäubli Robots: Sterility, Quality and Safety Assured For pharmaceutical and biotech labs tasked with processing complex small batches, there can be no compromises when it comes to precision, flexibility, reliability, IPC, and protection from contamination. Thus Stäubli’s six-axis TX2-40 and TX2-60 Stericlean robots, which excel in meeting these requirements, are integral to the GENiSYS® R. They are entrusted with a variety of delicate and repetitive yet critical tasks that could otherwise put product quality, the operator or the end user at risk.

In addition to its past experience with Stäubli, AST had a variety of reasons for choosing Stericlean robots for the GENiSYS® R. As CEO Joe Hoff explained, “We needed robots that are reliable over a long period of time, extremely precise, and completely sterile, and the Stericlean line is designed for exactly that.” Stäubli’s Stericlean range is suitable for GMP grade A and grade B tasks, and known for high performance in aseptic and sterile conditions. Extremely low particulate generation and VHP-resistant design enable the robots to reach cleanliness level ISO 5. They feature a fully enclosed IP65 arm with IP67 wrist, as well as an entirely smooth surface free of retention areas and coated with a high-resistance surface treatment. The arm is also equipped with specialised lip seals, and cables run through the arm and out vertically through the base. Critical parts are made of stainless steel. A spherical work envelope and compact size make TX2 robots easier to integrate within machines like the GENiSYS® R. They can work nimbly in tight workspaces, and their small footprint allows optimisation of the surrounding workspace. Speed and repeatability are also important considerations. Stäubli robots are known for their ability to maintain high speeds without sacrificing performance: The GENiSYS® R can process up to 20 units per minute, depending on container, product, and IPC rate. Several unique attributes make this possible, even when using NSF H1 food-grade oil. Chief among them is Stäubli’s own patented

The IPC provides real-time fill weight feedback and control, which can be used to identify issues early on, ensuring quality, minimising waste, and maximising product yield. Electronic batch record (EBR) software records key production data that can be 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2022 Volume 14 Issue 2


Application Note

shorter cycle time, and greater productivity. Flexibility from Opening to Closing Depending on the level of automation desired within the GENiSYS® R system, the TX2-40 and TX2-60 Stericlean robots can handle or assist with critical steps in each stage of the aseptic process: bag and tub opening, filling, stoppering, sealing/closing, and reject handling. If some tasks along the production line need to be manual, the GENiSYS® R can easily accommodate that need while ensuring operator safety and product sterility. The robots offer reliable repeatability in their motions as they carefully manipulate the nest and vials, which is essential to reducing particle generation, air disturbance, unexpected vial shaking, and other potentially damaging variables. This helps prevent spills and other incidents that would otherwise result in unplanned manual interventions, which risks compromising the aseptic environment. The use of the Stäubli robots engineered for use in aseptic environments and endowed with exceptional dexterity play a significant role in the GENiSYS® R’s high flexibility, enabling the precise filling and closing of ready-to-use nested, pre-sterilised vials, syringes and cartridges. Without these advanced robotic capabilities, the changes between recipes and formats demanded in small batch processing would be impossible or prohibitively complex.

Stäubli Robotics Stäubli Robotics is a leading global player in robotics, consistently delivering engineering as effective and reliable as our service and support. A complete solutions provider for digitally networked production, Stäubli offers a broad range of 4- and 6-axis robots including robotic arms designed specifically for sensitive environments, autonomous mobile robots, driverless transport systems (AGVs) and cobots for human-robot collaboration. For more information please contact: Stäubli Robotics Cynthia Jamison-Brashier Marketing, Events Coordinator Robotics Division North America gearbox, which the company manufactures inhouse. This ensures minimum backlash and wwww.international-pharma.com

unmatched arm rigidity, allowing for extreme repeatability – translating to higher speed,

Phone: +1 864 764 4729 Email: c.jamison-brashier@staubli.com



Making a Case for a Fixed Dose Combination Drug Strategy Over the past two decades, pharma’s acute focus on the patient has driven great innovation and investment in ways to deliver active pharmaceutical ingredients (APIs) in finished drug products. Oral administration is the most convenient method of drug administration for patients due to the ease and flexibility of dosing. This makes it the route preferred by health care providers and drug developers.1 Every aspect of the dose and formulation – color and size, taste and texture, controlled release, and dosing frequency – can have an impact on therapeutic performance, which can affect the ability of the finished drug product to optimally treat the condition and the patient. Fixed dose combination (FDC) drug products are an oral solid dose (OSD) platform steadily gaining favor. Fixed dose combinations are defined by the World Health Organization (WHO) as a combination of two or more APIs in a fixed ratio of doses and in a single dose form.2 FDCs offer several potential advantages to patients and developers including: • • • •

Better pharmacokinetics and therapeutic synergies Simplified therapeutic administration and dispensing Reduced therapeutic polypharmacy Improved patient compliance

A systematic review of 21 studies including information on 27,230 subjects showed better compliance and therapeutic effect among patients receiving FDCs. According to the study, these findings were consistent with data from observational cohorts. The review’s authors noted a tendency towards greater virological suppression among patients receiving FDCs in randomised trials and observational cohort studies. In all studies reporting patient preference, FDCs were preferred. The study concluded that FDCs offer multiple advantages for programs and patients, particularly with respect to treatment adherence.5 The impact of prescription non-compliance on the overall cost of health care to society is well documented. When patients take their medications as prescribed, statistically their health outcomes improve. When patients fail to comply with doctors’ orders, health outcomes are more often poor and increase the potential for more costly types of care including hospitalisation and surgery. Recent studies examining the cost of patient non-compliance in the US put the figure between $100–$289 billion annually in increased healthcare costs. In addition, the lost productivity due to patients being sicker and debilitated potentially multiplies the total increase in health care costs by 2.3 times.6 Fewer pills per patient can help suppress the overall cost of patient

care. When the patient group is large, the potential for cost savings can be significant. Efficient Development Pathways Using FDCs FDCs are becoming more widely accepted because they offer developers a practical and more economical path for developing first- and best-in-class therapies.2 Although similar development to traditional monotherapies is involved, the presence of two or more APIs requires additional analysis including drug-drug interactions and doseranging studies to determine optimal API loads and ratios, which add to the complexity of FDC development. In practice, the above has driven FDC product developers away from combining two or more new chemical entities (NCEs) and towards developing combinations of previously approved, well-understood APIs. About 99% of FDC products approved in the past 20 years or more include at least one previously approved API where it is possible to leverage established clinical and patient data.4 This enables developers to focus solely on obtaining the data they need to demonstrate the safety and efficacy of the proposed FDC to regulators. Added to this is the option for FDC drug product developers to utilize the FDA’s 505(b)(2) approval pathway, providing a fast-track clinical development route,

Other tangible benefits derived from combining therapeutics into a single OSD further support the FDC business model. From a Cost-of-Goods (CoGs) perspective, commercial FDC drugs are more efficient to manufacture, distribute, and dispense than two or more finished dose forms.3 A Practical Strategy for Improved Patient Compliance Popularity and demand in the FDC market stems primarily from patient centricity because FDCs can improve patient compliance due to convenience of administration. 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2022 Volume 14 Issue 2

Manufacturing significantly accelerating time to market for FDCs. Technologies and Methodologies Ready to Close Gaps in FDC Business Model Two things support the success of any commercial OSD pharmaceutical product: 1.


Timely, cost-efficient development path to regulatory approval. Drug-drug compatibility studies and detailed risk assessments are particularly important to support timely FDC regulatory filings. A robust manufacturing strategy to deliver quality product to patients and markets.

Despite the obvious advantages FDCs offer all stakeholders, due to the challenges associated with formulating and manufacturing combined drugs, analysts noted that year-over-year the overall growth in the number of FDCs being commercialised was not as significant as one might expect.3 With increased access to advanced OSD processing technologies and drug-drug interface studies, combined with specialised equipment experience from pharma’s manufacturing partners, this potential “growth gap” in the overall business case for FDCs is fast closing. In a broad and sustained response, pharma’s manufacturers, along with pharmacologists, equipment and excipient suppliers have continued to innovate new solutions to overcome issues formulating FDCs. The pharma industry now has access to an impressive list of highly mature processing techniques and enabling technologies that are perfectly suited to doing the heavy lifting when it comes to processing drug substances into finished OSD forms. For OSD developers, it is likely a familiar list: • • • • • • • •

Wet granulation Dry granulation Blending Spray drying Hot-melt extrusion Spheronisation Tablet compression Coating

Although the above list of enabling technologies may not be perfectly complete, deftly applied, the methods provide significant latitude in controlling and managing the pharmacokinetic properties of small-molecule APIs in vivo. From creating amorphous solid dispersions (ASDs) to multiple-unit particulate systems (MUPS), wwww.international-pharma.com

pharma now has general access to key technologies that are more capable than ever to support the business case for FDCs. These established systems and process knowledge have proven highly capable in developing FDCs using pre-existing manufacturing capability. Contract Development & Manufacturing Organizations (CDMOs) Ready to Support FDC Innovation and Development Growth Now Developing any drug successfully involves risk, which is balanced against the potential reward from the program. Because the FDC concept is so patient-centered and features existing therapeutically beneficial compounds, development paths become less financially risky. Development paths are more predictable, even though developers must deal with the added complexities associated with formulating two APIs or more into a single dose. However, the impact of those complexities reveals another potential gap in the FDC business case – where to access the experience and enabling technologies required to develop these drugs successfully? To fulfill their FDC drug development strategies, pharma innovators are accessing key critical enabling technologies and capacity in a variety of ways. For a growing segment of pharma, it makes clear business sense to engage fully capable external partners to execute their drug programs expertly and cost-efficiently. The rise of the CDMO industry is predicated on that fact. Considering FDC’s commercial and patient potential, an FDC program developed with expert commercial partners is likely to be better able to generate the anticipated return whilst driving continuous innovation in OSD. Because the molecule will always dictate how the drug product is ultimately processed, engaging CDMOs, experienced in developing robust processes to combine and formulate FDCs makes good sense for business and patients. REFERENCES 1. 2. 3.

