Pharma Focus Asia - Issue 45

ISSUE 45

2021

www.pharmafocusasia.com

MODELLING SUCCESS What is a business model, and how can you build one?

Biologics to Open New Revenue Streams for Indian Pharma

Healthcare and Pharma Need to Build Immunity Against Cyber Threats

Moved by people qrcargo.com

Transformation through Digital Innovation The COVID-19 pandemic has accelerated change

Life sciences companies also realise the need

like never before and digital transformation is reshap-

to innovate and transform their business models to

ing business models across industries, including

address market saturation and increasingly complex

pharmaceuticals. Adaptability to changing market

regulatory systems. The eventual success of these

conditions has pushed companies to evaluate and

new business models depends on how well compa-

renew their business models around sustainability.

nies in pharma, biotech, and medtech collaborate

Integrating digitisation into strategic priorities has

to leverage existing and potential growth sources

helped life sciences companies transform the core

over the next few years.

business models and unleash the power of digital.

As companies look to leverage cloud technology

The use of digital technologies is not a new

and advanced analytics solutions, data monitoring,

phenomenon for the industry. Still, there is much

management and security will play a significant

to be done to drive digitisation of processes, from

role in digital strategies for growth over the next

R&D and clinical trials to manufacturing and logis-

few years.

tics. The drivers for industry growth have primarily

The latest issue of our magazine covers an

been innovation, mergers and acquisitions, and

interesting write-up by Brian Smith, Principal

geographic expansion. But addressing today’s

Advisor, PragMedic on business model innova-

complex regulatory regime requires companies

tion in life sciences industry. In this article, Smith

to leverage digital technologies for making data

outlines research into the business models and

available and accessible to all parties involved,

offers interesting perspectives on the evolution of

and comply with regulatory requirements.

pharma business models and evolving approaches

The pandemic was a wake-up call for companies with a significant dependence on overseas supply

to build a successful model. I hope you find this edition interesting and insightful.

chains. To address challenges such as supply chain continuity and cross-border data governance, pharmaceutical firms have to restructure their supply chains. They are looking at data analytics and insights to optimise inventories, reduce operational risks and maximise productivity.

Prasanthi Sadhu Editor

CONTENTS RESEARCH & DEVELOPMENT

COVER STORY

20 Vaccinated Young Adult Sera

A Cost-effective approach for protection and treatment of COVID-19

Ahmed S Ali, Department of Pharmacology; Faculty of Medicine, King Abdulaziz University

Abdelbagi Alfadil, Microbiology and Medical Parasitology, Faculty of Medicine, King Abdulaziz University

MODELLING SUCCESS What is a business model, and how can you build one?

24 Nanotechnology-based Drug Delivery

Potential, progress and the way forward…

Sai Akilesh M, Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research

Ashish Wadhwani, Faculty of Health Sciences, School of Pharmacy, JSS Academy of Higher Education and Research

34 The Promising Future of Stem Cell-Based Therapy for Kidney Diseases

Chee-Yin Wong, Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman

38 Liposomes in The Creation of a Covid-19 Vaccine

41 Dissemination of SARS-CoV-2 and the Pathogenesis of COVID-19

Something wicked this way comes

Andrew C Retzinger, Department of Emergency Medicine, Camden Clark Medical Center, West Virginia University

Gregory S Retzinger, Department of Pathology, Feinberg School of Medicine, Northwestern University

CLINICAL TRIALS 45 Design and Analysis of Cancer Clinical Trials for Personalised Medicine

Brian Smith Principal Advisor, PragMedic

Gregory Gregoriadis, University College London

Sin-Ho Jung, Department of Biostatistics and Bioinformatics, Duke University School of Medicine

INFORMATION TECHNOLOGY 56 Healthcare and Pharma Need to Build Immunity Against Cyber Threats

48 Biologics to Open New Revenue Streams for Indian Pharma

R B Smarta, CMD-Interlink, Vice President (HADSA)

51 The Link between Plant Performance & Maturity

Seeing the whole picture

2

Bernasconi M, Grothkopp M, Pirrone L, Friedli T University of St.Gallen

P H A RM A F O C U S A S I A

ISSUE 45 - 2021

Paul Prudhomme, Head of Threat Intelligence Advisory IntSights, a Rapid7

60 How Risk-based Approaches to Computer System Validation Support Cost-Effective Compliance and Improved Patient Safety

MANUFACTURING

06

Brendan Walshe, CSV Consultant, Zenith Technologies, a Cognizant Company

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Advisory Board

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

EDITORIAL TEAM Grace Jones Rohith Nuguri Swetha M

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

ART DIRECTOR M Abdul Hannan PRODUCT MANAGER Jeff Kenney

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

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

Frank Jaeger Regional Sales Manager, AbbVie, US

PRODUCT ASSOCIATE Veronica Wilson

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

CIRCULATION TEAM Sam Smith

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

Laurence Flint Pediatrician and Independent Consultant Greater New York City

SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam HEAD-OPERATIONS S V Nageswara Rao

A member of

In Association with

Confederation of Indian Industry

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

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

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© Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions.

The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates.

Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

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

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STRATEGY

MODELLING SUCCESS What is a business model, and how can you build one?

In recent years, the term ‘Business Model’ has come to dominate board-room conversations. Whether firms want to adapt their existing business model or create an entirely new one, the term has become ubiquitous amongst pharma business leaders. But what is a business model? How does it differ from strategy, structure or revenue model? Ask 100 people for a definition, you will get 100 answers to the question. Such confusion and vagueness is the enemy of change management. In this article, Brian D Smith looks at the research into business models and gives us a new, practical and useful definition, based on his study of the industry, that helps pharma business leaders understand what a business model is and how to build one.

Brian Smith, Principal Advisor, PragMedic

I

s your market the same as it was five years ago? Has it been unaffected by the advance of medical science and information technology? Have changes in healthcare systems, demographics or

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economics made no difference to your business? Of course not. Every life sciences company is caught in a whirlwind of change that offers a stark choice between adaptation or extinction.

As companies from Roche to Merck demonstrate, successful adaptation begins with a shared vision of the future business model. But therein lies the problem. What is a business model?

Despite it being peppered over every meeting and filling the media, there is no agreement amongst either academics or executives about the definition of this ubiquitous term. And, as the biblical story of the Tower of Babel tells us, there is no construction without clear communication.

In my research, which studies the Darwinian evolution of life sciences companies, the concept of business model is central and, in this article, my aim is to share that thinking with you. Stay with me to discover what a business model is and how you should build yours.

STRATEGY

Figure 2:

Lessons from nature

Although the metaphor can be stretched too far, business can draw many lessons from biology. A tropical rain forest, for example, supports a multitude of different creatures and this diversity is possible because evolution has led to speciation.

In Amazonia, the sloth, the piranha and the jaguar survive not by competing with

each other but by adapting to different habitats within the jungle and different niches within those habitats. Darwin observed how each species has different capabilities and is recognisable by distinctive traits and behaviours. He couldn’t know, as we now do, that those visible characteristics are the result of invisible, species-specific genomes and proteomes.

This conception of a species maps directly onto the definition business models. The thousands of companies in the in the life sciences ‘jungle’ are not identical but group into ‘species’ that we call business models. For example, Dr Reddy’s and Roche, although both pharmaceutical companies, do not look or behave the same. They do, however,

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STRATEGY

Biological species, with characteristic traits and behaviours

Business models, with characteristic structures, strategies and culture

model-specific sets of capabilities (their capabileomes) that are the expression of their model-specific sets of organisational routines (their routineomes).

Does your model fit?

Species-specific set of proteins (the proteome)

Model-specific set of capabilities (the capabileome)

Species-specific set of genes (the genome)

Model-specific set of organisational routines (the routineome)

Species-specific base-pair sequences

Model-specific set of microfoundations

Figure 1: Business Models are Analogous to Species

share traits with the likes of Ranbaxy and Novartis. Even within large companies like Pfizer, the divisions for mature products, innovative products and rare diseases are not the same business model. Just like biological species, business models have characteristic traits and behaviours, such as strategies and structures. And just like species, these observable traits are the outward manifestation of internal properties. My work on uncovering this is summarised in figure 1.

In practical terms, this means that your business model is not unique to your company. A business model is a group of companies (or parts of companies) that share the same traits and behaviours, enabled by the same capabilities and routines. Viatris, Organon, Sandoz and Teva are all minor variants of the same business model, for example. And, if you study them internally, they share very similar capabilities and organisational routines. Importantly, both those visible and internal characteristics are different from, say, Fresenius, Baxter or Braun, who fall into another, very different, business model.

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Speciation of business models

This equivalence between business models and biological species carries another important practical lesson for life science companies trying to adapt to the future. There is no such thing as the ‘best’ species. There are only species that are well adapted to their habitat within their environment. In the Amazon forest, sloths and piranhas each thrive in their place but wouldn’t survive in each other’s habitat. In exactly the same way, there are no ‘best’ or ‘worst’ life sciences business models, only models that are well- or poorly- adapted to their environment.

A research-intensive business model like AstraZeneca may thrive when creating exceptional clinical value for seriously ill patients in advanced economies. It would, obviously, struggle to compete in the habitat of providing generic small molecules to out-of-pocket patients in the world’s poorest companies.

My research uncovers no fewer than 26 different life sciences business models (see figure 2). Each of these models has characteristic strategies, structures, cultures and other traits. They also have

This conception of businessmodels-as-species is practically useful to life science leaders because it helps them answer two critically important questions: What should our business model be and how should we build it?

A firm’s choice of business model (business models in case of larger companies) is idiosyncratic. That is, it is a very individual choice driven by the firm’s past history, future goals and the trends shaping the market. The business-modelas-species concept helps leaders make this decision because it helps to identify their options. Also, by looking at other companies currently using the same model but in different markets or therapy areas, leaders can crystalise what their new model might look like.

In practice, by considering the 26 models revealed in figure 2, leaders are forced to clarify the strategic choices involved in selecting a business model. If they fail to consider those choices, or if they fudge them, their company risks ‘straddling’ – being adequate at many things but competitive at nothing.

How do you build it?

Choosing a business model is, of course, only the beginning. The real work lies in transforming your existing model into one that is better adapted to the future.

In many cases, this transformation fails not because the new model was wrong but because the transformation effort was superficial. Leaders change names and move around the boxes on the organisation chart but without any substantial impact on the firm’s traits, behaviours or capabilities. To extend the biological metaphor, those leaders try to turn a

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STRATEGY

What capabileome will our new business model need?

What routineome will our new business model need?

What microfoundations will we need to change?

Figure 3: The Critical Questions of Business Model Transformation

ATTRIBUTES

Building microfoundations

Creating new organisational routines that express themselves as new capabili-

The connectivity between work groups involved in the routine

GROUP PROCESSES

CONFLICT MANAGEMENT

Figure 4: The Microfoundations of Routines

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Modelling success

Not every life sciences company needs a new business model. Yours may be working well and not affected by the way the world is changing. But given the pace of social and technological change, most life sciences leaders need to review their present and future business models. To do so requires a clear understanding of what a business model is and the model-as-species idea helps them choose their future model and to make the transformation.

TEAM STRUCTURES

The knowledge skills and behaviours of those involved in the routine

The processes that occur within the groups involved in the routine

10

tion. Similarly, models that create value beyond the product require capabilities in extended and augmented value proposition design. Both of these capabilities require organisational routines that are not common in life science companies that target large markets. And engineering the routineome, just like engineering the genome, requires precise manipulation of its components, known as microfoundations.

The mechanisms of conflict resolution supporting the routine

AUTHOR BIO

chimpanzee into a human by training them to talk. But without the necessary genome and proteome, this transformation can’t be any more than superficial.

The business-model-as-species concept helps leaders to effect genuine, substantial business model transformation by guiding them towards the three critical questions they must ask (see figure 3).

In most cases, business model transformation is an evolution, requiring incremental but carefully-considered change. For example, business models that involve small target markets require advanced capabilities in market segmenta-

ties requires much more than a new process. New processes don’t work unless those involved make it work.

In practice, this means developing the microfoundations of routines, as shown in figure 4.

What figure 4 reveals is that, to make a new organisational routine work effectively, it is necessary to think through the details. Are the people capable? Are the right sub-processes in place? Are teams connected appropriately? Are there mechanisms in place to avoid and resolve inevitable intraorganisational conflict? This process is as pain-staking as genetic engineering and it is no coincidence that the four types of microfoundations have the acronym ACTG. (see figure 4)

Brian D Smith is a world-recognised authority on the evolution of the life sciences industry. He welcomes comments and questions at brian. smith@pragmedic.com

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RESEARCH & DEVELOPMENT

Nanotechnologies for Intranasal Drug Delivery

Among the more recent applications of colloidal drug delivery systems (DDS), intranasal (IN) application is drawing a great attention from the researchers. This highly tolerated route for drug administration can allow designing specific formulation aimed at a local action, or to pulmonary delivery and systemic drug adsorption, or also to the nose-to-brain delivery to reach some central nervous systems areas by-passing the natural barriers that impede most drugs to act at that level. Merging these opportunities offered by the IN route with the features and performances of innovative DDS would support the clinicians with highly potent and safe therapeutic tools in the near future..

Rosamaria Lombardo and Rosario Pignatello Department of Drug and Health Sciences, University of Catania

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O

ver the last two decades, science has made enormous progress in nanotechnology and in the applications in various medical fields, opening the route for efficient gene therapy, personalised medicine, and other innovative therapeutic strategies. Controlled release or targeting to specific sites or tissues of active compounds, even at a sub-cellular level, can dramatically increase their pharmacological efficacy and reduce most side effects.

Among the newly explored routes of administration of these DDS, the IN one holds promise for therapy and clinical uses. Microspheres

RESEARCH & DEVELOPMENT

(MPs), microemulsions, polymeric and inorganic nanoparticles (NPs), lipid nanocarriers, liposomes, dendrimers, quantum dots (QDs), virus-like and self-assembling protein NPs, nanogels and nanoemulsions are the most investigated carriers for IN application in the recent years. These systems make it possible to administer either lipophilic or hydrophilic drugs, gene material, proteins or peptides via IN for various therapeutic scopes.

epithelium and release the drug in the mucosa where it is absorbed by passive diffusion to reach the systemic circulation. Size apart, the surface charge of these carriers can prolong the time of contact with the nasal mucosa. Since mucin possesses a net negative charge, positively charged MPs, for instance those made with chitosan, will adhere longer to the nasal mucosa, improving the time of diffusion of the drug and its effectiveness especially at a local level.

Nano-sized carriers are the principal subject of studies for the N2B route.

This pathway has generated considerable interest among researchers, since the nasal cavity is the only part of our body that connects the central nervous system (CNS) with the external environment: the olfactory nerves are not protected by the blood brain barrier (BBB) and arrive directly in the nasal cavity where they can re-uptake the drug via intracellular and extracellular pathways and lead it directly into the CNS. For instance,

IN administration opens the way to different sites for drug action

We know that a drug loaded in a colloidal carrier and applied into the nasal cavity can exert its action at different levels: topical, pulmonary, systemic, and also cerebral through the so-called ‘noseto-brain’ (N2B) route. NPs cross the mucosal membrane better than MPs, for their smaller size and volume, since the tight junction pores of nasal epithelium are smaller than 15nm. Hence, larger particles, such as MPs, do not cross the

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recently Cometa et al., prepared solid lipid nano-carriers (SLN) loaded with dopamine for IN administration. The aim was to allow the drug to reach the brain, since the free form is not able to cross the BBB because its hydrophilicity, and to find a valid alternative to conventional therapy (L-Dopa) for Parkinson's disease.

IN-DDS has also shown excellent results at systemic and pulmonary levels. Since many years the scientific community has recognised then as a valid alternative to oral and parenteral routes to bypass many of the associated drawbacks. Many studies have shown that parameters such as absorption, bioavailability, efficacy and rapid onset of the pharmacological activity are clearly improved for intranasally applied drugs comparing to oral and parenteral administration.

Examples of how IN-DDS can act at the various levels

A microemulsion composed of oleic acid, Tween 80 and propylene glycoland loaded with diazepam showed a better pharmacodynamic profile in epileptic seizures after IN application compared to a clinically available drug intravenous solution. To improve the drug absorption and bioavailability, authors realised that addition of chitosan was advantageous. Chitosan is a positively charge and mucoadhesive polymer, able to increase the time of contact between the DDS and the nasal mucosa and to open the tight junctions between epithelium cells, a consequent increase of drug absorption. For instance, diazepam flux through porcine nasal mucosa was 6-times higher for the optimised DDS formulation that for the drug parenteral solution. Also the in vivo pharmacokinetic data testified a better performance of the chitosan-added diazepam microemulsion.

