Pharma Focus Asia - Issue 47

ISSUE 47

2022

www.pharmafocusasia.com

Naveen G V Corporate Officer & Managing Director, AAPAC

DR REDDY’S WITH BENCHMARK ESG

On digital transformation to enhance safety & sustainability processes Ravi JR Lead Program Manager-SHE Gov. & Audit Sarang Pande Head- Digital Transformation and Process Excellence- OSD

Strategic Instincts

A Digitalised Future for Pharmacovigilance

CHAPTER 3

LET’S STAND TOGETHER

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Future of Pharmacovigilance Emerging role of AI Healthcare data plays a key role in improving quality of life as accurate data can help doctors, patients and other stakeholders involved take the right decisions. Artificial Intelligence (AI) has been contributing to the patient data collection more efficiently with improved systems like natural language processing (NLP) applications that can analyse unstructured clinical notes on patients, giving incredible insight into understanding quality, improving methods, and better results for patient. AI also reduces case processing costs and cycle times to improve pharmacovigilance (PV) activities. AI and Machine Learning (ML) and can play a vital role in pharmacovigilance.

During the early stages of COVID-19 pandemic, numerous approved drugs were repurposed and released off-label to treat patients. In this health emergency, it was extremely critical in evaluating the potential risks of the off-label drugs used. The rate at which new drugs are being introduced into the market resulted in increased drug usage. Thus, the need to analyse benefits and potential risks of drugs too rose making PV extremely important. And today, real-world data and real-world evidence play a key role in the risk-benefit analysis of a drug.

What used to be mere data compilation and information provision for regulators is now transforming into a system for enhancing risk-benefit profile of drugs, enabling caregivers to choose the best possible treatment. Advanced technologies such as automation, advanced analytics and cognitive technologies have played a key role in this transformation. Digital pharmacovigilance enables life sciences companies to embed AI/ML for improved

data quality and insights from regulatory activities.

PV collects, evaluates and act upon adverse events (AEs) by detecting, assessing, and preventing AEs. The increasing amount of data received from individual case safety reports (ICSRs) needs to be properly managed for further references. With the increased number of ICSRs yearly, it is estimated that more than 90 per cent of AEs go unreported, creating an opportunity to apply AI and Machine Learning techniques to improve drug safety assessment.

At the core, automation helps simplify repetitive, mundane tasks allowing the staff to focus on more value-driven activities. And in PV, automation helps with adverse events processing, a critical activity consuming enormous resource time. Now is time for the industry to harness AI for transforming pharmacovigilance and make it more sustainable with a focus on innovation. This way, life sciences companies can unlock future of AI-powered drug monitoring to influence the global healthcare ecosystem through improved patient safety and optimised care.

However, challenges like establishing a database for an AI-based pharmacovigilance system, lack of human resources, weak AI technology and insufficient government support remain.

Prasanthi Sadhu Editor

CONTENTS STRATEGY

COVER STORY

06 Strategic Instincts

20

Brian D Smith, Principal Advisor, PragMedic

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Pharmaceutical Promotional Material Gloobal laws overview Manan Ambani, Senior Team Lead, Freyr Solutions’ Medicinal Products Division

RESEARCH & DEVELOPMENT 23 Stem Cells for Cancer Therapy

Dhruv Kumar, Professor, Cancer Biology and Assistant Director, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University

EHS & ESG DIGITALISATION IN 06 PHARMACEUTICAL INDUSTRIES Naveen G.V Corporate Officer & Managing Director, AAPAC

Sibi Raj, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University

Ravi JR Lead Program Manager-SHE Gov. & Audit

32 Benchmarking Pharmaceutical Quality Control Labs Holistic assessment of operational excellence in pharmaceutical companies

Sarang Pande Head- Digital Transformation and Process Excellence- OSD

Gian-Andri Steiger, Lorenzo Pirrone, Marten Ritz, Thomas Friedli Institute of Technology Management.

37 Environmental and Sustainability Requirements in Drug Procurement Josep M Guiu, Director, Pharmacy and Medicines, Consortium of Health and Social Care of Catalonia; Adjunct Lecturer, Clinical Pharmacy and Pharmacotherapy, Faculty of Pharmacy and Food Sciences, University of Barcelona

43 Drug Development in the Technology Era Legal considerations for computer-assisted drug design Lydia Torne, Partner, Simmons & Simmons LLP Samuel Wilson, Trainee Solicitor, Simmons & Simmons LLP

CLINICAL TRIALS

48 Current Trends in Pharmacogenomics that will shape Clinical Trials Ayaaz Hussain Khan, Global Head - Generics, Navitas Life Sciences

MANUFACTURING

52 Next-generation Cell Culture Media and Feeds Systems A multi-faceted approach for optimising monoclonal antibody manufacturing productivity Paul Gulde, Manager, Multi-Omics Research and Development Thermo Fisher Scientific Chad Schwartz, Senior Global Product Manager Thermo Fisher Scientific Ronny Priefer, Massachusetts College of Pharmacy and Health Sciences University

56 Ensuring Efficiency in Packaging Process should be a top Priority for Pharma Packaging Companies Siddharth Shah, Director, Bharat Rubber Works

59 The Use of Crystal Engineering to Effectively Target Lung Infections Hisham Al-Obaidi, Thermal analysis Lead, University of Reading

EXPERT TALK

62 Innovative Biotech Ecosystem in Singapore and Asia Daphne Teo, CEO and Founder, NSG BioLabs

INFORMATION TECHNOLOGY

65 A Digitalised Future for Pharmacovigilance Bruce Palsulich, Vice President, Product Strategy, Oracle

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C O N TA M I N AT I O N C O N T R O L S T R AT EGY

A CCS should serve to proactively identify, evaluate and control the risk of all forms of contamination to the overall process LAURA BRENNAN SENIOR GLOBAL CORPORATE ACCOUNT SCIENTIFIC PROJECT MANAGER Highly proficient in the execution of global customer disinfection validation projects Active collaborator on scientific projects and publications with pharmaceutical organisations Corporate cleaning & disinfection standards co-ordinator

Our international team of Global Technical Consultants know what they’re talking about

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Request the eBook from ecolablifesciences.com/CCS for more information or speak to your Ecolab account manager to arrange an in-depth assessment of your Contamination Control Strategy.

Advisory Board

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

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

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

Frank Jaeger Regional Sales Manager, AbbVie, US Georg C Terstappen Head, Platform Technologies & Science China and PTS Neurosciences TA Portfolio Leader GSK's R&D Centre, Shanghai, China 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

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

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

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EDITOR Prasanthi Sadhu EDITORIAL TEAM Grace Jones Rohith Nuguri Swetha M ART DIRECTOR M Abdul Hannan PRODUCT MANAGER Jeff Kenney SENIOR PRODUCT ASSOCIATES Ben Johnson David Nelson John Milton Peter Thomas Sussane Vincent PRODUCT ASSOCIATE Veronica Wilson CIRCULATION TEAM Sam Smith SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam HEAD-OPERATIONS S V Nageswara Rao

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

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STRATEGY

STRATEGIC INSTINCTS Four Strategic Instincts Separate Great Strategists from the Others.

Brian D Smith, Principal Advisor, PragMedic

Y

ou are probably all-too-familiar with the rigmarole of strategic planning – situational analyses and spreadsheets, slide decks and strategy reviews. If you’ve worked in more than one life sciences company, you have probably noticed that all companies have similar processes, even if they use slightly different jargon or acronyms.

This mimicry of processes is so common that academics have even given it a name: institutional isomorphism. But if your firm and its rivals use the same strategic planning tools in the same way, where does your competitive advantage come from? I’ve been fascinated by this question for decades and in this article

I’ll share with you what my research has uncovered.

Basic instincts

As a research professor, I go from company to company asking about what works, what fails and what makes a difference. It quickly becomes clear where competitive advantage isn’t coming from. Life science companies buy the same market research and use similar planning templates with comparable levels of skill. After all, in our incestuous industry people move around and share ideas so any ‘“secret sauce’ doesn’t stay secret for long.

No, the source of competitive advantage isn’t in the strategic planning recipe

they follow. It begins long before they have even begun the formal planning process. It begins with the strategic habits of their senior executives, their habitual, almost sub-conscious way of thinking about where and how to compete. These instincts are so deeply embedded, sometimes unconscious, that they are best described as “strategic instincts”. Strong strategic instincts lead to strong strategies and vice versa. In my research, I’ve uncovered four sets of these instincts, behaviours that make the difference between strategically competent executives and their less strategic colleagues.

In my work teaching strategic instincts, I shorten these to the acronym FACT (see figure) and I’ve explained them below.

Framing

Framing is a term from cognitive psychology that refers to how people see the same situation in different ways, often leading to different choices. In my research, I find that strong strategists ‘frame’ the market and their strategy differently from others. Instinctively, they think: • The market isn’t about products, it’s about solving the customers’ problems • Winning is about creating customer preference; sales and profit will follow • Strategy is your choices about what to do and not do to create customer preference.