https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3068890/ https://www.biospace.com/article/fixed-dosecombination-drugs-market-key-trends-andregional-assessment/ https://drug-dev.com/fixed-dose-combinationsfixed-dose-combination-products-a-review-part-1introduction/#:~:text=About%2099%25%20 of%20FDC%20products,perfect%2C%20is%20

4. 5. 6.

an%20acceptable%20outcome. https://www.drugdiscoveryonline.com/doc/ the-advantages-and-challenges-of-fixed-dosecombination-products-0001 https://onlinelibrary.wiley.com/doi/pdf/10.1111/ tmi.12297 https://www.elationhealth.com/blog/primarycare-innovation-blog/medication-compliance/

Rob Pratt Rob Pratt is a Technical Services Lead at Pfizer, Newbridge, Ireland. Rob has over twenty years' experience in the pharmaceutical industry, seven of which were in research and development. Over the past thirteen years, Rob has worked with technical transfers and continuous improvement projects for solid oral dosage forms manufactured at commercial scale. Proven ability to tackle complex projects and bring them to a successful outcome.

Dáire O'Donnell Dáire O'Donnell BSc, PgDip, PhD, is a Process Excellence Lead at Pfizer, Newbridge, Ireland, having joined in Nov 22. Dáire has 9 years' experience focused primarily on multi-particulate and fixed dose combination tablet product development from clinical, through scaleup to commercialisation. Daire is focused on delivering process excellence through innovation to meet patient needs.



Tackling Pharma’s Shadow Market: Getting ‘Smarter’ in the Fight Against Fake Pharmaceuticals If you were to ask a member of the public “what is the world’s most counterfeited product?”, it’s highly likely they’ll say designer handbags or watches. But, in fact, the world’s largest fraud market is pharmaceuticals – and by a large margin. The larger the industry supplying a consumer product, the more likely it is that criminals will try and exploit it. And with counterfeit and falsified medicine, the profits can be huge. But so too can the risks to public health and the industry’s reputation. And this risk is growing, accelerated by the disruption of the COVID-19 pandemic, complex global supply chains, widening access to healthcare in emerging economies and the rise of pharmaceutical e-commerce. An Important Distinction Between ‘Counterfeit’ and ‘Falsified’ Within the pharmaceutical shadow market there are two threats – ‘counterfeit’ and ‘falsified’. It’s important to distinguish between these different types as how criminals create and distribute them can differ, as well as the danger to consumers and a brand’s reputation. According to the European Medicines Agency, “a counterfeit medicine is made by someone other than the genuine manufacturer, by copying or imitating an original product without authority or rights and infringe trademark law”. This means counterfeit medicines try to pass themselves off as legitimate products, causing the impersonated pharma brands reputational damage if the drugs are less effective or dangerous to unsuspecting customers. Whereas falsified medicines are “fake medicines that pass themselves off as real, authorised medicines.” This could mean they contain ingredients of low quality or in the wrong doses, are deliberately and fraudulently mislabelled with respect to their identity or source, have fake packaging, 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the wrong ingredients, or low levels of the active ingredients. Falsified medicines pass themselves off as the real deal by mimicking (not copying) legitimate pharmaceutical products. It can be difficult, if not possible, to tell whether a falsified medicine is made by an authorised manufacturer or not. Both types of fake medicines can be equally dangerous to public health and have far-reaching consequences for healthcare systems and the global pharmaceutical industry. Pharma’s Growing Shadow Market is a $200bn-a-year Industry The pharmaceutical market has experienced significant growth during the past two decades, and pharma revenues worldwide totalled 1.27 trillion U.S. dollars in 2020.1 And as the legitimate pharmaceutical industry grows, so too does its shadow market run by criminal networks. The most recent trusted estimate of the size of the global annual market for counterfeit and falsified medicines stands at approximately US$200 billion2 according to data from the World Customs Organisation. And in March 2020, Interpol’s Operation Pangea XIII3 seized counterfeit pharmaceuticals worth more than $14 million worldwide, just months after the COVID-19 virus was first discovered. Since then, the situation hasn’t let off. The true cost goes beyond financial, though. It’s an issue that is both fuelled by and is fuelling widening health inequalities. While counterfeit and falsified medicines exist in every region of the world, they are most likely to be circulating at their highest in low-and middle-income countries, such as in Africa and Asia where demand for healthcare is growing. Technology is also opening new opportunities for fake pharmaceuticals to be marketed, bought, and consumed.

Criminal networks are leveraging the same digital channels, including e-commerce sites and social media platforms, to penetrate developed countries where barriers and regulatory frameworks are more advanced. In fact, WHO estimated in 2015 that 50 percent of drugs for sale over the internet were fake and this is only increasing as buying medicines and lifestyle products online becomes more common practice. Today, no country or company can afford to overlook their vulnerability, nor the opportunities available to reduce the threat of fake medicines and improve existing supply chain safeguards. Serialisation on Packaging – The New Global Standard Packaging technologies play an important role in hampering criminals’ ability to produce, transport and sell counterfeit and falsified medicine. To stay one step ahead of criminal networks whose approaches get smarter every year, packaging must become smarter too. A major leap forward came when a new worldwide standard for mass serialisation on packaging, often combined with ‘traceand-trace’ requirements’, was introduced. In 2019, two important pieces of serialisation regulation came into force – the EU’s False Medicines Directive and the U.S’s anticounterfeiting protocol The Drug Quality and Security Act. The EU’s FMD ensures complete product traceability from manufacturing to decommissioning, instead of placing the burden of authentication on any single stage of the process. The Drug Quality and Security Act requires authentication at every supply chain juncture, including wholesalers. Both don’t require product-level coding but rely on barcodes printed on secondary packaging which sophisticated criminal networks can quite easily replicate. Digital watermarking techniques are also becoming more widely used, providing an extra layer of protection by printing invisible, encoded data on packaging that can only be verified by Summer 2022 Volume 14 Issue 2

The packaging makes a difference!

Hypodermic Needles in Hard Plastic Unit Packaging Optimized packaging process Hard plastic unit pack | Takes littles space | Supports compatibility with feeders/automated pick-and-place systems | Enables in-line product identification

Smooth administrations Easy opening | Sharp lancet point | Excellent gliding performance | Tamper-proof label

Secure connection to syringes Hub complies to ISO 80369-7


NIPRO PHARMAPACKAGING INTERNATIONAL INTERNATIONAL PHARMACEUTICAL INDUSTRY 63 Blokhuisstraat 42, 2800 Mechelen, Belgium | pharmapackaging@nipro-group.com | www.nipro-group.com

Packaging specialist software. Invisible to the human eye, the watermarks can be captured using webcam, mobile phones and other specialist scanning equipment. We’re also seeing developments in holograms, designed so that they’re only visible behind each pill/capsule cavity on the back of each blister pack, thereby allowing the printing of dosage and marketing information on the area surrounding the recess. Supply Chain 4.0 and the Role of Big Data The comprehensive nature of end-toend drug traceability in a market which is increasingly global means FMD compliance shouldn’t be the final step. There’s a real opportunity for manufacturers, working in collaboration with packaging companies, to create the next generation of tamper-proof technology and become pioneers in digital packaging that can make tracking products across the supply chain much simpler. Perennial encryption technology is a largely untapped innovation, preventing duplication and replication of 2D and 3D unique identifiers. By issuing a singleuse URL, perennial encryption technology renders any cloning attempt useless. Only the secure cloud host knows the sequence of coding and any attempt to re-use the previous URL is detected by the cloud host and an invalid message is issued warning the product has been copied. The same process can be used to identify tamper evidence too. Intelligent tracking systems, built into medicine packaging, is also a developing science which will prove valuable in the fight against falsified and counterfeit medicine. As a live programme, the location of a product at any given time can be seen in real-time remotely together with its endto-end journey, revealing any unauthorised routes or interventions. Not only can technology aid the pharma industry in removing falsified products from its supply chain, but the data insights gained can also be used to increase efficiencies. Despite companies innovating in the field of science to discover, develop and market medicines more efficiently, many companies have failed to upgrade their supply chains. Collected data can highlight inefficiencies and bottlenecks which can be addressed to streamline processes and drive cost-savings. 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

With biologic and personalised medicine already re-shaping the industry, there needs to be a two-way street where information is being used to inform the downstream flow of products. Data holds the key to creating efficient, safe and demand-driven supply chains which benefit manufacturers, health systems and above all else, patients. Drug companies won’t necessarily have to build their own anti-counterfeiting ecosystems, either. Manufacturers can avoid the high up-front costs of developing an anti-counterfeiting system by handing off all or part of the work to external providers. A Leaner Supply Chain Will Help to Eliminate the Shadow Market As part of Pharma 4.0, there’s also a real opportunity for pharma manufacturers to work with packaging and supply chain management companies to develop innovative new digital-first solutions that help to eliminate ‘fake’ products from circulating. And to make the supply chain smarter and leaner. At the heart of transforming the supply chain is the application of lean principles. This essentially means using less human effort, less inventory, less space, and less time to produce high-quality products. It also means working as efficiently and economically as possible while being highly responsive to customer demand. However, becoming ‘leaner’ requires more than merely using the terminology or plugging in a new technical tool. Rather, it requires a fundamental rewiring of operation and management systems. Historically, pharma companies globally have relied on a network of hundreds of suppliers to manufacture, package, and deliver different products to market. It’s still not uncommon for multiple teams to be managing multiple international supplier sites. As a strategy, this is overly complex, largely inefficient, and very expensive. It also makes the industry easy picking for criminal networks looking to exploit it. A pragmatic solution is to simplify the supply chain, bringing it under one roof, merging the best of manufacturing, design and innovation, supply chain networking and infrastructure. When doing so, it’s important there are internationally dispersed sales offices, manufacturing cells and storage facilities in strategic locations.

