Pharma Focus Asia - Issue 43

ISSUE 43

2021

www.pharmafocusasia.com

GVK BIO IS NOW ARAGEN In every molecule is the possibility for better health Manni Kantipudi CEO Aragen Life Sciences (formerly, GVK BIO)

The Ecosystem Paradigm

The Future of Research

If you’re not thinking ecosystems, you’re not thinking

Importance of accelerated clinical trials for evidence-based treatments

How resilient is biopharma in your country?

We ranked countries on strength of their supply chains, talent, R&D collaboration, manufacturing and government regulation and policy

Dive into the key findings of Cytiva’s Global Biopharma Resilience Index at cytiva.com/resilience Cytiva and the Drop logo are trademarks of Life Sciences IP Holdings Corporation or an affiliate. ©2021 Cytiva For local office contact information, visit cytiva.com/contact CY 20065-31Mar21-AD

Life sciences and The Ecosystem Paradigm In April this year, three companies—US real estate investment company Harrison Street, UK real estate group Trinity Investment Management and Nottingham-based science business incubator BioCity—merged to create Britain’s largest life sciences ecosystem to strengthen R&D and drug discovery in the country. This merger would help bring together life sciences companies with potential partners, encourage technology transfer among academia, research institutions and the private sector. When lack of sufficient funds to develop new lab spaces appears to affect growth, investments such as this can help improve the scalability of businesses much faster. While it is a great way to develop such innovation hubs, these require intensive management and development of large networks establishing connections with pharma companies, government, researchers and academia. These initiatives can pave the way for the development and growth of successful life sciences companies.

Private and venture capital investments witnessed a significant uptick in 2020. There’s an increasing rise of start-ups and technology companies partnering with life sciences organisations to be a part of the life sciences ecosystem, growing their businesses with a common goal of developing drugs for achieving better medical outcomes. In the US, venture capital investment in life sciences hit a record US$17.8 billion and the National Institutes of Health’s funding in healthcare research and at academic institutions is also expected to grow. These investments fuel the rising need for life sciences, pharma companies to transform the way they run their businesses.

Innovation is at the core of life sciences companies. They are guided by the vision to improve patient outcomes with faster time to market while

following regulatory guidelines and managing their costs. There is an accelerated need for digital transformation as the pandemic has brought about a world of change in life sciences and healthcare industries, specifically clinical trials, drug development and telemedicine. Digital has taken centre-stage with the lockdowns pushing for faster, safer and more effective clinical trials.

At the same time, teleconsultations and virtual patient-physician interactions have become the need of the hour.

This requires the life sciences industry ecosystem to draw attention to continued collaboration to navigate through these challenging times. For life science ecosystems along with focusing on biological ecosystem, to sustain and thrive in today’s complex global environment, it is essential for pharma and medtech companies, governments and regulatory agencies to become inter-dependant and collaborate continuously. The more they focus on evolution and adaptation together, the more helpful it will be to deal with health challenges impacting the global population.

This issue covers an article that revolves around the need to consider the life sciences industry as an ecosystem. Brian Smith, the author, emphasises that this approach drives business thinking and helps address real-world challenges in the life sciences industry.

Prasanthi Sadhu Editor

CONTENTS COVER STORY

STRATEGY 06 The Ecosystem Paradigm

If you’re not thinking ecosystems, you’re not thinking

Brian D Smith, Principal Advisor, PragMedic

16 An Overview of Clinical Overview

Raghu Rama Setty Alur, Freyr Solutions

24 China’s New PRC Biosecurity Law

Key implications for international players

12

Michael Chin, Partner, Simmons & Simmon

GVK BIO IS NOW ARAGEN In every molecule is the possibility for better health

RESEARCH & DEVELOPMENT 34 The Future of Research

Importance of accelerated clinical trials for evidence-based treatments

Oli Cram, General Manager, Elsevier

37 Immune System and COVID-19

Management and potential therapies

Manni Kantipudi CEO, Aragen Life Sciences (formerly, GVK BIO)

CLINICAL TRIALS 56 Innovative Trial Designs

Sowmya Kaur, EVP, Navitas Clinical Research and BU Head Clinical APAC, Navitas Life Sciences (a TAKE Solutions Enterprise)

Atul Gupta, Global Medical Monitor, Clinical Research and Drug Safety Medical Professional, AVP, Medical and Scientific Affairs at Navitas Life Sciences (a TAKE Solutions Enterprise)

Rupesh K Srivastava, Department of Biotechnology All India Institute of Medical Sciences (AIIMS)

44 Nanotherapeutics

Recent developments and prospects for the treatment of various diseases

Nafiu Aminu, Department of Pharmaceutics and Pharmaceutical Microbiology, Faculty of Pharmaceutical Sciences Usmanu Danfodiyo University, Sokoto

52 How to Study Drug Transport at Biological Interfaces

Mohammad Sharifian, Department of Cell Biology University of Virginia

MANUFACTURING 62 Phytochemical-based Nano Formulations

A potential approach to address bottleneck issue of drug resistant cancer

Abhijeet Dattatraya Kulkarni, SRES’s Sanjivani College of Pharmaceutical Education and Research

65 Identifying Routine and Challenging Clinical Pathogens with MALDI-TOF MS

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Xinxin Lu, Director of the Department of Laboratory Medicine Beijing Tongren Hospital

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Advisory Board

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

EDITORIAL TEAM Grace Jones Swetha M ART DIRECTOR M Abdul Hannan

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

PRODUCT MANAGER Jeff Kenney

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

SENIOR PRODUCT ASSOCIATES Ben Johnson David Nelson John Milton Peter Thomas

Frank Jaeger Regional Sales Manager, AbbVie, US

Sussane Vincent 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 SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam

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

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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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

THE ECOSYSTEM PARADIGM If you’re not thinking ecosystems, you’re not thinking It has become fashionable in the life sciences industry to use the word ecosystem. Read the industry media or listen in at a conference and it won’t be long before you hear phrases like ‘patient-centred ecosystem’, ‘innovation ecosystem’ or ‘oncology ecosystem’. The term has become ubiquitous. But trying to find meaning in these various uses of the word is more difficult. More often than not, ecosystem is used as a modish synonym for a part of the market or a relationship between different organisations within the market. Language has its fads and it’s pointless to rail against this particular semantic trend. But thinking about our industry as an ecosystem has so much more value than sounding fashionably smart. In this article, I’ll guide you through how ecological thinking helps business thinking and addresses real-world challenges in the life sciences market.

Brian D Smith, Principal Advisor, PragMedic

T

o an ecologist, an ecosystem is a biological community of interacting organisms and their physical environment. This concept helps us to see that ecosystems in the life science industry are not simply sub-parts or the market or the industry. They have wide boundaries and those boundaries blur and overlap with other ecosystems. This definition also emphasises complex interaction, which is central to understanding how our industry works. Ecologists also subdivide ecosystems into the biotic and abiotic. The former is all of the biological organisms in the ecosystem whilst the latter consists of its non-biological elements, such as geology and climate.

Ecologists understand that the biotic components of the ecosystem, the different species of plants and animals, adapt not only to each other but also to the abiotic environment. To a lesser but important degree, the biotic component also influences the abiotic, such as when rain forests shape the weather and grazing animals change surface geology. As we will see, these fundamental concepts of biological ecology become useful when we start to think about how the life sciences industry works. www.pharmafocusasia.com

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From biology to business

If we eschew the fashionable but illinformed use of the term, thinking of ecosystems in the same way that an ecologist does gives us a powerful and practical way to understand and manage the industry that provides healthcare professionals with the tools to do their job.

The first idea to transfer from biology to business is the definition of an ecosystem. It is best to think of the life sciences ecosystem broadly rather than narrowly. It makes little sense to talk of an oncology ecosystem when it is connected at manufacturer, user and patient levels to most other therapy areas. Similarly, to describe the innovative ecosystem as innovative companies in big pharma and biotech is too narrow when it is so closely connected to payer systems and to publicly funded basic research. Oncology (and other therapy areas) and innovation (and other parts of the value chain) are really just parts of a wider life sciences ecosystem, just as the tree canopy and the ground vegetation are part of a rain forest ecosystem. Most misleading of all are terms such as patient-centred ecosystem, which is as platitudinous as calling the forest tree-centred. The life-sciences ecosystem is a community of interacting commercial, governmental, non-profit and other organisations, embedded in their sociological and technological environment that employs science towards the betterment of human health. Using this wider, biology-like, definition of our industry ecosystem also reminds us that, although distinct, our industry is adjacent to and intimately connected to adjacent ecosystems such as the health provider ecosystem and government finance ecosystem.

The second useful idea we can borrow from the biological ecologists is the biotic/ abiotic division. Looked at that way, the life sciences ecosystem includes a biotic component of many different ‘species’ of organisation, from pharmaceutical, device and diagnostic companies to distributors to contract organisations to regulators to Health Technology Assessors (HTAs).

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As in any ecosystem, pharma and medtech firms, government agencies and nonprofit organisations are interdependent and are in a constant state of co-evolution and adaptation.

As in any ecosystem, these species are interdependent and are in a constant state of co-evolution and adaptation.

Drug development and the regulatory environment are good examples of this.

So are how we sell our products and how our customers wish to buy them.

Equally, many pharmaceutical innovations today emerge from the way that big pharma has adapted to work with small, focused innovator companies. Overall, a truly ecological perspective helps us to see our industry as a massively interconnected network of many different and differing business organisations, just as a coral reef is a similar system of biological organisms.

Our industry’s parallels to the abiotic part of ecosystems are less obvious but just as informative. Whilst biological organisms adapt to geology and climate, business organisations in the life sciences ecosystem have to adapt to their sociological and technological environments.

The former includes laws and regulations but also political systems, demographics and social attitudes. The technological environment encompasses both directly relevant technologies, from CRISPR to the many ‘omics’, and indirectly relevant technologies, such as information technology and nanotechnology. Just as biological organisms can shape weather and geology, life science businesses can shape the sociological and technological environments. Consider, for example, how control of infectious diseases has shaped demographic and epidemiological trends. Or how companies such as Illumina have shaped the availability of genomic information. Overall, understanding that the ‘biotic’ life science companies co-exist and co-evolve with

the ‘abiotic’ sociological and technological environment is an important step towards understanding our industry’s complexity.

Transferring these concepts from biology to business, as opposed to simply throwing the word ‘ecosystem’ around, is of more than academic interest. It has many important practical implications, some examples of which I will describe in the following paragraphs.

Speciation

We often talk of the changing pharma business model or the evolving medtech business model. If we equate business models to species, both of these ideas are, from an ecosystem perspective, naïve and simplistic. In biological ecosystems, the evolutionary struggle for survival leads to speciation and biodiversity. Research into the evolution of the life sciences industry reveals the same speciation process. There is no longer a pharma business model, there are many. The medtech business model is not evolving, it is diversifying into many related but distinct models.

Practically speaking, this means that life sciences firms have to understand that speciation process and deliberately direct the evolution of their own business.

Holobionts

Biologists talk of ‘holobionts’, which are interdependent networks of distinct organisms that work together to survive.

A coral reef is a holobiont but so are you with your gut microbiome. From an ecosystem perspective, the idea of one company competing against another is again too simple. In nature, one holobiont competes against another and building and maintaining a holobiont is a critical survival skill for many organisms. The same is true in the life sciences industry,

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where external innovation and outsourcing mean than no company competes alone.

In practice, this means that life science firms need to build their capabilities to attract and retain partners. The holobiont concept has many lessons for how to do this.

Keystone species

The ecologists’ concept of keystone species refers to one that is widely and diversely connected to other species in the ecosystem. The concept is important because changes that affect a keystone disproportionately impact the whole ecosystem.

Bees, starfish and India’s Cullenia tree are all examples of keystone species. In the life sciences ecosystem, for example, elite universities and their associated teaching hospitals are keystone species. So too are certain global innovator companies.

Functionally, being aware of the keystone organisations in the life science ecosystem helps life science companies to drive change in clinical practice and to develop innovative markets.

Niche construction

Some biological organisms can modify the abiotic environment to improve their evolutionary fitness. Beavers’ dam building is the most often cited example but earthworms, termites and, of course, humans also change their own environment rather than just adapt to it. The concept of niche construction is important in explaining the success of certain species. In the life sciences ecosystem, some companies have extensively influenced their own environment. For example, industry-shaped regulation creates barriers to entry whilst laws around orphan drugs have created a profitable market sector. From a real-world perspective, niche construction activity is often a better competitive strategy than simple adaptation the environment. Again, biology has important lessons for business here.

Habitats

Ecologists define habitats as regions with specific characteristics and that are

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populated by specific species. Desert, forest, grassland and ocean are all examples of biological habitats. The concept is important to understanding why certain species thrive or fail in different regions.

In the life sciences industry, habitats are defined by how value is created and for whom. For example, many life science companies are limited to the habitat where value is created for institutional payers by means of technological innovation. By contrast, generic pharmaceutical companies operate in the habitats where value is created by operational efficiency and for either institutional payers or consumers.

The application of the habitat concept helps life sciences firms both to plan growth and anticipate competition.

Holism

The ecosystem perspective has allowed ecologists to develop practical approaches to managing natural environments based on some key principles. Central to this is the idea of holism, the opposite of reductionism. From an ecologists’ perspective, it is foolish to do one thing to an ecosystem and expect a single, direct consequence.

The complex interconnectivity of an ecosystem always leads to indirect effects.

The same concept of holism also means that ecosystems can only be improved or sustained by adjusting multiple factors

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

at once in order to keep the system in balance. The concept of holism applies well to the life sciences ecosystem. The introduction of Sovaldi and Harvoni, for example, transformed hepatitis C management but had unintended consequences for the financing of some health systems.

The human genome project did not have the immediate, direct consequences many predicted but had wider, indirect results.

The passage of a single act in the US, Hatch-Waxman, was intended to improve competitiveness but also transformed the global generics business. Understanding the holistic nature of the market is essential to crafting strategy in the life sciences.

The ecosystem paradigm

When executives in the life sciences industry set out to manage their businesses, they necessarily work within a certain paradigm that shapes their thinking. For many years, the pipeline metaphor was that thinking.

Others have seen the industry as a garden where tending to basic research grows new medicines. Like all metaphors, these have their limits. The ecosystem paradigm is a much more comprehensive, coherent and useful paradigm for anyone wanting to understand the global life sciences industry. It is more than a metaphor. It is the only way to make sense of the most important industry in the world.

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1.Could you share with our readers about the story behind the emergence of the new brand Aragen?

From our humble beginnings two decades ago offering chemistry and informatic services to a small group of clientele, we have now grown into a ‘Partner of Choice’ for both large pharmaceutical firms and cutting edge biotechs. We now offer a wide range of solutions and partner with customers from Concept through Commercialisation, and have a broad platform that includes small molecules and biologics. Over 95 per cent of our revenue comes from the West. Recognising the growth of the firm, and with our 20th year Anniversary this year, the Board and the Management Team decided that a name change that reflects the current firm would be more appropriate. We wanted the new brand name to represent more than just chemistry solutions, be recognisable in the West, and best show who we are today. After a 9 month process, several intense discussions, and in consultation with a brand agency, we identified the name Aragen. Aragen is a name that we already own, through our acquisition of biologics capabilities in the US. The new name Aragen Life Sciences (“Aragen”) combines our small molecule (GVK BIO) and the biologics (Aragen BioSciences) platforms into one seamless solution for customers.

GVK BIO IS NOW ARAGEN In every molecule is the possibility for better health 12

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2. Digging deeper into the name itself, how do you feel the Aragen Life Sciences name will drive your future and is there anything that fellow brand marketers should realise bringing a replacement name into the world?

Aragen is a name known for its scientific expertise and customer centric culture in the West. We are now investing in branding around the name – our initial feedback from both current and prospective customers has been very positive. They love the name, the colours, the purpose and our identity. Our employees are quite excited, as the social media chatter reveals. We expect the name to be a great foundation around which we can build a great future for the firm.

3. What big, bold bets is Aragen Life Sciences making to leap ahead of competitor and customer expectations to ensure sustained growth in the long-run?

We believe the new investment by Goldman Sachs, at this important juncture in our company’s development underscores the tremendous opportunity ahead. Working with Goldman Sachs, we are well-positioned to address the opportunities in front of us to become a leading, global player

Manni Kantipudi CEO Aragen Life Sciences (formerly, GVK BIO)

with comprehensive end-to-end solutions for drug discovery and development,” said Manni Kantipudi, CEO of Aragen Life Sciences.