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STRATEGY

FRAMING where and how to compete TASKING to the right people in the right way CONCENTRATING on what makes a difference

ASKING questions to create new knowledge

Figure: The FACT framework of four strategic instincts

These framing instincts are more important and consequential than you might realise. For example, strong strategists look at market opportunities as the number of people with a disease and not as the number of prescriptions written.

They focus less on the competitor with the highest share and worry more about the rival that is liked best by patients and prescribers, because where preference goes profit follows. And when considering what to do, they always think about opportunity cost, that is what doors their actions close. By comparison, their less strategic colleagues frame the market as the number of prescriptions written, focus on fighting the market share leader and decide what to do based on estimates of return on investment. Those less-strategically-effective instincts lead them unthinkingly towards imitative strategies. When I see a strong strategist creating a game-changing, highly differentiated competitive strategy, it’s almost always because their framing instincts were strong.

Asking

Asking is the the strong strategist’s instinct to know something important about the market that the competitors don’t know. In my work with strong strategists, I notice that they ask three kinds of questions: • If we did this, what do we think would happen?

• What explains the way the market is behaving?

• Which of our current ideas about how the market works best fits the facts?

Asking these questions has its logical foundations in deductive, inductive and abductive reasoning but many natural strategists ask them without knowing that because it has become their instinct to ask questions like this. The answers to these questions often reveal something that competitors haven’t realised. For example, asking what would happen if we increased the sales team might reveal that access to prescribers is the critical issue. Asking why the market behaves the way it does might reveal a market access mechanism that

no one fully appreciates. Asking about whether the market is driven by patients, prescribers or payers often reveals that the only theory that fits reality is that all three play a part. By contrast, those who fail to ask these questions tend to thoughtlessly follow conventional wisdom about how the market works, ideas that were often developed many years ago and have become obsolete as the market has changed. Without asking new questions to create new knowledge, firms fall into the ‘last year’s slide deck’ trap, when the strategy process just becomes an updating exercise or, as one of my research respondents called it, ‘putting lipstick on the pig’. Whenever I ask why a firm has adopted an original, winning strategy, I’m often told “Well, we know something our competitors don’t!”.

Concentrating

Concentrating is the strong strategist’s instinct to focus resources intensely where they will make a significant difference and to not waste resources on anything else. This instinct to concentrate has three particular features: • Concentrating on decision-making situations, not on types of people, product or accounts • Concentrating on the factors that affect customer preference, not those that are easy to talk about • Concentrating intensely but shifting resources away from where they can’t make a big difference.

The instinct to concentrate is probably the one that is most characteristic of strong strategists because it goes most strongly against the instincts of others. In most companies, information is structured around people, such as prescriber types or patient categories.

This means it takes real determination to force the strategy to concentrate on situations, such as when a particular prescriber type is treating a certain kind of patient in a specific payer environment.

Concentration also runs counter to the ‘detailing instinct’ of concentrating on a drug’s features and benefits because

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Tasking

Tasking is the strong strategist’s instinct to ensure their strategy is implemented through people. When I observe this happening, it’s very obviously different from how execution in managed in weakstrategy companies. The tasking instinct has four parts: • Deciding what the critical success factors are • Deciding who in the organisation should own each critical success factor • Ensuring that the owner of each critical success factor has the authority and resources they need • Ensuring that owner of each critical success factor is motivated.

The tasking instinct is often hidden because weak strategists execute by doing something that looks superficially like, but isn’t, these four things. Most pharmaceutical companies build elaborate execution plans of spreadsheets, schedules and project plans with team leaders and “SMART” goals. These documents become ends in themselves rather than means to an end, resulting in endless unnecessary meetings to achieve ‘“alignment’. By contrast, the instinct of strong strategists is to identify only a handful of critical success factors, things that must happen for the strategy to work. Then they give ownership to whoever is most capable of executing, even if it means 8

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that crosses functional boundaries. The instinct of strong strategists is then to enable the owner with decision making power and ample resources and to make them feel responsible and motivated.

When I watch this in action, it’s really very different from the ‘death by endless meetings’ that I see in firms with less strategic capability.

FACTs can be taught

It has taken me many years of serious academic research to work out what makes some pharmaceutical companies better at making and executing strategy than others. That’s because the differences between strong and weak strategists aren’t explicit and can’t be found in the processes they use or seen in their organisational charts.

What differentiates strong strategists from the others is implicit and tacit. It can only be seen in the instinctive way they frame the market, ask the right questions, concentrate resources and task for implementation. Seeing and understanding these implicit instincts, which are often subconscious behaviours, is much harder than just watching their explicit processes. I compare it to understanding what makes someone a strong musician or sports player. The obvious is easy to see, the intangible is hard to understand. But you can learn to play the piano or to play tennis.

A few people are “naturals” but many more can learn to be very good without those natural gifts. The same is true with strategy instincts; whilst a tiny minority are strategy naturals, most strong strategists aren’t. They learned their instincts like any conscientious musician or tennis star.

There are two keys to learning strategic instincts. The first is to know what they are, to recognise what good strategic instincts look like. That’s what I’ve covered in this article and summarised in the acronym FACT. Knowing FACT is necessary but not sufficient. The second key is learning the right way. Like musical or sporting skill, the FACT strategic instincts can’t be learned quickly or by

rote. It requires coaching, practice and reflection. When I ask strong strategists where they learned they instincts they usually tell me that had a mentor or teacher. Some were lucky to find that in their organisation, such as their boss, but most were not that lucky and learned from others outside their firm.

I could write much more about how I teach strategic instincts but that’s outside the scope of this article and beyond my word count.

The takeaways from this article are very simple and I hope relevant to you. Strong strategies are made by strong strategists. Strong strategists have strong strategic instincts. A good way to remember strong strategic instincts is the F(raming) A(sking) C(oncentrating) T(asking) acronym. FACT can be taught but don’t fool yourself you can learn it quickly in a classroom. Strategic instincts make a difference and nothing that makes a difference comes easily.

AUTHOR BIO

it means focusing like a laser on those issues that drive the prescribing decision.

Strong strategists often build their value propositions around minor advantages that shape customer preference rather than significant USPs that are irrelevant to the market. Finally, concentration is often resisted by those with pet projects or special interests. For example, moving resources from the sale team to increase medical science liaison or giving up congresses to give resources to digital channels are both hard to achieve but are often important to achieve concentration.

Whenever I talk to a strong strategist and ask what their strategy is, they frequently begin with “Let me start by telling you what we’ve stopped doing…”.

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

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Developing a Robust Contamination Control Strategy Ecolab’s approach

A Contamination Control Strategy is a regulatory requirement for pharmaceutical manufacturers to have in place. It should be a living document and a process that is continuously revised. This article explores the challenges of adapting and developing a CCS and how Ecolab’s approach to supporting the development of a robust CCS for cleaning and disinfection can help.

David Keen, Director, Pharmaceutical Microbiology & Consulting, EcoLab

As most readers will be aware, Annex 1 of EudraLex Volume 4 (GMPs) is being updated. The process has been somewhat protracted with multiple versions being reviewed, updated, and discarded. What has not changed throughout these numerous revisions is the requirement for a site to have a Contamination Control Strategy (CCS) in place. While there is plenty of literature out there to explain what a CCS is, there is minimal direction on the practicalities of implementation.

The Annex 1 CCS requirement will place sites in one of three broad categories; having a CCS already in place (possibly under a different name), having identified the elements that will form a CCS but may need a refresh to comply and finally, those that need to define and develop a complete CCS. As anyone who has spent even a limited amount of time in the industry will know, changes to a site strategy and closing any gaps between existing practice and regulatory requirements can be like trying to turn the proverbial oil tanker – or perhaps steering one through the Suez Canal.

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So what can you do to leverage existing data, people or processes to aid in the formulation of your CCS in the most efficient and least disruptive way possible? My suggestion would be to break the process into four areas - gathering expertise, performing the assessment, gathering supporting documentation and validating any mitigation actions.

First and foremost is to identify the people who can help. It isn’t likely that one individual has all the necessary knowledge or expertise to put together a site wide CCS on their own. A team approach is required with the relevant expertise available to help. The bulk of the heavy lifting will be provided by your in-house SMEs or those from corporate functions. However, don’t be afraid to reach out to your suppliers to help too. Good suppliers will have expertise on hand and will be happy to help a customer on a specific aspect of their CCS. In fact, the experts employed by a good supplier may well have a greater depth of knowledge on specific subjects than those that can be found on a manufacturing site. For example, Ecolab’s Technical Consultants are able to bring insights of regulatory requirements, updates and industry best practise related to a variety of areas of contamination control.