Beyond helping to eliminate the shadow pharma market, consolidating the supply chain brings a host of benefits including reduced risks and overheads, greater innovation, increased speed to market, assurance of supply and compliance, tighter quality control and local availability via regional distribution sites on a global scale. Anti-counterfeiting solutions are becoming smarter every year. But so too are criminal networks. There is a real opportunity here for pharma companies with the foresight to invest in Supply Chain 4.0 to set the stage for new business models that can create value in many ways – and limit counterfeit activity in the process, too. REFERENCES 1. 2. 3.

https://www.statista.com/topics/1764/globalpharmaceutical-industry/#dossierKeyfigures https://www.sciencedirect.com/science/ article/pii/S2666535222000167#bib7 https://www.interpol.int/News-and-Events/ News/2020/Global-operation-sees-a-rise-infake-medical-products-related-to-COVID-19

Rich Quelch Rich Quelch is an experienced global marketer within the healthcare and pharmaceutical sector. He has led the development of the Origin brand, positioning it as a world-leading supplier of innovative and groundbreaking pharmaceutical packaging devices, as well as offering a unique supply chain model which is disrupting the pharma industry.

Summer 2022 Volume 14 Issue 2







www.aurenalabs.com • contact@aurenalabs.com wwww.international-pharma.com


Health Outcomes

Shared Care: Strengthening Self-management Support for Chronic Patients In recent years, converging healthcare trends have been creating more empowered patients. Before the pandemic, patients could already monitor their own condition through connected devices such as glucose monitors for diabetes. Self-administration of injectable medication had become more prevalent; the development of biologics for subcutaneous administration coincided with the need to treat rising cases of chronic diseases, and an ageing population presenting comorbidities. In the UK, people aged 65 and over are projected to make up 24% of the population by 2043.1 15 million people in England have long term conditions,2 constituting approximately 26.5% of the population but absorbing 70% of acute and primary care budgets for their treatment and care.3 The possibility for patients with rheumatoid arthritis, multiple sclerosis or Crohn’s, for instance, to inject medication on their own, is therefore highly beneficial for healthcare services. The pandemic further highlighted the value of enabling self-monitoring and treatment. Care for chronic patients was disrupted as healthcare systems dealt with the immediate pressures of containing the outbreak. This shift in attention also created a backlog of patients needing diagnosis or follow-up.4 Healthcare systems and patients were forced to trial remote consultations in a short space of time, revealing the possible advantages of integrating telehealth into everyday care. In a 2021 survey of almost 3,000 clinicians globally,5 49% agreed the majority of healthcare will be provided in a patient’s home in 10 years’ time. A significant 86% believe the rise of informed patients is driving healthcare change, while almost two thirds (62%) believe the role of the clinician will change to be more of a partnership with the patient in the future. Person-centred Care Patients may spend more time self-managing their condition than with health and care professionals. Activities such as health maintenance, illness prevention, monitoring 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and management activities6 are likely to be predominantly carried out by patients, carers and community professionals. Without proper and ongoing access to support, these self-care activities may not be carried out optimally. Patients who inject, for instance, may suffer from anxieties or even phobias, discouraging long-term adherence to their treatment. A number of studies cite poor medication adherence among diabetes patients,7 attributed to patient demographics, beliefs and perceptions, but also non-patient factors such as a lack of integrated healthcare. In Europe, the first ever standard on patient participation in person-centred care was published in 2021, following a four-year long discussion process. The standard serves as a guide for implementing person-centred care, but the writers also envisaged that it could be used to support health and care actors, patient organisations, researchers, businesses and other participants in a number of different ways.8 The standard represents an important step in improving understanding of what is meant by personcentred care and implementing collaborative practices on a wider scale. For its part, the UK’s National Health Service commits to shifting to more ‘person-centred care’ rather than a one-size-fits-all approach in its Long Term Plan.9 An essential component of this is supported self-management, where interventions such as health coaching, selfmanagement education and peer support are systematically used to increase the knowledge, skills and confidence a patient has to manage their own health and care – referred to as ‘patient activation’. The NHS model estimates that the recommended model of supported self-management could achieve 9% fewer GP appointments and 19% fewer emergency department attendances.10 The American Medical Association has created a range of resources to enhance patient communication and patient-centred care, including toolkits on health coaching, building a patient experience programme, and empathetic listening.11 However, a shift in healthcare models may be needed to facilitate implementation of this advice.12 Self-care & Adherence A more collaborative relationship between

healthcare practitioners and patients can have far-reaching benefits. If patients are more engaged in the treatment of their own condition, rather than the passive recipients of advice and prescriptions, they are more likely to adhere to treatment13 or even make lifestyle changes to support treatment. This potentially reduces the need for further, more serious, interventions later on, and ultimately reduces some of the burden on healthcare systems, freeing up strained resources. Studies across multiple conditions demonstrate that effective selfmanagement support can strengthen patient confidence in their ability to reach specific goals, improve health-related behaviours and, as a result, overall health.14 One study found that people who had received diabetes education were 2.5 times more likely to perform self-management and those who practiced self-management were 1.5 times more likely to achieve target glycaemic values.15 A complicating factor is the presence of multiple conditions, as more tailored support may be needed. Older patients, for instance, are more likely to have multiple illnesses, and cognitive or physical impairments that affect their ability to treat themselves. Depression is also prevalent among diabetes patients and may affect their approach to self-care. Providing self-care support to sufferers of depression has been found to improve their confidence in managing their conditions and to maintain lifestyle changes, even in times of stress. More efficient self-care then leads to improvements in depression.16 However, further research on self-management support is needed since, in practice, it is still not widely implemented,17 perhaps due to a lack of training, resources and time among healthcare professionals. Supported Self-administration Key to delivering collaborative care is self-administration of medication, where patients are able to administer their own treatment outside of the traditional healthcare setting. For self-administration to be effective, patients need support in the initial stages, as they become accustomed to their treatment. Healthcare professionals may have limited time with each patient, and may also be lacking sufficient guidance on Summer 2022 Volume 14 Issue 2

Health Outcomes (Pegfilgratim) was made available to cancer patients in a formulation for subcutaneous delivery, reducing hospital stays and clinic visits. Additionally, more concentrated biologic formulations are being developed to reduce the frequency of injections, but these may require modifications to device design in order to accommodate higher viscosities.

how to train patients, as well as the need for follow-up consultations and interventions. A study of injection-naïve patients found that only 50% reported receiving a visual representation of the self-injection from a healthcare provider. 13% reported having the opportunity to demonstrate the selfinjection process on themselves in front of their healthcare provider and to receive feedback.18 From the patient perspective, fixed time slots with their general practitioner or consulting professional may discourage them from sharing concerns or asking questions. To help address this issue, pharmaceutical and drug delivery device providers are providing training to educate patients about their disease and its treatment. Companies are providing holistic patient service packages and resources based around a drug and where applicable its delivery device. As well as training, this includes adherence monitoring, helplines, assistance with payment, patient stories and more. This approach can allow faster detection of any issues, since patients may have more time with a trainer, or easier access to specific support. wwww.international-pharma.com

Innovation in Drug Delivery To facilitate self-administration of medication, pharmaceutical companies are increasingly moving from syringes and vials to drug delivery devices which have more patient centric designs. Auto-injectors have been in common use since the mid-80s and the rise in self-administration is fuelling further demand for injection products that are accessible, intuitive and designed to reduce the risk of needlestick injury. In 2021, the global subcutaneous drug delivery devices market was estimated to be worth US$ 25.53 billion, and is expected to grow to over US$ 56.9 billion by 2030, a CAGR of 9.3%.19 This market includes devices such as prefilled syringes, reusable and disposable pen injectors, and auto-injectors. Designers of delivery devices also have the challenge of keeping up with innovations in drug formulations, as pharmaceutical companies do their part to improve the injection experience. Intravenous drugs that are typically administered in acute care are being reformulated for subcutaneous preparations. In one example, Neulasta

Traditional design parameters for subcutaneous delivery devices are no longer appropriate for biologics that are higher in viscosity or volume. Injectate volumes have already moved from 1mL to include 2mL, but larger volumes – over 2mL and even over 3mL – could become possible in future. New excipients that numb the injection site and dilate the injection area could make the administration of larger volumes more comfortable. This introduces a new challenge, however, since higher volume syringes are required, and patient hold times during administration may be prolonged beyond a comfortable duration. Sophisticated advancements in needle technology include near invisible 34G needles, degradable microneedles and thin wall needles, where the outer diameter is reduced with no change to the inner, thereby accommodating higher volumes and flow rates without increasing pain. A further solution to reduce injection time and frequency is long-acting or extendedrelease formulations. As formulation scientists may make changes to a drug during development and through commercialisation, pharma-ceutical companies may favour a platform approach to delivery devices in order to reduce risk and complexity and ensure speed to market. Platform delivery devices aim to accommodate a variety of fill volumes, and can be adapted to include new features, while preserving the original design and maintaining optimal ease of use and patient familiarity. In an increasingly competitive market for injectables which includes growing numbers of biologics and biosimilars, improving user-centric designs offer pharmaceutical companies a differentiating factor for their combination products. Digital Opportunity The introduction of digital capabilities to drug delivery devices could further enhance patient engagement in their treatment and drive adherence. The connected medical device market is expected to register a CAGR of 18.92% from 2022 to 2027.20 Data generated by digital devices may include basic date and time of injection as well as more detailed information such as drug INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