Chlorpheniramine maleate (CPM) is associated with a low oral bioavailability.

In order to improve this parameter and reduce the frequency of administration,

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RESEARCH & DEVELOPMENT

a system based on chitosan NPs loaded with CPM and embebbed in a Poloxamer 407 and Carbopol 934P-based mucoadhesive thermoreversible gel was designed to act direct in the nasal cavity for the management of allergic rhinitis. The in vitro drug permeation studies show a percentage drug permeation in the range of 71-91 per cent. In vivo studies on rabbits provided a significantly higher bioavailability of CPM for the IN formulation than the oral drug solution.

Propst et al., demonstrated that nano-aerosolised QDs loaded with levofloxacin and administered intranasally are active at a lung level to treat pulmonary murine Francisellatularensis subsp. novicida infection. The IN nanoformulation showed to reduce the required effective drug dose by 8-fold compared to an intraperitoneal injection and by 94-fold compared to oral conventional administration.

A field with undisclosed potentialities

Many studies have been published in recent years in which IN-DDS have been designed to deliver vaccines or gene materials, such as an mRNA encoding for tumor-associated antigens which was encapsulated in liposomes to protect it from nucleases and guide it to the target site (lung cancer).

AUTHOR BIO

Rosamaria Lombardo received her Master's degree in Pharmacy at the University of Catania (Catania, Italy) in 2018. Within the thesis work she frequented the Italian Research Council (CNR) with a study onionic liquids withantimicrobial and antitumor activity.

In 2019 she spent a period at School of Pharmacy, University of Nottingham (U.K.), with an Erasmus Plus Traineeship project on "How acute pain turns into chronic paindepending on protein translation in the axon, andcordycepin action".

Rosario Pignatello is full professor of pharmaceutical technology and legislation at the University of Catania (Italy). He is at present the Director of the Department of Drug and Health Sciences of the same university. He is coauthor of about 160 scientific papers dealing with pharmaceutical technology and innovative drug delivery systems, in particular for ophthalmic application. He is the scientific responsible of NANO-i, the Research Centre for Ocular Nanotechnology of the University of Catania.

At present she is a PhD student in Neuroscience at the same University, under the supervision of Prof. Rosario Pignatello and developing a project on "Intranasal drug delivery systems forneurological diseases". A side study is dealing with the production of food-grade carrier systems for the controlled release of natural active compounds.

The scientific community is also giving a substantialinterest on IN-DDS as a possible strategy to overcome the problems of traditional vaccines in fighting the COVID-19 pandemic event or other viral infections.

What we reported are just few examples showing the relevant outcomes achieved in IN-DDS research. Many more are actively being published in the literature reported supporting the progress of nanotechnology science aiming at safe, personalised and precision medicine.

References are available at www.pharmafocusasia.com 14

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Catering to an Expanding Parenteral Drug Market How drug manufacturers can adapt packaging for injectables to meet evolving patient needs Massimo Mainetti, Global Head of Marketing and Product Management, Datwyler

Pre-pandemic trends can feel like a distant memory, but prior to the onset of the Coronavirus, demand for parenteral drugs was already on the rise. In 2018 alone, there were nearly 500 parenteral drugs in the pipeline.

The spread of COVID-19 only exacerbated this growth as drug developers worked tirelessly to produce a vaccine. Considered one of the most efficient drug delivery techniques, parenteral drug delivery can help achieve easier administration, advanced safety, more accurate dosing, and a minimum risk of contamination.

Following oral solids, parenteral administration is the most common form of drug delivery.

However, manufacturing parenteral drugs— especially large molecule drugs—often comes with significant challenges. Formulations can be highly sensitive to potential contaminants, requiring greater resources, and time to manufacture and package.

These complexities can make scaling up production to match demand particularly arduous. However, drug developers and manufacturers can anticipate these hurdles and better identify the right parenteral drug packaging solutions to protect formulation integrity, ensure efficient delivery, and improve adherence.

What Makes Parenteral Drug Administration the Preferred Option?

A few factors continue to drive the expansion of this market, including the increasing need for COVID-19 vaccines available around the globe. As new variants emerge and still a long way to go towards reaching

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global herd immunity, vaccine developers are exploring new delivery methods for their vaccines, including prefilled syringes. While vials have been the standard in COVID-19 vaccine packaging, prefilled syringes are the logical next step due to ease of administration, reduced risk of contamination, minimised risk of injuries during use, and improved accuracy.

Amid a pandemic, medical professionals are looking for alternative ways to treat non-COVID patients without the need for a hospital visit whenever possible. Parenteral drug delivery devices like auto, wearable, and pen injectors can allow patients the convenience of receiving treatment in the comfort of their own home. Especially in the case of large volume parenterals that require a large amount of medication to be delivered, wearable devices can help patients receive consistent dosing that better integrates into a patient’s lifestyle. Prior to the outbreak, the self-injection device market was already valued at $34.4 billion and projected to reach $228.84 billion by 2027.

At-home care which is often needed for a patient’s comfort and is more cost effective, presents an opportunity for medical device and drug manufacturers to adapt to the ever-evolving industry with custom solutions to address unique needs and meet rising patient expectations. To achieve market differentiation, manufacturers must develop custom, patientfriendly products that not only support the efficacy of the treatment but also offer convenience, support compliance, and most importantly, ensure safety.

Understanding and Overcoming the Hurdles in Parenteral Drug Packaging Unlike oral drug treatments, injectable biologics are developed from less stable, large molecules, making them more susceptible to contamination, more difficult to manufacture and often, more costly. They can be incredibly sensitive to contaminates such as silicone, cellulose, and airborne particulates. Should contamination occur, the entire batch must be disposed of, prompting developers to take extra preventative measures to protect formulations.

Though packaging may seem like secondary components to drug products, it can significantly impact the efficacy of a treatment. Despite the numerous industry-standard quality audits and third-party oversight, parenteral drug contamination is common. In fact, because parenteral drugs like injectable biologics are at greater risk to foreign

contamination, the category has been met with numerous cases of protein aggregation, silicone sensitivity, loss of efficacy, and recalls.

What makes injectable biologics even more difficult to package is the higher immunogenicity risk to patients, which requires more stringent quality control for primary packaging solutions. This potential threat compels drug developers to ensure that manufacturing environments not only meet the more rigorous regulatory and quality demands, but also eliminate variability in the pharmaceutical packaging.

While the industry also continues to produce patient-centric treatments in formats that simplify both healthcare professional and patient use, the manufacturing process becomes more and more complex. With this shift, drug developers become tasked with delivering a virtually fail-safe drug delivery system for patients which require intricate

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safety measures for the product packaging. In the midst of these hurdles, the role of packaging components and sealing solutions is crucial.

Massimo Mainetti holds a master degree in business administration from the University of Milan. He started his career in a finance firm in London. A few years later, in 2003, he joined Panasonic Industrial Europe as Key Account Manager and then moved to a Distribution Manager role. In 2008, Massimo Mainetti assumed the position of Strategic Key Account Manager at Becton & Dickinson within the Pharmaceutical Systems business unit. In January 2015, he joined the global sales team of Datwyler Pharma Packaging as Key Account Manager InjectionSystems. And since June 2017, he has been acting in his current position.

Mitigating Drug Contamination: Prioritising Parenteral Packaging Components

By ensuring the quality of essential packaging components, drug developers can mitigate the risk of seeing entire batches of drugs rejected from the marketplace due to formulation impurities, or worse, in a recall. For highly sensitive drugs, drug developers can equip any plunger or stopper with full coverage of a no-silicone added fluoropolymer coating. This can create a robust barrier between the drug and rubber that ultimately minimises the impact posed by extractables and leachables.

Additionally, drug and device manufacturers can seek ready-to-use components in rapid transfer port (RTP) bags so that drug manufacturers do not also have to stretch themselves thin by sterilising components. Typically, stoppers are steam sterilised by the manufacturer, whereas plungers are supplied to the customer ready-to-use (in combination with ready-to-fill syringes packaged in tubs) using gamma irradiation. With more filling lines being developed to process ready-to-fill vials, cartridges, and prefilled syringes, the demand for ready-to-use stoppers and plungers is growing every year, and with more demand comes more variety in how these components are processed and sterilised by the pharmaceutical company.

Ensuring that elastomeric components undergo 100% camera inspection adds another layer of security that human eyes alone cannot achieve.

When using camera inspection, one can ensure that the packaging used in these critical devices is meeting the level of quality demanded for parenteral drugs. If a component that is inspected manually has a defect – it can result in a high cost if an entire batch of drugs are rejected. Camera inspected components help drug manufacturers avoid this risk, potentially streamlining production and saving what would be a costly error.

Finally, drug manufacturers should maintain an open channel of communication with their packaging component suppliers. With transparency, specifiers can easily identify and trouble-shoot potential sources of contaminants and eliminate common defects throughout the supply chain, detecting potential issues earlier rather than much later in the distribution stages.

Every Detail Matters As the industry continues to evolve with changing patient needs, parenteral drugs become more prominent, requiring drug developers to be flexible in order to meet growing demand. As we’ve seen with various COVID-19 vaccines, it is essential for pharmaceutical companies to have the necessary packaging available when operating on accelerated timelines because of an unprecedented surge. While packaging may seem like a small detail in the grand scheme of a treatment, it can mean the difference between helping secure a drug’s efficacy or rendering it useless. It is in these moments that it becomes essential to partner with suppliers that ensure the utmost quality in the packaging components that enable these treatments to reach patients safely.

DATWYLER Datwyler is focusing on high-quality, system-critical elastomer components and has leading positions in attractive global markets such as healthcare, mobility and food & beverage. With its recognised core competencies and technological leadership, the company delivers added value to customers in the markets served. With more than 20 operating companies, sales in over 100 countries and more than 7,000 employees Datwyler generates annual sales of more than CHF 1’000 million. Within the healthcare solutions business area, Datwyler develops, designs, and manufactures solutions for injectable packaging and drug delivery systems to facilitate customers to create a safer medical environment of tomorrow.

Looking back onto more than 100 years of history, Datwyler is a reliable partner, now and in the future! www.datwyler.com Advertorial

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RESEARCH & DEVELOPMENT

Vaccinated Young Adult Sera A Cost-effective approach for protection and treatment of COVID-19 In some groups, like kidney transplant recipients, the efficacy of COVID-19 vaccines has been questioned.

The sera of COVID-19 vaccinated young individuals are most likely a feasible method for illness prevention and early treatment in such patients. To assess the risk/ benefit ratio, clinical studies should be conducted.

Ahmed S Ali, Department of Pharmacology; Faculty of Medicine King Abdulaziz University Abdelbagi Alfadil, Microbiology and Medical Parasitology Faculty of Medicine, King Abdulaziz University

Low efficacy of Covid-19 vaccines in special populations

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic caused by SARSCoV-2, a highly contagious respiratory

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virus. As of the end of August 2021, more than 200 million cases have been recorded and led to more than 4 million deaths. Advanced age, diabetes mellitus, cancer, cardiovascular diseases, autoim-

mune diseases are among many other risk factors for developing severe COVID-19 infection as well as increased mortality rate. Several vaccines were developed and approved for global use with good efficacy and safety in the general population.

However, there is a concern of reduced efficacy in the special population such as kidney transplant patients (KTP). Given the negative impact of immunosuppressive drugs on immune response, the efficacy of COVID-19 vaccines is likely to be reduced in KTP patients. There have been some reports of KTP limited early antibody response upon receiving the vaccination.

The majority of repurposed drugs for the management of COVID-19 exhibited limitations. Approximately 30 per cent of the possible COVID-19

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RESEARCH & DEVELOPMENT

Blood Donation

ELISA / PCR

COVID 19 Vaccines Healthy Young Adults

Prophylaxls & Treatment

Serum Neutralizing Antibodies

medications are supported by moderate or high confidence. For example, lack of efficacy of lopinavir; conflicting results of hydroxychloroquine and so forth.

The FDA-approved drug, Remdesivir, is limited by its high cost, need for hospitalisation, and potentially serious adverse effects. The WHO Solidarity Trial conducted among the hospitalised COVID-19 patient revealed that the following drugs: Remdesivir, Hydroxychloroquine, Lopinavir/Ritonavir, and Interferon; did not have a significant effect on total mortality, ventilation initiation, or length of hospitalisation compared to the standard treatment. Furthermore, limited access to intensive care unit (ICU), shortage of oxygen supply, complicated the management plans especially in low or moderate-income countries.

Neutralising monoclonal antibodies for the treatment of COVID-19

Neutralising monoclonal antibodies against SARS-CoV-2 (NMAB) is imme-

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diate and passive immunotherapy that has the potential to decrease COVID-19 progression, ER visits, hospitalisations, and mortality. More trials are going on and may provide a conclusion with high certainty. Practical guidelines were suggested for optimal uses of some NMAB such as Bamlanivimab and Etesevimab.

Because monotherapy of Etesevimab was found to be less effective and may be associated with worse clinical outcomes in hospitalized COVID-19 patients it should be used only in combination with etesevimab. These drugs were associated with the potential for serious hypersensitivity reaction, including anaphylaxis and clinical worsening after administration, especially in critically ill COVID-19 patients. The high cost and limited supply represented a major limitation for their use in counties with low income.

Convulsant plasma therapy

Several studies have been published on the encouraging outcomes obtained with

convalescent plasma therapy in the treatment of COVID-19, the most notable characteristic being the lack of side effects.

The use of COVID-19 convalescent plasma to treat critically sick patients has been approved by the FDA. Several requirements were provided to ensure the favourable outcome of this approach. A protocol for the production of anti-SARSCoV-2 sera was suggested.

The main issue is getting a sufficient number of donors with a COVID-19 history. An early meta-analysis came to the following conclusion: Convalescent plasma treatment appears to be safe for COVID-19 patients, with significant decreases in serum viral loads and most patients becoming virus-free following transfusion.

Sera of COVID-19 vaccinated young adults

In adults <35 years a high antibody levels, against SARS-COV-2, was documented in the serum samples after 2nd dose of

two authorised COVID-19 vaccines, the efficacy and safety of authorised COVID19 vaccines was assured in several systemic reviews and meta-analysis.

Taking blood samples from young adults who have received two doses of COVID-19 vaccines is likely easier than taking blood samples from recovered patients. Authorised incentives could be implemented. Techniques are available for analysis of COVID-19 neutralising antibodies in serum.

AUTHOR BIO

RESEARCH & DEVELOPMENT

Ahmed Shaker Aliv is an Associate professor of pharmacology, faculty of medicine, King Abdulaziz University, KSA. Arabia. Assistant professor of pharmaceutics, Faculty of pharmacy Assiut University Egypt. He has experience in clinical pharmacokinetics, delivery systems and phytomedicine. He contributed to 40 publications and two books.

https://orcid.org/my-orcid?orcid=0000-0002-3341-8177 https://www.researchgate.net/profile/Ahmed-Ali-289

Conclusion Abdelbagi Alfadil is an Associate professor of Microbiology and Medical Parasitology, Faculty of Medicine, King Abdulaziz University, Saudi Arabia. He has extensive experience in research related to Infectious Diseases and deployment of antifungal drugs.

Sera of COVID-19 vaccinated young adults likely represent a logical approach to be investigated for prophylaxis and early treatment of special population as kidney transplant patients against COVID-19.

The risk/benefit should be assessed through well designed clinical trials.

References are available at www.pharmafocusasia.com

https://www.researchgate.net/scientific-contributions/Abdelbagi-Alfadil-2105091171

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RESEARCH & DEVELOPMENT

Nanotechnology-based Drug Delivery Potential, progress and the way forward… and technology has made it possible for nanotechnology-based products to be commercially available; and since the early 1990’s, many nano-pharmaceuticals have gained US Food & Drug Administration (FDA) approval. Modern approaches combined with advances in genetic and molecular biology can eventually pave the way for personalised medicine and therapies in the future.

Need for nanotechnology

Nanotechnology offers an innovative platform for the development of multivalent therapeutic systems with advanced pharmaceutical properties. Nano-particulate drug delivery systems have gained a lot of attention due to their characteristic features such as sustained drug release, targeting capability along with reduced toxicity profiles. In recent years, this potential has translated into commercially available products for the management of various diseases.

Sai Akilesh M, Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research Ashish Wadhwani, Faculty of Health Sciences, School of Pharmacy, JSS Academy of Higher Education and Research

T

he concept of nanotechnology was first described by Nobel laureate Richard Feynman in a popular lecture he gave entitled ‘There’s Plenty of Room at the Bottom’ on 29 December, 1959. The initial applications conceived through nanotechnology were limited to atomic scale physics and information stor-

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age. Today, nanotechnology has reached far greater heights and is applied in diverse fields such as high-performance capacitors and batteries, optical imaging / contrast agents and most importantly, as drug delivery systems for the clinical management of various diseases such as cancer and HIV. The advancement of science

Nanotechnology refers to the applications of nanoscale materials to achieve innovation. Nanomaterials offer unique properties and characteristics, which are completely different from bulk matter.