Once the team of relevant knowledgeable people has been assembled, a good next step would be to look at what a site already has in place that can contribute to the CCS, and what gaps there may be. Annex 1 itself provides a comprehensive list of what a regulator would expect to form the

backboneof your CCS. Once the requirements of a CCS are known, an assessment can be performed to identify foundations that are already in place and gaps that exist. Utilising the team of assembled experts should ensure that qualified people are looking at your processes to identify contamination control risks. Again, the use of a supplier as a fresh pair of eyes may prove invaluable here. Experts with specific, in-depth knowledge in a particular area of contamination control may see what has previously been overlooked, offering information to help steer you to perform appropriate risk identification and assessment. For example, Ecolab offers on-site and virtual technical support in assessing risks from personnel cleanroom behaviours, contamination control risks from cleaning and disinfection practices, risks from incoming goods through transfer disinfection steps and critical zone contamination risks through isolator loading and decontamination assessment.

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As a key part of any site’s contamination control strategy, cleaning and disinfection validation is a great example of where a customer should turn to suppliers for help. As an example, Ecolab experts routinely perform in-depth analysis of current and planned validation strategies for disinfection and decontamination including ensuring compliance across different regulatory agencies. We optimise validation plans utilising our extensive Validex data package, through bespoke customer validation project management or by customers utilising our online validation portal to capture validation rationale, data and reporting.

On a final note, there is (as yet) no fixed template that a regulator would recognise as a CCS. A site’s CCS will and should be a living document and a process that changes with the site. The CCS will need revision when manufacturing changes or when a site stops a process. It should also be regularly revised, audited and inspected.

It is likely, there will be future citations in industry from CCS that are found lacking. Don’t let it be you!

Ecolab are here to help, now is the time to start, not when the Annex is finally published.

A site’s CCS will become part of a regulator’s inspection agenda. This means hard evidence, and documentation, will be required by the site to demonstrate what they have put it in place. The vast majority of the documents required as part of this evidence will be live documents already in place, such as risk assessments, QMS metrics and SOP’s.

As with performing a gap assessment against the CCS requirements, these documents should be reviewed to ensure that they meet the identified CCS requirements.

As most readers will be aware the tranche of documents created by a working site can be vast.

Utilise your assembled team to perform an in-depth analysis on your current documentation and identify gaps. Ensure your suppliers provide robust technical documentation to help close out the gaps in your CCS such as technical data, rationale documents and validation documents. The final part of any approach to mitigating identified gaps is the potential task of performing additional or new validation. Validation should not be undertaken without good reason; it is costly and resource intensive.

David is an experienced pharmaceutical microbiologist working in primary and secondary manufacturing, sterile and non-sterile dose forms, for FMCG, CMO and clinical trial manufacturing. He is a contamination investigation specialist and an expert in sterility assurance, water systems and biofilm management. He is the current chair of the Pharmig organisation.

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STRATEGY

Pharmaceutical advertising or prescription/non-prescription drug promotion will remain a widely debated topic, perhaps until a global understanding of regulations surrounding it is established. When it comes to promoting prescription and non-prescription drugs, evolving laws and regulations bring about a complexity like none other in pharmaceutical regulatory Affairs. In multiple countries, the primary source of educating the end users/prescribers is a unidirectional promotional material flow. For a company aiming to launch a molecule in multiple markets insight of the regulations in that market and drawing a comparison to regulated/semi-regulated/unregulated markets may help understand and navigate precedents and complexities. This piece consolidates the current thought process behind promotional material globally and the author’s opinion on pharmaceutical advertising utopia.

Manan Ambani, Senior Team Lead, Freyr Solutions’ Medicinal Products Division

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The reasons why the recent news is focused on pharmaceutical advertising and promotions, is- the changing regulations and stricter laws surrounding promotions, put into place by health authorities to keep in check, pharmaceutical manufacturers from often unknowingly making-flawed, misleading, and unlawful statements about their products. Rising fines, notices of violation and cease-anddesist letters cost pharma a lot, and as an industry-wide movement, pharmaceutical companies are now moving towards performing a medico-legal-regulatory review that they should have taken up before beginning to market their products.

With about US$ 1.6 billion spent by pharma in print advertising, approximately US$ 565 million in programmatic ad spend between January 2020 and August 2021, and an expected US$ 15 billion expenditure on influencer marketing by the end of 2022, it’s no doubt that people are talking about pharmaceutical advertising and promotions. The way promotions are done is changing, and it’s time that the laws governing promotion are decoded and communicated to marketeers in a manner that aids compliance.

Where exactly is the problem?

O

ne of the most important tasks of any regulatory body is to ensure that pharmaceutical products are developed in accordance with the local/regional regulatory requirements. It not only includes the process of regulating and monitoring the manufacturing of medicines but also the processes of their distribution and promotion.

Therefore, for any global pharmaceutical marketer, it is important to analyse the differences and commonalities of regulatory requirements and pharmaceutical legislation around the world.

Over the last few years, pharmaceutical companies have faced several challenges when it comes to their ad campaigns.

Based on the analysis of an independent survey of over one thousand (1000) recent healthcare advertisements, it was found that: • About 9 per cent of the advertisements contained false or misleading claims • 14 per cent of the ads contained "unsolicited, inappropriate, deceptive, unsupported, or irrelevant advertising" • 44 per cent of the ads included language that would mislead a consumer who did not understand the medical condition and what the product or treatment could do • 12 per cent of the ads misrepresented facts about a specific product or service, and 15 per cent were redundant or inappropriate.

Those are alarming numbers

One may ask why they are even observed with the current set of laws in place.

What is the root cause for these misleading advertisements and promotions? The answer to this question is rather simple.

Each country and its regional laws - the existing, the adapted and/or translated, and the deep grey chasms in between, and the inconsistencies in understanding, consolidating differences, and similarities in said laws are the pain points in creating globally compliant promotional material.

Logic demands universally applicable laws, albeit slurred with a slight variation to suit regional nuances often referred to as regional contextualisation.

Therefore, when a comparison was drawn between developed and regulated markets and semi/unregulated ones on promotional material for pharmaceuticals, it was found that almost every country follows the developed nations and regulated markets with slight deviations, However, here the deviations seemed to arise from the ability, or lack thereof, of a statutory body to be able to regulate, legislate and govern while keeping a watchful eye over what’s happening. Or it stemmed from the lack of confidence in developing selfregulation parameters.

Another reason could be that the pharmaceutical manufacturers aren’t looking at specific markets as potential earners and are yet to start heavy promotions there. But we can only speculate.

Let’s take a few examples

Globally, the mandates are rather similar, –barring certain small deviations.

• DTC (Direct-to-Consumer) is risky, so do it with care in a mannerism of education • Self-regulate, and we trust you to not mislead the consumers • Do not claim that which is untrue.

Some examples of country-specific deviations are as follows:

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• Larger regulated markets like the US and Europe have multiple regulatory authorities, while semi-regulated have a single, or sometimes no specific authority to monitor the promotions • Countries like Ethiopia, Fiji, Zimbabwe, Uganda, Tanzania, Ghana, Venezuela, and Estonia don’t have recent updates and don’t adopt newer methods (especially digital/social) of medical promotions • In countries like Portugal, Estonia, Belarus, Denmark, Ireland, Belgium, and Norway, the definition of advertisement is perceived as being informative rather than communication-focused as compared to others • Finland, Belarus, Czech Republic, Iceland, Portugal, etc. have specifically called out that they do not allow direct comparison with competitor products directed to the general public as compared to other countries Prescription advertisement is prohibited in all countries except New Zealand and the US. Google Ads allows manufacturers to advertise digitally in Canada with certain restrictions • Pharmaceutical manufacturers promote over-the-counter medicines in countries like Australia, Austria, Brazil, Canada, China, Czech Republic, France, Germany, Hungary, Hong Kong, India, Italy, Japan, Kenya, Mexico, Netherlands, New Zealand, Norway, the Philippines, Poland, Portugal, Russia, Slovakia, South Korea, Spain, Sweden, United Kingdom, and the US • The US, UK, North Macedonia, Venezuela, etc., actively monitor promotional material before it is broadcasted to the public and health professionals.

However, in a few countries, advertisers do not require pre-approval of their promotional material before being broadcasted.

Advertisers, in terms of copy or creatives, are under immense pressure to follow global mandates and guidelines and are sometimes forced to sacrifice creativity in the pursuit of compliance. This frenzy, clutter in

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Drug-marketing will have to focus on users, taking a patient first; not a pillfirst approach to communication.

tracking, memorising, and complying with individual country laws have often resulted in global pharma marketers losing track or sometimes completely forgetting submissions, resulting in fines and notices of violations.

Now, what can one do to avoid this confusion? What is the ideal solution for this?

The role of a RAP specialist

At a pharmaceutical company, the regulatory advertising and promotion (RAP) team or the promotional review committee (PRC) is responsible for understanding and interpreting the laws, rules, codes, and guidelines governing prescription drugs' advertising and promotion.