Health Outcomes


9. 10. 11. 12. 13. 14. 15. 16.

temperature and expiry checks. Through this data, clinicians can gain an insight into the efficacy of treatment for a patient and make tailored adjustments. There may be greater appetite for this following the pandemic, since patients who were not previously accustomed to digital applications began using them out of necessity, and may now be more receptive – if the benefits are compelling enough. Companies are also seeing an opportunity to market digital health products to consumers, blurring the lines between patient and consumer. The medical device company Abbott, for instance, is using its expertise in glucose monitoring to launch a range of ‘biowearable’ health devices for consumers. The new line could encourage consumers to take preventative measures for their health. By tracking key biomarkers in the body, such as glucose, ketones, lactate, and eventually alcohol, users will be able to better understand their general health and take action.21 If such devices take off among the wider population, this could make self-care a more attractive concept. We may also see the trend work in reverse, with drug delivery devices for patients being designed in a more consumer-oriented fashion. Ultimately, though connectivity offers exciting possibilities, its benefits cannot be achieved if devices are not intuitive and convenient and maintain simplicity for the patients that use them. Additionally, the cost and risk of securing data privacy must be given serious consideration.

professionals may need additional resources and the scope to put person-centred care into practice. Industry can support this shift, by creating user-centric, intuitive products that facilitate self-administration of medication, giving patients greater control of their own treatment. Pharmaceutical and drug delivery device businesses can also provide support and training, easing some of the pressure on healthcare services while ensuring that their products are being used optimally and producing the desired outcomes. Increasingly sophisticated digital tools could create new possibilities for collaboration between patient and healthcare professionals, with patients increasingly informed about their own health, and therefore more engaged.

Removing Obstacles The benefits of supported patient self-care and self-administration are clear. However, for wider implementation, healthcare



17. 18. 19.

20. 21.

articles/PMC4966497/#:~:text=Poor%20 medication%20adherence%20in%20 T2D,and%20managing%20complications%20 of%20diabetes. https://www.gu.se/en/gpcc/innovativestandard-for-patient-participation-in-personcentred-care-now-available#What-thestandard-can-be-used-for https://www.longtermplan.nhs.uk/areas-ofwork/personalised-care/ https://www.england.nhs.uk/wp-content/ uploads/2019/01/universal-personalisedcare.pdf https://www.ama-assn.org/practicemanagement/ama-steps-forward/practiceinnovation-strategies-patient-centered-care https://www.healthaffairs.org/do/10.1377/ forefront.20120124.016506 https://bmjopen.bmj.com/content/3/1/e001570 https://bmchealthservres.biomedcentral.com/ articles/10.1186/1472-6963-13-117 https://www.diabetesresearchclinicalpractice. com/article/S0168-8227(18)30727-7/fulltext https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3628828/ https://bmchealthservres.biomedcentral.com/ articles/10.1186/1472-6963-13-117 gonoble.com/2021/09/09/recommendationsincrease-training-consistency/ Precedence Research, Subcutaneous Drug Delivery Devices Market (By Product Type: Auto-Injectors, Pen Injectors, Prefilled Syringes, Wearable Injectors, and Needle-Free Injectors; By Distribution Channel: Retail Pharmacies, Hospital Pharmacies, and Online Pharmacies) - Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2021 – 2030 https://www.precedenceresearch.com/ subcutaneous-drug-delivery-devices-market https://www.mordorintelligence.com/industryreports/connected-medical-device-market https://pharmaphorum.com/news/abbottceo-ford-showcases-new-biowearable-lineat-ces/





6. 7.

https://commonslibrary.parliament.uk/ research-briefings/cbp-9239/#:~:text=The%20 number%20of%20people%20in,2043%20 (17.4%20million%20people). https://www.kingsfund.org.uk/projects/timethink-differently/trends-disease-and-disabilitylong-term-conditions-multi-morbidity https:// www.ons.gov.uk/peoplepopulationand community/populationandmigration/ populationestimates/bulletinsannualmid yearpopulationestimates/mid2020 https://www.england.nhs.uk/ourwork/clinicalpolicy/ltc/house-of-care/#:~:text=The%20 15%20million%20people%20in,primary%20 care%20budgets%20in%20England. https://www.bma.org.uk/advice-and-support/ nhs-delivery-and-workforce/pressures/nhsbacklog-data-analysis https://www.elsevier.com/connect/clinicianof-the-future https://www.sciencedirect.com/science/ article/pii/S0020748919302093#bib0064 https://www.ncbi.nlm.nih.gov/pmc/

Michael Earl Michael Earl joined Owen Mumford as Director of Pharmaceutical Services in November 2020. He was previously the Commercial VP at Bespak, leading the commercial team there to drive growth in their substantial medical devices business. Prior to that, he worked for a number of pharma, biotech and device companies. In a career spanning 35 years, he has been responsible for all aspects and stages of drug and device development and commercialisation. Michael has also completed a substantial number of commercial, licensing and M&A transactions.

Summer 2022 Volume 14 Issue 2

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Health Outcomes

The Benefits of Patient Centricity in Clinical Trials: How it can Support Clinical Operations and Study Adherence Patient centricity in clinical operations and study adherence is growing in popularity. A patient-centric approach means that the needs of patients are placed at the forefront of all decisions and actions within healthcare organisations. This includes all aspects of care, from research and development of new treatments to delivery of care. Patient centricity can be summed up by the phrase "the patient comes first." There are many benefits to implementing a patient-centric approach in clinical trials. Patients feel more valued and respected when their needs are considered in all aspects of the clinical trial. This can lead to increased satisfaction and compliance, with fewer missed visits and improved data capture from off-site data capture devices like electronic patient reported outcomes (ePRO) diaries and other electronic devices. Wearable devices can continually capture patient data, but also involve the patient compliance and keeping the wearable device on. A patient-centric approach can improve clinical outcomes as more robust data is collected for the trial, in real-time with high quality data for analysis, but also it can improve patient recruitment as more flexible and easier trial designs can become less of a burden on patients and make it easier to attract and enrol patients into a clinical trial. In a patient-centric approach to clinical development there several are emerging trends: 1. Decentralised Clinical Trials Clinical trials have traditionally been conducted in centralised, highly controlled environments with the perceived benefits of increased efficiency and better data quality. Patient centricity is driving the need for decentralised and virtual trials as patient engagement and experience are key factors in the success of clinical trials. The transition of clinical trials from investigator sites to subjects' homes promotes a more patient-centric approach while also reducing stress on clinical trial staff with 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

fewer subjects coming to site. It also opens many exciting possibilities for the collection of real-time data via wearable and other modern technologies. 2. Adaptive Trial Designs Traditional clinical trials are designed with a fixed, predetermined endpoint. However, patient-centricity is promoting the need for adaptive trial designs. This simply means that an element of the study (e.g., sample size, treatment arms, population of interest) may change during the study if predefined and specific rules are triggered. This flexibility within the adaptive design framework can lead to improved use of available resources (e.g. by dropping an ineffective treatment arm) which results in reduced visits or smaller patient samples and less burden on subjects as they can finish a trial earlier. We are seeing Bayesian adaptive designs being increasingly used in early phase development. These designs use data from the study as it is being generated to adapt the design on-the-fly. This can allow for more efficient trials by reducing patient exposure to ineffective treatments or by increasing enrolment in a trial that is proving efficacious. This can help identify optimised dosing for novel therapeutics. 3. Optimised Dosing In oncology trials, we are seeing more patient-centric approaches with optimised dosing under the FDA’s recent project Optimus. This project challenges the status quo in current oncology studies of finding the maximum tolerated dose (MTD) for the highest efficacy on clinical benefits to the cancerous cells. Instead, the trial design focuses on the efficacy of a wider range of doses and not the MTD which has the highest allowable toxicity to a subject. This is a patient-centric approach because the impact of the trial drug on the patient’s wellbeing is receiving greater attention. There are increased expectations on evaluating and performing additional research and analysis on the efficacy of smaller doses. These smaller doses are perhaps less toxic but may hold the desirable efficacy in relation to meeting the oncology-specific trial endpoints.

4. Personalised Medicine Modern oncology therapeutics are increasingly becoming personalised medicines as patient populations are more frequently defined by their molecular characteristics, rather than the location of their tumour. This means that trial designs and patient recruitment strategies must be responsive to the unique needs of each individual patient. One of the main benefits of personalised medicines is that they are tailored to each patient's specific genetic make-up. This means that the patient is more likely to respond to the treatment, as it is specifically designed for them. Personalised medicines have grown in popularity as the industry has the genetic markers to identify disease subtypes. We are also seeing that drug combinations are increasingly being investigated. For example, a patient with a lung cancer might receive a combination of therapies, each of which targets different molecular pathways in the cancer. Personalised medicines work best for a smaller population of patients who have a specific genetic makeup that is known to respond to that treatment or combination of treatments. This makes it more likely that the patient will respond positively to the medication and experience fewer adverse events. Due to improved efficacy, we can expect reduced patient population sizes in trials. But as the definition of the disease is more specific, a challenge still exists for the pharmaceutical companies to recruit enough patients and those with specific disease enrolment criteria to the trial may be spread across the globe. Therefore, realworld data (RWD) can be used and the FDAs recent announcement on the ease of use of RWD will help drug makers with their patient recruitment. Patients can be enrolled from across the globe and they would not have to travel to site as data could be taken from their own homes. Also, there may be existing data within patient registries, medical records, and other databases available for analysis in the clinical trial. Summer 2022 Volume 14 Issue 2



Peer Reviewed, IPI looks into the best practice in outsourcing management for the Pharmaceutical and BioPharmaceutical industry.