Goldman is one of the largest financial institutions in the world, among the most prestigious, and has deployed more than US$3.6 bn in capital in India since 2006. We are excited by the opportunity to work with the global Goldman team, harness their intellectual horsepower, leverage their strategic thinking, and judiciously invest our new access to significant capital. We have some big ideas that I expect we will pursue over the near future, but what will not change is our fundamental intent: invest in solutions that will accelerate our customer’s journey to market. We will continue to be solely a service company, with no conflict of interests by competing with our customers. The outsourcing market is an exciting one for us, and there are more than enough opportunities there to propel our long-term growth.

4. Rebranding goes way beyond a logo change or a marketing exercise. What is your approach with making a steady and cohesive message that traverses all components and channels of your brand?

During the re-branding exercise, we delved deep into the most intricate details of the organisation to identify the personality of the organisation at large, re-visit our brand purpose and accordingly renew our brand purpose – ‘In every molecule is the possibility for better health’. Our brand personality AURA is the acronym for Ambitious yet Understated, Resilient and Agile makes us an organisation that is quick to adapt to changes and deliver outcomes to support our customers.

5. Can you brief our readers how your logo colours share certain emotions about your brand and why does that work best over others?

Aragen’s brand colors are loaded with symbolism and meaning. Deep Blue conveys the possibilities of science. It also cues confidence, strength and resilience.

Vibrant Orange symbolises life and better health.

It also conveys ambition and energy. Measured Grey balances the colour palette and conveys the understated in us. The acronym of the symbol AURA (Ambitious, Understated, Resilient and Agile) as mentioned earlier, has an in depth meaning to it.

Known to be ambitious, we are far sighted and we think big. We seek to be the preferred discovery, development and manufacturing partner to the

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global life sciences industry. In spite of that, we are understated. We support so that our customers succeed. We are focused on results and deliver value to customers with quiet confidence. We also believe that resilience is in our DNA. Whatever the challenge, we make it work. Any challenge that does not break us, will only make us stronger. Being an agile organisation, we are quick to respond, always listening to our customers’ requirements and continuously adapting to their changing needs.

6. What are the key elements that drive you and Aragen?

The key elements that drive me and Aragen are defined by our purpose and promise made to ourselves. Aragen’s brand purpose (In every molecule is the possibility for better health) has evolved from the fact that customers come to us because they know that we look at every program as the most important program we have. Aragenites are engaged and energised knowing that their work is making a difference to human health.

Our inspiring and powerful purpose is like our north star, it guides us at every step of the way.

Aragen is known around the world for its focus on every molecule, every program, every customer, irrespective of how big or small they may be. Our focus is driven by our belief that possibilities lie within every molecule, and it is up to each one of us to find solutions for better health.

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Our renewed promise of ‘Together Ahead’ is to our employees, customers and other key stakeholders: • Your Science. Our Solutions. Together Ahead • Our Support. Your Success. Together Ahead • Aligned Values. Diverse Talents. Together Ahead • Global Clients. Local Presence. Together Ahead

Our Values

E

Empowerment

T

Teamwork

H

Honesty & Integrity

I

Freedom to make a difference.

One Team. One Purpose.

Say what you do. Do what you say.

Innovation

Unlocking our collective genius.

C

Customer Focus

S

Safety & Compliance

Exceed expectation consistently.

First and Always.

Value Differentiators

Agile Partnerships

Our advantage is driven by the customer centricity the organisation offers for stakeholder’s success.

We ensure the customer is always at the centre surrounded by empowered teams with an innovation mind-set. Through our agile partnerships, technology enabled platforms and process excellence, we drive programs from concept to commercial to accelerate the success of our partners.

7. How do you see Aragen evolving over the next decade?

I see Aragen evolving as a global organisation in the next decade. We were the first CRO to make an overseas acquisition in 2017. Inorganic growth will continue to be one of our approaches to scale our range of capabilities and solution offerings to our customers across the small and large molecules.

We have made significant investments in our current facilities which will also propel us in our ambition to be seen as one of the global leaders in this space.

8. Would you consider rebranding as an opportunity to strengthen and reaffirm your company’s identity and values, both internally with your employee base and externally with your customers?

Most definitely yes. The re-branding exercise has given us an opportunity to re-discover our strengths as an organisation and build upon it. The company has grown from strength to strength over the last 20 years. While our values remain the same, it is now aligned to the new brand promise and purpose. Our promise and purpose is something that is carried by each and every employee of the organisation During

Concept to Commercial

Technologyenabled Platform & Operational Excellence this exercise, we were able to streamline quite a bit to bring in a structure to our vision for success.

We are expanding our employee base and we are looking at a new hiring strategy in the year to come.

9. What according to you are the steps to ensure a smooth transition into the new name for your clients and other stakeholders?

We have constantly been updating our employees and clients on the name change and the new identity.

The brand personality, purpose and promise has been defined keeping in mind every employee’s mindset within the organisation. It is rooted in our DNA and the same is being shared with our customers too.

10. Final Comment for our audience?

Aragen is now well positioned to be a partner of choice to our customers. With a strong track record performance and a clarity on what we want to accomplish in future, we will be able to bring in cutting edge solutions to advance our customer’s assets.

AUTHOR BIO

Customer at the Center

Innovation Mindset & Empowered Teams

Manni’s journey with Aragen (formerly, GVK BIO) started way back in 2007. He joined as the President and then became the Director and CEO in 2009. Over the years, the company has emerged as a leading R&D and manufacturing solutions provider to the global life science industry under his leadership. During this tenure, Aragen Biosciences (based out of CA, USA) was acquired to expand service offerings for large molecules. Aragen (formerly GVK BIO) was probably the first Indian CRO to make an overseas acquisition as a part of our inorganic growth. Manni is responsible for the overall growth, providing strategic direction and shaping the culture of the company.

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An Overview of Clinical Overview Clinical Overview is a document presenting a critical analysis of Pharmacology, Efficacy, and Safety of the pharmaceutical agent. This document is developed for multiple objectives like product registration, justification for labeling document, and so on. A clinical overview helps the reviewer to understand the objective of the application and clinical development plan for a product in scope.

Raghu Rama Setty Alur, Freyr Solutions

A

Clinical Overview is an integrated document intended to provide critical analysis of Pharmacology, Efficacy and Safety of the pharmaceutical agent in humans. It is one of the important documents of Module 2 of the

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Common Technical Document (CTD) i.e., Module 2.5, which refers to the data provided in the comprehensive clinical summary, the individual clinical study reports presented in Module 5 and other relevant reports. It provides concise infor-

mation about the conclusions and the implications of the clinical data provided in the dossier with a conclusive interpretation on the benefit-risk assessment of the medicinal product in scope.

The main sections of a Clinical Overview include product development rationale, overview of biopharmaceutics, overview of pharmacology, overview of efficacy, overview of safety, benefits and risks conclusions and applicable references.

The CTD enables the customisation of the subsections based on the requirement, purpose of the clinical overview and the data available for the specific product in scope.

A Clinical Overview provides a brief discussion and interpretation of safety and efficacy findings related to

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the product, along with other relevant information (e.g., pertinent animal data or product quality issues that may have clinical implications), based on the findings from the clinical studies and/ or published literature. Providing the strengths and limitations of the development program and study results help in analysing the benefits and risks of the medicinal product for its intended use.

It serves as a reference to the overall clinical assessment of the product and supports the information provided in the prescribing information.

The Clinical Overview is developed for a variety of requirements in today’s scenario. Accordingly, there are two (2) types of Clinical Overviews: The Prospective and Retrospective Clinical Overviews. A Prospective Clinical Overview can be solely developed based on studies conducted by the innovator (for a new drug application to get the product registration) or data from studies conducted by the innovator and published literature data (for a hybrid application or 505b2 type of submissions, wherein the applicant rely on some of the safety and efficacy information derived from the Clinical Studies conducted by the Original Innovator) or solely developed by using data from published literature references (for Generic submissions or other submissions such as “Well Established Use” or “Bibliographic Submissions”).

In all the above situations, the purpose of the Clinical Overview is to support the application as a part of marketing authorisation.

With regards to Retrospective Clinical Overview, this document is generally not submitted to regulatory agencies as a part of registration dossiers.

However, it is developed as a substantiation/justification for the core labelling documents (e.g., Company Core Data Sheet (CCDS) or Company Core Safety Information (CCSI)) developed by the innovator, to have company’s standpoint on the information related to safety and efficacy of a particular medicinal product in scope.

In a scenario where the Clinical Overview is developed entirely based on literature data (for generic or bibliographic or well-established use submissions), it is very important to consider the level or quality of evidence (hierarchy of evidence) to identify the literature articles.

When a Marketing Authorisation Holder (MAH) has multiple registrations for a product across the globe, the format and extent of content (volume and depth of information) of the product information available in each country’s labelling document vary significantly.

This creates an ambiguity to consider what is the actual safety and efficacy information of the product in scope. In these situations, the MAHcan select one of the registered country’s labelling documents as Reference Safety Information (RSI) or create Core labelling documents (CCDS or CCSI).

In experience, most MAHs prefer to develop the core labelling documents to represent the Company’s standpoint on the safety and efficacy of a particular medicinal product by using all the relevant information already available with them for that product, hence the term used retrospective development.

The process would not end by developing only core labelling documents, it is required to develop the justification or substantiation document for the information available in the core labelling documents. This is the beginning of the development of a retrospective Clinical Overview to have the evidence for the safety and efficacy information

available in core labelling documents. This process is evolving and every time there is an update to core labelling documents (life cycle management), the Clinical Overview also needs to be updated to provide evidence to the changes made to core labelling documents.

The update to Core labelling documents can be either safety or non-safety related. The trigger to update can be internal or external. Internally driven changes are based on safety monitoring, resulted from post-marketing studies or post-authorization safety studies, and may be due to open signals,whereas the externally driven changes include the changes suggested by Regulatory Agencies. Whether the safety changes are internally driven or externally driven, post-validation of the changes, the update to core labelling documents, country labelling documents (in case of Agency driven) along with the justification document (Clinical Overview) is required.

As the Clinical Overviews developed for internally driven or externally driven safety changes related to specific safety information and only safety section of the Clinical Overview needs to be developed, these are termed as Abbreviated Clinical Overviews.

Additionally, these simpler versions of the Clinical Overviews are developed and submitted to Regulatory agencies as a part of life cycle management activities and/or market extension for a particular medicinal product. These overviews are used to substantiate the labelling changes during the post-approval part of the medicinal product’s/drug’s life cycle.

Apart from internally or externally triggered safety changes, these overviews can focus on the specific update to the labelling documents related to efficacy, pharmacology or any other information. These overviews are termed as Abbreviated Clinical Overviews (ACO), Addendum to Clinical Overviews (ACO), Tailored Clinical Overviews (TCO), Customised Clinical Overviews (CCO), etc., as these documents are confined to specific information updates related to

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the medicinal product. Although the terminologies may differ based on the company’s specific processes, the purpose it serves is the same.

Irrespective of the type of Clinical Overview and the time of its submission, the level of evidence is very important.

When the Clinical Overview is developed solely based on the clinical studies conducted by the sponsor for a new chemical entity, it is the first consolidated document that talks about the product’s safety and efficacy. In this scenario, the Clinical Overview should reveal the strengths and limitations of the clinical development program and study output.

It should also provide the benefits and risks of the product for the intended use.

When the Clinical Overview is developed for Hybrid applications or the evidence comes from both the studies conducted by the sponsor and the literature data, the purpose and development strategy of the Clinical Overview should be clearly presented to help the reviewer. Development of hybrid Clinical Overview may trigger by introducing some novelty to the existing approved product. This may be a change in indication, new indication, new dosage form, new strength, new route of administration, new combination, new presentation, new target population (introducing paediatric indication), etc. The pros and cons of the change must be mentioned with the available evidence.

In a scenario where the Clinical Overview is developed entirely based on literature data (for generic or bibliographic or well-established use submissions), it is very important to consider the level or quality of evidence (hierarchy of evidence) to identify the literature articles. It is recommended to take help from medically qualified personnel in this process.

In general, the well-accepted quality of evidence can be presented based on preference as follows.

• Clinical Practice Guidelines • Meta-analysis and/or Systematic reviews • Randomized Controlled Trials • Active Treatment Controlled Trials

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A Clinical Overview provides a brief discussion and interpretation of safety and efficacy findings related to the product, along with other relevant information (e.g., pertinent animal data or product quality issues that may have clinical implications), based on the findings from the clinical studies and/or published literature.

• Placebo Controlled Trials • Uncontrolled Trials • Cohort Studies • Retrospective Studies • Case Series • Case Reports • Expert Opinions • Narrative Reviews • Editorials In the cases where a lot of information is available, the literature with highquality evidence would be preferred to use to develop the Clinical Overview.

It is acceptable to omit the lower level of evidence when a significant amount of data is available with a high level of evidence. Few other points to consider while identifying the information for Clinical Overview are the impact factor of the journal, relevance of the information, the objective of the article, statistical parameters used, results of the trials or meta-analysis, statistical significance, power of the study, subset of the population enrolled, efficacy or safety parameters used and precision of analytical methods used (but not limited to).

The information mentioned in each subsection of the clinical overview should

be relevant to the subsection with the proper flow of the information. This helps the reviewer to understand your case and the objective of the document. Below is the information that can be covered in each subsection of the Clinical Overview.

Product Development Rationale section should provide the details on pharmacological class of the product, give details on the pathological conditions in which the product is intended to be used, describe the existing therapeutic options available for the current condition in scope, how the product in scope is superior with regards to safety and/or efficacy or improve the condition/ compliance (once daily versus multiple administrations, oral administration versus parenteral administrations,) etc.

This section should also cover the clinical development programme with details like completed, ongoing and planned clinical studies and the basis for the application. A summary of the scientific advice received (if any) from the regulatory agency can be provided.

Overview of Biopharmaceutics should represent the critical analysis of the problems related to bioavailability or bioequivalence of the product that might directly or indirectly affect the safety or efficacy of the product in scope. In case of generic submissions with Bioequivalence studies are part of the submission, a summary on the bioequivalence parameters and how the marketed formulation is equivalent to reference products (90% confidence intervals for Cmax, AUC 0-t and AUC0inf) can be provided. If there is any study conducted to show the influence of food on the product’s rate and extent of absorption can be provided.

Overview of Pharmacology should cover the information related to Pharmacokinetics and Pharmacodynamics of the product.This section should address pharmacokinetics in healthy subjects, patients and special populations (paediatric, geriatric, pregnant women, lactating mothers, patients with renal impairment, patients with hepatic impairment, obese patients, cancer patients, patients with

STRATEGY

proper reasons. If there are any studies conducted in special populations, they should be clearly mentioned and if there are no studies conducted, support should be provided to extrapolate the efficacy data from the general population to the special population.

Overview of Safety should cover the critical analysis of the safety data with regards to adverse effects (details on common, nonserious and serious), warnings and precautions, drug interactions, safety in special populations, overdose and its management. The adverse events data should be provided in detail with relevant

AUTHOR BIO

human immune deficiency virus, etc.).

It also covers intrinsic factors (age, sex, race), extrinsic factors (diet differences, smoking, concomitant drugs) and pharmacokinetic interactions and their output.

Details on rate and extent of absorption, distribution details, information related to metabolism and metabolites, excretion are included. With regards to pharmacodynamics, mechanism of action, receptor binding, onset of action, pharmacokinetics/pharmacodynamics relationships and pharmacodynamic interactions can be covered.

An overview of efficacy should provide the critical analysis of the efficacy of the product in intended use in the intended population. The analysis should cover the relevant data and should explain why and how the information supports the proposed use and the data in prescribing information. The quality of evidence should be considered and if there are any issues with efficacy parameters employed in the study or premature termination of the studies can be described with

tabulations and frequency of the adverse events, nature of patient population and extent of exposure to be provided.

The benefits and risks conclusions section should provide the succinct, integrated and properly explained assessment of the product for the intended use. If multiple indications are proposed, the benefits and risks conclusions should be provided for each indication. This section should be developed based on the proper weighing of key benefits and the key risks without any ambiguity. Finally, a list of references used in developing the Clinical Overview to be listed.

Raghu Rama Setty Alur is a Pharmacologist with 16+ years of experience in Medical Writing, Clinical Research and Labeling. He has proven track record in developing the high-quality documents related to clinical, non-clinical and toxicological domains. He has few international publications to his credit. He has been part of Freyr for more than 5 years and currently heading the Medical Writing Department at Freyr. Raghu has successfully managed projects in the fields of clinical pharmacology, Medical Writing clinical and medical affairs, regulatory affairs, preclinical research, toxicology, and publication (Scientific) writing.