They range from nanoparticles which are simple and are about 1-100 nm in dimension to more complex structures such as dendrimers, solid lipid nanoparticles, core-shell nanoparticles, and conjugated drug delivery systems. The most fundamental aspect of nanomaterials is their nano-dimension. Its associated implications on the overall drug profile can be exploited in the way of new formulations and delivery systems.

Their unique and intrinsic properties can be directly attributed to the increase in surface to volume ratio at the nanoscale. Surface functionalisation through suitable chemical moieties and specific markers helps in targeted drug delivery and masking from immune system. Their bio-compatibility can be improved; even anatomically reserved sites such as the

RESEARCH & DEVELOPMENT

blood-brain-barrier can be accessed.

(Figure 1 – Need for nanotechnology) Improved bioavailability and retention periods

Potential and benefits of nanotechnology-based drug delivery systems

Nanotechnology-based drug delivery systems offer superior pharmaceutical properties when compared to conventional dosage forms, mainly through entrapment of the drug into a nano-system.

The important pharmaceutical parameters such as bioavailability and bio-distribution can be regulated and limitations can be overcome through nano-pharmaceuticals.

Increased circulation times and sustained release are also an accompanying feature of nanotechnology-based drug delivery systems. The nano-dimensions provide increased surface area and, as a consequence, bioavailability and drug permeability increases, achieving the desired therapeutic effect.

The pharmacokinetic and pharmacodynamic profile of a drug can be regulated through numerous approaches and one of the ways is through the design and synthesis of nanotechnology-based drug delivery systems. Targeted drug delivery and access to reservoir sites has been a long-standing hurdle to scientists and pharmacists in drug research and development. Specific chemical moieties and functional groups can be used as probes for targeting particular sites and receptors.

This has been proved to be successful in the case of cancers, where there needs to be a distinction between normal tissue and tumour affected region. Through ligand based targeting mechanisms, intracellular drug accumulation and uptake by the targeted tissue can thus be regulated.

Advances such as the development of pH- and thermo-sensitive polymers have enriched the targeting potential of nanotechnology. Therapeutic efficacy at the terminal site of action has been an important pharmaceutical parameter of drug molecules and anatomically privileged reservoir sites can be accessed and effectively treated through nanotechnology-based drug delivery.

Effectiveness even at reservoir sites

Optimized and targeted delivery of drugs

NEED FOR NANOTECHNOLOGY Encapsulation to prevent detection by the immune system

Decreased cytotoxicity and adverse effects

Chemical stability during systemic circulation Figure 1: Nanotechnology-based drug delivery

Adverse effects and dose-related toxicities of many therapeutic agents may prove to be a hindrance in the effective management of diseases. However, by employing nanotechnology-based interventions, these issues can be easily overcome. Nano-particulate drug delivery systems have markedly improved permeability characteristics along with increased intracellular drug accumulation and hence, lower doses with reduced side-effects are possible through nano-based approaches.

Importantly, reduced toxicity profile of drugs can be achieved while retaining therapeutic efficacy.

Progress, trends and development

Nanotechnology-based drug delivery of pharmaceutical drugs has been attempted with varying degrees of success. The early objectives and benefits perceived through nanotechnology were limited to improved efficacy, PK-PD parameters and safety

profile. The progress in science and technology has helped in the overall growth and evolution of nanotechnology-based drug delivery. Complex designs and mechanisms of fabrication are a reality and such nano-carriers conjugated with drug molecules are proving to be gamechangers in the pharmaceutical industry.

Majority of FDA approved nano-drugs are liposomal or polymeric in nature or synthesized as nanocrystals and are currently available.

During the last three decades, close to 50 nano-based pharmaceutical drugs have gained FDA approval and marketed commercially. Also, more than 70 nanopharmaceuticals are undergoing clinical trials, with many of them initiated in 2014 or later (Bobo et al., 2016). FDA approvals of nano-drugs peaked between 2001 and 2005, followed by a substantial drop after 2006, possibly due to lower investment caused by the economic crisis

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RESEARCH & DEVELOPMENT

Micelles 2% Nanocrystals

28%

Proteins 7% Inorganic and Metal based 10% Liposomes 21% Polymers 32%

Figure 2: FDA approved nano-pharmaceuticals

of 2008. There has been a gradual rise in the number of nano-drugs that have received investigational new drug (IND) approval from the FDA to undergo clinical trials since 2007. The years from 2013 to 2015 had the highest number of nanoformulations entering clinical trials and this suggests an increase in the availability of FDA-approved nano-drugs in the future (Ventola, 2017).

Conventional methods and mechanisms of drug delivery have their own limitations and drawbacks such as limited efficacy and to an extent, a lack of selectivity. Many pharmaceutical drugs have variable absorption rate (oral administration) and also the digestive enzymes and acidic environment can break down some of the drugs before they enter blood circulation and become bio-available. Lack of specificity and selectivity of drug molecules arises due to poor bio-distribution and as a result, other tissues and organs can be damaged due to their toxicity.

Nanotechnology-based drug delivery approaches are ideal for the clinical management and treatment of various diseases. Such systems have primarily shown to increase the circulation and retention times, thereby improving the half-life and bio-availability of drugs and ultimately leading to their greater efficacy. Also, as most drugs are hydrophobic in nature, their solubility can be enhanced through nano-based approaches.

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Sustained, targeted, and controlled release of drugs can be achieved using nanotechnology. Many such nanotechnology-based drug delivery methods and systems have been approved for use in the management of various diseases.

Cancer

Cancer is the uncontrolled growth of abnormal cells with the potential to spread to other parts of the body. According to the World Cancer Report, in 2018, the number of new cancer cases was estimated to be 1.16 million and around 784,800 cancer deaths in India. Treatment options for cancer include chemotherapy, radiation therapy and surgery. Primary treatment involves the administration of chemotherapeutic agents and most cancer drugs have dose limiting toxicities accompanied with severe adverse effects and can increase the risk of secondary cancers, especially due to alkylating agents.

Most nanotechnology-based drugs were granted approval by the FDA based on their lower toxicity compared with conventional formulations and many more are in clinical development and trials. Doxil (Janssen) was the first nanotechnology-based drug to be granted FDA approval in 1995. It is a liposomal formulation of doxorubicin hydrochloride. The traditional dosage form was reported for its cardiotoxicity and the nano-drug (Doxil) was approved on the

basis of significantly lower adverse effects.

It has been in use for more than twenty years and is still widely used for the treatment of Kaposi’s sarcoma, ovarian, breast and other cancers (Ventola, 2017).

Emend (Merck) is the nano-crystalline form of the anti-emetic drug aprepitant and was granted FDA approval in 2003.

It is mainly used to prevent chemotherapy associated nausea and vomiting. The absorption of aprepitant occurs in the upper gastro-intestinal (GI) tract and aprepitant is insoluble in water. Emend has its main advantages in increased absorption rates in the GI tract and improved bio-availability.

Drug molecules can be conjugated to biomolecules, polymers and nanoparticles to significantly increase their sitespecificity and subsequently, reducing the adverse effects. Onivyde (Merrimack Pharmaceuticals) is another nanotechnology-based liposomal formulation of irinotecan and is mainly used in the treatment of metastatic pancreatic cancer and received FDA approval in 2015. The main advantages are increased delivery to the tumour site and reduced systemic toxicity.

Abraxane (Celgene) is a nanotechnology-based drug formulation containing paclitaxel bound to albumin NPs and was approved by the FDA in 2005 for metastatic breast cancer. Abraxane is significantly more tolerable than conventional dosage form of paclitaxel and can be administered at a much higher dose, giving rise to increased efficacy.

Thus, the dose-limiting toxicities associated with conventional chemotherapeutic and anticancer agents can be overcome through nanotechnology. Various cancer drugs are essentially hydrophobic and poorly soluble in aqueous solutions. Therefore, the need arises for solubilising agents which increase the overall toxicity and often these drugs require dose reduction to reduce systemic toxicity. To overcome the toxicity and solubility related issues, nanotechnology-based drug delivery offers an innovative and promising means (Farjadian et al., 2019).

RESEARCH & DEVELOPMENT

The human immunodeficiency virus (HIV) primarily targets the CD4+T cells and eventually weakens the immune system, leading to the Acquired Immunodeficiency Syndrome (AIDS).

Since 1980’s, it has gradually become a devastating pandemic and caused significant burden to the global health scenario. There is no cure or vaccine yet and only suppressive therapeutic interventions are currently available, known as HAART (Highly Active Antiretroviral Thearpy). Also, the dosing regimen of HAART is an important criteria for its success. Nanotechnology based drug delivery approaches have been employed to circumvent these plaguing issues.

The antiviral efficacy of HAART therapy is limited by the distinct pharmacokinetic profiles of partner therapeutics which lead to varying bio-distribution and associated adverse effects. Li and colleagues developed a new cocktail-like drug delivery vehicle using biodegradable polymeric nanoparticles which contained a non-nucleoside reverse transcriptase inhibitor (NNRTI) and another HIV-1 fusion inhibitor conjugated to the surface.

These nano-vehicles showed increased cellular uptake and circulation times and potent in-vitro activity against HIV (Li et al., 2016).

Kumar et al., attempted a triple drug combination of first line HIV drugs which were loaded into lactoferrin nanoparticles.

The combination of zidovudine, efavirenz and lamivudine in lactoferrin nanoparticles exhibited greatly improved pharmaceutical properties with lesser tissue-related inflammation. The in-vitro activity against HIV virus was also appreciable and better when compared to the free drug combination (Kumar et al., 2017).

HSV

The herpes simplex virus (HSV) causes persistent HSV infections, which are characterised by the lesions or sores in the oro-labial region or the genitals. This infection if left untreated, can lead to severe conditions such as herpes keratitis

or herpes meningoencephalitis. Nucleoside analogues such as acyclovir are generally prescribed to suppress the symptoms and offer relief. One main factor affecting the usage of acyclovir is its limited oral bio-availability and efficacy, due to its low permeability across the GI tract. To overcome this issue, Al-Dhubiab and co-workers used acyclovir loaded into nano-spheres, which were then incorporated into a film for buccal administration and such a nanotechnology-based drug delivery system showed significantly increased bio-availability, circulation times and greater efficacy (Al-Dhubiab et al., 2015).

The way forward…

The impact of nanotechnology-based drug delivery approaches and systems has transcended beyond the pharmaceutical industry and is currently felt in many more clinical applications such as imaging, diagnosis and treatment of various diseases. They have numerous advantages when compared with conventional drug delivery strategies. Nano-based systems are comparable in size with biomolecules and hence, their interactions can be tailor-made to suit clinical applications.

Lately, a growing number of researchers and academicians are shifting their focus from simple nanoparticles to more evolved and complex systems.

AUTHOR BIO

HIV & AIDS

Currently, most of the approved nanobased drugs are simple nano-formulations consisting of previously approved FDA drugs. The number of nanotechnologybased drugs entering clinical trials has increased in the recent years and the trend of many more nano-drugs gaining FDA approval is bound to increase. The translational potential of nanotechnology-based drug delivery will continue to grow and prove to be a game-changer for academics, researchers, clinicians and the overall pharmaceutical industry at large.

With progression of newer research and knowledge gained from the complex interactions between host-organ systems and nanomaterials, the future of more innovative nanotechnology-based pharmaceutical products being developed and gaining regulatory agencies’ approval also increases. The promise of personalised medicine can be realised through such nano-based multivalent therapeutic interventions and the ever-elusive cure for many complex and rare diseases can be found. However, for wider applications and usage of nanotechnology in the pharma industry, further research involving in-vivo studies and clinical trials are needed to understand their toxicity and long-term benefits.

References are available at www.pharmafocusasia.com

Ashish Wadhwani did his M. Pharm and Ph.D in Pharmaceutical Biotechnology from JSS University, Mysuru.

After completing his Ph.D, he worked as Research associate at National AIDS Research Institute, Pune for DBT-ICMR joint project. He has handled six projects as PI/Co-PI from Government of India, published 65 research/review papers in peer reviewed high impact factor journals and published 02 Patents. He has received various awards at national and international conferences for his research findings.

Sai Akilesh M is a Doctoral Research Fellow pursuing his Ph.D. in the Department of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research – JSS College of Pharmacy, Ooty, Tamil Nadu, India. His research interests are mainly in the field of nanotechnology and biotechnology.

He has published several papers in international peer reviewed journals and also presented his research findings in international conferences.

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Quaternary ammonium compounds (Quats) against Viruses Quaternary ammonium compounds (Quats) such as Benzalkonium Chloride (BKC/BAK/ BZK) are well-known antiseptics, effective against bacteria, fungi (yeast and mold) and algae.

But what about viruses? Quats are indeed effective against enveloped viruses. To name a few, activity against adenoviruses, enteroviruses, rotavirus, norovirus, influ-enza virus, severe acute respiratory syn-drome coronavirus (SARS-CoV), rhinovirus, chlamydia, HIV, herpes simplex and hepatitis A and B virus have been reported.

In these pandemic times, we are being reminded of the importance of using effective, yet safe antisep-tics.

This has tremendous significance in the healthcare sector, where exposure to viral agents is high, and keeping workers and patients free from these agents is paramount.

Benzalkonium Chloride is a wellestablished antiseptic ingredient in several ophthalmic, nasal, oral and topical formulations. In topical products, it is often reported to be effective against viruses at 0.5% concentration or less.

Benzalkonium Chloride is recommended by several national agencies as an effective compound against coronaviruses, and it presents several advantages compared to using alcohol.

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Quaternary ammonium compounds (Quats) such as Benzalkonium Chloride are well-known membrane-active agents interacting with the cytoplasmic membrane of bacteria and the plasma membrane of yeast.

The Quats’ hydrophobic activity also makes them effective against lipid-containing viruses. Quats disrupt lipid membranes, thus are more potent against lipophilic, enveloped viruses than against hydrophilic, nonenveloped viruses. Quats also interact with intracellular targets and bind to DNA. Benzalkonium Chloride (BKC) is a well-established antiseptic ingredient in several ophthalmic, nasal, oral and topical formulations. It is effective against bacteria, yeast, molds and enveloped viruses. For example, activity against enteroviruses1, rota-virus2, norovirus3 4, influenza virus5, severe acute respiratory syndrome coronavirus SARS-CoV6, rhinovirus7, chlamydia8, herpes simplex8 and hepatitis A virus9 have been reported.

1. WA Rutala, DI Weber, SL Barbee, MF Gergen, MD Sobsey. (2000) Evaluation of antibiotic resistant bac¬teria in home kitchens and bathrooms. Infect Control Hosp Epidemiol, 2000 21:132.

2. A. Bosch. Human enteric viruses in the water environment: a minireview. (1998) Int Microbiol 1998, 1:191 196.

3. S.L. Bolton, G. Kotwal, M.A. Harrison, E. Law, J.A. Harrison, Cannon JL. (2013) Sanitizer efficacy against murine no-rovirus, a surrogate for human norovirus, on stainless steel surfaces when using three application methods. Appl Envi-ron Microbiol 2013, 79:1368–1377. doi:10.1128/ AEM.02843-12 4. A.M. Wilson, K.A. Reynolds, L. Jaykus, B. Escudero-Abarca, C.P. Gerba. (2020) Comparison of estimated norovirus infec-tion risk reductions for a single fomite contact scenario with residual and nonresidu-al hand sanitizers. American Journal of Infection Control, Volume 48, Issue 5, May 2020, Pages 538-544 5. J.J. Merianos. (2001). In Block SS (ed), Disinfection, sterilization, and preservation. Surfaceactive agents, 2001, p 63–320 6. Ansaldi F., Banfi F., Morelli P., Valle L., Durando P., Sticchi L., et al.. (2004) SARS CoV, influenza A and syncitial respiratory virus resistance against common disinfectants and ultraviolet irradiation. J. Prev. Med. Hyg. 45, 5–8 7. Schmidbauer M. (2015). Dorithricin acts antiviral (in vitro). Pharm Ztg.160 (38):48-52.

8. Bélec L., Tevi-benissan C., Bianchi A., Cotigny S., Beumont-mauviel M., Si-mohamed A., et al..

(2000). In vitro inactiva-tion of Chlamydia trachomatis and of a panel of DNA (HSV-2, CMV, adenovirus, BK vi-rus) and RNA (RSV, enterovirus) vi-ruses by the spermicide benzalkonium chloride.