Peer Reviewed, JCS provides you with the best practice guidelines for conducting global Clinical Trials. JCS is the specialist journal providing you with relevant articles which will help you to navigate emerging markets.



Listen to industry experts on the latest in drug discovery, development, research, industry regulations and much more at Pharma,s DNA, the podcast channel by Senglobal Ltd., available on Sound Cloud, Spotify, iTunes and YouTube.





Peer Reviewed, IAHJ looks into the entire outsourcing management of the Veterinary Drug, Veterinary Devices & Animal Food Development Industry. wwww.international-pharma.com

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Health Outcomes These personalised medicines are often orphan drugs and can result in an expedited submission process and bigger treatment effects will be identified in a smaller patient population. 5. Quality of Life (QoL) Endpoints We are seeing improved patient centricity with more trials including improved QoL in clinical development and a trial’s endpoints. Not only is the drug efficacy analysed, but its impact on patient’s quality of life is also going to be considered as a higher priority. To make this a reality we need to see more patient involvement in disease specific questionnaires to help measure and report on this QoL, we also need to ensure compliance with the completion of these QoL questionnaires at home in the patient's own environment. However, now, there are barriers in the adoption of these questionnaires, there is some stigma associated with the adoption of technology to capture questionnaire data from subjects. The industry can help the adoption of personal devices by explaining clearly to subjects enrolled in trials that by allowing a bring your own device (BYOD) will increase compliance and the probability of capturing data as it is all done from a single device. There also needs to be a level of validation on the questionnaires to show that the responses are meaningful and related to the specific disease to demonstrate the validity of QoL endpoints. The design of studies to validate the questionnaires should involve patient groups. 6. Use of Technology to Communicate with Patients Technology has made it easier for patients enrolled in a trial to bring their own devices. These devices can be configured to automatically send notifications to patients to complete questionnaires or diaries. In turn increasing compliance as data is more likely to be entered which improves the quality of these important patient-centric data. Patient care and quality of life must be the focus, the use of technology to communicate and gather information has dramatically increased during the past two years and so now is the time to push patientcentricity further. The industry must come together to simplify processes as opposed to creating barriers. 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Identification of key data is essential to patient adherence. It is not patientcentric to make subjects come to sites at an increased frequency to undergo many assessments. Improvements in design and data collection will enable the subjects to have an increased QoL and companies to streamline the analysis of data by capturing only the essential data.

used and managed. Questionnaire data are still perceived as just additional external data which are expensive and time-consuming to setup. As an industry we need to see how we can make the adoption of innovative technologies easier such as wearable sensors. We should be opposed to the concept that patient-centric data is an expensive option, limited only to the richest of companies: biotechnology companies need to embrace a patient centric approach for the successful development of their pipeline of personalised medicines.

Drug developers need to embrace technology to enable improved patient adherence and its especially important if RWD is being collected rather than from a designed study. To make this a reality we are seeing: •

The increased user experience of mobile apps to help capture RWD.

More education is needed on the use of Electronic Clinical Outcome Assessment (eCOA) data (which measures and records how a patient is feeling or functioning) and how it is

An understanding on how we utilise the data from patient centric devices, we know the consistency between outputs from smart watches can differ by user, so we need to be clear from the start how we adopt and interrogate this data.

There are some barriers with the adoption of these latest technologies such as the validation of data that is required. Summer 2022 Volume 14 Issue 2

Health Outcomes Traditionally, clinical trial data would be source verified onsite (unless done remotely) but RWE data that is collected outside of a controlled environment without a study nurse on-site does not have the level of source data validation a controlled trial has. For RWE studies, the data that is entered is still checked against the source documents where possible such as prescription and/ or any lab report/values and a copy of the source has to be saved for future audit purposes. There are certain remote source data verification tools that allows this with the use of scanning or taking screenshots of these source documents. However, this still does not cover the SDV of RWD from wearables and eCOA devices. These devices focus on the most efficient and strict data transfer processing abilities possible, and are carefully validated so that data enters the database which will be analysed without any complications. However, due to the natural of there being no source documentation (think of a wearable on heart rate always providing real time data), the regulatory are still concerned

about SDV from these devices and the area is still debated today. Conclusion There are many benefits of patient centricity in clinical trials for both the patient, their families (when supporting patients with site visits etc) and the company conducting the trial. The patient needs are placed higher on the agenda of the trial which helps recruit patients and keep patients in the study, participating in a trial is easier and becomes less of a burden. This helps the drug developers as they will benefit from improved compliance and capture of data. However, there are also some barriers to adoption that need to be considered when adopting patient-centric technologies, such as the validation of data from wearables and eCOA devices. There also needs to be an understanding from the industry how we move forward with the standardisation and adoption of eCOA and wearable data to ensure we can roll these offerings out to patients without the associated heavy start up times, therefore making them accessible to everyone and not just the companies that can afford the technology.

Pharmaceutical companies, Clinical Research Organisations, technology providers and regulatory agencies need to address these barriers and challenges and find solutions that still upload the high standard of patient safety and drug efficacy but also now consider that patient centricity is no longer a trend, but a central tenant in many operations.

Karen Ooms Karen Ooms is Executive Vice President and Head of Statistics at Quanticate, who is responsible for overseeing the Statistics department at Quanticate. She is a Chartered Fellow of the Royal Statistical Society and has a background in biostatistics spanning more than 25 years. Prior to joining Quanticate in 1999 (Statwood), she was a Senior Statistician at Unilever. She earned her MSc in Biometry from the University of Reading.

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Health Outcomes

Listening to Healthcare Professionals and Patients Through Co-creation Working in partnership with patients and healthcare professionals is becoming a core part of the design of patient education. But how should pharmaceutical companies balance the needs of multiple different stakeholders? Alex Merckx, Director of Marketing and Partnerships at Cognitant, explains how listening and discussion can deliver successful cocreation. The importance of supporting patient education is increasingly recognised as critical to the success of the pharmaceutical industry. But no amount of training can allow someone to fully understand what it’s like to live with a chronic condition from a patient’s point of view. Health information can provide people with the knowledge and confidence they require to understand and manage their own health, which plays an important role in adherence and improved health outcomes. For such an approach to be effective, health information must be accessible, engaging and understood by the target audience. Therefore, placing patients and their families, as well as healthcare professionals, at the centre of the design process of patient education is critical. But if the sector is to adopt this approach more widely, how can we balance the needs of different stakeholders?

health, we need to move towards the idea of co-creation. Co-creating Education Materials with Patients Co-creation of patient education materials involves working in partnership with stakeholders from early on: from research and development, through to design and delivery. Co-creation with patients has been shown to contribute to the empowerment of patients, leading to better health outcomes, improved patient satisfaction and more efficient resource use,2 while increasing advocacy and trust in pharmaceutical companies. The co-creation process is commonly seen as understanding the needs and experiences of ‘expert patients’ and their caregivers. However, it should also involve Patient Advocacy Groups (PAGs), families, and healthcare professionals who diagnose conditions and prescribe and monitor treatments. It is key to consider the patient’s perspective as this can differ significantly from that of a clinician or other stakeholders. For example, a 2018 study by Bayer found that women’s real contraception needs differed markedly from the perception of those needs by healthcare professionals (HCP).3 The double-blind online survey found that 73% of the European women aged 18–49 surveyed were interested in a long-acting reversible contraceptive, for example. In contrast, the 676 HCP also surveyed estimated that only 38% of women would be interested in this option.

Creating an Unbiased Environment The co-creation process needs to create a safe and unbiased environment to ensure people are not influenced by other stakeholders. It is important to make sure everyone around the table is consulted and the diversity within the group is considered to ensure every voice gets heard as they are all valid and potentially different. Building in Diversity – Viewpoints from Different Demographics and Backgrounds Critical to the success of co-creation is the balancing of different stakeholders’ opinions and recommendations. Participants from different demographics and backgrounds can have quite different perspectives, and co-creation helps explore this. For example, healthcare professionals have extensive clinical training, experience of routine practice, and are aware of unmet needs. Meanwhile, co-creation with patients allows a pharmaceutical company to walk in a patient’s shoes, bridge gaps, and therefore identify the most logical and engaging solutions that can have the biggest impact on supporting them to manage their condition. Pharmaceutical companies need to design their patient education materials to speak to a diverse range of patients. Many patients are not able to understand complex medical or pharmaceutical language. Patients may have varying cultural expectations, have a first language that is different from the educational material, or want to access different materials due to age or other barriers.