It is imperative that all statements made in advertising, whether express or implied, can be fully substantiated. This is due to the level of accuracy, quality, and honesty required by pharmaceutical and biotechnology companies to support the promotion of medicines and products. This is exactly where the RAP specialist plays a crucial role.

The RAP specialist provides advice on strategic adjustment before and after marketing activities when risk-based

cross-functional decision-making is critical. When providing strategic advice on drug advertising and promotion, the ability to think broadly and paying attention to detail ensures compliance with the local health authority rules and guidelines.

Those working as RAP (usually medical, legal, and regulatory professionals; a.k.a. MLR committee at times) specialists need a deep understanding of the regulatory framework to ensure business compliance. They should provide strategic regulatory guidance to businesses throughout the pharmaceutical product lifecycle. It is critical that legal, regulatory, and medical teams take the time to understand business goals and support achieving those goals within legal and regulatory constraints.

Equally important is that the business groups value the role of external auditors and specialised promotional material consultants in ensuring that products are properly marketed.

In the Advertising Review Committee, friction can often arise between the marketing team and members representing the medical, legal, and regulatory issues. Integrating content with the medical, legal, and regulatory review processes delivers more value to patients and consumers, reduces the cost of producing content, and helps an organisation become a more efficient company. The costs associated with setting up, training, and sustaining a RAP committee can often run into hundreds and thousands of dollars. Hence, smaller companies, and often even large multinationals, are choosing to outsource this function to specialised medico-regulatory consultants and auditors while keeping only legal teams in-house.

On the future of pharmaceutical advertising

The drive to be rational has led people to trust and conjure laws and regulations bound tightly by universal applicability and generalisation.

STRATEGY

regulations is the fact that considerations need to be made to susceptibility and the potential influenceability of the intended audience by drawing up certain measures of maturity and self-deci-

AUTHOR BIO

But context, on how people think, behave and act, is perhaps missing when it comes to pharmaceutical advertising.

One of the guiding factors that need to be incorporated in promotional material

Manan Ambani is a Senior Team Lead in Freyr Solutions’ Medicinal Products Division. A pharmacist and MBA graduate from Narsee Monjee Institute of Management Studies (NMIMS) Mumbai, he believes that there is a place for innovation in the everyday lives of all stakeholders, internal as well as external. He holds experience across the pharmaceutical and healthcare value chain, ranging from formulation development and R&D to healthcare advertising and communications.

sion-making capabilities with regards to health by the nation’s populace.

When added to self-regulation norms, it makes for better content. A touch of personalisation as a mandate would also generally benefit the sector. For example, if a group values prevention and community medicine, pharmaceutical companies should develop approaches for that group, knowing that traditional pharmaceutical marketing won't work.

Instead, they need to understand the social, cultural, economic, and ethical impact of their medicines and use this knowledge to personalise their approach towards consumers. They can no longer focus solely on the positive or negative health effects of drug usage.

Despite limited cost controls, regulatory constraints, and global competition, the drug-marketing space will have to focus on users, taking a patient-first, and not pill-first approach in the future.

One thing is for sure, interesting promotions lie ahead.

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SGS QUALITY-DRIVEN SOLUTIONS Discovery to commercialisation We offer high-quality analytical testing solutions for pharmaceutical and biopharmaceutical products through all phases of drug development, from discovery through early development and commercialisation.

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ur bespoke testing and clinical service offering, which covers full clinical development from Phase I first-in-human trials to Phase II and Phase III studies in patients, provides reliable and accurate results that ensure the safety of your products and protect patient health. Our experts, working with small and large molecules, use the latest equipment and techniques at our state-of-the-art laboratories and clinical trial facilities in North America, Europe and AsiaPacific. They can assist throughout the development process, providing a range of mission-critical formulation and manufacturing services. We also offer expert guidance from our experienced consulting 18

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and project management teams, so you can get your products to market quickly, safely and cost-effectively.

Analytical testing Using the latest technologies and state-of-the-art equipment, our scientists ensure the quality and safety of pharmaceuticals and biopharmaceuticals during all phases of drug development. We offer a wide portfolio of services, including: • Method development and validation • Analytical chemistry • Microbiology testing • Stability testing

• Bioavailability enhancement • In vitro toxicology • Extractable and leachables testing • Medical device testing

Specific biologics solutions Our global centers of excellence will cover your testing needs for specific biopharmaceutical products, including vaccines, cell and gene therapies, biosimilars and other biologic products. The solutions that we offer include: • Structural characterisation and confirmation • Qualitative and quantitative impurity analyses • Physicochemical properties analysis • Biosafety testing

Contract development and manufacturing We specialize in the development and manufacture of innovative new chemical entities, biologicals and live biotherapeutics for global markets. We offer solutions around: • Preformulation and CMC support • Formulation development (and the development of supporting analytical methods) • Bioavailability enhancement • Dosage form optimisation, improvements and differentiation • First-in-human supply • Microdosing • Process optimisation • Clinical, specials and commercial manufacturing (including packaging and supply)

Integrated CRO network: Using state-of-theart equipment, our scientists and experts verify the quality, efficacy and safety of therapeutics by providing comprehensive solutions within an integrated CRO network. This encompasses everything from exploratory development and clinical development to commercial QC and postmarket testing.

Accelerated drug development: We use innovative techniques that provide patients with better, safer treatments and contribute to your organisation’s success.

Global regulatory compliance: Through our global network of laboratories and clinical trial facilities, we offer integrated services and expertise that provide organisations with knowledge, flexibility and the ability to scale while staying compliant at all times.

Customer focus: Our specialists deliver multifaceted, customer-centric programs at local and international levels – supporting your commitment to delivering high-quality, compliant biopharmaceutical and pharmaceutical drugs and medical devices.

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Clinical development We run clinical trials all the way from study design to clinical trial execution, delivery of the final data analysis and producing a clinical study report. Our experts are available to support your studies and to assist with all aspects of formulation development: • Bioanalysis • Drug development consultancy • Early-phase clinical development • Biometrics support • Global clinical trial management

SGS Health Science is much more Scientific expertise: We provide a diverse range of trusted formulation development, analytical testing, phase-appropriate manufacturing and clinical research solutions that match your needs and help you navigate your journey to market.

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EHS & ESG DIGITALISATION IN PHARMACEUTICAL INDUSTRIES Dr. Reddy’s partnered with Benchmark ESG | Gensuite to digitalise and enhance their safety culture.

Naveen G.V Corporate Officer & Managing Director, AAPAC Ravi JR Lead Program Manager-SHE Gov. & Audit Sarang Pande Head- Digital Transformation and Process Excellence- OSD

1. HOW CAN PHARMACEUTICAL COMPANIES KEEP UP WITH AND EXPAND IN TODAY'S WORLD, WHERE DIGITALISATION AND TECHNOLOGICAL ADVANCEMENTS ARE DRIVING THE INDUSTRY'S EVOLUTION? In Pharma, as in other industries, we’re in an age where the needs and obligations of companies are evolving by the second – from accelerated product cycles to keeping up with investor and government demands for Environmental, Social, & Governance (ESG) metrics. Digital transformation, in this context is truly an enabler in keeping up, adapting, and moving at the pace of the industry and importantly, adopting a best-practice based digital solution gives companies access to benchmark with global trends, while still being

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able to configure the solution to suit specific business’ need. Digitalization can help companies quickly adapt to changing trends, challenges, and opportunities with confidence.

I agree! The evolving regulatory landscape, old and new diseases, and the need for efficient manufacturing operations mean that pharma companies need to step up and fast.

Boosting their digital infrastructure is the only way to succeed in a world where disruptive technologies are changing the pharma landscape at a pace that is faster than businesses’ adaptive capacities. Companies that hope to thrive should look at the digital opportunities in their entire ecosystem – from enhancing their product’s journey through production and delivery to empowering employees and unlocking new revenue streams.

Naveen G V is an Environmental, Health & Safety (EHS) and Management professional with 23+ years of experience spanning across Government, Consulting and Industry sectors.

He is currently the Managing Director, AAPAC & Corporate Officer for Benchmark Digital Partners LLC, US & Benchmark ESG Pvt. Ltd., India, a US headquartered Company offering software solutions to global customers in managing their Environmental, Social & Governance (ESG) program. In his earlier role, Naveen was the EHS Leader at General Electric (GE) at Bangalore. Naveen has a Master’s degree in Environmental Engineering and is also a Lead Auditor for ISO 14001: Environmental Management System and RC 14001: Responsible Care Management System covering environmental, health, safety, security, product stewardship and outreach activities.

2. EFFICIENT MANAGEMENT OF ENVIRONMENTAL, HEALTH, AND SAFETY (EHS) IS CRITICAL FOR EVERY ORGANISATION. HOW CAN DIGITALISATION ENHANCE EHS MANAGEMENT IN PHARMACEUTICAL INDUSTRIES? EHS digital transformation is the key to keeping your safety culture proactive! It can help pharmaceutical companies improve employee wellness and workplace hygiene, streamline compliance and reporting, increase sustainability, and improve programme performance. Now automating and streamlining

workflows is just one aspect of digital transformation.