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Emirates SkyCargo

In the time of COVID Julian Sutch Manager Global Pharma Sales, Emirates SkyCargo

The year 2020 was shaped by the COVID-19 pandemic and pharma being at the forefront of efforts to combat the virus was vulnerable and also impacted by the lockdown. How did the pandemic impact EKSCand what steps did you take to deal with it?

The COVID-19 pandemic had a massive impact on the aviation and air cargo industry globally. As part of our normal business, we transport cargo on dedicated freighter aircraft and also in the bellyhold of our passenger flights. The latter plays quite a key role as prior to COVID-19, around 70 per cent of the total freight we transported were carried on passenger aircraft.

When COVID-19 forced the complete suspension of

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passenger flight operations in late March, this entire capacity suddenly was no longer available to us and we were left only with operations on our 11 Boeing 777 freighter aircraft.

At this point of time, worldwide, there was still demand for the transportation of cargo. This covered goods that were urgently required by people across the world- PPE, medical equipment such as ventilators, pharmaceuticals as well as food items.

Given the distributed nature of the global economy, these critical commodities needed to be transported from the markets where they had been produced to communities across the globe. And so, we had to innovate very quickly, almost reinvent our complete

business model overnight and ensure that we were fulfilling our social responsibility by transporting these urgently required commodities across the world.

Our main response was focused on two streams- streamlining our operations here at Dubai and making additional air capacity available to our customers for transport of essential goods through Dubai to the rest of the world.

As restrictions on international travel exposed frailties in supply chains & lockdowns, we could foresee a situation where there would no longer be adequate cargo capacity available in the market to transport essential supplies. How did you overcome such a situation?

Julian Sutch is commercially responsible for Emirates SkyCargo’s global pharmaceutical division having been appointed in August 2016. Julian has been in the logistics industry for nearly 15 years since university, spending 10 of those in freight forwarding in Dubai predominately setting up the Middle East regional distribution for GlaxoSmithKline and opening an Pharma hub facility for API in the Dubai Airport Freezone.

Our first order of business was to restore air cargo connectivity to markets around the world so that we could continue transporting essential commodities that were required in the response to COVID-19.

In order to do this, we started operating our Boeing 777-300ER passenger aircraft as cargo only aircraft. This had never been done before and our team had to work within a very short time to plan our new route network, work with our partners across the world and also work with the relevant authorities www.pharmafocusasia.com

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to get the required permissions to operate the flight.

Our Boeing 777-300ERs are widebody aircraft with around 40-50 tonnes of bellyhold capacity (without passengers).

We were able to deploy these and increase our destination network from about 35 (served by our 11 Boeing 777 freighters) at the end of March to around 50 by April. Over the next two months, we further increased our network to more than 75 destinations.

Currently we’re flying to more than 130 destinations across six continents.

In the meantime, we also came up with other innovative solutions to increase the amount of air cargo capacity. This included loading cargo on the seats of passenger aircraft and in the overhead bins.

Of course, before we introduced this, we also had to make a complete safety evaluation and develop guidelines for our worldwide team to follow. All this was done in an extremely short period of time as the market continues to evolve rapidly.

In the month of June, we also removed seats in Economy Class from 10 Boeing 777-300ER aircraft to convert them into what we like to call ‘minifreighters’. We now have 16 of these aircraft in our fleet to complement the air cargo capacity that we offer on our full freighters and passenger aircraft.

What innovative strategy did you come up with to bolster the cargo capacity?

We reacted quickly to changing circumstances and have endeavoured to maintain trade lanes across the world during these challenging times with our flights.

Our most important change to operations during the COVID-19 crisis was to operate our passenger aircraft as cargo only to maintain connectivity for essential goods including medical supplies, pharmaceutical cargo and food. Over one year, we operated more than 27,800 cargo only flights on passenger aircraft, transporting more than 100,000 tonnes of food and pharma on these flights.

We also operated a record number of charter flights as and when requests came in from our customers for transporting critical commodities. The investment in our modern aircraft fleet, infrastructure at our hub and development of processes, helped us stand the test and face extremely difficult market conditions.

In terms of our hub operations, in early April, we decided to consolidate all our cargo handling operations at Dubai International Airport (DXB) from our previous dual airport hub model with both DXB and DWC with the latter handling cargo transported

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on the Boeing 777 full freighter aircraft. Given the reduced number of passenger flights, we were able to streamline our processes with all flights taking off from DXB. However, we have had a finger on the pulse of the market and started preparing very early on for the eventual transportation of COVID-19 vaccines.

Since late 2020, we have been flying these much needed vaccines on our flights and so far we have transported more than 75 million doses of COVID-19 vaccines to more than 60 cities on 250 flights, mostly to developing countries. We have a dedicated GDP certified COVID-19 vaccine hub in Dubai and have also partnered with entities in Dubai and with international organisations such as UNICEF to be able to expedite the movement of COVID-19 vaccines through Dubai to developing countries.

Emirates Sky Cargo marks a year of PAX-freighter flights. What are some of the hurdles in operating a cargo-only flight as a passenger aircraft, and what factors do you attribute the success to?

Prior to the COVID-19 pandemic, no air cargo carrier including Emirates SkyCargo had operated a cargo only flight on a passenger aircraft. Passenger freighters came into play only because of the severe capacity crunch in the global market for the transport of urgently required PPE, medical equipment, pharmaceutical supplies and food.

Setting up passenger freighter operations on a global scale was a complete shift in our usual business model and this meant that our teams had to work from the ground up, getting approvals for flight operations from various authorities, drawing up a destination network and schedule based on demand for cargo in the various markets, evaluating and drawing up new operational safety guidelines and working closely with our ground handlers across the different markets we operate for any additional resources and equipment required for cargo loading/ offloading especially in cases where cargo is required to be loaded inside the aircraft cabin.

Over a period of one year from 16 March 2020, Emirates SkyCargo operated more than 27,800 cargo only flights on its fleet of widebody passenger aircraft. This was by far the most number of passenger freighter flights operated by a single carrier in the industry. We attribute our success to the fact that we have been agile and kept an open mind, working closely with our customers and responding quickly to the rapidly evolving market dynamics. Of course, none of our successes would be possible

without the support and hard work of our teams and our partners around the world.

How would EKSC’s partnership with UNICEF act as a blueprint for collective global partnership in the face of future health and humanitarian crises?

Emirates SkyCargo has over two decades of expertise in transporting pharmaceuticals, vaccines and other relief materials. We also have experience working with various international organisations to help deliver relief efforts. Over the years, we have deployed many charter flights on our Boeing 777F aircraft transporting aid and relief materials to areas impacted by humanitarian crises including natural disasters.

One of our strongest partners is the International Humanitarian City (IHC) located in Dubai who are the world’s largest humanitarian hub based in Dubai.

Emirates SkyCargo has worked closely with IHC to operate humanitarian flights. In October 2020, we also signed an MoU with IHC to combine our mutual but complementary expertise to deploy relief efforts more rapidly and effectively across the world. The IHC are also one of our partner organisations in the Dubai Vaccine Logistics Alliance and our primary aim is to use our Dubai hub to rapidly distribute COVID19 vaccines from manufacturing locations to the rest of the world.We are also working with UNICEF to support the COVAX facility by expediting shipments

of COVID-19 vaccines on our flights. So far, we have flown more than 75 million vaccines on our flights.

We feel that it is our social responsibility to use our expertise in logistics to help communities across the world stay connected to the goods they require.

What according to you is the greatest lesson learned from the COVID-19 pandemic, and what lasting effects do you foresee over the next 5–10 years?

If there is one lesson that COVID-19 has taught us it is that we must always stay on our feet. We cannot become complacent just because we have developed the best product or solution. The pandemic has demonstrated to us that even the most carefully laid out plans can be changed overnight. The only option is to work closely with our customers, continuously innovate and stay ahead of the game.

The aviation and air cargo industry are currently still coping with the effects of the pandemic.

However, one thing that the pandemic has done is to encourage outside the box thinking. We have implemented measures that we thought were never possible before- such as operating cargo only flights on passenger aircraft or loading of cargo on the seats of the aircraft. The industry that emerges from the crisis will be much more responsive, agile and resilient in dealing with such worldwide disruptions.

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China’s New PRC Biosecurity Law Key implications for international players

The article focuses on the key implications for international players of the PRC BioSecurity Law, especially by introducing the administration scheme emphasized by this new law on the administration of the collection, preservation, use and provision of human genetic resources.

Michael Chin, Partner, Simmons & Simmon

set of regulations in the following areas: • epidemic control of infectious diseases for humans, quarantines for animals and plants • research, development, and application of biology technology • establishment and security of pathological microorganism labs • administration of human genetic resources and biological resources and • prevention of bioterrorism and defending threats of biological weapons.

Regulation of human genetic resources

A

gainst the background of the COVID-19 global pandemic, China fast-tracked and passed last year its first national biosecurity law (‘Biosecurity Law’). The law, which took effect on 15 April of this year, adds another key component to China’s overall national security.

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As a comprehensive and somewhat ambitious set of laws covering a wide range of areas under the broad definition of ‘biosecurity’, the Biosecurity Law attempts to address the absence of punishment against biotechnology related misuses in China over recent years and brings together an existing piece meal

Specifically and of importance to international players, the Biosecurity Law confirms the importance China places on the administration of Human Genetic Resources (HGR) by asserting sovereignty over China’s HGR and further strengthens current regulation over the collection, preservation, use and provision of China’s HGR under the existing Regulation on the Administration of Human Genetic Resources of 2019 (HGRAC Regulation).

The Biosecurity Law adopts the same legal principles as provided in the HGRAC Regulation (which remains effective unless expressly amended by the Biosecurity Law) but introduces some noteworthy changes which may have key implications for foreigners.

Similar to the restrictions provided under HGRAC Regulation, the Biosecurity Law confirms that foreign persons are generally prohibited from collecting or preserving HGR in China or providing HGR abroad. Foreign persons

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It is noteworthy that HGR may also be considered as personal data under the new Draft PRC Personal Data Protection Law, which is currently under review by the State and is expected to be promogulated soon.

In addition, it is noteworthy that HGR may also be considered as personal data under the new Draft PRC Personal Data Protection Law, which is currently under review by the State and is expected to be promogulated soon. As the Draft PRC Personal Data Protection Law provides a long-arm and extra-territorial application to certain personal data processing activities outside the PRC, foreigners will also need to take into consideration the requirements under this new data protection law.

Limitations arising out of collaborative international research projects

will have limited rights to acquire and/ or use China’s HGR through scientific research activities conducted in collaboration with Chinese entities but only with the prior approval of China’s Ministry of Science and Technology (MOST).

The only exception to the requirement of obtaining approval is for clinical trials conducted through international cooperation at clinical trial institutions for the purpose of obtaining the license for the listing of drugs and medical devices in China that does not involve any export of China HGR materials. Such clinical trial collaboration must still be pre-registered with MOST. The definition of ‘foreign persons’ under the Biosecurity Law remains the same as under the HGRAC Regulation, which includes any overseas organisations, individuals and any institutions established or actually controlled by such overseas organisations or individuals. In practice, the criteria is not clear in determining whether an entity is controlled by an overseas organisation or individual.

For example, it is not clear whether a variable interest entity structure (often used where foreign investment is prohibited or restricted) would be considered as ‘foreign persons’ with respect to HGR protection.

Another example would be whether a Chinese entity engaging in research activities based on China’s HGR could have foreign individuals on its research team.

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Another important requirement under the Biosecurity Law is that permitted collaborative international research projects must ensure that the Chinese entity and its researchers substantively participate in the research throughout the process and share relevant rights and interests in accordance with the law.

This requirement follows the principle provided in the HGRAC Regulation however the HGRAC Regulation provides more detailed requirements focusing on the joint ownership of the technical achievements.

One frequently asked question in practice is whether the collaborative parties are able to contractually agree for the technical achievements to be solely owned by the foreign party. The general principle under the Biosecurity Law is that the Chinese party should be entitled to share the interests and rights arising from the collaborative international research project. The HGRAC Regulation provides that patents deriving from a collaborative international research project involving the use of HGR must be jointly applied and owned by both the foreign and Chinese entities. The relevant provision under the HGRAC Regulation go on to provide that rights relating to other (being nonpatented) technical achievements arising out of such project, including use rights, transfer rights and profit shares, can be agreed contractually.

As the collaboration international research project involving the use of China’s HGR must be submitted to MOST for prior approval, upon its review, MOST will review the agreed distribution plan for any potential scientific achievements by the parties and only approve a plan which they consider as reasonable, clear and accords with the contribution of the parties. MOST will also request that the definitive agreement sets up consistent distribution plans with regards to any technical achievements.

Therefore, it would be against the spirit of the Biosecurity Law and the HGRAC Regulation to allow parties to contractually assign patent rights so as to only be owned by the foreign party.

Similarly, if the parties sought to change the original patent related arrangement approved by MOST without approval, this would also be considered as against the relevant provisions of the Biosecurity Law and the HGRAC Regulation.

This limitation on the joint ownership of technical achievements substantially restricts the negotiation ability of the collaborative parties with respect to the research project. Foreign players are going to be reluctant to share internal confidential research and technical resources with their Chinese counterparts.

Biosecurity review

The Biosecurity Law highlights the importance of biosecurity review by providing that the State shall establish a biosecurity review system. For any major matters in the biological field that affect or may affect national security, the authority shall conduct biosecurity review to effectively prevent and eliminate biosecurity risks. This biosecurity review scheme should also apply to HGR which is one important resource in the biological field. This is consistent with the current review scheme established by the HGRAC Regulation. However, there is no clear threshold in deciding whether a matter should be considered as ‘major’ or ‘substantial’ which may lead to some biosecurity risk until more detailed

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Increased legal liabilities and penalties

The legal liabilities and penalties have been substantially increased under the Biosecurity Law when compared with the HGRAC Regulation, especially for foreign parties. For example, where illegal income is equal to or greater than RMB 1 million, the foreign violators can be subject to fines of up to 20 times the illegal income. and the authorities have the power to impose suspension orders of up to 5 years as well as revoke operation permits and licenses.

In addition, according to the Amendment (XI) to the PRC Criminal Law, which took effects on 1 March 2021 provides that any serious breach of laws by illegally collecting the HGR of China or illegally export the HGR of China and endangering the public health or social and public interest should be considered as a crime and would be sentenced to up to imprisonment of 7 years and a fine in especially serious scenarios. This is a

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The HGRAC Regulation provides that patents deriving from a collaborative international research project involving the use of HGR must be jointly applied and owned by both the foreign and Chinese entities.

newly added crime with regards to the protection of China’s HGR and could show the attitude of the authority in this field.

Approval and recordal system for biotechnology research and development

With the demand for innovative biomedical technologies around the world, another significant development under the Biosecurity Law is the introduction of an approval and recordal system for biotechnology research and development and application. Specifically, it categorises biotechnology R&D activities into high, medium or low risk categories determined based on the risk of harm to public health, industrials, agriculture and ecology. Foreign entities are prohibited from conducting high or medium risk biotechnology R&D activities in AUTHOR BIO

implementation rules are promogulated.

It is also provided under the Biosecurity Law that a ‘report’ with backup information shall be submitted to MOST before any HGR is provided or made available to a foreign person.

This is a noteworthy change under the Biosecurity Law when compared to HGRAC Regulation where only a filing with backup information needs to be submitted to MOST. It is unclear how the ‘report’ requirement under the Biosecurity Law is to be implemented.

It is also not clear whether the submitting party should wait for the biosecurity review decision, if applicable at all, or whether the ‘report’ to MOST is sufficient in order to provide China HGR to a foreign person. Some experts in the industry are of the view that the ‘report’ requirement changes the ‘filing’ scheme under the HGRAC Regulation and requires the approval of MOST before providing any HGR to a foreign person, while under the original filing scheme, notice to MOST is sufficient.

China; in other words, they will need to be conducted by a legal entity in China and obtain the necessary approval or recordal. Further details of the approval and recordal requirements are still to be released.

Due to the increasing demand of innovative biomedical technologies and the rapid development of biopharm, and the fact that the mainland China government actively welcomes foreign investment in technological innovation, especially in biomedical technology innovation areas, it is believed that the issuance and implementation of the Biosecurity Law will have significant implications for both international and Chinese companies in a wide range of industries such as pharma, healthcare, biotech, cosmetics, food and agriculture, especially for global and regional R&D labs.