J. Antimicrob. Chemoth¬er. 47 685–693.

9. J.N. Mbithi, S. Springthorpe, S.A. Sattar. (1990) Chemical disinfection of hepatitis A virus on environ-mental surfac-es. Appl Environ Microbiol 1990, 56: 3601–3604.

The alkyl (fatty) chains os Quarts have a good affinity for bacterial membranes

Figure 1: Illustration: Novo Nordisk Pharmatech A/S

Table 1: Summary: effect of BKC on viruses www.pharmafocusasia.com

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Mode of action The cationic ‘headgroup’ of BKC is progressively adsorbed to the negatively charged phosphate heads of phospholipids in the lipid bilayer, and as a result, increases in concentration.

The consistent increase of BKC concentration results in reduced membrane fluidity and thus, the creation of hydrophilic gaps in the membrane. In addition, the alkyl chain ‘tail’ component of BKC further perturbs and disrupts the membrane bilayer by permeating the barrier and disrupting its physical and biochemical properties. Protein function is subsequently disturbed, and the combina-tion of these effects results in the solubilisation of the bilayer constituents into BKC/phospholipid micelles. BKC also interrupts inter-cellular targets and compromises the conformational behavior of DNA10.(Figure 1) Fazlara and Ekhtelat11 report that through membrane destruction, BKC is efficient to act against bacteria, some enveloped viruses, fungi, yeasts and protozoa.

10. A.P. Golin, D. Choi, A. Ghahary. (2020) Hand sanitizers: A review of ingredients, mechanisms of ac-tion, modes of deliv-ery, and efficacy against coronaviruses. American Journal of Infection Control: Volume 48, Issue 9, P1062-1067 11. A. Fazlara, M. Ekhtelat. (2012) The disinfectant effects of benzalkonium chloride on some important foodborne patho-gens. American-Eurasian J. Agric. Environ. Sci., 12 (1), pp. 23-29

The length of the alkyl chain groups can also greatly affect the antimicrobial activity. Methyl group lengths of C12 to C16 usually show the greatest antimicrobial activity12.

Effective on a wide range of enveloped viruses

Enveloped viruses such as HIV, hepatitis B virus and influenza virus are all susceptible to BKC113. BKC was found to inactivate influenza, measles, vaccinia, canine distemper, meningo-pneumonitis, rabies, fowl laryngotracheitis, Semliki Forest, feline pneu-monitis and herpes simplex viruses after 10 min of exposure at 30°C or at room temperature14. Saknimit et al.15 investigated virucidal activity of BKC against the canine coronavirus (CCV) and mouse hepatitis virus (MHV), Kilham rat virus (KRV) and canine parvovirus (CPV).

BKC showed sufficient efficacy and could readily 12. C.P. Gerba. (2015) Review: Quaternary Ammonium Biocides: Efficacy in Application Applied and Envi-ronmental Microbiology. Volume 81 Number 2, page 464-469 13. G. McDonnell, A.D. Russell. (1999) Antiseptics and disinfectants: activity, action, and resistance. Clin-ic. Microbiol. Rev., 12 (1) (1999), pp. 147-179 14. J.A. Armstrong, E.J. Froelich. (1964) Inactivation of viruses by benzalkonium chloride.

Appl. Environ. Microbiol., 12 (2), pp. 132-137 15. M. Saknimit, I. Inatsuki, Y. Sugiyama, K. Yagami. (1988) Virucidal efficacy of physicochemical treat-ments against coro-naviruses and parvoviruses of laboratory animals. Jikken Dobutsu, 37, pp. 341-345

Table 2: Ability of Different QACs to Inactivate Viral Loadings Based upon Literature findings 21)

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Figure 2: Comparing the viral envelopes (membranes) to that of bacterial membranes. Note that both influenza and SARS-CoV-2 have phospholipid membranes similar to that of mammalian phospholipids due to method of infectivity and replication. Figure made in Biorender. Illustration: Ref. 21)

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Coronaviruses Numerous studies report a virucidal effect of BKC against coronaviruses, even if as pointed out by Schrank et al.21 in 2020, the cumulated data on BKC-based products against the family of known CoV’s is not uniformly asserted. This can be seen in their review of scientific papers: (Table 2).

In general, Quats are reported to be effective against influenza viruses21. Hence, Schrank et al. pos-tulate the potential efficacy of such compounds against SARS-CoV-2, based on the comparable outer membranes structure (relatively similar phospholipid bilayers) between influenza and SARS-CoV-2 virus.

(Figure 2)

SARS-COVID: Quats are recommended by several governmental agencies

The use of Quats-based disinfectants to deactivate SARS-CoV-2 has been recommended by several jurisdictions. For example, the US Environmental Protection Agency (EPA) has provided a list of suit-able disinfectant products: US Environmental Protection Agency ‘List N’: disinfectants for use against SARSCoV-2’ (US EPA, Washington, DC, 2020): https://www.epa.gov/pesticide-registration/list-ndisinfectants-use-against-sars-cov-2 16. Romanowski E.G., Yates K.A., Shanks R.M., Kowalski R.P. (2019). Benzalkonium chloride demonstrates concentration-dependent antiviral activity against adenovirus in vitro.

J. Ocu. Pharmacol. Therap., 35 (5), pp. 311-314 17. Lazzaro D.R., Khaled Abulawi, Ph.D., and Mohammedyusuf E. Hajee, M.D. (2009).

In Vitro Cytotoxic Effects of Ben-zalkonium Chloride on Adenovirus. Eye & Contact Lens 6: 329_332 18. Meister T.L. et al.. (2020). Virucidal Efficacy of Different Oral Rinses Against Severe Acute Respiratory Syndrome Corona-virus 2. J Infect Dis. 2020 Jul 29 : jiaa471 19. Rabenau H.F., Kampf G., Cinatl J., Doerr H.W. (2005). Efficacy of various disinfectants against SARS coronavirus. J Hosp Infect, 61, pp. 107-111 20. Wood A, Payne D. (1998). The action of three antiseptics/disinfectants against enveloped and non-en¬veloped viruses. Journal of Hospital Infection 38:283–95 21. Schrank C.L., Minbiole K.P., Wuest W.M. (2020) Are quaternary ammonium compounds, the work-horse disinfectants, ef-fective against severe acute respiratory syndromeCoronavirus-2? ACS Infect. Dis, 6 (7), pp. 1553-1557

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As of 16th April 2020, List N contained 370 recommended products. Of these, 171 (48%) products contain Quats ingredients alone, and a further 33 products contain Quats formulated with at least one other class of active ingredient.

Quats up to 0.2% are also among proven disinfectants suggested by the US CDC against enveloped SARS-CoV-2.

BKC remains on the FDA list for hand sanitizers: https://chemicalwatch.com/76526/us-fda-bans-28substances-from-hand-sanitisers

Is Quats/BKC a good choice for healthcare sanitization?

Chemical-based disinfection is easily achieved by alcohol contact (ethanol or isopropanol) or other classic anti-viral and anti-bacterial compounds found in many commercial products. Alcohol offers momentary disinfection by contact and evaporation, while longer lasting effects that can be provided by less volatile active compounds such as Quats (BKC), remaining on surfaces. Alcohol-based hand sanitizers (ABHS) are less user-friendly on skin than Quatsbased, non-alcohol hand sanitizers (NAB-HS). ABHS predominate in healthcare settings given their low cost, however they are more worrisome due to their flammability and abuse potential.

AUTHOR BIO

inactivate coronaviruses, whereas the two parvoviruses (non-enveloped) were relatively less susceptible.

A BKC concentration of 0.1% was found virucidal for Adenovirus Ad19, Ad3, Ad7a, Ad5 and Ad3716, which are strains causing ocular infections. Similar results were obtained at lower concentrations by other authors17.

Belec et al.18 demonstrated in vitro inhibition of adenovirus at varying concentrations of BAK with greater inhibition seen over longer exposure times.

Testing methods and concentrations differ greatly between scientific publications. We have summa-rized some results in Table 1.

Chantale Julien has a current position as Global Product Manager for Insulin Human AF for cell culture media and Quaternary Ammonium Compounds (Quats) for use as APIs and excipients. Julien has a Masters degree in Life Sciences from Université Laval, Québec, Canada. She has experience from the food and pharmaceutical industries and has been working in the pharmaceutical industry for Novo Nordisk Pharmatech since 2006. Previous work experiences count the Canadian Food Inspection Agency, Chr. Hansen A/S and William Cook Europe.

For more information If you would like to learn more about our pharmaceutical grade Quats portfolio and applications, please visit our website novonordiskpharmatech.com.

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Helping you raise the bar, from development to delivery.

Learn more about our full range pharma grade Quats at novonordiskpharmatech.com

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RESEARCH & DEVELOPMENT

The Promising Future of Stem Cell-Based Therapy for Kidney Diseases Kidney disease is a prevalent global health problem. Stem cells are an attractive candidate as a form of regenerative medicine for kidney diseases. There have been increasing scientific evidences demonstrating the roles of stem cells in minimising damage while improving the function of kidney.

Chee-Yin Wong, Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman

K

idney disease is a prevalent global health problem. According to the World Health Organization, as many as five to ten million people die annually from kidney diseases worldwide. Chronic kidney disease (CKD) is projected to be the fifth leading cause of death worldwide by 2040.

To date, the current available drugs or treatments can only delay the progression of the kidney disease yet cannot reverse the progression into the end-stage kidney disease.

There has been no significant breakthrough in the medical treatment of kidney diseases.

The current therapeutic choices to prolong the lifespan of patients with end-stage kidney

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RESEARCH & DEVELOPMENT

disease are limited to kidney replacement therapies, such as dialysis and organ transplantation. Due to the high medical cost involved in dialysis therapy, it is is not an ideal solution because it fails to restore or substitute all kidney functions while also compromising the patients’ quality of life. Meanwhile, the severe shortage of organ donors and the risk of potential organ rejection limit the practice of kidney transplantations.

Therefore, researchers should consider focusing on exploring innovative therapies that can improve the quality of life for people living with kidney illnesses.

Stem cells are cells that can self-renew and can transform into a variety of cell types. Moreover, stem cells can be easily expanded in vitro.

Stem cells have been widely studied under in vitro, in vivo and clinical

trial settings to treat many diseases including cardiac, neurological, vascular, immunological, and kidney diseases. This form of intervention can pave the way as the next regenerative medicine for human diseases.

Embryonic stem cells

Embryonic stem cells (ESCs) are pluripotent cells with unlimited differentiation potentials whereby one ESC can transform into a whole body cell type, including kidney cells. With the unique power of this type of cell, several research groups have demonstrated that mouse ESCs can integrate into kidney compartments suggesting the potential value of stem cells for kidney repair. To bring this idea further, researchers are working on generating the whole kidney structure from ESCs, termed as organoids.

However, despite its clinical potentials, the use of ESCs for regenerative medicine is compounded by the risks of tumour formation and the ethical concerns on the source of ESCs in the first place. ESCs are primarily made from cells found in a human blastula, one of the earliest stages of human life. There are views that destroying a blastula for its cells is akin to destroying an unborn child.

Induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) share many regenerative properties as ESCs. This was a breakthrough finding that became a landmark in stem cell research. The development of iPSCsbased therapies could overcome the specific issues related to the use of ESCs, such as ethical concerns due to the cells’ source and the risks of cell rejection by the recipient patient. The potential of iPSCs in kidney regeneration have been explored, including establishing unique methods to stimulate human iPSCs to differentiate into kidney cells or three-dimensional structures of the kidney.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) were first found in bone marrow. Over the years, researchers have found that MSCs can be isolated from various organs or tissues. These stem cells have been demonstrated on their ability to differentiate into three lineages such as ectoderm, mesoderm and endoderm.

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In the field of kidney disease, MSCs are among the most efficient type of cell population for activating regeneration in a damaged kidney. MSCs have demonstrated their ability to transform into renal components cell in vitro. When MSCs were injected into an animal with kidney disease, results showed that it can reduce further kidney damage.

MSCs have three unique properties that enhance its potential in regenerative medicine. Firstly, MSCs have homing effect whereby after MSCs are injected into the body of an animal, the cells can migrate to the injury site. Secondly, MSCs have immunomodulation ability to decrease the inflammation at injury site which can reduce further damage. Thirdly, MSCs do not trigger immune response when transplanted to the recipient, which eliminates the risk of cell rejection by the recipient.

From commercial point of view, MSCs are a good cellular candidate to use under commercial setting because MSCs can be easily obtained from various organs or tissues and then grown into hundred- or thousand-times therapeutic dosage, and can be transplanted between individual humans i.e., allogeneically. Based on these many positive points, MSCs have become the main choice of stem cell in human translation research for regenerative medicine purposes.

Clinical trials of stem cells for kidney disease

Until March 2021, there are more than 40 clinical trials involving the use of stem cell-based therapy (mainly MSC) in the treatment of kidney diseases, either on-going or completed, registered in the U.S. National Library of Medicine .

The first few trials using MSCs from different tissue sources (bone marrow, adipose, umbilical cord, etc.), either autologously or allogeneically, suggested that these cells can be given safely to humans. In one study, few patients who had a high risk of post-operative

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AKI, underwent cardiac surgery, while concurrently received allogeneic MSCs. The patients had a shorter hospital stay and did not need readmission. In addition, this study concluded that the MSC infusion was safe and well-tolerated.

There are many human trials that use MSCs to treat CKD. A few pilot studies, assessing the safety and clinical feasibility of administration of MSCs for patients with CKD, reported that the cells were safe and did not result in any adverse effects. At the same time, improvement in kidney function was observed.

Currently, many clinical trials are still on-going and will provide more insights into and possibly further support these achievements with cellbased therapy for kidney diseases.

Stem cell-derived extracellular vesicles

Other from stem cells-based therapy, researchers are exploring the usage of stem cell-derived extracellular vesicles.

Extracellular vesicles (EVs) are small membrane vesicles secreted by various cells and found in most body fluids.

The benefits of using EVs, as demonstrated by the researchers, are preventing tissue injury, reducing inflammation, inhibiting programmed cell death, and inducing cell cycle re-entry of resident cells, leading to cell proliferation, tissue self-repair and regeneration.

There are several advantages of using stem cell-derived EVs in clinical applications including avoiding most of the safety issues associated with stem cell treatment, i.e. cellular contamination with oncogenic cells and tumorigenicity.

Furthermore, EVs offer a wide variety

of possible modifications to the carrier molecules for the purpose of improving the distribution and desired effects.

Several studies show that intravenous MSC-derived EVs reduce cell damage and programmed cell death in the kidneys while enhancing the proliferation of the renal cells, resulting in improved kidney function. When EVs were administered in animal models with AKI and CKD, the animals experienced a reduction in kidney injury suggesting that the risks of cellular rejection is remarkably decreased.

Conclusion

Research on exploring stem cell-based therapies for kidney regeneration has shown promising results from in vitro and in vivo studies, and a well-accepted safety profile from early-phased human clinical trials. However, it will take some time before stem cell-based therapies become more significant proof of clinical efficacy for kidney diseases.

Follow-up data from longer term is crucial to understand the potential long terms side effects of stem cell therapies on kidney diseases, especially to address the concerns on the use of live stem cells. More research can be done to evaluate EVs as a possible alternative to live stem cells especially as stem cells-derived EVs that can mimic its parental cells' effects in protecting the kidneys. A great future in the field of regenerative medicine is in store for stem cell therapy especially with regards to kidney regeneration.

References are available at www.pharmafocusasia.com AUTHOR BIO

Wong Chee Yin is affiliated with University Tunku Abdul Rahman, Malaysia. With his vast experience of 20 years in stem cells research, he has published many related articles covering from lab-based to clinical translation studies.

Rousselot_Biomedical_ad_PFA_11-2021_vectorized.indd 1

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LIPOSOMES IN THE CREATION OF A COVID-19 VACCINE Messenger RNA (mRNA) is the basis of a vaccine against the Covid-19 virus and viral proteins are potential vaccine candidates. The novel Corona virus spike protein, chosen as a target antigen, is incorporated in the form of mRNA in liposomes which on injection are endocytosed by cells.

Within the cytoplasm, the endocytic vacuoles open to release the mRNA which is then expressed as the spike protein promoting an immune response that kills the invading virus.

Gregory Gregoriadis, University College London

M

essenger RNA (mRNA) is a versatile and safe platform for the expression of proteins.

Unlike DNA, mRNA is not integrated into the host genome and its translation machinery resides in the cytosol. Recently, mRNA has become the basis of vaccines against Covid-19 and viral proteins were identified as potential vaccine candidates, in particular the mRNA coding for the spike protein of the Corona virus.