There’s also the immensely powerful EHS data that possesses the ability to inform of critical safety decisions, allocating resources in the right direction, preventing accidents, and saving lives! By deploying a single digital EHS management platform that can manage companywide safety data, EHS teams can drive measurable improvements and use analytics to uncover hidden risks to the safety of employees.

3. WHAT WERE THE DRIVERS FOR DR. REDDY’S TO DIGITISE THEIR EHS AND ESG PROGRAMMES? At Dr. Reddy’s, we prioritise workplace safety by using the My Safety Index (MSI), a quantitative tool to monitor safety culture and management across our sites, measuring parameters like the LOTO index and Contractor Safety Management (CSM) index. As testament to our commitment to sustainability, we’re the first Indian pharmaceutical Company to commit to the Science Based Targets (SBTi) and our EHS Policy has been revised to take a holistic approach towards sustainability throughout our value chain. You can see that safety and sustainability are top priorities! When we looked at the scope of our safety and sustainability programmes, we identified the need for a digital system that could streamline workflows and increase efficiency across our EHS and ESG programmes.

4. HOW DID DR. REDDY’S GO ABOUT THE PROCESS OF IMPLEMENTING DIGITAL TECHNOLOGIES FOR THEIR EHS AND ESG PROGRAMMES? It was important that our EHS digital partner was aligned with our core values of sustainability and our commitment to workplace safety. We zeroed in on Benchmark ESG | Gensuite, drawn to their best-practice-based EHS and ESG digital platform and a strong legacy of supporting organisations across the world in creating safer workplaces. We expressed our needs for an intuitive and user-friendly platform that can streamline workflows and help our safety leaders make critical decisions.

When we implemented Gensuite digital system for our EHS and ESG needs, we adopted a phased approach. Implementing across two phases, we created smaller milestones, aiming at efficiently driving critical safety actions to closure,

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engaging employees in enhancing workplace safety, and meeting compliance needs. To date, we’re continuously innovating to improve our safety and sustainability culture, exploring newer opportunities and other advanced technologies.

5. WHAT VALUE AND RETURNON-INVESTMENT (ROI) HAS DR. REDDY’S SEEN BECAUSE OF THEIR EHS DIGITAL TRANSFORMATION? (DR. REDDY’S) Our employees are at the heart of our EHS programme! Digitalising our EHS processes has created a lasting impact on our safety culture, engaging employees, and empowering leadership to take critical decisions through impactful safety and sustainability data stories. Sure, we’re saving time, cutting down on costs, and experiencing enhanced employee productivity, but we’re exceptionally proud of the strong safety culture we’ve been able to build due to our digitalisation efforts. We can’t wait to dive deeper into the digital world, reaping all the benefits that advanced technologies like artificial intelligence (AI) have to offer in keeping our teams safe and the environment thriving.

6. WHAT APPROACH WOULD YOU RECOMMEND TO YOUR PHARMACEUTICAL INDUSTRY PEERS WHO ARE LOOKING TO START THEIR EHS DIGITAL JOURNEY? Under the larger umbrella of the pharma industry, each company is unique with diverse culture and values. However, building a digital EHS & ESG management system from scratch can be timeconsuming and it may take years before you develop meaningful workflows. Look for a best-practice-based digital provider like Gensuite who can quickly automate your EHS workflows and customise their platform to meet your unique needs. As a next step, secure leadership buy-in by showing your leaders the power of data and technology in securing the safety of your teams. When implementing these technologies, start with smaller pilot projects. Use these as a guide to initiate enterprise-wide implementation, moving towards imbibing digital EHS into your organisation’s safety and sustainability culture. We believe that choosing the right digital partner is key – someone who listens to your unique needs, has the

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domain expertise and works carefully to meet these long after the initial implementation!

7. HOW DO YOU SEE THE FUTURE OF DIGITALISATION IN EHS IN THE PHARMACEUTICAL INDUSTRY? Advanced technologies, especially AI, are taking the pharma industry by storm! From drug development to epidemic prediction, AI is fostering innovation, improving productivity, delivering better results across the value chain, and creating new business models. And EHS is no exception! It’s critical to processes across every function of pharma companies. With advanced technologies like AI, machine learning (ML), and predictive analytics, EHS professionals in pharma companies can identify and prevent fatal injuries and improve safety performance with increasing accuracy. Take Benchmark ESG’s PSI AI Advisor™ for instance. It identifies risk factors for potentially serious injuries (PSIs) in real time, helping safety leaders prevent the occurrence of workplace incidents that have the greatest potential for harm, saving lives in the process.

8. IS THERE ANYTHING MORE YOU'D LIKE TO SAY TO OUR GLOBAL AUDIENCE? The ESG spotlight is on companies worldwide and pharma companies are no exception! With mounting pressure from investors, government, regulators, and consumers, to report investmentgrade ESG data, pharma companies need to address the challenge – initiate climate action, reduce their Global Greenhouse Gas (GHG) emissions, report progress, and simultaneously keep their businesses sustainable and thriving in the long-term. Benchmark ESG’s intuitive and userfriendly digital solutions help you achieve your sustainability goals by seamlessly collecting and reporting investment-grade ESG data across global frameworks like GRI, CDP, SASB, BRSR, etc. Additionally, our solutions help you harness the power of detailed data and precise analytics to inform ESG strategies & maximise your performance.

It’s exciting to see how advanced technologies and digital transformation can enhance safety and sustainability processes in pharmaceutical companies. We encourage organisations to be open to this transition and dive into this exciting landscape with hope and optimism.

For more detail visit: www.benchmarkdigitalesg.com/contact-us/

RESEARCH & DEVELOPMENT

STEM CELLS FOR CANCER THERAPY Despite the recent advancement in cancer therapy, the death rate of cancer is increasing every day. Stem cell therapy emerged as highly successful therapy for several cancers. In recent years, the stem cell manipulation and development of induced pluripotent insistent cells have shown tremendous potential to treat cancer.

Dhruv Kumar, Professor, Cancer Biology and Assistant Director, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Sibi Raj, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University

D

espite several advances research cancer remains one of the deadliest diseases across the world.

The type of treatment provided depends upon the type and progression of cancer.

Surgery is the first option recommended to remove solid tumours from a single area. Radiation, chemotherapy, cancer vaccines remain some of the other options to choose to slow down or stop tumour growth. However, stem cell therapy has provided new hopes in this fight. It could possibly improve the therapeutic efficacy due to its enhanced specific target on tumours. Metastatic cancer cells generally

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RESEARCH & DEVELOPMENT

cannot be eradicated using traditional surgical or chemoradio therapeutic strategies, and disease recurrence is extremely common following treatment. However, therapies involving stem cells show increasing promise in the treatment of cancer. Stem cells can function as novel delivery platforms by having the ability to target both primary and metastatic tumour foci. Stem cells engineered to stably express various cytotoxic agents decrease tumour volumes and extend survival in preclinical animal models.

They have also been employed as virus and nanoparticle carriers to enhance primary therapeutic efficacies and relieve treatment side effects. Stem cells have unique properties, such as migration toward cancer cells, secretion of bioactive factors, and immune suppression, which promote tumour targeting and circumvent obstacles currently imped-

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ing gene therapy strategies. Preclinical stem cell-based strategies show great promise for use in targeted anti-cancer therapy applications. In addition to their self-renewal and differentiation capabilities, stem cells have immunosuppressive, anti-tumour, and migratory properties.

Because stem cells express growth factors and cytokines that regulate host innate and cellular immune pathways, they can be manipulated to both escape the host immune response and act as cellular delivery agents. Stem cells can also secret factors, such as CCL2/MCP-1, and physically interact with tumour cells, changing co-cultured tumour cell phenotypes and exerting intrinsic anti-tumour effects.

Stem cells, most commonly neural stem cells (NSCs) and mesenchymal stem cells (MSCs), can be modified via multiple mechanisms for potential use in cancer therapies. Common modifications include

the therapeutic enzyme/prodrug system, and nanoparticle or oncolytic virus delivery at the tumour site.

NSCs and MSCs can be designed to express enzymes that transform non-toxic drugs into cytotoxic products. When modified stem cells are transplanted to tumour models, they are positioned in tumour tissue. The exogenous enzymes convert the prodrug into cytotoxic molecules, ultimately damaging tumour cells.

As a result, the amount, timing, and location of drug release can be precisely controlled. Enzyme and pharmaceutical therapy is also known as suicide genetic therapy, and is the first therapeutic application developed in NSC and the first to be introduced into clinical trials. Stem cells can work as in situ drug factories and secrete long-term anti-tumour agents, and can overcome various cancer therapy limitations, such

RESEARCH & DEVELOPMENT

specific iPSCs could also potentially benefit immunotherapy approaches. The pre-rearranged TCR gene is retained in T lymphocyte-derived human iPSCs, which can be further induced to differentiate into functionally active T cells.