Depending on the detailed activities of international players’ commercial operations, they will need to take proper compliance and risk management actions, such as reviewing current on-going programs, setting up appropriate internal governance structure for biosecurity, and conducting internal training to business and technical team to ensure a proper understanding of the requirements under the Biosecurity Law. Specifically for businesses which may involve the utilisation of HGR, prior communication with MOST is to ensure compliance with laws and to avoid the extremely high fines for breach of the laws.

As the Biosecurity Law covers a wide range of areas under a broad definition of ‘iosecurity’, it is expected that detailed implementation rules will be promogulated to better interpret the principles provided under the Biosecurity Law.

Michael Chin has over 20 years' experience advising on a broad spectrum of corporate transactions in the Asia-Pacific region. As an Australian Chinese having worked in Australia, Hong Kong and China, Michael has a unique ability to bridge the cross cultural gap, often critical to completing deals in the region.

Pharmaceutical Grade Quats and Recombinant Insulin

A global and leading supplier

Novo Nordisk Pharmatech supports the world´s largest pharmaceutical and biopharmaceutical industries reducing their risks related to raw materials, by using pharma-grade products with a high level of consistency, purity, quality, and reliability.

The company’s mission is to enable better medicines by providing sustainable pharmaceutical materials through innovative and customised solutions

Mitigating Raw-Material Risks During a Pandemic

Marie-Louise Lyster is Global Marketing Manager at Novo Nordisk Pharmatech A/S, Denmark

Novo Nordisk Pharmatech A/S is a global and leading manufacturer of pharmaceutical ingredients for the pharmaceutical and biopharmaceutical industries.

The company is specialised in producing Quaternary Ammonium Compounds (Quats) used as Active Pharmaceutical Ingredients (APIs) and excipients, and Recombinant Insulin for use in cell culture media to enhance cell growth, viability, and productivity.

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For many pharmaceutical and biopharmaceutical companies, the COVID-19 pandemic has put supply chains to the test, while regulatory requirements are increasingly tightening.

The crisis has reinforced the importance of having a strong supply chain and a risk-management and business-continuity plan. How can you mitigate your raw-material risk, especially during a pandemic?

Risks When Choosing a Raw Material Supplier

How do you select your critical raw-material suppliers?

What selection criteria and which risks have you identified? To understand risks related to supply, demand, material supplier capacities, and so on, you need information that can come only from communicating with your supplier about the stability of supply, production capacity, and transportation and distribution chain.

A large organisation such as Novo Nordisk Pharmatech can secure a continued source of raw materials. The past year they have experienced significantly increased freight fees and limited availability of transportation for both recombinant human insulin and quaternary ammonium compounds (also known as Quats) APIs. Despite that, and thanks to close cooperation with the customers, Novo Nordisk Pharmatech has been delivering their products as promised and without disrupting planned manufacturing processes.

Working Together A transparent communication is essential. To best manage unforeseen situations such as a pandemic, contingency planning is performed based on the customers’ needs. Furthermore, the company´s supply chain is secured by building partnerships, exchanging forecasts, and discussing foreseen changes, and performing joint planning. Sometimes, doing so is easier said than done. One way to facilitate those processes is by creating supply agreements.

Entering into numerous supply agreements and Quality Assurance Agreements (QAAs) with our customers, has helped maintaining clear expectations from both sides and provide peace of mind.

Minimising Raw Material Variability The customers want to source materials from reliable sites that deliver as agreed on quality, purity, and consistency between batches and shipments.

Delivering a high level of consistency in both the

quality and supply of pharmaceutical grade Quats and Human Insulin AF, Novo Nordisk Pharmatech helps the customers reduce their risk. The cornerstone of the organisation is an effective quality management system, which helps to achieve that goal. The comprehensive documentation package and tailored support, which continues through the whole product life cycle, gives you total peace of mind.

Novo Nordisk Pharmatech is monitored stringently by international regulatory authorities and customers. The company has an outstanding track record of compliance and customer satisfaction because they learn from each audit, monitor compliance requirements, and strive for continuous improvement.

One-Stop Regulatory Compliance If you manufacture products for markets beyond your own, ensuring regulatory compliance can be a particular challenge: from staying up to date with changes, to navigating language barriers, or even meeting requirements above the official guidelines.

While many countries are working towards harmonising regulations, experiences show that some customers still require more documentation than officially specified.

Audits can cover the Good Manufacturing Practice (GMP) level of a supplier, but supplier qualification consists of many aspects. Those include regulatory requirements and available risk assessments as well as a supplier’s overall compliance, noncompliance, and recall history.

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Novo Nordisk Pharmatech takes pride in providing a simple, hassle-free, ‘one-stop’ compliance and regulatory package. All Novo Nordisk Pharmatech activities including dedicated QA and regulatory affairs teams are gathered at one site in Europe (Denmark), making supply chain audits easy. The customers are issued up-front access to a full package of certificates from authorities (e.g., current GMP as well as International Organisation for Standardisation (ISO) 9001, 14001, and 45001); qualification dossiers, statements, and declarations; change notifications, questionnaires, stability and analysis documents; and more.

Being qualified as a supplier is only the beginning of a journey. The support of the customers lasts throughout the whole product life cycle, with premium service and documentation. This is part of the ambition to remain a preferred supplier and contribute to improving pharma and biopharma processes.

The products Insulin Human AF Novo Nordisk Pharmatech´s high purity, nontherapeutic Insulin is sourced directly from parent company Novo Nordisk, the world’s largest insulin producer. It consists of insulin human crystals,

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biosynthetically produced by recombinant microbial expression in yeast.

Recombinant Insulin stimulates the proliferation of mammalian cells and enhances the yield and is a key component in serum free growth media.

The Insulin Human AF is used for manufacturing of monoclonal antibodies, virus vaccines, gene therapy products and other biological drug products approved by regulatory bodies worldwide, including FDA and EMA. Novo Nordisk Pharmatech’ s Insulin Human AF is manufactured in accordance with internal quality systems, based on ISO 9001 and cGMP and is analysed according to the current European (Ph. Eur.) and US (USP) Pharmacopoeias. The product is manufactured in Novo Nordisk’s parent cGMP facilities, packaged in HDPE bottles, and supplied

by Novo Nordisk Pharmatech A/S. Insulin Human AF has a shelf life of 60 months and the company has enough packed off-the-shelf Insulin Human AF in stock for at least five months of consumption, to be able to respond immediately to your specific requirements.

With Insulin Human AF from Novo Nordisk Pharmatech, you avoid the risk of impurities such as mycoplasmas, which can pass line to line from the upstream bioreactor and contaminate your whole line.

Pharmaceutical Grade Quats As the world’s leading supplier of pharmaceutical grade quaternary ammonium compounds (Quats), Novo Nordisk Pharmatech provides only the best and safest ingredients for the pharmaceutical and personal care industries. The Quats products are sold globally in more than 70 countries across Europe, Asia, North America, South America, and Africa.

Novo Nordisk Pharmatech is a specialist and dedicated manufacturer of Quats in an unequalled, full cGMP grade ensuring exceptionally high purity and batch-to-batch consistency. The Quats product range (including Benzalkonium Chloride, Cetrimide and Cetrimonium Bromide/CTAB) is suited for a wide range of pharmaceutical applications that require high purity and quality, such as vaccine production and as preservatives (excipients) or active ingredients (APIs) in many ophthalmic, nasal, oral and topical drugs and in a variety of solutions, ointments, gels and creams.

Novo Nordisk Pharmatech’ s Quats have excellent antimicrobial and surface-active properties, and are

active against a broad spectrum of microorganisms, such as gram + and – & acid-fast bacteria, yeasts, moulds and enveloped vira such as HIV, herpes and corona. They are effective through a wide pH range, are surface active/adhesive cationic agents and do not add unpleasant odour/colour to finished formulations.

The multi-compendial range of Quats complies to the highest regulatory guidelines, including ICH Q7, the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopoeia (USP). Some Quats products also follow the Japanese Pharmacopoeia (JP), the British Pharmacopoeia (BP) or the Chinese Pharmacopoeia (ChP).

Combining high-purity products and regulatory services have made the company an approved supplier to many of the world’s leading pharmaceutical companies. With more than 70 years of experience in producing Quats and more than 30 years CGMP manufacturing, Novo Nordisk Pharmatech deliver the same high-quality products batch after batch.

The Company´s History and Structure

Novo Nordisk Pharmatech A/S was established in 1949 as Ferrosan Fine Chemicals, part of the Ferrosan Group that was acquired by Novo Industries in 1986, becoming part of Novo Nordisk A/S with the 1989 merger of Novo with Nordisk Gentofte. On September 1, 2015, the company changed its name to Novo Nordisk Pharmatech A/S, operating as a division of Novo Nordisk A/S from Køge, south of Copenhagen.

The entire value chain from Research and Development, Manufacturing, Quality Assurance, Quality Control to Sales and Marketing is located on site in Køge giving the company significant advantages in terms of agility.

More than 70 years of experience have given Novo Nordisk Pharmatech the know-how to ensure maximum product purity and keeping impurities to even lower levels than pharmacopeial standards.

This has made the company a leading global supplier of high-quality ingredients - enabling the customers to make even better medicines.

For more information, visit www.novonordiskpharmatech.com, www.linkedin.com/company/novonordiskpharmatech or contact the company at nnprinfo@novonordiskpharmatech.com Advertorial www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

THE FUTURE OF RESEARCH

Importance of accelerated clinical trials for evidence-based treatments

O

ver the past year, the COVID-19 pandemic has heightened the urgency for clinical research to understand the disease, uncover treatment plans, and develop vaccines to treat a disease that was once unknown to the world. It was equally crucial that findings were swiftly made available to the public, to prevent misleading information from undermining the public health response.

As we look ahead, we must continue to take what we learnt from the accelerated trials and apply them to other diseases. At the same time, we must ensure that patient safety and quality are not compromised as we make progress in evidence-based treatments for patients.

How data helps clinicians make quick and accurate plans

Over the past 12 months, the COVID-19 pandemic has heightened the importance of clinical research and its dissemination. It was and continues to be vital that clinical research is carried out rapidly in order to provide clinicians with an effective, evidence-based, response to the global healthcare crisis. As we look ahead, it is important that we re-evaluate the process of accelerated research trials and understand what healthcare organisations can do to ensure that patient safety and quality is not compromised in the path towards progressing evidence-based treatments for patients.

Oli Cram, General Manager, Elsevier

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Healthcare data plays an increasingly important role in aiding clinicians and researchers to develop an effective, evidence-based response to tackle the global healthcare crisis.

The World Health Organization 1 (WHO) has published over 199,000 pieces of scientific literature on SARSCoV-2 virus since its outbreak. And the figure will continue increasing with discoveries made every day.

When real-time datasets collated from the population are made immediately available, it enables quicker disease pattern analysis, earlier detection, and reduces trials and errors.

1 https://search.bvsalud.org/global-literature-on-novelcoronavirus-2019-ncov/

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RESEARCH & DEVELOPMENT

Fostering cross-country collaboration for a more diverse representation

Partnership among researchers is crucial in ensuring mutually beneficial knowledge, skills, and techniques are shared in an effective way.

Since the outbreak of the COVID19 pandemic, clinical researchers from various countries and institutions have gathered with the common goal of learning more about the disease and finding the right treatment. Along with research trials, the initiation of rapid, collaborative research has been vital in facilitating the continuation of care for COVID-19 patients.

One such initiative WHO lauds is the Global Initiative on Sharing Avian Influenza Data (GISAID) 2. GISAID allowed researchers to post large numbers of SARS-CoV-2 genome sequences online while protecting data providers’ rights.

The safe and secure sharing of knowledge among the global scientific community allowed researchers to access the genome sequences of people from diverse backgrounds, helping to inform and guide the research work on COVID-19.

2 https://www.gisaid.org/

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Sustaining strong international collaboration remains important in the days ahead. It encourages the sharing of skills and expertise and diversifies patient populations for clinical trial research. Most importantly, strong international collaboration facilitates the continued provision of standardised, quality care to patients worldwide.

Paving the future of research by embarking on digital transformation

The future of research will be defined by the lessons learned from the COVID-19 pandemic. As we embark on this journey, we need to ensure that healthcare organisations are structurally ready to accelerate clinical trials – a process that involves the exchange and reusing of large volumes of standardised data.

The acceleration of digital transformation across healthcare systems is integral to enabling access to available data.

This allows clinicians and researchers to refine their knowledge, optimise decision support to identify needs, and predict and prevent future crises. Contributed datasets need to be cleaned, standardised, and validated before use to ensure accuracy and quality. They are then integrated into a single repository that holds all the global data so researchers can rapidly perform meta-analysis to answer further research questions.

AUTHOR BIO

This means clinicians can make quick and accurate action plans to improve public health outcomes – especially in the case of the COVID-19 pandemic, where pre-existing information and knowledge are not available.

Case in point, the swift development of accurately targeted vaccines for COVID-19. The first COVID-19 vaccine was approved within 12 months, a process that traditionally takes 10 to 15 years.

What put the development and approval process on fast track was clinicians having access to knowledge about the disease. Speed was the top priority, as was the rigour of the scientific methods used to develop a vaccine backed by evidence-based knowledge. Carefully planned clinical trials were run simultaneously, which generated data that was comprehensive and reliable.

As we embark on this journey, we need to ensure that healthcare organisations are structurally ready to accelerate clinical trials – a process that involves the exchange and reusing of large volumes of standardised data.

For example, Elsevier’s COVID-19 Healthcare Hub3 has amalgamated all the latest frontline clinical tools and resources (including the Coronavirus Research Hub 4 ) for clinicians and researchers focused on coronavirus vaccine, drug, clinical, and other related research, to freely access these evidence-based solutions for their work.

There is also a need for wider adoption of data standards, where healthcare professionals are guided by international practices and research frameworks to allow them to continue working in a sustainable way to deliver patient care and highquality clinical research. This way, we can ensure that patient safety and quality are not compromised by the accelerated research developments, as research methodology and data are backed by evidence and verified by quality checkpoints.

Conclusion

With a coherent and efficient research response which leverages the power of data analytics, we can be better prepared for a future pandemic. Having a transparent and trusted system that clearly communicates what data is being collected — and why — allows clinicians and researchers to access credible, standardised, and integrated data that informs actions in times of a global healthcare crisis.

More importantly, we need to create a culture of collaboration that promotes high-quality research across countries and institutions. This is all underpinned by digital transformation, the foundation for the collection of high-quality healthcare data that can influence clinical reasoning and impact patient care.

3 https://elsevier.health/en-US/covid-19/home 4 https://www.elsevier.com/clinical-solutions/coronavirusresearch-hub

Oli has worked providing clinical research solutions since 2006 and in that time, he has been a programmer, a tester, test manager, customer support manager, Software as a Service manager and is now general manager at Elsevier. His vision is to use this breadth of knowledge and the support of his experienced team to deliver the next generation of clinical research software solutions. Oli has an Honours degree in Genetics and a Master’s degree in computer science.

RESEARCH & DEVELOPMENT

Immune System and COVID-19

Management and potential therapies SARS-CoV-2 is highly transmissible and infectious coronavirus which is spreading across the globe at an alarming rate. As of 18 May 2021, there are 163,642,990 confirmed cases and 3,390,316 deaths reported from COVID-19. Here, we review the current knowledge regarding the immunopathogenesis and potential therapies for management of COVID-19.

Rupesh K Srivastava, Department of Biotechnology, All India Institute of Medical Sciences (AIIMS)

I

n December 2019, a pneumonia outbreak occurred in Wuhan city of China that quickly spread across the world and posed serious public health emergency. On 9 January, 2020 novel coronavirus severe respiratory disease syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause of outbreak in Wuhan. Later on 11 February 2020, the World Health Organization (WHO) named the disease caused by SARS-CoV-2 as coronavirus disease-2019 (COVID-19).

Coronaviruses infect humans and animals and are associated with various respiratory, gastrointestinal, and neurological disorders. SARS-CoV-2 is the seventh coronavirus that is recognised to cause infection in humans. The other six coronaviruses are known to cause only mild symptoms. However, there are two notable exceptions: SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). SARS-CoV is responsible for an epidemic that started from China in the year 2002-2003. This outbreak resulted in 8000 infections and 774 fatalities across 37 countries. MERS-CoV was first detected in 2012 in Saudi Arabia and caused 2,494 confirmed cases and 858 fatalities. SARS-CoV-2 shows 79.6 per cent sequence identity with the SARSCoV. However, bat coronavirus RATGI3 seems to be its closest relative, showing over 96 per cent sequence similarity.