Within a relatively short period, Pfizer/ BioNTech and Moderna developed and marketed anti-Covid-19 vaccines based on the so-called lipid nanoparticles which served a two-fold function: to protect the mRNA from the biological environ-

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ment and to facilitate its entry into the cytosol, the very place where mRNA would eventually be expressed into the spike protein which would generate an immune response and the inactivation of the invading Corona virus. The vaccines have now been administered to millions of people worldwide and countless lives have already been saved. There is, however, a long past to the story spanning over half-a-century of work.

The Long Past of the Coronavirus Vaccines

Long before the appearance of the Corona virus, scientists were interested in the targeting of therapeutics in the body.

Targeting of drugs and vaccines would potentially reduce their side-effects and also facilitate or augment their pharmacological action. Fifty one years ago, in 1970, the idea of using liposomes for drug and vaccine delivery was born at the Royal Free Hospital School of Medicine in London when the author and the late Brenda Ryman thought of using liposomes as a drug delivery system.

Liposomes, discovered a few years earlier by the late Alec Bangham and colleagues at the Babraham Institute in Cambridge, were used as a model for the study of membrane biophysics. Liposomes were originally named ‘Bangasomes’ (to honour their discoverer), ‘Phospholipid Vesicles’,

RESEARCH & DEVELOPMENT

‘Smectic Mesophases’, and ‘Liposomes’.

The latter, a more user-friendly name representing their structure, comprised of the Greek words ‘lipos’ for fat and ‘soma’ for body. Eventually, the more user-friendly name ‘liposomes’, proposed by the late Gerald Weissmann, dominated internationally and became part of book titles and a Journal, biotech industries, conferences and products, including anticancer and anti-microbial agents, and Dior perfumes. More recently, the term ‘Lipid Nanoparticles’ was introduced, a name that does not seem to add significantly to its meaning as liposomes can also be of nano size.

Work by Gregoriadis and Ryman during 1970-1972 established liposomes as a promising drug delivery system.

Subsequently, work by the author and colleagues, notably the late Anthony Allison at the Clinical Research Centre in Harrow, London, demonstrated the immunological adjuvant action of liposomes using tetanus toxoid as a model antigen. The liposomal system was eventually adopted by a myriad of workers with dozens of enzymes, drugs and antigens and many other actives

entrapped in liposomes of varying sizes, lipid composition, surface charge, ability to accommodate water soluble or lipid soluble materials and, if needed, provide a pegylated vesicle surface, thus leading to the production of liposomes for multiple uses. These included a variety of therapeutics for cancer, anti-microbial therapy, lysosomal storage diseases (eg.

Gaucher’s disease), and conventional or genetic vaccines. A great variety of liposome-based products have been already marketed.

Liposomes and Nucleic Acids

It was predicted early in the use of liposomes as a drug delivery system that the system would play a significant role in employing the use of nucleic acids, including mRNA delivery. However, a variety of problems associated with the stability of liposomes in the circulating blood, their rapid removal from the blood circulation, and the limited extent by which drugs could be accommodated within liposomes had to be first

resolved. It was, for instance, essential that liposomes were rendered stable in blood. It was established that liposomes were destabilised because of the removal of phospholipid molecules from the liposomal bilayers and the creation of leaky pores through the action of plasma high density lipoproteins. Removal of phospholipid from the bilayers was prevented by the incorporation into the structure of liposomes of cholesterol that was equimolar to the phospholipid and by the choice of a high melting phospholipid, eg. distearoyl phosphatidyl choline. High entrapment values of nucleic acids were achieved by inserting cationic lipids into the bilayers of liposomes which would then bind to the anionic nucleic acid thus leading to high values of nucleic acid (eg. mRNA) association with or entrapment into liposomes. It was shown that plasmid DNA (pRc/CMV HBS coding for the hepatitis B surface antigen (S region), entrapped in liposomes of a composition identical to that just described, and injected through a variety of routes, not only expressed itself to produce the protein antigen, humoral and cell-mediated immune responses to the produced antigen were far greater than when the free plasmid was injected. Experiments with a plasmid coding for a variety of other antigens, gave similar results.

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Such work has allowed the theoretical creation of an anti-Covid-19 vaccine as follows. mRNA coding for the protein spike of the Corona virus would be incorporated into liposomes that are expected to remain stable in blood until they are taken up into cells by endocytosis. Within the cytosol, destabilisation of the liposomal membrane will occur through the lateral diffusion of anionic lipids from the cytoplasm-facing endosomal monolayer and mRNA will be displaced

and released into the cytosol where it will be expressed as the spike protein.

This will in turn promote an immune response to the protein which will kill or inactivate the invading Corona virus.

Regardless of the exact mechanisms involved in the processes described, it is a fact that liposome-based vaccines have been created by Pfizer/BioNtech and Moderna. It should be noted that both vaccines developed within the last two or three years are manufactured with

components previously shown to preserve the stability of liposomes in the blood and to promote immune responses. The components include distearoyl phosphatidyl choline which provides the liposomal bilayer in turn protecting the mRNA from degradation as well as forming the basis of liposomal adjuvanticity; cholesterol which contributes to the stability of the liposomal membrane in the presence of blood; a cationic or ionizable lipid which contributes to the liposomal adjuvanticity; the pegylated surface of liposomes ensuring the generation of liposomes that are free of vesicle surface to surface interaction. It can therefore be assumed that without the liposomal bilayers and the components within, there would not be a liposome-based anti Covid-19 vaccine.

Notwithstanding the issues of vesicle onomatopoeia, it is of interest that it took over half-a-century for the two technologies, mRNA and lipid vesicles, to come together at more or less the same time of their need.

AUTHOR BIO

The Future of Liposome-based mRNA Vaccines

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Gregory Gregoriadis is Professor Emeritus at University College London and the Founder of Xenetic Biosciences Inc. He has published extensively on the use of liposomes as a drug and vaccine delivery system and has been the organiser and Chair of numerous international conferences on the subject. Professor Gregoriadis is the recipient of several research awards including the Control Release Society Founder’s Award.

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It appears certain that for the immediate future, mRNA vaccines against Covid-19 will progress at great speed to include a variety of improvements in terms of stability, availability and costs. It will also enhance research for other protein antigens, for instance those from viruses, bacteria and parasites. It has been argued that as mRNA vaccine technology can be adjusted to include any pathogen for which a protein can be identified as an antigen that can lead to protective immunity, such technology could render some of the current vaccines obsolete, for instance those for influenza which require previous knowledge of the likely virus variant, in turn interfering with flexibility of vaccine production. On the other hand, it could potentially allow the rapid development of new vaccines, for instance those for HIV. References are available at www.pharmafocusasia.com

RESEARCH & DEVELOPMENT

Dissemination of SARS-CoV-2 and the Pathogenesis of COVID-19 Something wicked this way comes Mould spores appear to compete with SARS-CoV-2 for Toll-like receptor 4 on pulmonary epithelial cells, with the periodicity of incident COVID-19 a consequence of seasonal factors that influence availability of the competing species. This new understanding should prompt novel treatments for the pandemic, which, despite widespread vaccinations, continues unabated.

Andrew C Retzinger, Department of Emergency Medicine, Camden Clark Medical Center, West Virginia University Gregory S Retzinger, Department of Pathology, Feinberg School of Medicine, Northwestern University

A

n inverse relationship between aerosolisation of mould spores and incidence of seasonal influenza-like illnesses (ILI), including COVID-19, has been demonstrated in Chicago. Early in the spring, the number of cases of viral respiratory illnesses falls as the atmospheric concentration of mould spores rises. Mould spores, the reproductive elements of fungi, are aerosolised in the spring and throughout the summer and early fall, a consequence, in large part, of natural and agricultural disruption of soil, figure 1.

Following the first frost, the atmospheric concentration of mould spores falls abruptly, coincident with the dramatic rise in cases of viral respiratory illnesses. The cycle repeats itself annually, figure 2.

On the basis of the inverse seasonality, it was concluded relevant bioaerosols, including respiratory viruses and mould spores, compete for a common www.pharmafocusasia.com

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Figure 1: Mould spores are disseminated by soil disruption as occurs, for example, by farming practices.

receptor on pulmonary epithelium. By inference, the receptor was proposed to be Toll-like receptor 4 (TLR4), a pathogen recognition receptor of the innate immune system and a homolog of the eponymous anti-fungal Toll receptor of Drosophila. Whereas engagement of mould spores by TLR4 generally confers an immunological benefit to the host, engagement of SARS-CoV-2 virions by TLR4 yields symptoms characteristic of COVID-19. Inasmuch as engagement of mould spores by TLR4 is essential for preventing respiratory fungal disease,

mould spores not bound to the receptor are free to propagate and grow within the nasopharynx and pulmonary tree, causing, for example, Aspergillus or mucormycotic superinfection in humans and, likely, white-nose syndrome in bats, the presumed source of SARS-CoV-2. In humans, fungal superinfections are most evident at the end of an ILI season, when respiratory viruses are still dominant, but dwindling.

In many ways, COVID-19 is a toxicological problem. The relative engagement of competing bioaerosols

is influenced both by the affinities of the various species for TLR4 and by the ambient atmospheric concentrations of those species. The bioaerosol that prevails at any given time will be the one of highest atmospheric concentration and/ or highest affinity for TLR4. Measures that influence either of these, whether natural, such as blanketing precipitation, or contrived, such as farming, as well as measures that influence the native availability/operability of TLR4, such as advancing age, will influence susceptibility to viral respiratory disease.

Figure 2: Influenza-like illnesses (including COVID-19) and mould spore aerosolisation are seasonal processes.

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The interaction of the various bioaerosols with TLR4 is proposed to occur akin to the operation of hookand-loop adhesives, such as Velcro®.

Instead of loops, however, the bioaerosol features that interact with TLR4 ‘hooks’ are protuberances of molecular dimensions, i.e., spikes, such as exist on the surfaces of SARS-CoV-2 virions and mould spores of many fungal genera. The large extracellular domain of TLR4 likely accommodates protuberances of a host of bioaerosols, with relevant interactions occurring on cells lining the environmental-facing surface of the respiratory tract.

The Role of Innate Immunity

Because many persons infected with SARS-CoV-2 are asymptomatic, humans must necessarily have some innate immune defense against the virus, preventing virions from pathological engagement of TLR4 on the surface of the respiratory tract. As to the relevant effector, surfactant protein D (SP-D), an immune opsonin secreted by pneumocytes and operative on the epithelial surface, is ideally positioned.

It neutralises seasonal respiratory viruses both directly and via regulation of antiviral phospholipids. If a viral dose is one that is less than that of the capacity of available SP-D, no respiratory illness ensues. If, however, a viral dose is one that exceeds the capacity of available SP-D, then free virions engage TLR4 yielding, in turn, all of the symptoms characteristic of COVID-19, figure 3.

Not surprisingly, because intracellular and alveolar pools of SP-D are highest in younger individuals,it is the young who are least susceptible to the adverse outcomes of COVID-19.

Because the degree of up-regulation of SP-D and its phospholipid entourage by all symptomatic persons is not the same, the outcome of SARS-CoV-2 infection in all symptomatic persons is not the same. Those whose up-regulation yields over-exuberant production of SP-D/ phospholipids, i.e., high responders, are

Figure 3: Cartoon depicting the dose dependence for SARS-CoV-2 infection

prone to ‘happy hypoxia,’ a condition of respiratory distress in which gas exchange is severely compromised. Those whose SP-D up-regulation is limited, i.e., low responders, are prone to a more typical acute respiratory distress syndrome (ARDS) in which both gas exchange and pulmonary compliance are significantly challenged, figure 4.

Importantly, corticosteroids increase SP-D production whilst insulin decreases it, accounting for the therapeutic benefit of the former in some and disease exacerbation of the latter in others, such as diabetics.

Potential Therapies

The symptoms and morbid consequences of COVID-19 — most notably ‘cytokine storm’ — follow engagement of SARSCoV-2 virions by TLR4 on the environmental-facing surface of the pulmonary tree. Further, the multivalency of spikes on the virion promotes clustering and/or

cooperative engagement of neighbouring TLR4 molecules, which undoubtedly contribute to viral pathogenicity.

Measures that prevent such engagement are expected to abate the symptoms and consequences of COVID-19. Inhaled therapies seem ideally suited to this purpose. Depending upon the state of infection, materials that might provide benefit when inhaled in nebulised form include relevant bioaerosols, SP-D, antiSARS-CoV-2 antibodies, and monomeric TLR4 ligands, including spike protein homologs/analogs and the C-terminus of the fibrinogen gamma chain. Because multimerisation, registry and clustering of TLR4, an integral membrane protein, are influenced by the rafts that constitute the lipid milieu of the receptor, modification of those rafts by, for example, nebulised ethanol or various lipids, including some repurposed lipophilic drugs, might also prove beneficial. Finally, as a supplement to heparin preexisting in the

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lungs, nebulised heparin, by dissociating interlocked fibrin(ogen) molecules on the surface of the respiratory tree, might help limit the fibrosis that ensues the ARDS of severe COVID-19.

Apart from pharmaceutical measures that might be taken to prevent/abate COVID-19 infection, immunological and horticultural means might also be exploited. Intramuscular or nebulised and inhaled vaccines that promote the production of secretory IgA in the lungs might be especially useful.

Notwithstanding allergenic potential, horticultural means might involve indoor cultivation of pollenating plants, including their mould-rich fertilisation. The latter schemes would best be undertaken following determination of plant – mould pairings suited to the task.

The Good, the Bad and the Very, Very Ugly

Figure 4: Schematic of the pathways to COVID-19 outcomes

reproductive elements of the latter. At the interface of the respiratory tree, TLR4 on epithelial cells seems ideally positioned to provide that coping mechanism. On the worrisome side, the seasonality of

COVID-19 risks being lost if the virus mutates so as to bind more effectively to TLR4 than do its seasonal competitors.

More worrisome is the possibility the virus will mutate so as to be unrecognised

by SP-D but still recognised by TLR4, in which case populations now spared from severe disease may no longer be.

References are available at www.pharmafocusasia.com AUTHOR BIO

On the positive side, the COVID-19 pandemic has made obvious a remarkable interplay between bioaerosols that influence the respiratory health of man.

Because on an evolutionary timescale humans have co-existed with plants, fungi and viruses for an extended period, it stands to reason that the respiratory system of the former would have developed means to cope with significant seasonal inhalational exposure to

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Andrew C Retzinger is an emergency medicine physician practicing in the Midwestern United States. His research interests are the disease processes that afflict his patients. At this time, COVID-19 has his attention.

Gregory S Retzinger is an immunologist, clinical pathologist and Vice Chair of Clinical Pathology at the Feinberg School of Medicine, Northwestern University, Chicago, Il USA. His primary research interest is the operation of fibrinogen at interfaces, a topic relevant to many diseases, including COVID-19.

e-mail: andrew.retzinger@gmail.com.

e-mail: gretzing@nm.org.

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CLINICAL TRIALS

Design and Analysis of Cancer Clinical Trials for Personalised Medicine Cancer clinical trials for personalised medicine should be appropriately designed and analysed reflecting the various factors. Biomarkers play a key role in the development of personalised medicine. In this article, we review the design and analysis of two phase II cancer clinical trials of personalised medicine, one with a predictive biomarker and the other with a prognostic biomarker. We discuss statistical testing method and its sample size calculation method for each of the trials.

Sin-Ho Jung, Department of Biostatistics and Bioinformatics Duke University School of Medicine

P

ersonalised medicine for caner is a treatment module tailored to individual patients based on various factors including biomarkers.

Different types of biomarkers are measured from the tumour, blood or urine using molecular, biochemical, physiological, anatomical, or imaging method

before treatment or during the course of treatment. Observed biomarkers can be used for the selection of personalised treatment for cancer patients. For example, predictive biomarkers are used to predict the response to a specific treatment and prognostic biomarkers are used to measure the aggressiveness

of a disease for patients with no or a non-targeted treatment.

These biomarkers can be used to select a treatment for cancer patients.

However, biomarkers should be validated before being used to select a treatment in clinical trials. If a biomarker has not been validated through a clinical trial yet, it can be used as a stratification factor of a randomised clinical trial.

In such a case, the biomarker can be validated through the trial.

The methods required for design and analysis of a clinical trial with a biomarker-guided personalised medicine can be different depending on the type of the biomarker. In this sense, it is impossible to present a unified design and analysis method for clinical trials of various type of personalised medicines.

Various design issues of randomised clinical trials with biomarkers has been widely discussed by Freidlin et al. (2010).

In this article, we discuss design and analysis methods for two cancer clinical

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trials of personalised medicine, one with a predictive biomarker and the other with a prognostic biomarker. We use a time to event endpoint in this paper, but the same concept can be used for any kind of endpoints including a dichotomous one, such as tumour response.