Functional T lymphocytes, specific to the tumour antigen, can be produced in vitro by reprogramming selected T cells into iPSCs and then differentiated again into T lymphocytes for infusion in patients. However, the safety of T cellderived human iPSCs must be further validated.

Challenges to stem cell therapy

Tumours commonly relapse regardless of strong initial therapeutic effects. Like most chemotherapy, the use of singlemolecule stem cell therapy is generally not capable of eliminating tumours.

Consequently, it is necessary to select the optimum combination of drugs rationally. Many combinations of therapy have been tested to improve the long-term effectiveness of treatment. For example, combined with antigen/suicide genes, immunotherapy using IFN- antibody has shown a synergistic therapeutic effect on human colorectal cancer. Irradiated tumour cells can induce the production of factors that stimulate the invasion of the SMC by the whole membrane of the soil, which increases the number of the SMC in the tumour. Combining stem cell-based immunotherapy and AUTHOR BIO

as high systematic toxicity and short drug half-life. TNF- -related apoptosisinducing ligand (TRAIL) is one of the most widely used, secreted therapeutic agents, and induces tumour cell apoptosis. However, its short half-life reduces its therapeutic effectiveness in vivo. Stem cells can also be modified to selectively deliver growth inhibitory proteins (e.g., IFN- ), rendering the microenvironment inhospitable to tumour growth. Ling, et al. studied the migration of IFN-expressing MSCs and their engraftment into primary breast tumour sites, and found that tumour cell growth was suppressed, and hepatic and pulmonary metastases were alleviated. Oncolytic viruses (OVs), unlike traditional attenuated viruses, conditionally replicate in tumour cells. OVs have increased spread in the body and hide from the immune system. OV-transduced NSCs are still able to home to tumour cells, and NSC-delivered OVs showed better antitumour effects than the viruses alone against GBMs in vivo. Virus delivery

by MSCs is also a promising approach for targeted cancer therapy. Ong, et al. demonstrated that the potent oncolytic activity of attenuated measles virus combined with the unique immunoprivileged and tumour-tropic properties of MSCs could combat hepatocellular carcinoma.

As stem cells have the ability to self-renew and differentiate, they can be used to repair human tissues after chemotherapy. HSC transplantation has been widely used in clinical practice to facilitate life-long hematological recovery after high dose radiotherapy or chemotherapy treatment of malignant patients. This treatment is aimed at reconstructing bone marrow under conditions of bone marrow failure (e.g., aplastic anaemia) and treating genetic diseases of blood cells, and works by supplying stem cells that differentiate into a desired type of blood cell. The transplantation and successful transplantation of a single HSC can restore hemopoiesis to the recipients. Patient-

chemical radiotherapy can minimise the residual volume of the disease and give glioma cells a CRAd-S-pk7 (OV CRAd-Survivin-pk7) sensitivity during radiotherapy. Kim and colleagues found that TMZ stimulated glioma cells to apoptosis induced by TRAIL by modulating apoptotic machinery and improving MSC-TRAIL gene therapy’s anti-tumour effect. Epidermal growth factor receptors (EGFRs) mutated and exaggerated in several tumours have low prognosis and reduced survival rates. TRAIL and the immune conjugation of stem cells of nanobodies specific to EGFR have improved the results of treatment. The risk profile of stem cell based medicinal products depends on many risk factors, which include the type of stem cells, their differentiation status and proliferation capacity, the route of administration, the intended location, in vitro culture and/or other manipulation steps, irreversibility of treatment, need/possibility for concurrent tissue regeneration in case of irreversible tissue loss, and long-term survival of engrafted cells.

Together these factors determine the risk profile associated with a stem cell based medicinal product. The identified risks (i.e. risks identified in clinical experience) or potential/theoretical risks (i.e. risks observed in animal studies) include tumour formation, unwanted immune responses and the transmission of adventitious agents.

Dhruv Kumar is a Professor of Cancer Biology and Assistant Director of Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Noida, India. His current research focuses on Translational Cancer Research, Cancer Metabolism, Cancer Genomics, Cancer Stem Cell, Stem Cell and Drug Discovery.

Sibi Raj, ICMR-SRF, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University

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GMP Biotech Fast-Track Manufacturing Facilities Supported by new modular solutions Luca Mussati, VP, Technology & Innovation at Exyte Biopharma and Lifesciences

1. Who are the crucial service providers engaged in the domain of new modular solutions to GMP biotech fast track manufacturing facilities?

Developing and delivering an innovative modular solution for biopharmaceutical manufacturing requires knowing both the cleanroom technology and the process design of these facilities. Therefore, a functional and innovative new modular concept can be developed only by a multidisciplinary team of experts. The experts must collect the lessons learned in previous modular projects and take into consideration the feedbacks of clients. This was Exyte’s approach when we started the ExyCell development in 2018, and it is still the basis for the current product developments: robotics for human-less operations, digitalisation, digital twins, plug and produce solutions embedded into the ExyCell modules are in the works right now, always trying to stay connected with the real world of our clients, with their medicines at the core of our project.

The ExyCell is a ceiling modular skid, 9.6m x 2.4m, available in 7 versions and unlimited combinations of accessories, that can be combined to realise a turn-key biopharmaceutical manufacturing facility up to ISO 5 (according to ISO 14644-1) and Bio Safety Level BSL-2.

To achieve this simple, innovative modular solution, our architects and engineers worked together with construction, logistics, supply chain experts and clients. But the real sweet spot was reached with an “industrial consortium” approach, combining the resources and know-how of Exyte and OEM companies, process owners and technology providers. Since the beginning we invited to the ExyCell initiative a number of

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highly innovative partners such as Miltenyi Biotec, Siemens, Steris, Syntegon, OUAT! and Univercells Technologies. Their exceptional contributions to the ExyCell ecosystem greatly accelerated and improved our new modular product.

We can now offer standardised yet customisable and scalable GMP facilities for cell and gene therapies, vaccines, mAbs, mRNA, biologics and new medicine modalities, shortening dramatically the design and construction phases.

As a further example, the next revision of guidelines such as the EU GMP Annex 1 for the Manufacture of Sterile Medicinal Products offers plenty of room for innovative, prefabricated modular facilities.

If we look at the business drivers, a modular biotech facility is the best option to achieve the shortest time-to-market, thanks to the parallel off-site prefabrication of cleanrooms and process equipment and onsite construction of the building and utilities. We should not forget that being first-or secondto-market with a new mAb, cell therapy or vaccine is critical to secure the expected return on the investment. According to a McKinsey research, first entrants obtain in average a higher market share even after ten years from the launch of a new medicine, with fast-followers however doing still well .

Going for a modular, pre-engineered and standardised facility based on the ExyCell system can help to hit the market faster.

Another strong driver today is the pandemic preparedness or fast pandemic response, with governments and institutions financing the realisation of manufacturing plants to secure a local, independent sourcing of vaccines and drugs.

We see these trends converging to generate a strong interest in our modular solutions. A recent example is a new

2. What are the recent trends fuelling the approval of modular construction solutions in the pharma or biotech industries?

When it comes to a modular facility producing medicines for human use there is no shortcut: compliance with the cGMP is a must, exactly as a traditional stick-built one. We took this commitment very seriously and the ExyCell is designed to be safely cGMP compliant with the all the main national and supra-national health regulatory guidelines. It is based on proven HVAC and clean utility solutions, with appropriate cleanroom finishes and GAMP-compliant building and process automation systems. Indeed, once finished it looks exactly like any other conventional pharmaceutical facility – or better!

However, during our recent exchanges with the regulatory authorities, we noticed that they are very interested to support proactively both the reliability of the drugs supply and the fast introduction of the new therapeutic modalities. In this perspective we usually establish a productive dialogue with the medical regulatory authority during the design phases, considering holistically the production premises, the support systems and the production processes. All this must cope with the accelerated approval and shorter life cycle of the new generation of medicines. This “fast-track” approach to new medicines development is reflected in several publications by the FDA , EMA and others.

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Pandemic Preparedness facility launched in Germany, where the client selected Exyte as general contractor together with our ExyCell modular cleanrooms, in order to meet their ambitious schedule.

3. What are the noteworthy benefits of a modular box-in-box biotech facility?

The box-in-box approach has been developed over the past decade by the pharmaceutical community to rationalise the design of manufacturing plants and reduce the investment costs and completion time. One of its most successful applications is a modular cleanroom system enclosed in a light, cost-effective prefabricated building. The two “boxes” are built in parallel whereas a traditional stick-built facility has all the works executed in sequence. We saw that the schedule can be reduced from 30 per cent up to 50 per cent, as in our Shanghai Cell Factory realised for Miltenyi Biotec.