SARS-CoV-2 is highly contagious and causing more infections and deaths than both SARS-CoV and MERS-CoV. As a result, WHO declared COVID-19 a pandemic on 11 March, 2020.

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RESEARCH & DEVELOPMENT

Pathogenesis of COVID-19

SARS-CoV-2 is respiratory virus and mainly transmits through droplets produced when an infected person sneezes or coughs. However, recently US Centers for Disease Control and Prevention acknowledged COVID-19 as airborne disease which means that it can be transmitted by respiratory fluids also.

Respiratory fluids also known as aerosols are fine droplets that are produced during respiration. Therefore, a person can be infected on inhalation of aerosols formed when a COVID-19 patient exhales, speaks, sings, shouts, coughs and sneezes. SARS-CoV-2 can cause mild infection to severe respiratory failure in infected patients. Typical symptoms associated with SARS-CoV-2 infection are fever, dry cough, fatigue, weakness,

Figure 1. Pathophysiology of COVID-19

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chest tightness, loss of smell and taste, pain and aches, sore throat, diarrhoea, chills, rashes, headache, conjunctivitis and in severe cases dyspnea and Acute Respiratory Distress Syndrome (ARDS).

ARDS is chronic respiratory disorder characterised by difficulty in breathing, hypoxia, and pulmonary edema. SARSCoV-2 infection in children and young adults is mostly asymptomatic. But the older population (> 60 years) particularly those having Figure 1. Pathophysiology of COVID-19 the comorbidities (hypertension, diabetes, cardiovascular diseases) are at high risk of developing the severe disease.

Sex related differences also determine the clinical outcome of COVID-19 as men are more prone to infection than women

and also have a high mortality rate. In severe cases, COVID-19 also results in multiple organ failure which is characterised by acute liver failure, Cardiovascular Diseases (CD), neurological disorders, Acute Kidney Injury (AKI) and several hematological abnormalities. Once inside the body the first step involved in the pathogenesis of COVID-19 is the binding of the SARS-CoV-2 to host receptor Angiotensin Converting Enzyme 2 (ACE2) that is expressed on host cells viz. lung cells. The binding of SAR-CoV-2 to ACE2 receptor allows the entry of viral genetic material into host cells followed by their replication and multiplication.

The newly formed viral particles then exit the infected cell and start invading other adjacent epithelial cells resulting in lung damage. Apart from lung, ACE2

RESEARCH & DEVELOPMENT

VACCINES APPROVED

DEVELOPER/ COUNTRY OF ORIGIN

EFFICIENCY

STORAGE CONDITIONS REQUIRED

APPROVAL STATUS

1.

mRNA-1273 (mRNA-based vaccine)

Moderna US

94.5 per cent

-150 C to -250 C

Approved

2 doses (At the gap of 28 days)

Effective against B.1.1.7 and B.1.351 variants but not against B.1.6I7 variant

2.

Sputnik V (adenovirus vectored vaccine)

Gamaleya Research Institute of epidemiology and Microbiology, Health Ministry. Russia

91.6 per cent

-180 C

Approved

2 doses (At a gap of 21 days)

Effective against B.1.17 variant but not against B.1.351

3.

BNT162 (mRNAbased vaccine)

Pfizer/BioNTech Multinational

90 per cent

-800 C to -600 C

Approved

2 doses (At a gap of 21 days)

Effective against B.1.1.7 variant (first identified in UK) and B.1.351 variant (First identified in South Africa) but not against double mutant B.1.6I7 (Indian variant)

4.

Covaxin (whole virion inactivated vaccine)

Bharat Biotech India

81 per cent

20 C to 80 C

Approved

2 doses (At a gap of 28 days)

Effective against B.1.17 and B.1.617

5.

Sputnik Light (adenovirus vectored vaccine: rAd26)

amaleya Research Institute, Acellena Contract Drug Research and Development Russia

80 per cent

20 C to 80 C

Approved

Single dose

Effective against all strains of coronavirus (till date)

6.

BBIBP-CorV (Inactivated vaccine)

Beijing Institute of Biological Products China

78.1 per cent

20 C to 80 C

Approved

2 doses (At a gap of 21 days)

Effective against the B.1.1.7 variant and modestly efficient against B.1.351

7.

ChAdOx1 nCoV-19 or Covishield in India (adenovirus vectored vaccine)

The University of Oxford, UK

70 per cent

20 C to 80 C

Approved

2 doses (At a gap of 4 to 12 weeks)

Effective against B.1.1.7 and B.1.617 but not against B.1.1.351

8.

CoronaVac/ Sinovac (Inactivated vaccine)

Inactivated vaccine (formalin with alum adjuvant) China

67 per cent

20 C to 80 C

Approved

2 doses (At a gap of 14 days)

ffective against the B.1.1.7 variant and modestly efficient against B.1.351

9.

Janssen Ad26.CoV2 (adenovirus vectored vaccine)

Johnson and Johnson,

66 per cent

20 C to 80 C

Approved

Single dose

Efficient against B.1.351 and P.2 (first identified in Brazil) variants

10.

Convidecia Recombinant vaccine (adenovirus type 5 vector)

CanSino Biologics China

65.28 per cent

20 C to 80 C

Approved

Single dose

NA

11.

EpiVacCorona (Peptide-vaccine)

Vector Institute, Russia

NA

20 C to 80 C

Approved

2 doses (At a gap of 21 days)

NA

12.

CoviVac (Inactivated vaccine)

Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products, Russia

NA

20 C to 80 C

Approved

2 doses (At a gap of 14 days)

NA

S. NO.

Table 2: Different vaccines approved for treatment of COVID-19

DOSE REQUIRED

EFFICIENCY AGAINST DIFFERENT MUTANT STRAINS

Source: https://www.raps.org/news-and-articles/news-articles/2020/3/ covid-19-vaccine-tracker #NA- Data not Available

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RESEARCH & DEVELOPMENT

S.NO.

IMMUNE CELLS

GENERAL IMMUNE RESPONSE

IMMUNE RESPONSE IN COVID-19

IMMUNOPATHOGENESIS

1

Monocytes/ Macrophages

Monocytes and macrophages engulf the antigen and kill them by directly producing toxic substances

Increase in number

Induce cytokine storm

2

Dendritic cells (DCs)

DCs are antigen presenting cells and are responsible for initiation of adaptive immune response

Decrease in number

Impaired adaptive immune response

3

Mast cells

Mast cells produce various soluble factors and have important role in defense against pathogens

Increase in number

Cause inflammation

4

Basophils

Basophils like mast cells are granulated cells and undergo rapid degranulation when activated

Decrease in number

Improper protection against virus

5

Eosinophil

Eosinophil has important role in defense against parasitic infections and allergies

Decrease in number

Decrease in number of eosinophils in COVID19 is associated with acute respiratory deterioration

6

Neutrophils

Neutrophils provide the first line of defense against the pathogen.

Increase in number

Increased neutrophil numbers and NET release is positively correlated with thrombosis, coagulation, ARDS and worst oxygenation conditions reported in COVID-19 patients

7

NK cells

NK cells produce various cytotoxic compounds like perforin and granzyme to kill the pathogens

Decrease in number

Impaired antiviral response

Table 1. Response of different immune cells during COVID-19

receptor is also expressed by almost all tissues e.g. heart, intestine, kidney, bladder etc..

Immunopathogenesis of COVID-19

Viral infections activate our immune system. Immune system which constitutes of special organs, cells and chemicals protects our body from invaders like viruses, bacteria and other foreign bodies.

Immune system is mainly characterised under two categories: Innate and adaptive immune system. Innate immune system is the first line of defense and is non-specific to pathogens. On the other hand, adaptive immune system is the second line of defense and is pathogen specific. Well-coordinated innate and adaptive immune responses generally protects against various types of bacterial and viral infections. However, in case of SARS-CoV-2 immune response gets hampered that results in immune pathology. Immune system is activated when immune cells recognised certain 40

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molecular patterns associated with the pathogen. Activated immune cells then secretes various soluble molecules called the cytokines and chemokines.

These cytokines/chemokines have role in recruitment of various innate immune cells such as monocytes/macrophages and neutrophils at the site of infection. These immune cells further produce cytotoxic substances to eliminate viral infection.

Although these substances protect from viral infection but can also cause damage to the host tissues. In case of COVID19 there is exaggerated production of cytokines (cytokine storm) resulting in uncontrolled influx of monocytes and neutrophils in the lung tissue. The cells notably the neutrophils and macrophages then produce toxic substances which cause acute lung injury and ARDS resulting in respiratory failure. COVID-19 also impaires the production of interferons which are chemicals secreted by host cells in response to viral infection. After pathogen recognition, host cells produce

interferons that have important role in eliminating the virus but SARS-CoV-2 through several mechanisms inhibits the generation of interferons and thus escape the host immune response. SARS-CoV-2 infection also modulates the activity of various immune cells (Table 1).

Potential Therapies for COVID-19

Till now there is no effective therapy available for the prevention of SARSCoV-2 infection. Nevertheless, several drugs such as antivirals, immune modulators and antibiotics have been repurposed for combating COVID-19.

Currently, human clinical trials on 92 vaccines and 419 therapeutic drugs are going on for management of COVID19. Drugs like chloroquine, hydroxychloroquine, remdesivir, tocilizumab, etc. received intense attention worldwide as they showed positive results in preliminary studies. Remdesivir was the first drug authorised by the Food and Drug Administration (FDA) for

RESEARCH & DEVELOPMENT

between these drugs and decrease in mortality, duration of hospital stay and the need of mechanical ventilation.

Therefore, clinical trials do not support the use of these drugs for hospitalised COVID-19 patients. Favipiravir which is originally designed against influenza is one of antiviral drugs that has been repurposed to halt the progression of COVID-19. Favipiravir is orally administered and appears useful in the treatment of mild to moderate SARS-CoV-2 infections. As 85 per cent of the COVID-19 cases are mild or moderate, favipiravir is considered as a potential therapy for large number of the patients. Now, a randomised controlled trial showed that favipiravir reduced the need of mechanical ventilation and duration of hospitalisation and therefore can be also used for hospitalised patients. Thus, favipiravir can be a promising therapy in decreasing the stress on global healthcare system due to COVID-19. Ivermectin is FDA approved anti-parasitic drug that has broad spectrum antiviral activity also. It is observed that ivermectin can inhibit SARS-CoV-2 replication. Various small-scattered studies back the efficacy of ivermectin in management of COVID-19. As the use of hydroxychloroquine has largely debunked for COVID-19 prevention, ivermectin is becoming wildly popular as a preventive measure for COVID-19. However, WHO warned against the use of ivermectin due to lack of convincing evidence that merits the ability of ivermectin in controlling SARS-CoV-2 infection. The interest in immunosuppressant such as corticosteroids is also refreshed for cure AUTHOR BIO

the treatment of severe COVID-19.

Remdesivir perturbs viral RNA replication. Data from the placebo-controlled trials showed the clinical effectiveness of remdesivir in shortening the recovery time of hospitalised COVID-19 patients who require oxygen support. Although there are clear indications of its efficacy against COVID-19 but no study till now has evidenced the role of remdesivir in mitigating the mortality rate. But due to lack of other potential treatment options remdesivir is in extensive use in hospitals for patients (with comorbidities) having severe COVID-19 disease. Chloroquine and hydroxychloroquine are used for the treatment of malaria and now found to be effective in the management of COVID19 in some clinical trials. Chloroquine / hydroxychloroquine prevents the entry and exit of SARS-CoV-2 virus from the cell and have immunosuppressive properties. Chloroquine and hydroxychloroquine had shown the promising results in preventing COVID-19 in various clinical settings during first wave. But current data from several randomised controlled trials evidenced no clinical benefit of these drugs in treatment of COVID19 during second wave. Azithromycin is an antibiotic having potential antiviral and anti-inflammatory properties also.

A small non-randomised trial aimed to evaluate the effectiveness of azithromycin has revealed that azithromycin in combination with hydroxychloroquine has significant antiviral activity against SARS-CoV-2. But in contrast to this, a recent study demonstrated that there is no meaningful benefit of azithromycin in reducing recovery time and risk of hospitalisation. Another solidarity trial tested the combined effects of two antiviral drugs lopinavir and ritonavir. These drugs were initially developed against Human Immunodeficiency Virus (HIV).

Lopinavir and ritonavir were also used against the SARS infection and it was observed that treatment with these drugs ameliorated ARDS at day 21. Given their effectiveness against SARS-CoV they were tested for SARS-CoV-2. However, the clinical trials showed no association

of COVID-19 as in the past they were widely accepted for preventing SARSCoV outbreak. However, in COVID-19 patients corticosteroids treatment resulted in poor outcomes. But later a widely publicised press release and subsequent results from RECOVERY trial noted the benefit of dexamethasone in preventing severe cases. The RECOVERY trial concluded that dexamethasone therapy reduced the death rate by one third in severe COVID-19 patients who are on respiratory support but is inefficient in preventing non-severe cases. Other corticosteroids like budesonide and methylprednisolone are also observed effective against COVID-19. Use of tocilizumab, an immunosuppressive drug mainly recommended for rheumatoid arthritis is also reinforced for COVID-19. Despite the fact that there is widespread use of tocilizumab as off-label treatment the efficacy and safety of tocilizumab in the management of COVID-19 has yet not proven. Convalescent plasma therapy in which antibodies are given to the infected person also give mixed results. Till now, it is observed that most safe, simple, and effective method for protection against coronavirus are vaccines which can control this pandemic. Several vaccines are approved for COVID-19 which are summarised in Table 2. But as there are not enough vaccines doses currently available for the entire world, we have to depend upon supportive treatment strategies till the time we vaccinate all our populations.

References are available at www.pharmafocusasia.com

Rupesh K Srivastava is currently working in the Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, India. His group is actively involved in deciphering the cellular and molecular interactions between the Immune and Bone systems i.e. ‘Osteoimmunology’. His group for the first time highlighted and summarized the specific role of immune system in the development and pathophysiology of post-menopausal osteoporosis leading to establishment of a new field of biology proposed by him as “Immunoporosis: The Immunology of Osteoporosis”.

He has been awarded with the prestigious “G. P. Talwar Young Scientist Award”- TWICE. He has authored over 45 publications, 07 book chapters, along with Google Scholar H-Index of 16 and over 1094 citations to his credit.

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41

Toxic-sterile Charging Isolator for Preparation Vessel

Tailor made solutions for your needs

FPS is an Italian company specialised in the design and manufacture of containment systems and micronisation solutions for the handling and production of active pharmaceutical ingredient and sterile pharmaceuticals; FPS is focused on pharmaceutical, biotech and chemical companies all over the world.

Eighteen years after its foundation, FPS has three sites: the headquarters in Como, a large production plant in Fiorenzuola d'Arda (Italy) and a sales office in Philadelphia (USA).

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With almost 100 employees and over 1,300 systems in operation worldwide for handling pharmaceutical substances, FPS has remained very flexible and can easily adapt to very different customer needs.

FPS has recently designed a toxic-sterile charging Isolator for a preparation vessel. The user, a Pharmaceutical European company, needed to weight & charge a High Potent API into a process vessel under Grade A-ISO 5 conditions.

After carefully listening of the customer needs and studying and the challenges of their process, we highlighted the most critical: - Keep the product sterile during the process (10-6 SAL) - Protect the operator from High Potent API (OEB 5) - Avoid back injuries (because of heavy bags handling) - Risk of cross contamination from processing different products.

After this initial analysis, we used our deep experience in this field to design the isolator, challenge our solution through an ergonomic study (testing with the user on a mockup model at scale) and we proceeded with manufacturing.

The solution proposed by FPS nullifies the risk of exposure for operators. As a result, they don't need to use PPEs which creates better ergonomics and leads to higher productivity. In addition, the system can assure Grade A sterile conditions inside each isolator chamber by using an integrated VPHP generator.

Finally, the system can be used for Potent-Sterile API because it can operate both under a positive or negative pressure regime. Another useful feature: the

isolator-Vessel connection doesn’t interfere with the loading cells.

The custom isolator hosts a VHPH generator & H14 HEPA filters and a CIP/WIP system to avoid cross contamination.

It works in positive pressure, so the product is kept sterile during the entire process, but the isolator can switch to negative pressure during CIP/WIP to protect the operator.

Heavy bags are moved on a stainless-steel cart inside the isolator and the process vessel has loading cells for accurate weight.