Readers may refer to Jung (2018) for the details of statistical methods that are discussed in this article.

Methods A Phase II Trial with a Predictive Biomarker

A predictive biomarker provides information on the likelihood of response to a specific chemotherapy. For example, Sun et al. (2011)observed that non-small cell lung cancer (NSCLC) tumours expressing high thymidylate synthase (TS) levels were resistant to pemetrexed in a preclinical study, but

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it was not validated by a clinical study yet. A phase II trial (Sun et al. 2015) was conducted to investigate whether TS expression was a predictive biomarker for pemetrexed+cisplatin (PC) or not in patients with nonsquamous NSCLC. In this trial, gemcitabine+cisplatin (GC) was used as a non-targeted control treatment. PC was expected to be more efficacious than GC in TS-negative group, while the two regimens would be similarly efficacious in TS-positive group.

To test the hypothesis that TS is a predictive biomarker of PC, patients were randomised between GC and PC arms stratified by TS-positivity. This trial was designed with overall response (OR) as the primary endpoint and progression-free survival (PFS) as one of secondary endpoints. In this article, we assume that the study was designed using PFS as the primary endpoint. For the final analysis of PFS, the hypoth-

esis was tested on the interaction term between treatment indicator (taking 0 for PC and 1 for GC) and TS-positivity using a Cox(1972) proportional hazards model with covariates of a treatment indicator, the TS-positivity, and their interaction. If we want to test if GC is really untargeted therapy or not as a preliminary analysis, we will test if TS-positivity effect is significantly different from 0.

For PFS, the sample size will be calculated by specifying: 1. The expected hazard rates of PC for TS-positive and TS-negative groups, and that for GCC for the whole patient population (Note that GC is expected to have the same PFS distribution between TS-positive and TS-negative groups.)

2. TC-positivity 3. Accrual rate and additional followup period

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4. Alpha and statistical power If one wants to calculate the sample size for the primary endpoint OR, we need to specify response rates, instead of hazard rates of the two treatments in #1, of the two treatment arms for TS-positive and TS-negative patients.

And, in the final data analysis, the Cox regression model will be replaced by a logistic regression model.

A Phase II Trial with a Prognostic Biomarker

A prognostic biomarker provides information on the aggressiveness of a disease for patients regardless of a specific treatment. We review a trial with an imaging prognostic biomarker.

Chemotherapy ABVD (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine) had been a standard regimen for patients with non-bulky stage I and II Hodgkin lymphoma. In a previous study (Straus et al. 2011) on 6 cycles of ABVD, each patient had an FDG-PET (fluorodeoxyglucose positron-emissiontomography) imaging after 2 cycles of ABVD, and the patients with a negative PET image and those with a positive PET image were found to have a 3-year PFS of 86 per cent and 52 per cent, respectively, with an estimated hazard ratio(HR) of HR0=4.3.

In a new single-arm phase II trial (Strauss et al. 2018), the patients with a negative PET image after 2 cycles of ABVD were treated by additional 4 cycles of ABVD as in the previous study, whereas those with a positive PET image after 2 cycles of ABVD were treated by 4 cycles of a more aggressive chemotherapy BEACOPP (bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, prednisone) plus radiation therapy (RT).In this trial, investigators wanted to show that, by treating PET-positive patients with the more aggressive therapy BEACOPP plus RT, their PFS would become closer to that of PET-negative patients who were treated by the standard chemotherapy ABVD. The HR between PET-positive

Personalised medicine for caner is a treatment module tailored to individual patients based on various factors including biomarkers.

inferiority log-rank statistic (Jung et al. 2005), then we would conclude that 4 cycles of BEACOPP plus RT is more efficacious than 4 cycles of ABVD for PET-positive patients. The required sample size for the study was calculated using the formula proposed by Jung and Chow (2012) by specifying: 1. The expected hazard rates of PFS for 6 cycles ABVD for PET-positive patients and for PET-negative patients, and that for 2 cycles of ABVD and RT plus 4 cycles of BEACOPP for PET-positive patients 2. PET-positivity 3. Expected accrual rate and additional follow-up period 4. Alpha and statistical power Discussions

group and PET-negative group would be as high as HR0=4.3 if both patient groups are treated by ABVD, while it was expected be able to lower it to HR1=2 by treating PET-positive patients with BEACOPP plus RT. If the estimated HR from the resulting data was shown to be significantly smaller than HR 0=4.3 by the non-

The sample sizes and statistical power for the example trials discussed above depend on the prevalence of the biomarker positivity. So, if the observed prevalence is very different from that assumed at the sample size calculation, then the calculated sample size may be underpowered. To address this issue, we may check the observed prevalence before closing patient accrual and recalculate the sample size based on the observed prevalence.

Although we demonstrated the two trials based on the endpoint of PFS, the design and analysis concepts discussed in this article can be used for any other types of endpoints References are available at www.pharmafocusasia.com AUTHOR BIO

Sin-Ho Jung has been collaborating on cancer studies for 30 years in the cooperative cancer trial group setting as well as within an NCI-designated cancer center setting. Jung’s recent methodological researches include design and analysis methods for clinical trials, high throughput projects, and health big data.

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Biologics to Open New Revenue Streams for Indian Pharma A

leader in generic drugs production, India has emerged as a ‘generic hub’ in recent years.

Now, biotech-based drug development and production is also taking rooting in India.

Generics Vs Biologics and hence the Biosimilars

Before diving into the ocean of Indian scenario for biologics, let’s get some basics right.

The question which confuses people many a times is: are generics and biologics the same? And the answer is no, they are not the same. Let’s find out how.

Biologics are basically the products which are developed and produced from living organisms like human, plant or animal cells and, of course, microorganisms (bacteria, yeast, etc.). Having no definite structure, biologics are large and complex molecules which undergo sophis-

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The Indian biologics market is expected to account for around US$12 billion by 2025 (a CAGR of 22 per cent) buoyed by its dominance in simple biologics including insulin, erythropoietin, monoclonal antibodies, drugs for cardiovascular and autoimmune diseases, etc. In this article, R B Smarta highlights some of the key elements that will play a defining role in driving this industry.

R B Smarta, CMD-Interlink, Vice President (HADSA)

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ticated procedures while being developed and manufactured. Monoclonal antibodies, hormones, enzymes, insulin, etc. can be referred to as biologics.

Generics are simple molecules and exact copies of approved brand drugs.

Contrary to biologics, generics are easier to synthesize, purify and manufacture.

Drugs such as phenytoin, omeprazole, metformin are common generics. Almost 70 per cent of India’s retail pharmaceutical market is represented by branded generics, which shows their dominance in the country.

Another commonly seen term is biosimilars. As the exact copies of branded drugs are called generics, the highly similar copies of approved biologics are what we call biosimilars. It’s a very generalized definition, however, several crucial factors are considered while defining more precisely.

Both biologics and biosimilars require considerable investment. India is increasingly exploring this space in recent years and opening new streams of revenue generation. Let’s have a look at how India is poised to grow in this space.

How far has Indian pharma come on Biologics?

Healthcare scenario worldwide is undergoing a shift with more focus on preventive health than curative approaches. This shift making the way for biologics in terms of immunization and hence the demand of monoclonal antibodies, vaccines, biosimilars is on the rise.

Indian pharmaceutical market is ranked 10th in terms of value. However, it’s positioned 3rd in terms of volume of pharmaceutical products, which is a great achievement to mention. The ability to invent affordable, novel and globally competitive vaccines and biosimilar makes Indian pharma unique in many ways.

India received approvals for over 98 biosimilars in the domestic market till September 2019, more than any other country. Further, India continues to get more biosimilars approvals in regulated markets. Interestingly, around 40 biosimilars or more have reached clini-

The goal of manufacturing the APIs in India by 2023 looks realistic owing to government’s willingness towards setting up a promising fund of nearly US$1.3 billion for pharmaceutical companies.

cal development stage in India, a huge number compared to the United States and on par with the European economic zone. Moreover, India has around 200 biosimilars in the pipeline and are collectively contributed by more than 52 Indian companies.

India’s dream of ‘expanding beyond generics’ looks realistic if the cards are played well in the space of biologics and biosimilars. More than ten blockbuster biologics will lose patents in coming 2-3 years. This is an excellent opportunity for Indian bio-pharma players to test their efforts in biologics.

The recent trend of prioritizing biosimilars and biologics over chemical-based drugs presents an amazing opportunity to explore bio-tech-based drug development.

Market and potential

Indian biologics market is expected to account for around US$12 billion by 2025 with the CAGR of 22 per cent, which is pretty promising. At this point, Indian market is dominant in terms of simple biologics including insulin, erythropoietin, monoclonal antibodies, drugs for cardiovascular and autoimmune diseases, etc. In the Asia-pacific region, India could be the fastest growing country

by 2025 in terms of complex biologics like monoclonal antibodies.

In terms of biosimilars (or what we call as ‘similar biologics’), Indian pharma accounted for about US$300 million in 2015, and out of this, around US$250 million were domestic sales. In addition to this, biosimilars export from India to emerging and highly regulated market represents about $51 million which is impressive at the same time.

Favorable factors for Indian Pharma 1. Lower development costs - The ultimate weapon

As mentioned earlier, Indian pharma’s ability to develop drugs at lower cost allows it to remain competitive in the global market and hence the faster development is possible. While the European Union (EU) takes approximately 8 years to develop a biosimilar, India only takes three to five years to do so. The EU and United States invest around $100 to $ 200 million in the development of biosimilar. in India, this cost goes down to around $10 to $20 million, which is around 10 times lower.

Lower cost of recruiting patients, appointing labor and comparatively flexible (or less stringent) criteria for regulatory approvals for biosimilars in India make the development go smoother and faster.

If the pricing decisions of such drugs are further optimized, pharma market can experience glorious growth in India.

2. India has got some strong market players in biologics

Biocon, the very first Indian company to launch indigenously developed novel biologics, holds potential to flourish in international market. It has developed novel monoclonal antibodies, namely, BIOMab EGFR for head and neck cancer treatment (developed in 2006) and Alzumab (itolizumab) for psoriasis treatment (developed in 2013). They have collaborated with global companies and also launched novel antibodies in different countries. With their first biosimilar

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3. Vaccines are shaping biologics market differently in India

The critical focus on R&D and mass manufacturing of vaccines in India is enabling the nation to fulfil more than 50 per cent of global vaccine requirement, making India the largest supplier of vaccines in the public market. The increased funding and investments in R&D of vaccines by Indian governing bodies such as Department of Biotechnology (DBT), the Indian Council of Medical Research (ICMR) and the Ministry of Health and Family Welfare (MoHFW) is highly encouraging for the industry.

Different approaches in terms of improved compliance, stability, modifying formulations, etc. are the elements which are considered while innovating in this space. Typhoid conjugate vaccine, “ecofriendly” recombinant Hepatitis-B vaccine (free of cesium chloride and thiomersal) and the Serum Institute’s liquid rotavirus vaccine of Bharat Biotech are some of the innovative approaches by Indian pharma players. Upgrading and enhancing the existing formulation for common diseases is an excellent strategy to explore and can be considered as a promising way to generate revenues through vaccines.

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4. Bio-tech-based drug development

To promote the companies to manufacture active pharmaceutical ingredients (APIs) domestically, Indian government is proposing excellent initiatives in recent scenario. The goal of manufacturing the APIs domestically by 2023 looks realistic owing to government’s willingness towards setting up a promising fund of nearly US$1.3 billion for pharmaceutical companies. This can emerge as one of the boosting factors for country’s bio-techbased drug development as well.

Biotechnology Industry Research Assistance Council (BIRAC) and DBT’s efforts to promote biotechnology-based innovations in India will also generate considerable impact on biologics. The approaches are manifold and mainly consisting of new and beneficial policies, promoting entrepreneurship, influencing partnership between industry and academic institutes, etc. To gather more funding and investments from industry, investors or other agencies, public-private partnerships are also being promoted by these governing bodies.

Towards the golden future of Indian pharma, with biologics

Given our population, the demand for affordable and safe biosimilars is here to stay in India. With biosimilars and biologics, the nation can march toward the better healthcare system in the coming

AUTHOR BIO

for Herceptin and Neulasta, Biocon, in collaboration with Mylan entered the US market.

One more must-mention pharma market player in India is Zydus Cadila, who are exploring the use of long-acting interferon alpha-2b in the treatment of COVID-19. If these efforts are paying off for Zydus Cadila, Indian biologics can rock in the international markets in coming years. Moreover, the company already commercially manufactures the biosimilar version of this immunomodulator in the treatment of Hepatitis B and C. If played well, with innovations in formulations, Indian market players will not only propel the growth of domestic market but also can increasingly penetrate the international markets and expand the reach of Indian pharma industry.

years. Resolving issues related to regulation and manufacturing of biologics is necessary to stay strong in domestic as well as international markets. Despite having the largest number of approved biosimilars in India, very few companies have been able to penetrate the US and European market. The reason behind it is non-compliance of regulatory guidelines of India with these highly regulated markets.

In the coming years, critical attention is required even at the developmental stage of biologics and biosimilars in India.

Improving clinical trials with the greater number of patients and improved animal testing can be one of the essential steps to work on. Moreover, testing requirements need to be straightened further in order to come up with evidence-based outcomes.

The government’s support towards strengthening the infrastructure, improving funding, enhancing global collaboration can shape Indian pharma industry in a different and better manner. Certain efforts toward bridging the knowledge and technology gaps are being made by Indian government including collaborating with foreign universities. An industry-academia collaborative mission called ‘National Bio-Pharma Mission’, initiated by the DBT and the World Bank (implemented by Biotechnology Industry Research Assistance Council), is an excellent initiative to mention in terms of foreign collaborations. These collective efforts are instrumental in achieving the golden future of Indian pharma, with biologics.

R B Smarta is the Chairman and Managing Director of Interlink Marketing Consultancy Pvt Ltd. Through Interlink he has added value to corporate brands, therapeutic brands, fast moving healthcare brands, inorganic and organic growth of corporates and sales & marketing ROI of corporates. He is also a member of CII Drugs and Pharma National Committee for the Year 2007-08.

He is currently working on Business Models, Business Strategy, Emerging Markets and Global Business Opportunities for Pharma, Healthcare Industries.

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The Link between Plant Performance & Maturity Seeing the whole picture Understanding the link between maturity and performance provides a competitive advantage for companies on their way to continuous improvement. This article illustrates the St.Gallen operational excellence (OPEX) model’s concept of site performance and maturity, bringing both perspectives together in a holistic framework.

Bernasconi M, Grothkopp M, Pirrone L, Friedli T University of St.Gallen

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harmaceutical plants are increasingly concerned with improving their respective maturity. The numerous initiatives are labelled with terms like ‘lean maturity assessment and improvement’, ‘Quality Management

Maturity Improvement’, etc. What is less clear, though, is if this will have a visible impact on the performance. Plant performance has always been and will always be in the centre of management attention. The true performance of a

system cannot be measured with isolated metrics, but requires a holistic, balanced approach to be assessed and managed (Friedli & Bellm, 2013). In 2002, the U.S. Food and Drug Administration (FDA) announced the pharmaceutical current good manufacturing practice (cGMP) for the 21st Century initiative.

Goal of the initiative was to encourage industry in adopting modern and innovative manufacturing technologies to improve quality, performance, and patient security within the pharmaceutical industry (FDA, 2004). As results, lean thinking and OPEX became not only a suitable instrument to improve operations but also regulatory expectations (Friedli & Bellm, 2013).

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FDA’s efforts to shift operations in the pharmaceutical industry from a lagging state of OPEX implementation to a more mature and efficient state have left a mark (Eich et al., 2020). In fact, the industry has invested numerous resources in developing some of the most sophisticated OPEX production systems in the world (Friedli et al., 2013). These investments did not only improve quality but also generated a pay-off in better overall manufacturing performance. This article discusses the relationship between plant maturity and plant performance. Firstly, both concepts of performance and maturity are introduced. Successively, the operationalisation of the two elements is explained based on the St.Gallen OPEX model. Finally, the link between performance and maturity is analysed and presented.

Plant Performance & Maturity

Since the development of the DuPont system in the 1920s, many different key performance indicator (KPI)-systems have been presented, of which some are also discussed as competing approaches of the same origin. With the criticism of such traditional KPI-systems emerging in the 1970s and 1980s, the performance measurement revolution was initiated (Eccles, 1991). This revolu-

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tion led to the development of several new approaches which, in contrast to traditional KPI-systems, consider performance from a broader perspective (Bourne et al., 2000). Therefore, performance measurement does not only refer to financial or past-oriented indicators but rather can be understood as the structure and use of several KPIs from different dimensions such as costs, time, quality, innovation capability or customer satisfaction (Kaplan & Norton, 1997). These dimensions are then used to measure and evaluate both the effectiveness and efficiency of a system (Gleich et al., 2011). A major advantage of this holistic view is that dysfunctional behaviour in favour of a short-term or unit-based view is avoided (Bititci, 1994; Neely et al., 1997). This implies that for long-term success, production sites should measure performance on a holistic level and not only on single KPI level (Friedli & Bellm, 2013).