Moreover, the inner “box” with the production cleanrooms can be installed in an existing building, accelerating further the schedule.

This simple concept allows also effective function-based value engineering, since the function of the external “box” is limited to providing shelter from the elements and supporting the plant utilities. Following this concept, a light pre-fabricated building can be realised very quickly at a cost comparable to a warehouse: either in Europe or Singapore we can build a single-storey, pre-engineered, prefabricated outer “box” in few months’ time at around 800-1,000 euro/m², depending on the area and level of finishes.

The flexibility of the layout and the speed of execution are additional benefits of the box-in-box modular construction. A truss-beam building can provide long spans without

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columns, thus allowing plenty of unhindered space for the process equipment.

But the biggest evolution for the modular delivery is linked to standardisation and repeatability: our vision is to have simple, standard building blocks that can be assembled to create standardised yet customisable processing units, which can be combined to realise large bioprocessing facilities.

And with our standardised building blocks we eliminate the special transports and complex logistics of the traditional large room modules: a regular truck can transport two ExyCells, occupying less than the space of a 40 ft. container.

Leveraging the concept of pre-defined building blocks Exyte launches at the Interphex in New York a new web-based 3-D layout configurator based on the HakoBio tool by OUAT!.

This new tool enables anyone – end-users, production managers, investors, engineers, consultants – to build their biotech facility from scratch. It features a database of some 1,000 pieces of process and support equipment and a library of pre-designed functional areas that can be deployed in a 3D environment with simple drag-and-drop techniques. From the facility conceptual layout we can move quickly to the detailed design and bill of materials: we call it “conceptioneering”, which condensates concept and detailed design in a single workshops and few days or weeks of work. Many pharma clients are already working with our Exyte-HakoBio layout tool. I let you imagine the collaborative power of this new tool!

4. How can modular manufacturing equipment aid scale-up steps?

We differentiate between “scale-up” and “scale-out” approaches to cope with an increased demand of a given product. A scale-out consists of the replication of a series of

similar modular production units to obtain a multiple of the production capacity, as opposed to the classical scale-up consisting of the addition of progressively larger equipment with bigger capacity. A modular manufacturing platform – for example, the Miltenyi Prodigy CliniMACS – can be easily scaled-out by adding more pieces of equipment of the same type and capacity. This technique is particularly suitable for the ATMP or personalised medicine, where an expandable array of semi-automated cell culture devices can be installed side by side in a ballroom to minimise both the facility footprint (lower Capex) and the production staff (less Opex). A modular cleanroom capable of seamless expansion as a ballroom represents the optimal solution for a fast scaleout of a production area. If the scalability is integrated into the design, one can expand it with minimal impact on the ongoing production. The Shanghai Cell Factory constitutes a good example of a scalable ballroom for C&GT– and anyone can book a visit there, either through Miltenyi Biotec China or Exyte China!

5. What types of product lines are dynamically supported by integrating modular solutions into facility design and construction?

Modularisation benefits mainly high added value products, where every month of additional revenues weights in the investment financials. As an example, we have executed in the recent past modular projects for mRNA vaccines, Viral

Vectors, mAbs (monoclonal antibodies) and cell therapies.

More in general, the CapEx projects that benefit most from a modular execution are the fast-track ones. When time is of the essence, a modular, off-site prefabrication of the plant in parallel with the civil works onsite can offer the shortest, safest schedule.

Even when the schedule of the project – the so called critical path – is not driven by the building and cleanrooms, for instance in the case of sterile fill & finish units with long lead times for the aseptic filling lines, a modular execution can be beneficial if the onsite construction workforce is limited either in skills or in quantity. In these cases, the offsite prefabrication of modules mitigates the risks and improves the productivity and efficiency.

6. Which regions are the current hubs for modular construction service providers?

The main hubs for the fabrication of pharma modular plants are in Europe (Germany, Ireland, Italy, Sweden and others), Singapore, Shanghai and the US. But the type of modules in the market is extremely differentiated. Large room modules are predominantly built in one single hub and shipped globally.

The smaller modules and pods embrace a more distributed approach, with many smaller regional workshops. Exyte opted for the latter, with several ExyCell manufacturing workshops in Asia, Europe and the US. The proximity of the module prefabrication to the construction site helps to reduce the

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7. What are the pros and cons of including modular equipment in conventional bio-manufacturing facilities for hybrid operations?

A hybrid modular facility combines the offsite prefabrication of high-tech parts such as the cleanrooms, HVAC equipment, clean utilities distribution and automation systems with local, stick-built construction of the traditional building components.

Concrete, steel structures, flooring and walls, steam boilers or softeners can be found almost anywhere at the right price and quality. A smarter engineering approach to the modular construction is then to “keep cheap parts cheap”: there is no advantage to prefabricate remotely elements that can be built on site, with the same quality and fast construction times. We decided to design the ExyCell with this hybrid approach, realising onsite the external “box” and the technical utilities. We don’t intend to add costs and complications where there is no advantage for the client! We aim also at reducing the transportation cost and the logistic complexity: we don’t transport “air”, as it is the case with the large room modules mostly consisting of empty rooms.

On the other hand, a hybrid modular solution works only in countries where we find the right construction trades. In the case of less developed countries, where industrial construction trades are not easy to find, we privilege the “all-in-one” room modules with complete off-site prefabrication.

8. Discuss the portability of modular manufacturing equipment. Can you brief our readers about how these portable systems might help in emergency situations?

In the recent past the concept of portable biolabs obeyed mostly to security purposes, for instance to respond to a biological warfare threat. Nowadays we see a renovated interest for biopharma manufacturing facilities that can be deployed quickly anywhere, let’s say in the order of few weeks, to fight pandemic outbreaks at their early onset. The new generation of mRNA vaccines are an important enabler for this development: they can be produced rather quickly, in millions of doses, with smaller equipment. But rather than a true portable plant we see a trend towards compact, dismountable autonomous clean rooms and equipment that can be transported, assembled and qualified on site, with footprints

the range of 100 m². Some pharmaceutical manufacturing companies are already offering this solution with containerised mRNA production plants. The idea is to integrate a) the process know-how, b) the modularised cleanroom system, and c) the process and support equipment. In our recent experience the most innovative vaccine developers are the best promoters of this new portable concept.

On the other side, the biggest challenge to this kind of facilities is still the approval process by the local authorities, both for the drug approval and for the authorisation of the manufacturing facility. This limits the usage of portable manufacturing facilities to the emergency situations – and it will stay so in the foreseeable future.

9. What are the regulatory approval challenges?

A prefabricated modular pharma facility is eventually inspected by the same authorities, using the same acceptance criteria of any other pharmaceutical facility. The inspectors expect to see the same quality of the finishes, of process and process support, of building monitoring and control and of the air treatment systems. The challenge, therefore, is to be at least on par with traditional stick-built premises in terms of quality, reliability, product and personnel protection.

The biggest challenges in our experience are a) the design of a GMP compliant module, that is a structure built in pieces that once assembled ensures the same performances of a traditional facility, b) the risks during the transportation, both for mechanical or water damages and for the potential contamination by molds, fungi or other pests.

We at Exyte leveraged our modular experience to mitigate these risks with clever design choices. As an example, the pharma walls of the ExyCells are either sourced locally or transported separately in bulk with sturdy water-proof protections. This simple solution prevents water damage and any related mold or fungi contamination – a serious threat to the business continuity.

10. Any closing thoughts on Exyte for the benefit of our readers?

At Exyte, we strongly believe in the power of innovation: “bring the future of technology to life” is our motto. We strive to combine this passion for innovation with a reliable, predictable delivery of our projects.

AUTHOR BIO

transportation costs and meet conformity to local codes and regulations. Our workshops are in Shanghai to serve the APAC, Italy for the European customers and North Carolina for the USA market. We plan moreover to open additional ExyCell manufacturing workshops in Singapore and Ireland.

Luca holds a degree in Chemical Engineering from the Polytechnic of Milan. Over 30+ years with major engineering companies he realized large CapEx programs of state-of-the-art biopharma facilities internationally.

Currently VP Innovation and Technology for Exyte, he develops and deliver innovative solutions for flexible, standardized modular GMP facilities.

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BENCHMARKING PHARMACEUTICAL QUALITY CONTROL LABS Holistic assessment of operational excellence in pharmaceutical companies

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T

Through the years pharmaceutical companies have managed to apply Operational Excellence (OPEX) and Lean-thinking to their operations. Nevertheless, the majority still lacks behind when incorporating an end-to-end perspective. A first step to holistically assess the performance of pharmaceutical companies necessarily incorporates quality control (QC) in addition to manufacturing. Therefore, the St.Gallen QC Lab Benchmarking helps to position pharmaceutical QC labs from a broad range of pharmaceutical companies against each other.