This special connection between the isolator and the Process vessel assures containment but also sterile conditions and avoids affecting the load cells.

"Our extensive experience in containment and a very close collaboration with the customer allowed us to design an isolator that can maintain the API sterility and protect his operators without using additional PPE," says Stefano Butti, FPS Sales Director. "This design also avoids the risk of cross contamination that can occur when processing different products.

This solution is the perfect combination of optimum productivity and total safety."

Advertorial

)

Process equipment integrated isolators )

))

Benefits of FPS Solution: 1

Safety: all operations take place inside the isolator (discharge, heel removal, sampling, cleaning,…)

2

Integrated custom conical mill: no product transfer, no risk of exposure

3

Safe change of Filter Dryer filtration disc under containment

WWW.FPS-PHARMA.COM - INFO@FPS-PHARMA.COM

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RESEARCH & DEVELOPMENT

Nanotherapeutics

Recent developments and prospects for the treatment of various diseases The recent applications of nanotherapeutics have shown remarkable improvements in various diseases treatment, and this led to a tremendous positive impact on healthcare delivery. Due to the high potentials and manifested benefits of nanotherapeutics, their popularity is increasing, and there is a shift of focus toward them in finding solutions to the limitations posed by conventional therapeutic systems.

Nafiu Aminu, Department of Pharmaceutics and Pharmaceutical Microbiology Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto

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anotherapeutics is the branch of nanotechnology that deals with the application of nanoparticulate drug delivery systems to treat or manage diseases, by specific delivery of a therapeutic agent to a targeted location in the body. Nanotherapeutic strategies have a wide-ranging impact on the medical field and are increasingly gaining more popularity and acceptability than their conventional counterparts due to their high promise in precise delivery of therapeutic formulations. It has also proved to be an emerging treatment strategy for the effective treatment of various medical conditions. This is attributed to the unique qualities of nanocarriers from physical, chemical, biological, optical, and electronic features that are of high interest in medical and engineering fields.

Nanotechnology is a science, engineering, and technology that deals with particles or structures in a size range of 1–1000 nm in diameter. The growing interest in nanotechnology on therapeutics through its offspring, nanotherapeutics,

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is connected to the search for alternatives to some conventional drug delivery systems which are characterised by lack of selectivity, short residence time, poor bio-distribution, poor aqueous solubility, low bioavailability, and an eventual limited effectiveness. These limitations are now being resolved through nanotherapeutic strategies by conveying therapeutic agents explicitly to the site of action through nanocarriers—this helps in maximising the therapeutic efficacy of the drug while minimising its undesirable side effects.

Several hard-to-cross barriers, including Blood Brain Barrier (BBB) and

difficult to reach tissues including tumours that are inaccessible tomany conventional dosage forms can now be accessed through the use of nanotherapeutic systems that include nanoparticles, nanogels, nanofibers, nanotubes, dendrimers, micelles, liposomes (Figure 1), among others.

Additionally, these nanocarriers can enhance the residence time of the loaded drug by shielding it from enzymatic degradation or from rapid clearance, improving solubility of poorly water-soluble drugs, improving stability of unstable drugs rendering them suitable for administration, reducing dose dumping by release rate control, site specific/targeted drug delivery, sustained and controlled drug release, possibility of concurrent delivery of multiple drugs for combined synergetic therapy, and enhancing drug’s pharmacokinetic profile and bioavailability, all resulting to improved efficacy.

The recent nanotherapeutic approaches focus on highly specific nanomedicines’ interventions for a reliable prevention, diagnosis, and treatment of diseases. Due to their high potentials and clinical success, nanomedicines have now dominated conventional dosage forms by more than 75 per cent of the total sales in the market [2]. These momentous changes are expected to continue in the formulation science and therapeutics, by enabling pharmaceutical companies to reformulate conventional medicines to more effective nanomedicines with better patience compliance and stability, longer shelf life, enhanced performance, and more cost effective.

RESEARCH & DEVELOPMENT

The nanotherapeutics applications brings significant advances in various disease therapies, ranging from localised diseases such as dermal, ocular, periodontal, pulmonary, etc., to systemic ones such as diabetes, hypertension, degenerative diseases, cancers, among others. Some these advances are briefly discussed below.

Drug crystallized in aqueous fluid

Hydrophobic tail

Encapsulated drug

Lipid-soluble drug in biolayer Liposome

Hydrophilic head Micelle

Dendrimer

Infectious diseases

Conventional dosage forms such as tablets and capsules for antimicrobial agents have been used for more than a century to treat different infectious diseases. However, several bacteria developed resistance mechanisms to these antibiotic products as time passes by, thus making the treatment of some diseases less effective.

Through the nanotherapeutic approaches, the resistance problem could be overcome by enhancing the effectiveness of antibacterial agents. The recent researches that focuses on this direction is to use of nanocarriers to increase the antimicrobial activity of drugs, especially those against drug-resistant bacteria. An example of these strategies is the use of organic and metallic nanoparticles for synergistic lethal effects with several conventional antibacterial, antifungal, and antiparasitic drugs.

According to a published review article [3], nanotherapeutic systems composed from polymers, lipids, and metals have been developed for the treatment of tropical diseases from protozoan origin, namely, leishmaniasis, Chagas disease, and African trypanosomiasis. Scientific evidences demonstrated that the developed nanosystems could improve targeting to pathogens, penetrate barriers within the host, and minimise toxicity by reducing the dose regimen and frequency of administration. In a similar development, Vijay Kumar Prajapati of the Institute of Medical Sciences, Banaras Hindu University, India, and co-workers developed a functionalised carbon nanotubes for delivery of amphotericin B to reduce the toxicity and improve the efficacy of the drug in the treatment of leishmaniasis. The researchers found this novel nanotherapeutic system to inhibit 99 per

Encapsulated drug Nanotube

Nanoparticles

Nanogels

Nanofibers Hydrogel cross linkage Nanoparticle

Figure 1: Some nanotechnology-based drug carriers, including liposomes, micelles, dendrimers, nanotubes, nanoparticles, nanofibers, and nanogels. Reprinted from Aminu et al. (2020), The influence of nanoparticulate drug delivery systems in drug therapy, with permission from Elsevier[1].

cent of parasite growth in hamster model, following a 5-days oral administration at 15 mg/kg body weight.

In a recent investigation published in 2020 by Laura Freitas of University of Sao Paulo, Brazil, chitosan nanoparticles loaded with an active compound called N’-((5-nitrofuran-2yl)methylen)2-benzhydrazide showed promising results against multidrug-resistant Staphylococcus aureus. The nanoparticles exhibited best results for inhibition of Staphylococcus aureus strains as compared with free drug and empty chitosan nanoparticles. The nanoparticles also demonstrated good influence on tissue regeneration which render them to be a promising alternative in the treatment of multi-drug-resistant infections, especially in burned skin areas.

Nanocarriers have an established role in various dental applications which include targeted drug delivery in periodontitis treatment. I and my co-researchers have developed nanotherapeutic systems, namely, nanoparticles and nanogels for the effective treatment of periodontitis. The

nanogels we developed demonstrated dual action (antibacterial and anti-inflammatory) due to entrapment of triclosan and flurbiprofen. It displayed pH-dependent swelling and erosion, and temperatureresponsiveness. An in-vivo study of the nanogels on experimental periodontitis rats confirmed the dual antibacterial and anti-inflammatory effects, which revealed an excellent therapeutic outcome.

The recorded successes of nanotherapeutics against infectious diseases, led to the further studies, i.e., clinical trials of some products. For example, Bedaquiline™ and delamanid™ are under clinical trials for their efficacy against multidrug resistance pulmonary tuberculosis. Arikace™, a liposomal amikacin is also under clinical trials for pulmonary nontuberculous mycobacterial lung disease. Similarly, clinical trials are ongoing for lipid nanosystems-based prophylactic vaccines against virus infections such as Zika virus, rabies, human metapneumovirus, influenza viruses, and human parainfluenza.

Certainly, many of these products will

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RESEARCH & DEVELOPMENT

Cancer diseases

The advances in nanotherapeutics have brought alternative approaches to overcome many limitations of traditional anti-cancer drugs. This was by enhancement of permeability and drug retention effect at the tumour sites in the treatment of cancers. The usual toxic effects of anti-cancers drugs on healthy cells and tissues can now be avoided by the use of nanocarriers for specific delivery of these drugs to the targeted cells, thereby minimising their detrimental effects on the healthy cells while maximising their therapeutic effect on the cancerous cells.

The flexible features of nanoparticulate systems that permit modifications of their physical and chemical properties such as size, shape, and chemical composition makes them a suitable candidate for targeting different types of specific tumour cells. This type of targeting can be active or passive.

Active targeting delivery of anti-cancer drugs is achieved by equipping nanoparticulate system with suitable ligands to enable their interaction with the tumour cells through molecular recognition. In this mechanism, targeting ligands are attached on the surface of the nanoparticulate system to facilitate targeting of tumour cells[1]. Doxorubicin and docetaxel are potent anti-cancer drugs that have been employed in the treatment of cancers like breast cancer, sarcomas, and lymphomas. However, several limitations such as hydrophobicity, cardiac complications, and systemic toxicity due to nonspecific distribution, restricted their clinical usage. Through nanotherapeutic systems, these drugs are brought back to clinical relevance by active targeting strategy. Mohamed Dawoud of Umm Al Qura University, Saudi Arabia and co-team have recently reported docetaxel-cubic nanoparticles (cubosomes) for targeted delivery to tumour. In another recent study by Afaf H. Al-Nadaf of Mutah University,

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Jordan, functionalised mesoporous silica nanoparticles loaded with doxorubicin was synthesised using lactose and hydrophilic polymer as a hepatocellular carcinoma drug delivery system. The researchers found that the synthesised nanoparticles are promising drug delivery system in hepatocellular carcinoma.

Passive targeting is also being employed in modern cancer therapies.

This approach relies on distinctive characteristics of the tumour milieu which are usually absent in healthy tissues, to facilitates deposition of nanomedicines in and around the tumour tissues. Therefore, the delivery of nanoparticulate systems to the targeted tumours is determined by factors that are inherent to the targeted tumour’s microvasculature in addition to the factors that are associated to the nanocarrier, i.e., size, shape, density, surface charge, etc. A product of this strategy is SP1049C™, a novel formulation of P-glycoprotein targeting micellar loaded with doxorubicinis already under clinical trials. It exhibited promising effectiveness in the treatment of adenocarcinoma.

Neurodegenerative diseases

Parkinson’s disease, Alzheimer’s disease, dementia, Huntington’s disease, and amyotrophic lateral sclerosis are neurodegenerative diseases that are characterised by gradual degeneration of the structure as well as the function of a nervous system.

The available conventional medications for the treatment of these diseases are less effective as they suffer from poor solubility, low bioavailability, drug resistance, and lack of penetration of brain in an adequate amount to elicit desirable therapeutics action. The nanotherapeutic systems offer solutions to these problems by facilitating the entry of drug molecules across the AUTHOR BIO

scale through the clinical trials and eventually be approve for regular clinical usage in the near future.

BBB, faster absorption, targeted drug delivery, and controlled drug release.

Cristina de la Torre and Valentín Ceña of Universidad de Castilla-La Mancha, Spain summarised the roles of nanoparticles of polymeric, lipid, magnetic and gold sources; liposomes; dendrimers; and carbon nanotubes on the treatment of Alzheimer’s disease. They revealed that the lipophilic composition of liposomes and solid lipid nanoparticles offered them excellent feature to easily cross the BBB and improve circulation lifetime in the central nervous system, thereby efficiently deliver therapeutic compounds into the brain. The authors also reported that the nanotherapeutic systems could have their structures decorated by addition of peptides or polysaccharides on it to impart certain targetability characteristics to them toward the brain areas. An example of this is the decoration of dendrimers with transferrin to facilitate the passage of the dendrimers across BBB, by enabling interaction with specific receptors that are expressed on the surface of BBB endothelial cells. Therefore, these nanoparticulate systems have been proposed as potential carriers for drugs to treat Alzheimer’s disease.

Certainly, nanotherapeutics have brought a remarkable success in the modern drug therapy for various diseases by overcoming several limitations of conventional therapeutic systems and offering safer and more effective treatment options. With many of them entering clinical trial stages, we shall witness their outpouring in the drug market soon, and this will tremendously improve the modern therapeutics.

References are available at www.pharmafocusasia.com

Nafiu completed his PhD in Novel Drug Delivery Systems from Universiti Sains Malaysia (USM) in 2019. He passed his B. Pharm. and M. Pharm. (Pharmaceutics) with first division from Hamdard University, India in 2008 and 2010, respectively. Nafiu has been a lecturer at the Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto since 2013. He published several articles in international and national journals of repute and presented his research work in several international conferences.

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Do You Need Managed File Transfer or Just an FTP Server?

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Depending on the answers to the questions above, the wrong choice can lead to significant consequences like spending too much for a file transfer solution or worse fined for non-compliance with a data protection regulation.

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RESEARCH & DEVELOPMENT

How to Study Drug Transport at Biological Interfaces To design drugs with better absorption and distribution, scientists need to have a comprehensive understanding of the transport mechanism of drugs at biological interfaces. Thus, developing techniques capable of monitoring transport in real-time is crucial for pharmaceutical industries. Currently, fluorescence, SPR, and SHS are the most state-of-the-art approaches.

Mohammad Sharifian, Department of Cell Biology, University of Virginia

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rugs as small- or medium-sized molecules (1-2 nanometer in diameter) typically possess both lipophilic and hydrophilic properties. For a drug molecule to reach its intracellular target, it usually needs to cross several barriers including mucus gel layer, intestinal epithelial cells, capillary endothelium, and finally membrane of target cells. In all those interfaces, lipoidal diffusion and protein-mediated passive transport across lipid bilayers play an important role in its molecular entry. Thus, understanding the mechanism of drug transport at biological membranes provides us with a theoretical foundation for designing powerful drugs with better Absorption, Distribution, Metabolism, Excretion, and Toxicology (ADMET) properties.

Physicochemical properties of drug molecules, including molecular weight, surface charge, lipophilicity, acid/base properties, number of hydrogen bonds and rings determine their behavior in a solution and at membrane barriers. While the ‘Overton’s rule’ simply states that membrane permeability of a

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permeant, Pm (m s-1) is proportional to the product of its diffusivity, Dp (m2 s-1) and oil/water partition coefficient, Ko/w (unitless), in a quantitative structure-permeability relationship (QSPR) model, drug’s molecular weight, number of aromatic or non-aromatic rings, and hydrogen bond donors and acceptors are utilised to predict permeability of the molecule by which poor permeability is more likely for Ko/w> 100,000, molecular weight > 500 Da, hydrogen bond donors > 5, and hydrogen bond acceptor > 10 1.

The anisotropic and inhomogeneous nature of biological membranes has encouraged scientists to develop ‘inhomogeneous solubility-diffusion model’ which

considers depth-dependent partitioning, resistance, and diffusion parameters. As depicted in Figure 1, drug permeation is determined by two main equilibria of drug partitioning between the aqueous compartments and the lipid leaflets, and drug translocation between the two lipid leaflets by which for lipophilic compounds, the membrane may act as both a barrier and a sink. The following equation can be used to estimate the permeability of drug molecules at a lipid bilayer of biological membranes2, where, is the membrane viscosity (kg m-1 s-1), dm is the effective thickness of the membrane, Vp is the volume of the drug molecule (m3), is the size selectivity factor of the permeant, Kc ⁄w is the partition coefficient of drug between water and chloroform, and kB and T are respectively Boltzmann constant (1.38×10-23 m2 kg s-2 K-1), and temperature (K).

Model Membrane Systems in Drug Permeation Measurements

A monolayer of cultured colorectal adenocarcinoma-derived cells (Caco-2 cell permeability assay) is widely used to mimic a single layer of intestinal

Note that the universality of a theory or model is limited as the success or failure of each model will be highly dependent on the training set of molecules.Note that the universality of a theory or model is limited as the success or failure of each model will be highly dependent on the training set of molecules.

RESEARCH & DEVELOPMENT

epithelium in drug permeation measurements. In this approach, cells are grown on a porous filter separating two stacked microwells with the drug candidate added to one of chambers, and its transport through the interface is then probed, usually by fluorescencebased techniques. Due to complexity of the Caco-2 cellular membranes, and the time required for the preparation of stable monolayers of the cells in each experiment (up to 30 days), scientists prefer to use model membranes which also allow them to perform experiments under conditions that Caco-2 cells may not withstand. Moreover, they would be able to apply a variety of methods for permeation measurements, perform high-throughput analyses, and discern

the roles of lipids in drug permeation processes. Model membranes include: 1.)