While performance is an outcome measure concerned with effectiveness and efficiency, maturity is focused on capability building and enabling of the organisation. Capabilities are comprised of resources, such as skills and tools, and processes in place that in turn enable and build the basic requirements to achieve effectiveness

The link between maturity and performance can be best analysed in a framework that spans two dimensions: x-axis for maturity and y-axis for performance.

and efficiency (Wu et al., 2010). From our point of view, maturity reflects the degree to which an organisation has implemented skills, tools, methods and processes and concurrently has a supporting underlying culture. Ferdows and Thurnheer (2011) use an analogy from the sports world to describe this phenomenon: factory fitness. The theory behind factory fitness is that excellence in production is built on a common set of core capabilities. These core capabilities however are easier to be developed starting with one specific type of activity followed by another. Accordingly, each initiative facilitates the implementation of the next, and each subsequent activity extends and enriches the effectiveness of the previous activities (Ferdows & Thurnheer, 2011). Plant maturity in that sense refers to a set of capabilities that need to be developed in a stage-like and sequential structure. For a class of objects, usually consisting of numerous attributes, discrete stages describe an improvement and development path from an initial state to a target state.

The lowest level represents an initial

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state, which may be characterised, for example, by the fact that an organisation has few capabilities in the area under consideration. In contrast, the highestlevel stands for world class maturity.

In order to progress on the evolutionary path between the two extremes, a systematic development of capabilities, behaviours and processes is required.

(Becker et al., 2009) The own starting point on that path is usually defined with the help of maturity assessments.

These assessments typically consider different dimensions and areas in a plant, in which the specific characteristics and data are measured with Likert-Scales or binary queries. Maturity assessments are usually done with internal or external audits including the use of questionnaires or checklists.

St.Gallen Operational Excellence Model

Several excellence models, such as the European Foundation for Quality Management (EFQM) one’s, have been developed to describe the way to Excellence. All these models have some commonalities. They heavily focus on leadership for organisational improvements, consider people as a resource, and integrate processes (Friedli & Bellm, 2013). Nevertheless, in the

case of the pharmaceutical industry, the integration of subsystems is not straight forward because of a tendency to avoid the quality system when striving for OPEX. Moreover, some OPEX models and programs are mistakenly seen and accordingly managed as costcutting exercises. The St.Gallen OPEX model (see Figure 1), however, follows a holistic OPEX approach aiming for true integration. Its operationalisation is described below.

The model reinforces the importance of equipment and process stability to sustain product quality (Friedli & Bellm, 2013). It can be divided in two sections, on the top the technical subsystem focussing on the practices and techniques necessary to achieve OPEX. Simultaneously, the bottom part reflects the social sub-system which summarises leadership behaviour, employee empowerment, and work organisation. Figure 1 The technical sub-system is further structured in three major widespread operations management principles, total productive maintenance (TPM), total quality management (TQM) and justin-time (JIT). The model depicts the correct order in which principles should be implemented, starting from the left to the right. Starting with ensuring stable equipment, the plant can then

Figure 1: The St.Gallen Model for Operational Excellence (Friedli & Bellm., 2013)

aim at stable processes and eventually reduce inventories and streamline operations eliminating waste, all contributing to superior operational performance.

The first step is to improve TPM practices, promoting overall effectiveness by creating comprehensive productive maintenance system and maximising equipment reliability. Successively, the TQM philosophy will bring in continuous process improvement by connecting the value chain from supplier quality to customer requirements. Finally, JIT aims to reduce waste in order to establish the ‘zero-waste’ system and reduce all non-required elements. An additional technical sub-system element is provided by basic elements (BEs). BEs summarise all practices that are shared by TPM, TQM and JIT and that are not unique to either of the principles.

The social sub-system is divided in four central principles with the objective of describing how to motivate and align people to reach a common goal. To ensure the alignment, it is fundamental that the leaders formulate a strategy and provide direction setting to the employee. Moreover, to facilitate the change process management commitment is required. Management must promote a company culture which supports people in doing and improving their work. The next step is to guarantee employee involvement and continuous improvement, creating buy-in from all the employees and getting their willingness to improve. The last social principle is functional integration and qualification. Employees need multiple skills and knowledge based on the different technical principles to eventually support and bring continuous improvement to life.

Hayes and Wheelwright (1984) compared the competitiveness of manufacturing companies in the United States, Europe and Japan. The result of the study showed that the superiority of Japanese companies is due to superior production capabilities. Thereafter, the world class manufacturing (WCM) project was launched to identify

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Figure 1: Link between performance & maturity for pharmaceutical manufacturing plants

critical factors of successful manufacturing companies. Based on the WCM project, two crucial dimension structure OPEX. The first one refers to the effectiveness of a production system, the second to the effectiveness of applied approaches and practices (Hayes & Pisano, 1994). Building on the WCM project’s results, the St.Gallen OPEX model measures both performance and maturity of the practices comprised in the technical and the social sub-system.

On the one hand, the performance of the technical sub-system is measured in the dimension of TPM, TQM and JIT with the help of numerous KPIs. The performance of the social sub-system is operationalised under the term of effective management system (EMS) and measures the performance of the social practices. On the other hand, the maturity of the practices is measured with the help of enablers questions in all practices again structured along of the model’s categories TPM, TQM, JIT, EMS and BE. The measurement relies on a five-point Likert Scale system, where each stage of the scale is matched with an exact description of the respective maturity degree. This operationalisation of both KPIs and enablers in certain 54

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dimensions allows to identify specific performance gaps, respective levers to pull, and to derive the right implications.

The last system in the St.Gallen OPEX model is the structural factors system. Structural factors describe the specifics of a plant, for example product type, size, and complexity. The consideration of the structural factors ensures a holistic picture and the right interpretation of a plant’s current situation.

Maturity – Performance Link

Performance and maturity should not be analysed in isolation, which is why the St.Gallen OPEX model integrates both dimensions. Literature suggests a direct link between performance and maturity and poses the hypothesis of higher adoption of practices, namely maturity, leads to better operational performance (Voss et al., 1995). In addition, it is suggested that the implementation of practices should not follow a piece-meal investment approach but a rigorous, coordinated and integrated deployment approach (Schoenherr & Narasimhan, 2012).

The link between maturity and performance can be best analysed in a framework that spans two dimen-

sions: x-axis for maturity and y-axis for performance. Voss et al. (1995) conducted a four-country study that investigated the competitiveness of manufacturing sites in the respective countries, using such a framework to cluster the participating sites. Thereby, they came to two conclusions. On the one hand the four countries differed in their competitiveness because their sites had different performance as well as maturity levels. On the other hand, there was a positive correlation between performance and maturity.

We examined the link between maturity and performance in pharmaceutical manufacturing plants. Our data stems from the continuous St.Gallen OPEX Benchmarking, initiated in 2004, and currently counting data from more than 380 pharmaceutical manufacturing plants. A questionnaire, structured and operationalised with the St.Gallen OPEX model, is used to gather data from the sites. We aggregated an OPEX performance score based on the comprehensive KPI set and an overall OPEX maturity score based on the enabler questions, to map and cluster the sites in the Voss et al. framework1. The results of this analysis are shown in figure 2.

Our analysis reveals a positive correlation between maturity and performance. That is, higher maturity of a plant is associated with higher performance of a plant. Some plants, however, do not fall into this pattern. One cluster shows low performance with high maturity (Voss et al. called this cluster ‘promising’) and another cluster shows high performance with low maturity (named

by Voss et al. as “won’t go the distance”).

A possible explanation for the former is that these sites have just started their OPEX journey and the implementation will pay off soon or their approach does not follow an integrated approach (cf. Schoenherr & Narasimhan, 2012).

Sites in the latter cluster might have gained performance advantages by a 1 Our aggregation logic will be further explained in a forthcoming publication in Pharma Focus Asia.

AUTHOR BIO

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Matteo Bernasconi is a research associate at the University of St.Gallen. At the Institute of Technology Management, he works in the Operational Excellence team with a special focus on the pharmaceutical industry. Currently, his academic work concentrates on preventive risk quality management and data-driven decision-making.

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

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

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

short-term optimisation aggressively aiming at cost-reduction. Yet, their performance is not built on a profound and sustainable foundation, which is why they are expected to drop in their performance level eventually.

Outlook

The integration of various dimensions in performance measurement provides an exhaustive picture of the effectiveness and efficiency of a pharmaceutical plant. Performance is seen as the outcome from a plant’s OPEX maturity. The St.Gallen OPEX model brings both perspectives together and offers the possibility to holistically assess maturity and performance.

An external benchmarking provides a profound baseline for continuous improvements. Our forthcoming article will provide more insights into the setup of a meaningful benchmarking and will demonstrate how the pharmaceutical industry evolved in its OPEX approach over the years.

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HEALTHCARE AND PHARMA NEED TO BUILD IMMUNITY AGAINST CYBER THREATS

The healthcare and pharmaceutical industry has a complex and challenging cyber threat landscape. The current burden of the pandemic is further causing a priority shift away from security and towards usability and along with that comes multifarious danger.

From sale of healthcare data in underground forums to ransomware, the industry needs to urgently improve their risk profile and security posture.

Paul Prudhomme, Head of Threat Intelligence Advisory, IntSights, a Rapid7

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n August 2021, ransomware operators targeted the health department of the Italian region of Lazio and disabled its COVID-19 vaccination booking system, disrupting the scheduling of new vaccination appointments for days.

Since it contains the city of Rome and is one of Italy’s most densely populated areas, Lazio was an attractive target because of the strong desire among its people to get vaccinated and gain its Green Pass vaccine passport. Hackers likely believed that this would pressure the authorities to pay up the ransom to unlock the systems they had disabled through a cyberattack.

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Such hacks won’t be the last ones mounted on a healthcare or pharmaceutical organisation during one of the worst crises to affect the world.

In June 2021 alone, an underground criminal forum monitored by IntSights, a Rapid7 company, put up a database of COVID-19 vaccination records of nearly 7.4 million Italians for sale. A forum user also claimed to have maintained access to the data source.

Any hopes that hackers would pause their attacks during the almost two years since the pandemic arrived were quickly squashed by a number of high-profile attacks that not only caused severe disruption but probably cost lives.

In 2020, more large healthcare data breaches were reported than in any other year. In addition, 2021 saw five consecutive months (March through July) when industry data breaches were reported at a rate of two or more per day.

As the Lazio attack showed, hackers have looked to exploit confusion and fear during the pandemic, estimating that healthcare organisations would be more willing to pay a ransom.

But while incidents of ransomware have sharply increased in the sector over time, it won’t be the only type of cyber threat to come their way.

The personal details in protected health information (PHI) are handy for criminal groups that wish to commit identity and insurance fraud.

Unfortunately, once data such as social security numbers and medical diagnoses are out in the open, they are “gifts that keep giving” – the data can be exploited repeatedly by criminals.

Criminals are not the only ones targeting healthcare and pharmaceutical organisations, to be sure. Hackers backed by nation states are out to steal personal data that could enhance their cyber espionage and intelligence activities as well.

In other words, healthcare and pharma face multiple cyber threats due to their unique threat profile.

Today, healthcare organisations have to understand that ransomware has taken hold in the industry and will be a scourge for the long term. It will be part of a growing number of online threats in future.

Unique challenges

A fair question one might ask is why sectors with high regulations in terms of security and data protection can have such a high risk profile.

One issue is that many of these regulatory requirements are not enough to protect against the latest threats, which are increasingly sophisticated and hard to guard against if one were to just follow the basic requirements.

It may be good to check all the boxes in terms of compliance, but often that may not be enough to defend against threats and scenarios that are constantly evolving beyond what the compliance standards first envisioned.

Healthcare organisations should view these standards as the bare minimum and seek to go above and beyond what they require.

Indeed, attackers would usually look at what’s beyond these requirements because that would be the minimum in terms of obstacles in their way.

Ironically, their highly regulated nature also sometimes plays into the hands of cyber attackers.

Since healthcare organisations often have to pay severe penalties to government regulators or to victims of a data breach, hackers look to this as a form of leverage when it comes to demanding a hefty ransom to unlock a system or avoid dumping the data they have stolen in public.

The modus operandi for ransomware gangs today is to threaten to disclose compromised data, in addition to encrypting it for ransom. They often follow through on these threats by posting files from victims on dark web pages where they are accessible to other criminals for their own malicious purposes.

Regulations, perhaps indirectly, also sometimes hamper the updating of medical devices, which makes them vulnerable and at risk of compromise.

For example, in the United States, the Food and Drug Administration (FDA) only requires medical device manufacturers to submit for approval significant modification to previously approved devices. This, the regulator has indicated, does not include security updates.

Unfortunately, some manufacturers may be discouraged from issuing security updates, perhaps as part of “overcompliance.” This opens up vulnerabilities, especially with older or legacy devices that are no longer supported.

Many of these medical devices have long lifespans of a decade or more, allowing them to remain vulnerable for longer periods of time than conventional IT devices.

For cyber attackers, vulnerable medical devices can serve many roles, including being an always-open door into the networks of hospitals and other healthcare providers.

Finally, let’s not forget another unique challenge: the COVID-19 pandemic. With all hands on deck and lives to save, many healthcare organisations have lowered their tolerance for interruptions, downtime, or inconveniences to respond to urgent or timesensitive clinical needs.

By emphasising expediency, however, there is a cost in terms of cybersecurity.

Healthcare organisations may create more vulnerable attack surfaces.

Combined with the high value of certain types of healthcare data, these vulnerabilities make these organisations more attractive targets to threat actors.

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Specific threats to look out for

There are a number of threats that healthcare organisations should be alert to, but the largest ones concern the ongoing pandemic.

For a start, the surge of COVID-19 patients at hospitals has strained their resources impeding their ability to handle security threats.

For example, doctors and nurses at an overwhelmed COVID-19 ward may be more likely to open malicious attachments or links if they simply do not have time to scrutinise suspicious email messages.

The larger numbers of patients also mean steeper clinical requirements, which may, in some cases, have left the attack surfaces of many hospitals more vulnerable.

In the rush to set up ventilators and intensive care units (ICU), some may have added devices to their networks in ways that were even less secure than usual.

Since medical devices can increase the attack surface, an increase in ventilators on a hospital’s network to deal with an influx of COVID-19 patients can also give attackers more opportunities to compromise that network.

The COVID-19 pandemic has also altered the attack surface of the healthcare industry by creating new patient data sets for attackers to target, including COVID-19 vaccination records and test results.

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The healthcare industry was already a desirable target because of the greater value and detail of its patient data.

If a COVID-19 vaccination or testing record only contains a name and a date of birth, it is still useful to fraudsters, as dates of birth are a key ingredient in identity theft.

The advent of “vaccine passports” and other ways of verifying COVID-19 vaccination or testing status also brings new opportunities to cyber attackers.

In addition, pressure to show proof of vaccination is creating a black market for compromised or fraudulent digital vaccination or testing records that can be used fraudulently to access public places and services where such proof is required.

IntSights threat intelligence shows there is a market in both the United States and in Europe for the production of fraudulent digital COVID-19 testing and vaccination documents.

In many cases, these documents are being produced with the help of insiders so that they appear legitimate upon verification. The malicious insiders have legitimate access to systems at COVID19 testing and vaccination providers that generate genuine test results or record vaccination status.

Since the documents are genuine, they pass digital checks. These insiders may even manually enter unvaccinated people into the vaccination registry so that they appear legitimate and can receive otherwise genuine vaccination records.

Healthcare organisations need to be aware that access to compromised healthcare networks is up for sale on underground forums.

This black market for compromised network access has been here before the pandemic but has grown dramatically with the opportunities now presented by the pandemic and remote work.

Though this affects all industries, healthcare organisations are among the most common victims of these sales.

Through IntSights’ investigations, a data sample of these sales indicated that 19.5 per cent of all observed victims were from the healthcare industry, tied for second place with financial services and energy and industrials.

Interestingly, the price for this unauthorised access is usually lower than across industries. The cross-industry average price is US$ 9,640 while the median is US$ 3,000, compared to US$ 4,860 and US$ 700 for access to a healthcare network.

Why the lower price to access more useful personal data? This could have to do with the perception that it is easier to steal data from a healthcare organisation or simply that there is an oversupply of such information.