The Need for Health Education to Empower the Patient The pharmaceutical industry has embraced the idea that healthcare professionals and patients are more than just customers for therapies. If people understand their condition and treatment, they will be better placed to manage their own health and comply with medication regimes. This can have a direct impact on health outcomes, validated quality of life measures, and on the cost-effectiveness of healthcare interventions.1 To ensure that people are supported with information that empowers them to better understand and manage their 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2022 Volume 14 Issue 2

Health Outcomes Overcoming Different Perspectives in Co-creation To illustrate the importance of weighing up the perspectives of different stakeholders we can consider a series of virtual co-creation workshops we recently did as part of a natural history study. These were held with doctors, nurses, families and advocacy groups in Europe and the United States.The aim of the workshops was to aid with the design of an interactive animation series to educate and support the caregivers of children when enrolling in the PROspective Neurological Disease TrajectOry (or PRONTO) study for two rare neurological diseases. The co-creation workshops aimed to discuss unmet needs, what the curriculum should cover, as well as consider format and creative options to maximise the accessibility of the resource to the audience. Stakeholders were asked to discuss test concepts and approaches, and to feedback on the final product at the end of the process. What emerged during the various design phases was how the perspectives of healthcare professionals differed in comparison to what was important for families. For example, nurses and doctors were focused on emphasising that the study did not involve an investigational treatment, and were keen for the resource to clearly communicate the aims of the study, as this is usually a point of frustration for families. Caregivers and parents of children affected by the condition were more interested in the pragmatic and logistical issues raised by participating in a natural history study, such as inclusion criteria and the time commitment involved. Opinions also varied with the nationality of the cocreation groups. Spanish groups wanted less information to be shared with patients, US groups wanted to share everything, and UK groups were somewhere in the middle. Through productive and collaborative discussion, the educational curriculum and video materials were refined to produce something that met everyone’s key needs. Time in the workshop was dedicated, for example, to discussing differences of opinion with each group, including the pros and cons of various approaches. Individual patients and their caregivers were also asked to feed their opinions into each topic as well. Through collaboration and involving the patient community, as well as other stakeholders, a series of patient information wwww.international-pharma.com

A co-created educational resource for the PRONTO natural history study, designed by Cognitant with patients

materials were designed. These were regarded as highly innovative: PRONTO was the first rare-disease natural history study to use videos and animations for patient information. Each interactive animation is one to two minutes long and can be viewed at home. There is a video covering each stage in the study process, with the aim of informing families about next steps and preparing them for hospital visits. The videos are available in multiple different languages to make them more accessible to patients. The success of the project will be measured by user feedback and engagement metrics. How Can We Balance the Needs of Different Stakeholders? Variations in opinion are common in cocreation, and it’s crucial to explore this; for example, why is there difference in opinion? How strongly do they feel about this? Are there stronger reasons to follow one group’s advice over another, if consensus can’t be reached? By discussing as a group, it’s possible to examine why people think differently. The group may even discover that people align in their views when the issues are discussed further. If this isn’t the case, it may be helpful to liaise with relevant external advisors and to provide creative and practical advice to the groups to aid them in their decision making. Asking for opinions on pros and cons, as in the PRONTO study, is also a strong way forward. It is this co-creation process itself which helps to balance the needs of different stakeholders. Co-creation allows for listening and adjustment, and it ensures that the end result isn't just valuable to one party. Ultimately, co-creation delivers health education that is meaningful to the patient at an emotional, cultural, and mental level so that it will achieve the best health outcomes

for them. Going forwards, co-creation with multiple stakeholders promises to improve trust in the pharmaceutical industry and to lead to the creation of therapeutics that more effectively meet the needs of patients and healthcare professionals alike. REFERENCES 1. 2. 3.

4. 5.

Jing. J, et al. Factors affecting therapeutic compliance: A review from the patient’s perspective. Ther Clin Risk Manag 4(1):269 (2008) Russo, G., Tartaglione, A.M., and Cavacece, Y. Empowering Patients to Co-Create a Sustainable Healthcare Value. Sustainability. 11, 1315 (2019) Merki-Feld G.S., et al. Are there unmet needs in contraceptive counselling and choice? Findings of the European TANCO Study. Eur J Contracept Reprod Health Care 23(3): 183-93 (2018) Murphy, J. and Coster, G. Issues in patient compliance. Drugs 54(6):797-800 (1997) Goldhammer D.L, et al What do young Australian women want (when talking to doctors about contraception)? BMC Fam Pract 18(1):1-10 (2017)

Alex Merckx As Director of Marketing and Partnerships at Cognitant, Alex Merckx is responsible for identifying and nurturing partnerships with patient-centred organisations. Merckx is passionate about raising awareness of the power of co-created, innovative patient education to drive improvements in health outcomes. Merckx previously directed the Corporate Marketing Solutions team at Wiley and was Marketing Director and International Development Manager for M3. Email: alex.merckx@cognitant.com


Health Outcomes

Financial Barriers to Participation: The Missing Piece of the Patient Centric Jigsaw The patient centricity revolution has seen the industry pour resources into ensuring clinical trials place the needs of participants front and centre of drug development plans. Collecting insights to inform study design, for example, is a tried and tested method of increasing recruitment and retention rates – but that work is wasted if financial barriers render participation unfeasible. Modern automated payment systems that combine technology and the human touch can ensure people are paid quickly and efficiently and always have a point of contact if things go wrong or they need additional support. Pharma companies are pouring resources into patient centricity, but complicated or lengthy expense payment processes could be squeezing their return on this investment. In recent years, the pharmaceutical industry has invested heavily in patient centric programmes and initiatives in a bid to reduce costly patient dropouts and boost recruitment rates. This revolution in thinking has affected every part of the drug development pathway for several reasons – not least that designing a trial to suit the needs of the patient drastically improves clinical outcomes. Patient centricity in clinical trials can boost recruitment and retention rates in a multitude of ways. Patient-led trial design can, for example, ensure protocols are feasible for those who will take part by steering researchers away from multiple invasive tests or an excessive number of clinic visits. It can also ensure studies investigate elements of disease that matter to patients, thus increasing the attractiveness of taking part. More than 75% of people with diabetes, for example, say they want clinical trials to measure the condition’s impact on their quality of life, such as the onset of kidney failure and dialysis, or sight loss, rather than surrogate variables, like HbA1c, that tend to be used.1 The growing recognition that patient insights can help organisations to build and conduct studies people want to be part of, means sponsors and CROs have 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

put in increasingly more effort to work in partnership with participants. Patient and public involvement projects are now included at every stage of the clinical journey, including advisory boards and focus groups on everything from candidate selection and protocol design to submissions and marketing materials. However, many companies are still missing a crucial part of the engagement puzzle. Among the leading barriers to clinical trial participation are financial concerns, an issue that not only blocks access for individuals, but contributes to the enduring legacy of health inequalities. And by failing to address them, the very same patient engagement teams that spend their days seeking out, collecting, and utilising insights run the risk of wasting all of that hard work. Recruitment and Retention The gulf between the number of people who would theoretically be interested in participating in research and those who actually do is staggering. While more than 70% of the general population believe patients should be given the opportunity to take part, fewer than 5% of people with cancer, for example, enrol on a clinical trial.1 This has a huge impact on the sector, its progress, and its return on investment. Globally, more than 80% of studies fail to meet enrolment targets on time,2 delaying study initiation – at a cost of between $600,000 and $8 million a day3 – and extending already lengthy development timelines. In addition, poor recruitment

is the leading reason for the premature discontinuation of randomised clinical trials (RCTs).4 Yet even when trials have recruited adequate numbers to answer the research question, many patients drop out before the study completes. This leaves teams with underpowered studies, insufficient data, and having to choose between re-enrolling or terminating the trial: not an easy decision when replacing lost patients can cost, on average, $19,533 per participant in direct and indirect costs.5 None of this is news to the industry, which has been grappling with recruitment and retention issues for years. Back in 2014, for example, a working group of UK Clinical Research Collaboration-registered Clinical Trials Units decided its top two priorities were “research into methods to boost recruitment in trials” and “methods to minimise attrition”.6 Since then, there has been some success, but there is still much work to be done. There has, for example, been an increase in enrolment rates, with one study finding actual enrolment exceeded planned enrolment by 113% in 2019, compared to 96% in 2012.7 Yet while this success, which may be credited to improved recruitment strategies and greater awareness of trials among clinicians and patients alike, is promising, it has not been reflected in retention figures. In fact, trial drop-out rates grew from 13.2% in 2012 to 19.1% in 2019.7 Patient Centric Thinking The reasons people drop out of clinical Summer 2022 Volume 14 Issue 2

Health Outcomes trials are complex and wide ranging. individuals may face logistical issues, such as scheduling conflicts, they may forget their appointments, or become too ill to travel to the site. They may feel unappreciated, have some fear and anxiety around the process, or may not have fully understood the expectations placed on them at the start of the process, for instance. Another important barrier is financial constraints. People taking part in a clinical trial will often need to take time off work for site visits, and pay out of pocket expenses such as lodgings, meals, childcare, and transport. In some countries, these additional outgoings will be set to the backdrop of routine care costs, including co-payments and deductibles.8 Under the patient centricity banner, sponsors and CROs have been attempting to eradicate many of the well-known barriers to participation. Decentralised clinical trials, for example, can help remove travel issues, and improved eConsent procedures help sites ensure patients are fully cognizant of the protocol. However, the financial obstacles tend to be overlooked. Often, participant expenses are still subject to complex claim procedures, and many people face lengthy delays to receiving the promised reimbursements. This can effectively price people from lower socioeconomic backgrounds out of taking part in clinical trials and, aside from the obvious human cost, the potential impact on study diversity and representation is huge. Patient populations with historically lower financial resources, including uninsured and those from minority backgrounds, are often underrepresented in cancer clinical trials, for example, whereas those patients with higher socioeconomic status tend to enrol more often. Downstream, these disparities in research cohorts contribute to a lack of data on certain therapies in certain patients, and perpetuate health inequalities.8 What’s more, this is a problem that is only set to get worse as the global cost of living crisis deepens, disproportionately affecting the poorest people in society. Automation Augments Human Interaction Modern automated payment systems streamline the payment and reimbursement process, helping to plug the affordability gap, thus increasing trial engagement, and boosting retention. Configured on pre-set, study-specific expense limits and policies, industry-leading payment technologies can integrate with all major banks across a range of countries, currencies, and payment thresholds, to deliver speedy payments to all participants, wwww.international-pharma.com

no matter where they live or how they bank. Such systems also enable sponsors and CROs to ensure they are fully compliant with the different international regulations on clinical trial payments, by viewing near real-time information about spend, transaction type, thresholds, reconciliation, and invoicing via a reporting dashboard.