Parallel artificial membrane permeability assay (PAMPA), 2.) Phospholipid vesiclebased permeation assay (PVPA), and 3.) liposomes in suspension. Similar to Caco-2 cell assay, in PAMPA and PVPA, porous filter membranes are used to separate two stacked microwells. Liposomes, including small (SUV; 20-100 nm), large (LUV; 0.1-1 m), and giant (GUV; 1-100 m) are biomimetic model systems that can reliably reproduce the bilayer structure. They also allow scientists to apply various techniques in their studies. Note that model membranes lack typical cell membrane characteristics such as membrane proteins, and therefore, biophysical interactions of drug

molecules with model membranes may not exactly replicate all the aspects of the cellular uptake processes. Thus, for an accurate extrapolation of in vivo drug permeation measurements, researchers should select a suitable membrane for the purpose in mind.

Novel Approaches in Drug Permeation Measurements

Fluorescence-based techniques, surface plasmon resonance (SPR), and secondharmonic light scattering (SHS) are the most recent approaches to study drug transport at biological interfaces 2.

Both spectroscopic and imaging modalities of fluorescence techniques have been applied in a wide range of model systems (PAMPA, Caco-2 cells,

Article talks about how drugs are transported at biological membranes.

FIGURE 1. Schematic illustration of passive membrane permeation processes.

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RESEARCH & DEVELOPMENT

Article talks about how drugs are transported at biological membranes.

FIGURE 2. Schematic illustrations of fluorescence-based (A), SPR (B), and SHS approaches (C) that are currently used in drug membrane permeation studies.

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causing them to resonate (surface plasmon). Any reaction occurring close to a metal surface leads to altered conditions for surface plasmon excitation.

Interaction of drug molecules with the immobilised liposomes on the sensor surface can be followed in real-time by measuring an optical response, usually expressed in response units, RU (see Figure 2B). A phenomenological model can relate the membrane permeability of the drug molecule with the time-resolved SPR responses, for example, to screen melittin- and aquaglyceroporin PfAQPmediated transfer of sugar alcohols and sucrose across liposome membranes.

SPR has the advantage of being easily combined with micro-fluidic devices, and perform multiple measurements on the same set of immobilised liposomes.

SHS is a label-free, real-time, and membrane-specific optical technique with high sensitivity. It, in contrast to

AUTHOR BIO

or liposomes) by which either the drug molecule is fluorescing under some conditions (e.g., at a specific pH) or a fluorescent probe is used to track the transport of the drug molecule (indirect measurement) (see Figure 2A). In microscopic modality, transport of the drug molecule can even be visualised with sub-liposomal spatial resolution.

Developing a phenomenological model in which membrane permeability of the drug is related to its concentration in the region of measurement (i.e., signal intensity is proportional to the concentration of the drug) will allow us to deduce membrane permeability value along with kinetic parameters, e.g., rate constants of sequential processes.

Fluorescence techniques have been widely used to monitor the transport of anti-cancer drugs and tetracycline antibiotics across liposomal membranes, and to determine the antibiotic uptake in bacteria at individual cell level.

Fluorescence techniques can also be combined with other approaches such as reflectometric interference spectroscopy.

In contrast to fluorescence, SPR is a label-free technique that is based on evanescent wave sensing by which a polarised light beam reflected from the sensor chip (gold or silver) is absorbed by the free electrons at the surface

fluorescence, involves coherent radiative scattering where incident light of frequency induces a polarisation of frequency 2 serving as a source of the SHS scattered light. In a typical experiment, a sample of an SH-active drug molecule is exposed to an incident laser beam supplied by a mode-locked Ti:Sapphire laser, and the scattered signal is selectively collected by using a band-pass filter and monochromator. Note that the SHS light from drug molecules in solution destructively adds to zero, but when molecules adsorb onto the membrane, they align with one another resulting in a coherent signal that scales quadratically with the drug concentration at the membrane surface. If the molecule diffuses across the membrane, signals from the oppositely oriented molecules on the inner surface cancel with the signal from the outer surface, which results in a real-time decrease of the signal (see Figure 2C). By subjecting the time-resolved SH signals to a phenomenological model, rate value of each step can be quantified. SHS has been applied to monitor the diffusion of druglike molecules across lipid membranes in liposomes and living cells, to study druginduced changes to membrane properties, and to quantify molecular transport in sub-cellular regions of individual living cells.

Overall, in modern drug discovery research, recently developed methodologies including fluorescence, SPR, and SHS can be exploited to elucidating how the molecular structure of the drug candidates relates to their membrane permeability.

References are available at www.pharmafocusasia.com

Working as a Postdoctoral Research Associate in the Laurie lab at University of Virginia (Cell Biology) immediately after receiving Ph.D. in Physical Chemistry (Temple University), Mohammad is currently studying the antimicrobial mechanism of tear lacritin peptide ‘N-104’ towards ocular pathogens.

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CLINICAL TRIALS

INNOVATIVE TRIAL DESIGNS The median investment to bring a new drug to market is estimated at US$ 985 million, which is expected to rise further in the current COVID-19 era. To improve efficiency of clinical trials, lower the costs, and enhance data quality—while ensuring patient access to new treatments—the drug development industry is pursuing new seamless approaches to clinical trial design. The innovative approach to contemporary clinical trial designs like integrated trials, basket trials, therapeutic repurposing during the trial etc. will not only optimise the cost and speed but will inspire both investigators and pharmaceutical companies for cutting-edge scientific discoveries.

Sowmya Kaur, EVP, Navitas Clinical Research and BU Head Clinical APAC, Navitas Life Sciences (a TAKE Solutions Enterprise) Atul Gupta, Global Medical Monitor, Clinical Research and Drug Safety Medical Professional, AVP, Medical and Scientific Affairs at Navitas Life Sciences (a TAKE Solutions Enterprise)

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CLINICAL TRIALS

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raditional drug development can be time-consuming and demands high investment. Recent advances in medicine with the availability of certain powerful tools are enabling researchers to understand the inner workings of human disease at the molecular level, therefore leading to increased demand and potential of discovering and developing innovative medicines. The field of clinical research is expanding tremendously, and the clinical development programmes are becoming more complex and costly, owing to factors such as increased regulatory scrutiny, the growing need to demonstrate safety,

efficacy and value of drugs, conducting trials in defined patient subpopulations or patients with rare diseases and various ethical considerations. Further, various environmental, biological factors contribute to increasing incidence non communicable diseases and new emerging infectious diseases which often pose unprecedented challenges for the global heath community as well as the conventional clinical development paradigm.

The median cost of conducting a study from protocol approval to final clinical trial report can be US$3.4 million for Phase I trials involving patients, $8.6

million for Phase II trials and US$21.4 million for Phase III trials. Many new approaches for clinical trials are using novel drug development tools, such as biomarkers, to identify patients that may respond to a therapy. To improve the efficiency of clinical studies, a spectrum of expedited clinical trial designs are being developed which aim for more efficient trials associated with reduced development timeline and less resource requirement. Especially in the global pandemic, e.g. COVID- 19, we are increasingly facing the need for efficient designs and analyses of clinical trials. Innovative trial

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CLINICAL TRIALS

designs are providing the possibility for researchers to shorten trials, improve success rates and increase the efficiency of clinical research. The innovative approach to contemporary clinical trial designs like integrated trials, basket trials, therapeutic repurposing during the trial etc. will not only optimise the cost and speed but will inspire both investigators and pharmaceutical companies for cuttingedge scientific discoveries. One of the FDA’s initiatives has been to operationalise complex innovative trial designs.

The FDA defines complex clinical trial designs as designs that are intended to advance and modernise drug development. Several generic drugs get approved on routine basis via this approach, reducing the huge costs and time associated with standard clinical RCTs .

Phase 0 clinical study

This phase includes exploratory clinical studies with less drug exposure than Phase I trials, to bridge the gap between preclinical studies and traditional clinical

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development and to facilitate decreased failure of drugs and improving the efficiency of drug candidates in later phases of clinical trials. Phase 0, also known as micro dosing studies, involve short processing time, early assessment of toxicity, efficacy and can provide the ‘go-or-no go’ decision making prior to a formal RCT. Phase 0 results guided with respect to required alterations for cell cycle-associated kinase inhibitor, AZD1775 for treatment of glioblastoma.

Seamless clinical trials

This approach integrates the 3-phaseprocessing of RCTs into a comprehensive clinical study without phase gaps.

Phase I/II is designed to examine the most efficacious dose based upon some surrogate end-points such as Objective Response Rate (ORR), this dose is then continued into the confirmatory stage for further testing without a timing gap, to obtain more definitive end-points such as overall survival.

Programmed death 1-blocking antibody Keytruda achieved Accelerated Approval (AA) by the FDA based on similar approach.

Inhaled indacaterol, a long-acting b2-agonist for treatment of chronic obstructive pulmonary disease, was clearly improved through a seamless (Phase II-III) clinical trial.

Master protocols

This approach allows evaluation of multiple treatments, target populations or both within a single protocol in a more efficient and ethical way. Master protocols are quickly emerging as a critical tool for evaluating potential promising COVID-19 therapies such as SOLIDARITY trial outlined by World Health Organization (WHO) involves evaluation of the benefits and risks for several preventive candidate SARS-CoV-2 vaccines.

Master protocols can be categorised into basket trials, umbrella trials or platform trials.

CLINICAL TRIALS

Basket clinical trials

The drug being tested is examined to reveal the therapeutic efficacy in wide spectrum of diseases simultaneously.

Basket trial involves selection of therapeutically sensitive disease types and patient sub-populations, with a biomarker-based diagnosis followed by the disposal of tumour types with futile response and further evaluation of subjects with promising results. Larotrectinib an selective Tropomyosin Receptor Kinases (TRK) inhibitor is approved for wide spectrum of tumour types, reflecting a dramatic success of basket clinical study. Aberrant TRK activation is expressed in more than 20 distinct tumor types. This approach can address the unmet clinical needs of combating the rare neoplasms in oncology drug development.

Umbrella trials

These trials evaluate multiple targeted therapies for a single disease in patients who have the same type of cancer but different gene mutations (changes)

or biomarkers. Plasma MATCH is an umbrella trial that evaluated five different therapies for advanced breast cancer based on different predictive biomarkers.

Platform trials

These trials include finding the best treatment for a disease by simultaneously investigating multiple treatments, using specialised statistical tools for allocating patients and analysing results which can involve dropping treatments for futility, declaring one or more treatments superior, or adding new treatments to be tested during the course of a trial. In 2013, the Innovative Medicines Initiative of the European Union (EU) announced platform trial for the prevention of Alzheimer disease to evaluate multiple treatments, from multiple sponsors, for persons at high risk for Alzheimer disease.

obtained regulatory approval or been tested in clinical trials for other disease indications. This could involve a new formulation, delivery route or dosage of the drug and may potentially also involve a different drug target relative to the original indication. This study design allows re-purposing of drugs to an alternative indication, if the drug was facing lack of efficacy or safety issues in earlier studies and optimisation of trial to cover more therapeutic areas on the basis of the emerging evidence.

The drug sildenafil was earlier designed for management of angina pectoris and was later redirected for treatment erectile dysfunction. In order to support therapy for COVID-19, the safety and tolerability of an anti-parasitic drug was tested on healthy volunteers.

Therapeutic repurposing

Real-world evidence and real-time data

Drug repurposing involves the identification of novel therapeutic indications for drugs which have previously

Real-world evidence (RWE) data involves the collection of demographics, family history, lifestyle, and

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genetics data which can be used to predict probabilities of diseases in the future. Real world evidence can be obtained from multiple non-interventional sources like patient registries, claims, observational studies, doctor visits, prescription data and connected devices. Clinical practice guidelines that have been using RWE-based insights include the National Comprehensive Cancer Network. Artificial intelligence is being utilised to for personalised medicine by identification of effect of comorbidities on therapy outcomes and subgroups in single disease. A recently published study that used RWE to compare cardiovascular outcomes between different therapies was the Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Type 2 Diabetes (CAROLINA) trial.

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Decentralised clinical trials

This is an approach to reduce costs and provide better access for patients by conducting trials directly with patients, also called ‘direct-to-participant’ trials.

This includes the single centre overseen by a physician principal investigator, but otherwise has no clinical sites and no clinical investigators. Recruitment of subjects can be accomplished by using internet and interactive sessions via smartphones. COVID-19 has pivoted decentralised clinical trials, with e-consent, site less trials and digital tools used to connect with patients.

Adaptive clinical trials

Adaptive clinical trials are trials that allow for continual changes to the trial design based on data available.

This helps in improving cost and

efficiency, with a relatively high likelihood of success. An adaptive design allows prospectively planned modifications to the trial and/or statistical procedures of the trial after its initiation without declining its validity and integrity. Adaptive trials also aid in mitigating risks and delayed timelines. An example of adaptive trials is when trial dosing information is obtained from a single two-year combined Phase II/III, that may have taken a greater number of years and consecutive trials when traditional methods are followed. Adaptive trials also aid in lowering sample size, as the same patients may be used in multiple stages of the study. Such trials will also help in early termination of the study and reassessment of treatment measures and patient subgroups.

A seamless Phase II/III was designed

CLINICAL TRIALS

Conclusion

Clinical trials play an essential role in evaluation the efficacy and safety of tested drugs for human use prior to marketing authorisation. The process of clinical trials is evolving continuously owing to the advancing research for pathophysiology and understanding of diseases on molecular level. However, due to increasing unmet need for development of drugs for various therapeutic areas, traditional clinical trials are facing challenges due to tedious procession, higher cost involvement, long duration of studies and stringent regulation. Unacceptable levels of attrition in the clinical stage of development are driving profound changes in the architecture, design, and analysis of

clinical trials.31 There is an extensive need of development of innovative trial designs to increase the efficiency of clinical research. These trials provide a boost in clinical research by cutting on the cost and time factor and are contributing for development of many new chemical entities and drugs in view

AUTHOR BIO

for 4vHPV vaccine according to which medium dose selected in Phase 2 was further used in Phase III confirmatory study and later own vaccine was licensed for the prevention of HPV 6/11/16/18 related cancer diseases.

of the evolving era of personalised and evidence-based medicine.32 In future, more and more companies will embrace innovative clinical trial designs, thus improving the success rate of drug development.

References are available at www.pharmafocusasia.com

Sowmya Kaur, Head APAC Navitas Clinical Research and Global Head Clinical Solutions at Navitas Life Sciences (a TAKE Solutions Enterprise), took on her new leadership role during the COVID-19 pandemic. With a career spanning over 18 years, Sowmya has worked across multiple aspects of the industry including operations, business development, and strategy with leading industry players like Cognizant, IQVIA, Kendle etc. She has a successful track record of building and leading Clinical Development engagements across Emerging Markets with successful delivery of a portfolio of projects.

Atul has over 16 years’ experience in Clinical Research, Drug Development and clinical practice. Atul has worked as Global Medical Lead (USA, Europe and Asia Pacific) in more than 50 studies, and has been involved in apt designing of complex trials.

Atul has experience in diverse therapeutic areas, in all the phases (I-IV), in both drugs as well as devices. Atul has multifaceted experience in medical writing related to clinical studies (Protocol, ICF, CSR etc..)

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PHYTOCHEMICALBASED NANO FORMULATIONS A potential approach to address

bottleneck issue of drug resistant cancer

More than 90 per cent cancer deaths are ascribed to Multi Drug Resistance (MDR). MDR is the condition, which is either intrinsic or acquired, characterised by resistance towards conventional as well as novel chemotherapeutics. Multifunctional, multi-targeting nanophytochemicals is now being considered as potential hope in the form of synergistic therapeutics.

Abhijeet Dattatraya Kulkarni, SRES’s Sanjivani College of Pharmaceutical Education and Research

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C

ancer is characterised by unrestrained growth of abnormal cells which have potential to alter genome, dynamically. Invasion of nearby tissues and ability to metastasise by such cells hamper the normal biofunction of healthy cells. According to recently published statistical reports, almost 90 per cent of advance stage cancer patient’s death can be ascribed to cancer drug resistance.