Incidentally, the lowest price in a data sample that IntSights obtained was just US$240, which was to access the network of a healthcare organisation in Colombia.

This should concern the healthcare and pharmaceutical sector.

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What can be done?

For cyber attackers, vulnerable medical devices can serve many roles, including being an alwaysopen door into the networks of hospitals and other healthcare providers.

threats before they affect them and to seize that window of opportunity to improve and tailor their defences against those attacks. Organisations should strive to strike the right balance in dealing with both criminal and statesponsored threats, depending on their risk profile.

Build robust ransomware defence: Eliminate the temptation to pay ransom

with offline backups and strong encryption. To avoid data being exposed through extortion, encrypt the most sensitive files, the disclosure of which would cause the greatest harm to the organisation.

Balance usability and cybersecurity: Finding the right posture here will benefit an organisation in the long run. Multi-factor authentication via a mobile app is easier to use and safer than SMS, for example. Organisations can also limit remote access to the bare minimum for users to do their jobs while working remotely.

Ultimately, there is no failsafe way to overcome the many challenges facing the sector today. Indeed, it is under unprecedented pressure today with the pandemic already making it difficult to operate normally, much less under the threat of cyberattacks.

That said, health organisations that do manage to find the right priorities, develop an effective defence strategy, and deploy the right tools, will emerge from the situation stronger and more ready for success in the years ahead.

AUTHOR BIO

There are many implications for healthcare organisations should their data be stolen, locked up or exposed.

Legal and regulatory compliance issues immediately come to mind. That’s not to mention a new tactic that hackers have adopted – extortion – which multiplies the damage done.

Instead of simply encrypting and locking up the data of victims, the cyber criminals will also leak the data in part, from confidential financial data to sensitive patient data like photos, diagnoses and more.

The goal here is to increase pressure on victims to pay ransoms and to undermine the value of backups as a defence against ransomware attacks.

In May 2021, when the Conti ransomware was used in an attack on Ireland’s Health Service Executive, the attackers demanded US $20 million in exchange for not disclosing compromised data, including patient records.

Such data disclosures are harmful to organisations in any industry, but the exposure of healthcare provider patient data means the victims face compliance violations, legal issues, breach notification costs, and the long-term risk and enduring effects of identity theft for exposed patients.

Today, healthcare organisations have to understand that ransomware has taken hold in the industry and will be a scourge for the long term. It will be part of a growing number of online threats in future.

What organisations in the sector need is a clear strategy that improves their risk profiles and security postures.

Here are four steps: Establish priorities: Address the most critical vulnerabilities first.

Healthcare and pharmaceutical organisations should prioritise the top threats to their respective businesses and then identify which assets are most likely to come under attack.

Integrate cyber threat intelligence: This enables organisations to learn about

Paul Prudhomme is Head of Threat Intelligence Advisory at IntSights, a Rapid 7 company. He was a leader of the cyber threat intelligence subscription service at Deloitte and individual contributor to that of iDefense. He was a contractor in the U.S. Intelligence Community. Paul specializes in state-sponsored cyber threats, particularly those from Iran. He has a Master’s degree in History from Georgetown University.

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How Risk-based Approaches to Computer System Validation Support Cost-Effective Compliance and Improved Patient Safety Computerised digital information and document handling systems are at the heart of almost all life science and pharmaceutical industry operations. From the earliest phases of development to the last post-approval study, the data and technical documentation these systems manage are essential to the safe, effective creation of medicines and therapeutics for patients.

Every passing year the life sciences industry’s approach to continuous improvement has seen the increasing application of computerised systems to deliver better results, ranging from lower-cost manufacturing and faster development timelines to breakthrough drugs and better patient health outcomes. But the industry’s increasing dependence on computer-based digital systems is not without its own capital investment and operational expense, and that includes the cost of computer system validation (CSV) and compliance.

Brendan Walshe, CSV Consultant, Zenith Technologies, a Cognizant Company

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A

t the heart of almost all life science and pharmaceutical industry operations are digital information and document handling systems. From the earliest clinical phases to the last post-approval study, the data and technical documentation these systems manage are essential to the safe, effective creation of medicines and therapeutics for all patients.

Every passing year, the life sciences industry’s approach to continuous improvement has seen the increasing application of computerised systems to deliver better results. Pharmaceutical Manufacturing’s fifth annual Smart Pharma survey found just over 88% of pharma manufacturers believe their company will choose to automate processes if given the option and approximately 90% of those responding had begun their digital transformation efforts1. It is a competitive imperative 1 https://www.pharmamanufacturing.com/articles/2021/ smart-pharma-survey-results-pharmas-digital-prowessput-to-the/

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the life sciences industry can’t ignore as it seeks lower-cost manufacturing and faster development timelines to more breakthrough drugs and better patient health outcomes. The industry’s increasing dependence on computer-based digital systems requires capital investment and comes with an operational expense that includes the cost of computer system validation (CSV) and compliance—typically estimated to be 25% of overall project costs.

The life sciences industry’s ‘test everything approach’ has become outdated, leaving GMP manufacturing facility operators spending more time documenting than testing. In this article CSV consultant Brendan Walshe, from Zenith Technologies, a Cognizant Company, frames his perspective on the industry’s appetite for change and outlines how best-practice risk-based approaches can help shift CSV quality systems management into a more efficient and compliant gear.

Managing the high cost of CSV compliance

Virtually every business and operational aspect involved in making pharmaceuticals, including each link in the global supply chain, is regulated for quality and safety. This includes validating computer system capabilities and demonstrating to regulators that system performance and data integrity support current Good Manufacturing Practice (cGMP). This creates the requirement for every FDA or EMA-regulated life science and pharmaceutical manufacturing organisation to validate all computerised systems that can influence the quality of its drug products.

Falling under quality systems management (QSM), CSV has had a place in quality and safety compliance for decades. However, because of the pervasiveness of computer systems across the complete spectrum of operations, CSV compliance has grown to be more time-consuming and costly. According to the FDA, Traditional CSV methodologies can see manufacturers spending as

much as 80% of the time documenting processes, and only 20% of time testing the efficacy of the solutions2.

For many life sciences companies, the expense and resources associated with traditional CSV methodologies are becoming increasingly unsustainable. This has become especially apparent considering the kinds of QSM approaches and higher standards regulators are looking for in support of better cGMP compliance from the industry.

Reduced patient risk increases industry’s Appetite for Change

Besides economic arguments, there is growing interest among life science leaders and business developers to introduce ‘true’ risk-based validation. And for good reason — it is a high-value business strategy and relevant to the performance and costs associated with quality compliance and patient safety. The FDA and other regulatory agencies are now strongly encouraging pharmaceutical manufacturers to accelerate their adoption of risk-based CSV approaches in QSM operations.

2 https://mdic.org/wp-content/ uploads/2020/10/2019.11.05-FDA-Leadership-MeetingCSA-Impact-Final.pdf

Adopting a risk-based approach provides companies with continuous QSM improvement and a financially sustainable way to optimise system performance and cost-efficiency. A risk-based CSV strategy allows companies to consistently scale and add new features. However, implementing such an approach does not come without its own challenges. It is important for the industry to note that when integrating risk-based CSV concepts into QSM, they should fully encompass existing processes, practices and services.

Engaging CSV to improve QSM performance and patient safety

Historically, risk-based CSV approaches have focused on functional risk assessments. In the past, countless hours and significant resources were leveraged to assess each function the computerised system provided, but then testing everything in an examinable way anyway.

Instead, operations managers should focus QSM validations more closely on relative risk and apply the fundamentals of validation to obtain better a compliance stance in the eyes of regulators.

Quality and validation processes are important aspects of demonstrating

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control to regulators and assuring safe and effective products are manufactured and marketed. As mentioned, the extent of validation and the level of documentation detail should be based on risk to support product quality and patient safety. The aim should be to have the critical quality attributes (CQAs) satisfied by the design, with the actual or determined risk to quality and patient safety establishing the additional need for validation.

Currently, the focus has been on producing documentation and testing for the sake of testing. Instead, QSM managers should focus on their standard operating practices (SOPs), as well as how they interact with suppliers and how well they are validating their systems for better CSV quality and performance.

Implementing a true risk-based validation approach can be challenging and intensive. That’s why more pharma and life sciences companies are turning to CSV service providers to support their compliance efforts more effectively and cost-efficiently.

Current best practice - A risk-based approach

To accomplish CSV, companies have traditionally used GAMP (Good Automated Manufacturing Practice) guidance to shape compliance efforts.

Designed to aid suppliers and users in the pharmaceutical industry, GAMP 5 describes the set of principles and procedures that help ensure that platforms and applications possess the required quality using the concept of prospective validation following a life-cycle model.

The System Development Life Cycle (SDLC) is a conceptual model used in project management that describes the stages involved in an information system development project, from initial feasibility through to maintenance of the completed application. SDLC can apply to technical and non-technical systems.

Other organisations are moving to adopt the approach outlined in American Society for Testing and Materials

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Pharmaceutical Manufacturing’s fifth annual Smart Pharma survey found just over 88% of pharma manufacturers believe their company will choose to automate processes if given the option and approximately 90% of those responding had begun their digital transformation efforts

(ASTM) guideline ASTM2500. The ASTM2500 guidance describes a riskbased and science-based approach to the specification, design and verification of manufacturing systems and equipment that have the potential to affect product quality and patient safety.

To a certain degree, elements of ASTM look similar to the GAMP 5 guidelines as requirements and design are defined and detailed through User Requirements Specifications (URS), Functional Requirement Specifications (FRS), and Design Specification (DS) type documents. The approach described in the ASTM2500 guideline applies concepts and principles introduced by the FDA’s seminal initiative, “Pharmaceutical cGMPs for the 21st Century—A RiskBased Approach.” The ASTM2500 guidance supports, and is consistent with, the framework described in: • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use considerations (ICH) guideline Q8 (R2) on pharmaceutical development • ICH guideline Q9, Quality Risk Management.

The FDA guidelines have created the framework for effective CSV efforts and will continue to define the way compliance is shaped and remodelled over time.

The ASTM2500 approach distributes the responsibilities of validation to earlier in the system’s development process.

A risk assessment can also help highlight where data integrity vulnerabilities are, such as those associated with human or machine interfaces where data manipulation occurs. The risk-based approach shifts focus toward assuring the identified risks to the process are mitigated and the executed process meets the target outputs.

Consequences of poorly executed CSV strategy

Inefficient CSV programmes can be costly and can generate more work and complexity than is necessary to achieve QSM goals and compliance. Without adequate planning and preparation, it’s not will the computer system validation process fail, but when.

When a pharmaceutical company is audited, the focus usually is on their QSM strategies and approaches as opposed to auditing to gain confidence that the system can compliantly meet all critical requirements. Without an effective strategy, computer system validation can encounter several problems, eventually leading to failure of the process.

Future regulatory guidance coming soon

The FDA is expected to release a new guidance document, “Computer Software Assurance (CSA) for Manufacturing, Operations and Quality System Software,” in the near future.

This new guidance is highly anticipated because it will outline the streamlining of computer software systems and validation compliance. The FDA is leaning towards a Case for Quality (CfQ) approach, allowing device manufacturers to focus on enhancing device quality and patient safety. With CSA, the FDA is placing the emphasis on what directly impacts patients or product quality and businesses will be able to define how much testing is required and only test based on risks and CQAs.

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Where to start - With expertise from the very beginning

2. Agile development The Agile SDLC model provides an opportunity for innovating new procedures, methodologies, and approaches. The agile approach of continually validating individual features lets you move through development faster with fewer revisions and bottlenecks. Agile development makes quality part of the process from the beginning and facilitates the use of automated testing for regression tests.

AUTHOR BIO

Current Macro Trends in CSV The three main macro trends driving CSV presently are the desire to go paperless, to employ the agile development model and scalable elastic cloud technology adoption.

1. Going paperless Current CSV manual practices are typically slow, cumbersome, and unreliable.

Companies are starting to move to digital validation lifecycle management solutions (Automated Validation). As the digital world evolves, new technologies including automation are hitting the marketplace and focusing on quality through automated testing and smart applications.

The FDA encourages the use of automation, their tools, and underlying IT solutions as they reduce errors in testing, optimise the usage of resources, and ultimately reduce patient risk.

Given the imperatives of drug product quality and patient safety, there is no time like the present to engage a proactive risk-based CSV strategy. It’s good for operations, it’s good for business continuity and great for patients.

However, not all pharma organisations have the internal resources to successfully develop an effective CSV protocol. To that end, more of pharma is turning to external information and systems technology vendors that have dedicated teams and technologies to craft a more practical, affordable approach to CSV compliance.

It remains best practice in QSM development to engage the best resources and partners available. This allows manufacturers to then leverage their expertise and experience to develop a clear strategy that can transition current CSV methodology so they can focus more comprehensively on data integrity, quality assurance and patient safety.

3. Cloud technology adoption Adopting cloud technology can help information technology organisations reduce operational costs, be more flexible, agile, scalable and quickly meet ever-changing business needs. Cloud deployment models such as IaaS, PaaS, SaaS require different CSV strategy and levels of documentation based on the model adopted by the organisation.

Various Cloud deployment model-based lab IT systems require different CSV strategy: 1. Infrastructure as a service (IaaS) lab IT systems would require qualification of the servers and applications, plus data validation on these servers.

2. Platform as a service (PaaS) lab IT systems would require organisations to qualify the application data depending on the extent of customisation/ configuration specific to their need, leaving server components qualification with the cloud vendor.

3. Software as a service (SaaS) based IT systems would be managed/ qualified by the software vendor, leaving the organisation’s IT system process validation with their IT teams.

Brendan Walshe, current role is Senior Validation and CSV Consultant working in the Cognizant Life Sciences Manufacturing Business Unit. He has more that 20 years of Validation experience across the Pharmaceutical, Medical Device and Biopharmaceutical Industry. He currently supports the global consultancy group in developing and implementing CSV strategies for our Life Science Sector clients.

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PRODUCTS & SERVICES Company........................................................................Page No.

Company........................................................................Page No.

STRATEGY Lonza...........................................................................................IBC Mist Ressonance Engineering Pvt. Ltd.........................................11 Novo Nordisk Pharmatech A/S............................................... 28-33 Rousselot SAS..............................................................................37 Swiss World Cargo.......................................................................09 Turkish Cargo............................................................................OBC Valsteam ADCA Engineering........................................................05 Qatar Cargo................................................................................ IFC

Quantys Clinical Pvt. Ltd...............................................................37 Rousselot SAS..............................................................................37 CLINICAL TRIALS Quantys Clinical Pvt. Ltd...............................................................37 MANUFACTURING Aragen Life Sciences Pvt. Ltd.......................................................15 Cytiva............................................................................................03

RESEARCH & DEVELO PMENT Aragen Life Sciences Pvt. Ltd.......................................................15 Cytiva............................................................................................03 Datwyler Pharma Packaging.................................................. 16-19 F. P. S. Food and Pharma Systems Srl.........................................23 Lonza...........................................................................................IBC Novo Nordisk Pharmatech A/S............................................... 28-33

Datwyler Pharma Packaging.................................................. 16-19 F. P. S. Food and Pharma Systems Srl.........................................23 Mist Ressonance Engineering Pvt. Ltd.........................................11 Novo Nordisk Pharmatech A/S............................................... 28-33 Rousselot SAS..............................................................................37 Valsteam ADCA Engineering........................................................05

SUPPLIERS GUIDE Company........................................................................Page No.

Company........................................................................Page No.

Aragen Life Sciences Pvt. Ltd.................................................... 15 www.aragen.com

Quantys Clinical Pvt. Ltd………………………………………..…37 www.quantysclinical.com

Cytiva......................................................................................... 03 https://cytiva.com Datwyler Pharma Packaging................................................16-19 www.datwyler.com F. P. S. Food and Pharma Systems Srl...................................... 23 www.fps-pharma.com Lonza........................................................................................ IBC https://pharma.lonza.com/lonza-and-me Mist Ressonance Engineering Pvt. Ltd...................................... 11 www.mistcreation.com Novo Nordisk Pharmatech A/S.............................................28-33 http://novonordiskpharmatech.com/

Rousselot SAS........................................................................... 37 http://rousselot.com/biomedical Swiss World Cargo.................................................................... 09 www.swissworldcargo.com Turkish Cargo......................................................................... OBC www.turkishcargo.com Valsteam ADCA Engineering..................................................... 05 www.valsteam.com Qatar Cargo............................................................................. IFC https://qrcargo.com

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it.

1.IFC: Inside Front Cover 2.IBC: Inside Back Cover 3.OBC: Outside Back Cover

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