2. 3.




Of course, technology alone is never the answer, and this is particularly true of the multifaceted issue of retention. Clinical trials take place over a period of months or even years, and participants’ circumstances are bound to change. If they want to keep people on trial, and the trial on track, sponsors and CROs must make sure people have everything they need to stay engaged, no matter what happens. This can only be achieved with human interaction and support. Tech-led chatbots or tick boxes are simply not up to the task of maintaining a relationship. That is why it is so important that any platform augments, rather than replaces, site staff. By enabling two-way communication, for example, automated payment systems provide the best of both worlds. Full-circle Centricity There is no denying that patient centricity is the future of drug development. But when companies are drawing up their plans and investing their hard-earned resources, they need to make sure they have all their bases covered. And that includes removing as many financial barriers to participation as possible. Enabling quick and easy payments during clinical trials, without removing any crucial in-person support, is a simple yet effective way to maximise trial efficacy, boost ROI on patient centricity activities, and, ultimately, tackle the health inequalities of the future. To learn more about mdgroup, visit: https://mdgroup.com/ REFERENCES 1.

Sacristán, J. A., Aguarón, A., Avendaño-Solá, C., Garrido, P., Carrión, J., Gutiérrez, A., ... & Flores, A.



(2016). Patient involvement in clinical research: why, when, and how. Patient preference and adherence, 10, 631. Desai, M. (2020). Recruitment and retention of participants in clinical studies: Critical issues and challenges. Perspectives in Clinical Research, 11(2), 51. Pharmafile. Clinical trials and their patients: The rising costs and how to stem the loss. (2016). Available at: http://www.pharmafile.com/ news/511225/clinical-trials-and-their-patientsrising-costs-and-how-stem-loss Last accessed: 25th May 2022. Briel, M., Elger, B. S., McLennan, S., Schandelmaier, S., von Elm, E., & Satalkar, P. (2021). Exploring reasons for recruitment failure in clinical trials: a qualitative study with clinical trial stakeholders in Switzerland, Germany, and Canada. Trials, 22(1), 1-13. mdgroup. The true cost of patient drop-outs in clinical trials. (2020). Available at: https://mdgroup. com/blog/the-true-cost-of-patient-drop-outs-inclinical-trials/ Last accessed: 25th May 2022. Crocker, J. C., Ricci-Cabello, I., Parker, A., Hirst, J. A., Chant, A., Petit-Zeman, S., ... & Rees, S. (2018). Impact of patient and public involvement on enrolment and retention in clinical trials: systematic review and meta-analysis. BMJ, 363. WCG CenterWatch. Recruitment rates rising, but retention rates fall, according to new study. (2020). Available at: https://www.centerwatch. com/articles/24543-recruitment-rates-rising-butretention-rates-fall-according-to-new-study Last accessed: 25th May 2022. Nipp, R. D., Hong, K., & Paskett, E. D. (2019). Overcoming barriers to clinical trial enrollment. American Society of Clinical Oncology Educational Book, 39, 105-114.

Caroline Jackson With more than 27 years of experience in the industry, Caroline brings a wealth of knowledge and understanding of the clinical development process to mdgroup’s Patient Service Department. In her role as Executive Vice President of Patient Services, Caroline helps our clients embrace new technologies and decentralised solutions to facilitate better patient care, increase clinical trial diversity and reduce drop-out rates by empowering patients. After graduating from the University of Southampton with a BSc in Pharmacology, Caroline then went on to work for companies including Bayer, PRA Heath Sciences and Synteract where she was Vice President of Vendor Management. Caroline is passionate about truly putting patients first and increasing clinical trial accessibility by giving patients more choice in how they participate.


Logistics & Supply Chain Management

Maintaining Integrity of the Pharma Cold Chain

Two years since the start of the Covid-19 pandemic, the social and economic implications are still being felt on a global scale. The pandemic has impacted practically every phase of our lives and it also greatly influenced the cold chain logistics industry bringing new challenges and requirements. It’s been a challenging time, but also a time with significant achievement within the pharma and transport industries. The Covid-19 vaccine development was much faster than any other vaccine in history, with production and distribution at unprecedented scale. Vaccine manufacture reached close to 1.5 billion doses per month according to the WHO,1 creating pressure for ultra-low cold chain considering the fragility of mRNA vaccines – where ultra-cold storage helps to slow down the chemical reactions that can tear them apart. This challenge is predicted only to get bigger as mRNA vaccine technology is applied to tackling other diseases – from cancer and flu to malaria and HIV. It’s a technology that’s revolutionising the pharmaceutical sector and ushering in a new era of vaccinology. This gives a clear sign that ultra-cold temporary storage, as well as 15–25°C and 2–8°C temperature ranges will be a common need for pharmaceutical transport and logistics into the future.

Regulations as a key factor in maintaining safety, integrity and efficacy of all biopharmaceutical products – not only the Covid-19 vaccines. GDP Regulations – Protecting Biopharmaceutical Shipments By some estimates, as many as 70 percent of products require some type of controlled temperature environment, including those that need to be maintained at a consistent “room temperature.” For most medical and biological products, the GDP guidelines require a temperature-controlled environment for several stages of manufacturing, shipping and storage. For a Cold Chain Solution Provider, Focusing the 4-stage GDP Qualification is a High Priority. Regardless of the mode of transport, it should be possible to demonstrate that the medicines have not been exposed to conditions that may compromise their quality and integrity. This requires a risk-based approach when planning transportation. If a deviation such as temperature excursion or product damage has occurred during transportation, it should be reported to the distributor and recipient of the affected medicinal products. A procedure should also be in place for investigating and handling temperature excursions. Temperature-sensitive products should be transported in qualified equipment (e.g.

thermal packaging, temperature-controlled containers or temperature-controlled vehicles) to ensure correct transport conditions are maintained between every step of the way – from the manufacturer, through the wholesale distributor and when reaching the customer. When using temperature-controlled vehicles, the temperature monitoring equipment used during transport needs to be maintained and calibrated regularly. Leading operators are equipping their fleets with integrated asset management systems that protect shipments by establishing critical controls at all points in the supply chain. Temperature mapping under representative conditions should also be carried out and should consider seasonal variations. The leading transportation refrigeration providers, enable customers to access information that demonstrate products have complied with the temperature storage conditions. The key elements of the site qualification and validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent document. And of course, qualification and validation activities should only be performed by suitably trained personnel who follow approved procedures. There are four stages of qualification outlined in the guidelines and they include: •

Design Qualification (DQ) – where the compliance of the design with good

Delivering confidence in the reliability of refrigerated pharmaceutical transport is key. Pharmaceutical companies rely more on partners that can offer the end-to-end solutions to ensure their products arrive safely at their destination – traveling across all modes of cold chain transport. These partners help fully understand the range of potential temperature requirements and their implication for logistics – mapping map out the supply chain, identifying potential bottlenecks and planning end-to-end innovative solutions. This also highlights the importance of Good Distributions Practice (GDP) 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Summer 2022 Volume 14 Issue 2

temporary cold storage from -70°C to -10°C THERMO KING SUPERFREEZER

COLD STORAGE SOLUTIONS F O R VACC I N E D I ST R I B U T I O N Plug in the Thermo King SuperFreezer unit anywhere and keep your precious cargo at the exact temperature you need, for as long as you need. Thermo King offers the complete package in combination with easily stackable ISO containers so you can seize business opportunities as soon as they emerge. Our SuperFreezer & container combos are immediately available to order. Contact your dealer today or go to TKpharmasolutions.com for more information


Summer 2022 Volume 14 Issue 2

Logistics & Supply Chain Management

manufacturing/distribution practice (GMP/GDP) should be demonstrated and documented. The equipment used is suitable and meets relevant criteria. •

Installation Qualification (IQ) – confirms that the equipment is installed and conforms to the approved design qualification and include but are not limited to: •

• • • • •

Verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications Verification of the correct installation against pre-defined criteria Collection and collation of supplier operating and working instructions and maintenance requirements Calibration of instrumentation Verification of the materials of construction.

Operational Qualification confirms that the equipment performs as designed throughout the anticipated operating ranges and provides operating guidance. This includes: • • •

3-temperature points calibration check of each equipment Operating guidance on the equipment usage Training for fleet operators, drivers and distribution managers around efficient loading practices, operating


procedures, preventative maintenance strategies. •

Performance Qualification provides mapping test results that prove that the equipment can perform effectively and reproducibly, based on the approved process method and product specification. This includes: •

Test conditions • Worst case scenario • Empty load space • Extreme Ambient temperatures: -30°C to +45°C • Test in climatic chamber • Better control of test conditions • Winter and summer tests to be done at the same time • Number of sensors: • 20 to 25 sensors in a vehicle (ATP standards) Qualification at 3 temperature ranges • +15°C to +25°C / +2°C to +8°C / under – 20°C, under -70°C. For Last Miles distribution • Additional tests with multiple door openings, empty and loaded tests, failure mode An extensive range of tests in climatic chamber to ensure the simulation of worst-case scenarios in real life conditions.