Cancer drug resistance is complex phenomenon and can be categorised as intrinsic or acquired resistance. In few cases, cancer cells survive even at the

MANUFACTURING

clinically relevant doses of established standard chemotherapy which is called as intrinsic resistance whereas at some instances after attaining promising result at initial phases, therapy suddenly turns out to be non-responsive and leads to recurrence of tumour growth. This acquired drug resistance often called as Multi Drug Resistance (MDR) when cancerous cells develop resistance and cross resistance to functionally or even structurally unrelated chemotherapeutics agents. The cancer drug resistance remains serious challenge and observed not only in chemotherapy but also with cancer immunotherapy and targeted anticancer drugs. Although it is feasible by liquid biopsy to detect drug resistance and cancer relapse at early stage with real time monitoring of patient’s therapy; however there lacks corresponding full proof treatment modalities.

Various mechanism of MDR have been put forward such as genetic alterations that occur after or during the treatment, signalling pathway feedback loops and bypass mechanisms, tumour microenvironment, tumour heterogeneity and tumour evolution. Many times, more than one mechanism is involved in the MDR which ultimately results in enhanced drug efflux, altered drug metabolism, increased DNA damage repair and reduced apoptosis. Dynamic genetic alterations, plastic and adaptable behaviour with the tumour microenvironment leads to somatic mutations associated with drug resistance and makes cancerous cells capable to survive even in increased concentrations of the drugs.

These epigenetic alterations may even induce surrounding normal tissues to secrets various enzymes to create camouflage effect or to change the overall microenvironment to suppress immune response signals. Current conventional treatment modalities include chemotherapeutics, radiation therapy or surgery which appears insufficient and suffers with many limitations. Ideally chemotherapeutics agents should selectively kill rapidly dividing cancerous cells sparing normal healthy cells. However, devoid

of such differentiation function, normal dividing cells (hair keratinocytes, intestinal epithelial cells, haematopoietic cells) are also killed significantly. This ultimately leads to chemotherapy induced side effects which may be short term (alopecia, myelosuppression, Stomatitis, nausea) or long term (cardiac dysfunction, infertility, secondary leukaemia, weigh gain).

In recent years, natural product and their derived phytochemicals have attracted a great deal of attention from researchers due to their potential ability to suppress the most chronic illnesses.

Specifically, in case of anticancer drugs approved world-wide over the last 6 decades, nearly 50 per cent were either plant based or directly derived from them.

If all plant inspired pharmacophores are to be considered then almost 75 per cent of all the anti-tumour drugs were natural compounds. This notable contribution from the plant-based chemicals emphasises its important role in the cancer drug discovery process.

The isolated fraction of these natural compounds often termed as phytochemicals (‘Phyto’ means plant). Basically, they are secondary plant-metabolite. They are generally produced as a defence mechanism and have protective function. They are developed against predators or to aid the organism adapting to its surrounding environment. The prolong evolution while

Phytochemicals can act on many molecular targets and through multiple signalling pathways, simulta-neously and perform multiple functions.

adapting to various stresses and natural selection process, have resulted into optimised, biologically active metabolites which can be highly potent and selective.

Phytochemicals based on their molecular structure were classified into phenolic compounds, alkaloids, lectins, terpenoids, isoprenoids, and quinones.

The majority of these natural products fall under phenolic compounds comprising polyphenols and flavanoids.

Now a day’s phytochemicals are being actively thought as adjuvant therapy or a combination therapy along with chemotherapeutic agents for their safety and reduction in chemo-toxicity.

Interestingly, phytochemicals can act on many molecular targets and through multiple signalling pathways, simultaneously and perform multiple functions.

These mechanisms may involve activation of caspases, p53, up-regulation of pro-apoptotic proteins, down-regulation of anti-apoptotic proteins, Inhibition of Akt/mTOR signalling pathways or phosphorylation of NF-kappaB, STAT3 and PI3K. Phytochemicals can work as MDR reversal agents by affecting expression or activity of efflux proteins (ABC transporters). In addition, they can exhibit synergism with other anticancer agents.

In spite of all their merits most of the phytochemicals suffers with poor solubility, permeability or stability issues. These constrains can be successfully managed by nanotechnology. Nano drug deliverybased carrier system were widely applied to deliver chemotherapeutic agents for thernostics applications. These vector systems found to deliver therapeutics in sufficient concentration at the site of action if decorated with targeting ligand.

These novel vectors helps to combat MDR by overcoming drug efflux associated with ABC transporters. Various form of nanoformulations (Polymeric nanoparticle, Solid lipid nanoparticles, Liposomes, Nanomicelles, Dendrimers) improves transportation across the cell membrane, bioavailability and therapeutic efficacy of phytochemicals. Selected phyto-nano formulations are applied for resistant cancers are depicted below. www.pharmafocusasia.com

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Polymeric nanoparticles are used to encapsulate the small molecular weight drug for controlled drug delivery at the targeted site. This encapsulation avoids degradation of the drug from surrounding enzymes.

Formulation of the nano size particles can be prepared by natural or synthetic polymers which are biodegradable. Gera et al. have developed nano composite encapsulated with phytochemical extract (BRM270) and tested against human hepatic cancer cell lines. As compared to free extract the phyto-nano-composite was found to be better at arresting cell growth at 12 μgmL-1. This extract was found to down-regulate certain proteins (MMP9, BCL2, IL6) and induce apoptosis.

Liposomes

Liposomes are vesicular structures in size range of 10 nm to 1μm. The composition of liposomes usually involves phospholipids and surfactants and co-surfactants, where both polar and non-polar drug payload can be delivered to the target site.

These lipidic structures are biodegradable and biocompatible. Shu et al. have surface modified liposomes encapsulating betulinic acid targeted towards myelogenous leukaemia. Mannosylerythritol lipid-A was used to increase the permeation ability. This enhanced transfection lead to increased apoptosis and corresponding anticancer effect was attributed to G1 stage inhibition. Similarly, Icariin, a flavonol glycosides, loaded phytosomes were fabricated by solvent precipitation and found to induce apoptosis in ovarian cancer cell lines.

Solid lipid nanoparticles

The composition of Solid Lipid Nanoparticles (SLN) consist of solid lipid core which is stabilised by phospholipids, bile salts or sterol as interfacial surfactants.

SLN can incorporate both polar and nonpolar drug moieties. Surface modification with suitable ligand enhances the targeted delivery of the SLN. Kumar et al. developed trans-resveratrol-chitosan coated ferulic acid loaded SLN. The developed SLNs were further conjugated with 64

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folic acid to target colon cancer. Chitosan coated formulation exhibited better cytotoxicity as compared to uncoated formulation. Western blot and flow cytometry confirmed high receptor binding with improved drug uptake.

ligand to target aptamer specific colorectal cell lines (SW620). Both in votro and in vivo experiments confirmed anticancer property.

Nanomicelles

Especially to address cancer drug resistance, multi-drug therapy approach have been put forward which involves management of cancer via multiple pathways simultaneously. This multifaceted combination approach of phytochemicals with chemotherapeutics, having non overlapping toxicities, is showing improved therapeutic response. This co-delivery of therapeutics has good potential to overcome drug resistance. Recently curcumin and siRNA loaded dendrimer applied to treat cervical cancer. This combination improved apoptosis causing synergistic inhibition of cervical cancer cell lines.

Liu et al. fabricated quercetin loaded mesoporous silica and co-delivered with paclitaxel. These NPs were surface functionalise with chondroitin sulphate.

It was found that prepared formulation overcome the MDR in breast cancer cells.

Nanomicelles are self-assembled submicroscopic colloidal system below 100 nm in diameter. The basic structural unit of micelle is amphiphilic monomer.

These amphiphilic polymer can accommodate both polar as well as non-polar drugs. Recently, Wang et al developed Honokiol (HK) loaded Rebaudioside A composed nanomicelles for treatment of oral cancer. Formulation found to induce ERK signalling by inhibition of DNA damage mechanism. Similarly, self-assembled mPEG-PCL micelles loaded with dihydroartemisinin (DHA) were fabricated which showed 1.38 folds apoptosis in HeLa cells as compared to free DHA. In vivo study also showed tumour reduction. Nanomicelles induces expression of angiogenesis markers leading to cancer cell invasion. Similar result was obtained by Mardani et al. who formulated curcumin loaded nanomicelles to treat lung metastasis. It has been observed than curcumin loaded nanomicelled act even at 20 μM concentration and promote apoptosis.

Dendrimers

Star-shaped nano sized branched structure is called as dendrimer. This tree like structure has central core, internal branches and exterior surface groups. Exterior surface groups can carry multifunctional drug molecules which are easily tunable. Ge et al. formulated celastrol biocojugate consisting of EpCAM aptamer with PAMAM which was used as targeting

AUTHOR BIO

Polymeric nanoparticles

Synergistic approach with phytochemicals for MDR reversal

Conclusion

Cancer drug resistance is complex phenomenon owing to involvement of multifaceted signalling pathways. Though in vitro cyctotoxic assays and preclinical studies are very encouraging with respect to phytochemicals and combination delivery with other chemotherapeutics.

However, more proof of concept and clinical trials will be required to justify the rational synergistic combinations. Yet the approach has great potential and demands further detail exploration from the scientific community to address over-pressing challenge of MDR in cancer.

Abhijeet Dattatraya Kulkarni is currently working at SRES’s Sanjivani College of Pharmaceutical Education and Research, Kopargaon Maharashtra. He has earned his Ph.D. from North Maharashtra University Jalgaon (M.S.). He has more than 12 years of teaching and research experience.

His research expertise lies in the polyphenol drug delivery.

MANUFACTURING

Identifying Routine and Challenging Clinical Pathogens with MALDITOF MS C The article focuses on the use of MALDI-TOF mass spectrometry (MS) for advancing clinical microbial identification, specifically in the Microbiology Laboratory at the Department of Laboratory Medicine, Beijing Tongren Hospital, which has sought to find an alternative to traditional culturing methods for pathogen diagnosis.

The article also explains the benefits MALDITOF MS technology has had on the lab and why conventional methods are not suitable for identification of challenging microorganisms, such as those causing fungal rhinosinusitis (FRS).x Xinxin Lu, Director of the Department of Laboratory Medicine, Beijing Tongren Hospital

linical microbiology research plays a vital role in improving the diagnosis of infectious diseases, drug guidance, hospital infection control and antimicrobial drug management. Traditional biochemical identification methods are relatively complex and cumbersome and cannot fully meet the requirements of turnover time, sample diversity, and identification accuracy. As a result, hospital laboratories are seeking alternatives to traditional culturing methods for pathogen diagnosis.

Unlike traditional biochemical methods, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) determines the protein profile of microbial highabundance proteins (mostly ribosome proteins) and compares their characteristic spectra with proprietary libraries holding reference spectra. Most microorganisms can be accurately identified at the species level. Species-conserved protein sequencing, extensive library references, and strict library quality control processes ensure the accuracy of MALDI-TOF MS identification.

Hospital-wide benefits

Using advanced MALDI-TOF MS technology, a single sample preparation can take only 20 seconds, and approximately 100 samples can be analysed in 60 minutes, greatly improving the speed of identification and the throughput of the hospital laboratory. For critically ill www.pharmafocusasia.com

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patients, obtaining the results 24 hours sooner than with traditional methods is important for rapid targeted antibiotic treatment.

The financial advantages of MALDITOF MS are also significantly changing clinical workflows, as the cost of biochemical identification typically prohibits the analysis of every potentially

contaminating bacterium, meaning some significant microbes may be missed. MS breaks down this barrier, with reagent costs nearly 10 times lower than that of biochemical methods. Identification accuracy is another key benefit. The difficult pathogens that cannot be identified using routine biochemical approaches, such as anaerobic bacteria, can be accu-

rately identified using MALDI-TOF MS. The MS database covers all types of bacteria and fungi, with a clinically common pathogen identification accuracy of more than 98 per cent.

Identifying challenging fungi

Unlike common bacteria and yeast, challenging pathogens are difficult to

Table 1: Comparison of the identification (ID) of the 153 FRS isolates obtained by conventional phenotyping and the MALDI Biotyper (microflex LT/SH system), Bruker Daltonics

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tion time of fungi species, bringing new possibilities for understanding and treating FRS. In 2017, the Microbiology Laboratory of Beijing Tongren Hospital evaluated the performance of MALDI-TOF MS (microflex LT/SH system, Bruker Daltonics, Bremen) in identifying 153 different FRS filamentous fungi isolates.1 The results showed that 151 out of 153 FRS isolates had correct species identification (98.7 per cent) (Table 1). The rate was significantly higher than that of the traditional phenotypic methods (93.5 per cent). MALDI-TOF MS was capable of identifying very closely related species including Aspergillus versicolor (1), Aspergillus flavus (3), Aspergillus fumigatus (2) and Aspergillus terreus (1), which were indistinguishable with conventional phenotypic methods. The MALDI-TOF MS method has proven to be more accurate and quicker than phenotypic methods for the identification of filamentous fungi in clinical microbiology laboratories.

baumannii.2 The detection accuracy rate of MALDI-TOF MS for enzyme-producing and non-enzyme-producing strains is up to 100 per cent, which proves that MALDI-TOF MS has great advantages over other existing phenotypic methods on carbapenemase detection.

The national average resistance rate for carbapenem-resistant Klebsiella pneumonia in China has reached 10.1 per cent (according to 2018 National Bacterial Resistance Detection Network)3 since it was first reported in Zhejiang Province in China in 2007. The mortality of nosocomial infections caused by CRE is as high as 33.5 per cent, and bloodstream infections are as high as 43.1 per cent.4 Because it is easy to spread, enzyme-producing strains accounted for more than 90 per cent of CRE. Rapid detection of enzyme-producing strains is very important for timely and effective clinical treatment. It is also beneficial to promote the rational application of antibiotics and ease the severe situation of antibiotic resistance.

Tacking antimicrobial resistance

Looking forward

MS-based microbial methods are not only changing the way clinical pathogens are identified, but are also aiding the fight against antimicrobial resistance.

Carbapenem-resistant Enterobacteriaceae (CRE) are a group of bacteria that are resistant to the last-line antibiotic carbapenem and pose a significant public health threat as a multi-drug resistant (MDR) pathogen. A study published in 2013 shows the ability of MALDITOF MS to detect carbapenem resistance in VIM-2-producing Pseudomonas aeruginosa, AmpC- and KPC-producing carbapenem resistant Enterobacteriaceae, and OXA-23-producing Acinetobacter

As an emerging rapid detection technology, MALDI-TOF MS is gaining traction as a routine clinical identification tool.

The technology has undergone rapid development in clinical microbiological testing in China over the past ten years, and further advancements such as bacterial typing and homologues analysis, pathogen antigens, serum antibodies, toxicity detection and pathogen identification through fluorescence, could make MALDI-TOF MS a complete solution for microbiologists over the next decade.

AUTHOR BIO

culture, and have slow metabolisms, diverse growth periods, and complex cell wall structures, making them hard to identify by conventional methods.

Filamentous fungi are a key example of pathogens that have, until recently, required cumbersome identification methods involving cultures, microscopic examination, or molecular sequencing.

In addition, the identification is highly dependent on the technical capability and experience of laboratory technicians. Fungal rhinosinusitis (FRS) – a broad term referring to a group of conditions caused by fungal infections of the paranasal sinuses – can cause serious disease if not treated promptly and with appropriate anti-fungal drugs. Misuse of anti-fungals and environmental pollution are both significant contributors to the severity of FRS. Misdiagnosis of FRS, particularly in the case of acute invasive FRS, may lead to treatment failure and can be fatal. Studies show that 80 per cent of FRS is caused by common pathogenic fungi Aspergillus spp. In addition, Fusarium spp., Mucor spp., Rhizopus spp., Rhizomucor spp., Penicillium spp. and Alternaria spp. could be causative agents. Conventional FRS diagnostic methods include clinical observation, endoscopic examination, imaging, pathology, and fungal morphology identification.

FRS pathogens are particularly challenging to identify in clinical laboratories, due to the wide variety of causative species with phenotypically similar characteristics, despite their genetic differences. Identification relies heavily on the experience of laboratory technicians. Identifying FRS pathogens with conventional methods often incurs high costs, results in long turnaround times, low throughput, and low selectivity, and cannot exclude colonisation.

Conventional methods are therefore not suitable for the identification of FRS pathogens. MALDI-TOF MS can identify the individual species using direct transfer to the target or extraction methods, and shortens the identifica-

References are available at www.pharmafocusasia.com

Xinxin Lu is Director of the Department of Laboratory Medicine and is Deputy Director of the Department of Experimental Diagnostics for Capital Medical University. Dr. Lu specializes in experimental diagnosis and pathogenic microbial testing and has been involved with research and teaching work at the university for more than 40 years.

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