These guidelines should be consulted in order to ensure appropriate procedures are

followed and measures taken to maintain product quality throughout the cold chain and limit risks during transport. Each temperature-controlled transport unit used for the transportation of pharmaceutical products needs to go through a qualification process. Qualification consists of a temperature validation process that maps the temperature performance of the unit operating in particular temperature ranges. Temperature sensors are placed in a number of locations throughout the box to identify if there are any hot or cold spots that could affect the transportation of the pharmaceutical products and to show that the equipment is suitable to operate in worst case scenario within upper and lower limits. Once the tests are completed, it is essential to complete the process of qualification by preparing the adequate documentation that ensures that the four stages of qualification have been completed correctly. At this time, a certificate can be provided to prove that the equipment is qualified for pharmaceutical operation. Considerations Before or During Transport of Pharmaceutical Products Preserving cold chain integrity and maintaining product quality will remain an increasing challenge for pharmaceutical companies and their partners in handling and transporting pharmaceutical products globally. As temperature-controlled shipments grow in volume and regulatory requirements change, pharmaceutical and biotech manufacturers need the support of their transportation industry partners Summer 2022 Volume 14 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



Development and manufacturing Belgium - Europe Phone +32- Website www.krautz.org Email info@krautz.org

Temax Americas LTD

Hanover park – Illinois – USA

ISO-9001:2015 certified

Summer 2022 Volume 14 Issue 2

Logistics & Supply Chain Management

to ensure compliance with regulatory requirements and the safety and integrity of their high-value shipments. Each cold chain partner company should always have a GDP-Trained Responsible in their team. This person should be regularly trained using a combination of general GDP awareness and technical/operational training on the different cooling units and basics of temperature-controlled transport. Other important factors to consider before or during transport of pharmaceutical products are: •

Load space configuration when the trailer body design is carried out, such as whether to include dividing doors,

• •

air shoots, return air bulkhead design. The load space should be kept clean at all times and only cleaning agents that will not affect the cargo should be used. To conform to temperature monitoring and recording obligations, the units are required to have on-board temperature recording and monitoring as well as printed delivery point tickets to prove the temperature integrity of the load space. Because the products have to stay within a particular range, both temperature and air management must be controlled within this range with no deviation allowed or any excursions limited to manufacturer specifications. Drivers are required to be trained to

show that they can operate the unit within the GDP requirements. Regular maintenance and service records should be kept for inspection if required by the pharmaceutical companies. A calibration check should be completed at least once per year; individual pharmaceutical companies may request more checks. A three-point calibration of the sensors is important to ensure that when the unit is operating it can maintain the load space temperature at the set points as listed above. To prevent risk of contamination to sensitive shipments in the compartment, cleaning standards in line with GDP guidelines should be enforced under the guidance of certified service personnel.

For cargo as precious and sensitive as life-saving medicines, active controls that can monitor for temperature, humidity and location are critical. With the solutions and technology that exists today, customers can be confident of the efficacy of their product while in transit or in storage.

Muge Suner Muge Suner, Pharma Key-Strategic Accounts Manager Europe, Middle East and Africa (EMEA), Thermo King.


Summer 2022 Volume 14 Issue 2




Summer 2022 Volume 14 Issue 2

14 & 15 September 2022 | Geneva, Switzerland

The new event at the heart of European pharma dedicated to innovative packaging, drug delivery systems, CDMO/CMO and filling & assembling processes

New event designed to drive innovation for pharma and biopharma businesses ‘Connect in Pharma’ is the new event that will bring together key players in the pharma and biopharma production industry. The event will take place on 14 & 15 September 2022 at major exhibition space Palexpo Congress Centre, in the heart of the pharma and biopharma industry and conveniently located next to the Geneva airport. Leading global events company Easyfairs say they are launching this new event after spotting a gap in the market.


FACTFILE When: 14 & 15 September 2022 WHERE: Palexpo, Geneva, Switerland EXHIBITORS: 100+ COST: Free to attend KEY SECTORS: Drug Delivery - Filling & Assembling - Innovative Packaging - CDMO FIND OUT MORE AND SECURE YOUR PLACE quote code 5017

Summer 2022 Volume 14 Issue 2

Bringing Together Innovators The event is designed to inspire collaboration and innovation between suppliers, specifiers and other influencers in four key areas of pharmaceutical production downstream from the molecule: packaging, medical devices, contract manufacturing (CMO/CDMO) and processing. Visitors to Connect in Pharma can expect to discover a range of innovations that are changing the way drugs are brought to market. With new developments in the field, including personalised treatments and nanotechnology among others, even greater changes are expected in the near future.

Isabelle Levy-Dessart, WW Marketing Communication Associate Director at BD, said: “We believe that Connect in Pharma will be an exciting new force driving business and innovation in the pharma market, and we can’t wait to meet the whole market in Geneva.”

Founding partners


Heike Lang, Head of Marketing & Communications at Sanner GmbH, said: “Connect in Pharma has the potential to become the top event for pharmaceutical packaging and for CDMOs in Europe. As one of the key players for primary packaging and medical devices, we want to be part of this development from the very start.”

Collaboration and Partnerships The event is partnering with leading associations such as Biopole SA, Polepharma, Lyonbiopole, BioAlps, Swiss Biotech, Bionow in the UK and more. Over 70 industry-leading suppliers and associations in the pharma and biopharma sector have already signed up to exhibit at the event, including Becton Dickinson SAS, Catalent, Uhlmann, Staubli Robotics, ARaymondlife, Essentra, Gerresheimer, IMA Automation, Körber AG, MARCHESINI GROUP SPA, Nextpharm, and Unither Pharmaceuticals, among others. A full list can be found at www.connectinpharma.com/ exhibitor/.

Stephanie Pellet, Marketing Manager at ARaymondlife, said the company was looking to showcase new injectable drugs and meet other companies. “We decided to join this new event because the pharmaceutical industry in Switzerland is a highly developed sector, from large corporations to small startups and research centres. This European-wide event is perfect in terms of the format and the time of year.” wwww.international-pharma.com


Get your

ticket now!

INSPIRING SUSTAINABLE CONNECTIONS #back2live: 22 – 26 August 2022 Frankfurt, Germany



World Forum and Leading Show for the Process Industries ACHEMA is the global hotspot for industry experts, decision-makers and solution providers. Experience unseen technology, collaborate crossindustry and connect yourself worldwide to make an impact. Are you ready? Join now!

Summer 2022 Volume 14 Issue 2

05th - 07th Sep 2022


Stavros Evangelakakis

Abdullah Bahadır Büyükkaymaz Turkish Cargo

Matt Way

Andy Faes

Kevin Doran

Nicola Caristo

Prof. Dr. Yvonne Ziegler

Cargolux Airlines

Tanner Pharma


Tower Cold Chain


Mytigate GmbH

Fabrizio Iacobacci

Marco Del Giudice

Miguel Rodriguez

Vijan Chetty

Gerton Hulsman

Francisco Rizzuto

Paul Bessems

BCUBE air cargo spa


Qatar Airways


Energy in Process


Weconomics Foundation

For more information on sponsorship and exhibition please contact Mo Banks – mo@evaint.com or Sohail Ahmad – sohail@evaint.com TEL: +44 (0) 208 253 4000

W W W. C A A S I N T. C O M The Reunion Sponsors

THE REUNION wwww.international-pharma.com


Advertisers Index

Page 86


Page 87


Page 65

Aurena Laboratories

Page 15

Biopharma Group


BSP Pharmaceuticals S.p.A

Page 23

ChargePoint Technology

Page 84 & 85

Connect in Pharma

Page 69

FUJIFILM Wako Chemicals U.S.A. Corporation

Page 49

Kahle Automation

Page 3

Klinge Corporation

Page 81

Krautz Temax


Natoli Engineering Company

Page 5


Page 63


Page 33

Owen Mumford

Page 11

PCI Pharma Services

Page 83

Peli BioThermal Limited

Page 7

RGCC International GmbH

Page 71

Senglobal Ltd



Page 53

Solid Technologies S.L.

Page 57

Stäubli International AG

Page 79


Page 37 & 73

Valsteam ADCA

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

IPI is also now active on social media. Follow us on:

Subscribe today at www.international-pharma.com or email info@senglobalcoms.com


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Summer 2022 Volume 14 Issue 2

Health Science Health Inspired, Quality Driven

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

Why use SGS

About SGS

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

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

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


Wide-range of laboratories and clinical research sites and qualified partners. Size and diverse testing capabilities matching biologics and small molecules needs International network across America, Europe and Asia-Pacific

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

Summer 2022 Volume 14 Issue 2





7 Filling lines working in full containment, to produce liquid and lyo vials Annual capacity: liq/lyo vials 31 Mill. units end 2022


7 Filling lines working in full containment to produce liquid and lyo vials Annual capacity liquid/lyo vials: 9 17 26 Million units 2022 2023 2024





41 | 2025


Conjugation of ADC’s from development (10mg - 5g) to clinical and commercial (20g - 5 Kg) Liposomal Bulk Solutions • Annual capacity: 410 Kg • Additional 900 Kg by end of 2022



Dedicated manufacturing area for tabs, minitabs, capsule, LFHC Development: 100g to 1000g GMP Clinical and Commercial: 4Kg to 100Kg Annual capacity: 50 Million units


Method validation and transfer Full testing of small and large molecules Stability and Photostability studies



Preformulation and formulation development Analytical methods Development Process Development: oral solids, conjugation, liquid and lyo formulations, complex formulations


Via Appia km 65,561 04013 Latina Scalo (LT) – Italy Phone: +39 0773 8221 Web: bsppharmaceuticals.com Mail: business.development@bsppharmaceuticals.com