Gian-Andri Steiger, Lorenzo Pirrone, Marten Ritz, Thomas Friedli Institute of Technology Management

he importance of Operational Excellence (OPEX) to drive business performance and sustainable growth has been recognised across industries (Mitchell, 2016). As demonstrated in our previous article St.Gallen OPEX Benchmarking for Pharmaceutical Manufacturing Sites – Measure Yourself Against the Best but Do It Right, pharmaceutical companies have embarked on their OPEX journey through the years.

Nevertheless, it can be observed that the industry’s major focus is limited to the manufacturing function (Friedli et al., 2013). However, to advance the company’s overall OPEX performance, an end-to-end perspective on the value chain needs to be incorporated (Bajaj & Reffell, 2018). In the recent past, OPEX in quality control labs has gained increased interest. This is due to the fact that quality control (QC) can become a key bottleneck of a pharmaceutical value chain (Barbarite & Maslaton, 2008; Friedli et al., 2018).

Acknowledging this critical position, the US Food and Drug Administration (FDA) integrated one specific QC lab quality metric next to two manufacturing quality metrics to identify companies at higher risk of compliance and quality failures (FDA, 2015, 2016). Furthermore, quality control labs do not solely fulfil their role as safeguards to ensure product conformity and compliance but can contribute to the overall delivery performance by efficient release resulting in competitive advantages (Ritz, 2022).

Specifics of Quality Control Labs

Pharmaceutical companies have been exposed to strong external economic forces that led them to organise themselves into more complex supply chain structures. Another driver for change is an increased interest in achieving operational excellence, in order to maintain their competitive advantages. Quality control takes thereby a critical role in the overall process structures, since its high degree of complexity in operations requires an effective strategy for laboratory management (Costigliola et al., 2017). Köhler (2019) outlined that www.pharmafocusasia.com

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even though there is a consensus among practitioners with respect to the high importance of operational excellence in quality control laboratories, only limited research has been conducted in that field.

Testing processes in quality control labs can be divided into various test types, each with specific requirements.

This, along with a wide range of products and materials to process, leads to a high degree of complexity in QC labs (RuizTorres et al., 2012). In the meantime, Laboratory Information Management Systems (LIMS) lack crucial functional solutions in the field of scheduling and planning (Costigliola et al., 2017).

In order to cope with the increased complexity levels and the perceived cost pressure, while fulfilling regulatory requirements, it is crucial for quality control labs to manage performance and strive for continuous improvement. By doing so, based on the findings of Ferdows & De Meyer (1990), it is assumed that only if the basic quality levels are met (process robustness), the foundation for subsequent improvements in cost efficiency is given. Only stable processes that show a mature quality performance will provide a company with sustainable and long-lasting efficiency benefits. In case that process stability is

not reached, efficiency gains would be offset in a short time by deteriorations of the process effectiveness, the quality performance for example. Consequently, this provides one with a sequential prioritisation of focus topics for OPEX initiatives. One should first work on process stability and quality, before focusing on increasing efficiency. Improvement initiatives in laboratories target at process quality, meaning the quality of the tests to be performed in the lab, rather than conformance of the product. Competitive advantages of quality control labs stem from stable test quality levels that enable a pharmaceutical company to realise efficiency and overall cost improvements building on this.

Similar to the area of manufacturing, the outcome performance of quality control labs shows a strong correlation with OPEX enablers (S. Köhler et al., 2020). This in turn means that for an effective lab management approach two dimensions need to be considered. Firstly, a holistic assessment needs to provide decision makers with the status-quo performance of a quality control lab.

Thereby, the efficiency and effectiveness of a quality control lab have to be both considered. Secondly, since the lab performance correlates strongly with

OPEX enabler implementation levels, those can be seen as decisive management tools for further performance improvements.

In order to perform this two-dimensional assessment of quality control lab performance, the St. Gallen QC Lab Benchmarking Model was developed, which is introduced in the following.

St.Gallen QC Lab Benchmarking Model

To drive the improvement of the organisation, performance measures have always been of major interest in academic research (Kennerley and Neely, 2003).

According to the St.Gallen understanding of OPEX, QC labs have to pursue a balanced management of cost, time and quality, while simultaneously focusing on the customer needs and addressing structural and behavioural changes. To holistically measure the performance of pharmaceutical QC labs, the St.Gallen QC Lab Benchmarking can be understood as supplementary assessment to the St.Gallen OPEX Benchmarking, which was presented in our previous article St.Gallen OPEX Benchmarking for Pharmaceutical Manufacturing Sites – Measure Yourself Against the Best but Do It Right. Thus, the St.Gallen QC

En

ab ie

r

Me tric s

Overall Quality Control Lab Performance

Productivity

Maintenance & Quality System

Quality

Planning & Steering System Cost Structural Factors

Figure 1: St.Gallen QC Lab Benchmarking Model

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Service

Management System

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Overall QC Lab OPEX Performance Score Efficiency Productivity Handled Samples/QC FTES Batches processed/QC FTEs Overall Tests/Direct QC FTEs1

Effiectiveness Cost Efficiency

QC Costs/QC FTES QC Costs?Total no. of Tests

Service

Quality

Average Lead Time1 Average Cycle Time1 Average Release Time1 Average Adherence to Schedule1 Average Adherence to Lead Time1

Lab Deviations/1'000 Test Recurring Deviations Lab CAPAs Overdue Overall RFT1 Overall Investigations/1'000 Tests1 Overall Inv. OOS/100'000 Tests1 Product Re-Tests due to Complaints

Figure 2: QC Lab OPEX Performance Score

Lab Benchmarking Model (Figure 1) represents the transfer of an industrytested holistic approach into the environment of QC labs. With more than 130 pharmaceutical QC labs represented, the St.Gallen QC Lab Benchmarking database is the world’s largest academic database to assess OPEX-performance in the pharmaceutical laboratory environment. Figure 1 First introduced in 2016 and continuously growing ever since, the St.Gallen QC Lab Benchmarking database enables a holistic assessment of a QC Lab’s performance. As performance cannot be measured without the consideration of specific approaches and tools, nor without the understanding of the specific situation and role, the QC Lab Benchmarking incorporates the specific context of production facilities. To allow a meaningful comparison to the peer group, the St.Gallen team defines a dedicated peer group which fits best to the respective lab. By considering the so-called structural factors, St.Gallen is able to identify those labs from the database, that have the highest comparable fit to the benchmarked lab. Examples for structural factors are the regional distribution of labs, the lab type (Drug substance and Drug Product Type),the lab volume, FTE structure, or the separation of testing. When setting up the peer group, the St.Gallen team has to consider the interplay between the right

size of a statistically relevant peer group and the best possible match of QC labs.

The St.Gallen QC Lab Benchmarking model also addresses the cost efficiency of quality control. Costs play thereby a twofold role. On the one hand costs represent a context factor, as they are depending on various factors such as the test types being conducted, the complexity of processes being performed or the country the QC Lab is operating in and the overall regional cost levels. On the other hand, cost efficiency already demonstrates one out of four performance categories, which are used in the St.Gallen QC Lab Benchmarking to assess the QC Lab's performance. A large number of key performance indicators (KPIs) allow the overall assessment of the lab’s performance. The overall performance score can thereby, as depicted in figure 2, be divided into two main sub-scores, the efficiency and effectiveness score. Efficiency is analysed in two aspects: The cost efficiency and productivity of the respective lab. The latter is assessed through KPIs which consider e.g., the handled samples, the processed batches and the number of tests being performed in relation to the number of QC FTEs. The effectiveness score is also divided into two sub-scores: The quality and service score. The service category considers KPIs such as Lead, Cycle and Release time. The quality section contains KPIs like lab deviations, CAPAs overdue

or recurring deviations. Figure 2 Besides being calculated for the QC lab which is benchmarked, the specific QC lab performance score is also calculated for each QC lab of the peer group. Within the peer group all metrics are normalised to define the high performer group, which provides the lab with an achievable target for subsequent improvement actions that aim at becoming an industry-leader.

The high-performer group includes those labs, which belong to the top 25 per cent regarding overall performance.

When comparing the specific KPIs of the QC Lab, a comparison is then made to the high performer group, which always stays the same. That way a comparison to the respective KPI value is made for the average value of those KPIs of the high performer group. Following this approach, it is possible to be compared to a group which reflects respective tradeoffs and not to an artificial virtual best practice value for each single KPI, the combination of which is hardly attainable in the real world.

Besides the status-quo performance assessment based on the abovedescribed set of KPIs, the St.Gallen QC Benchmarking model also incorporates a maturity assessment of the management approaches taken, using a dedicated set of questions evaluating the use of enabling improvement practices.

Those enabler questions are raised in the

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AUTHOR BIO

Gian-Andri Steiger is a research associate at the University of St.Gallen. At the Institute of Technology Management, he works in the Operational Excellence team with a special focus on the pharmaceutical industry.

Currently, his academic research focuses on quality assurance excellence in the pharmaceutical industry.

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

format of a self-assessment and cover various topic fields for which a direct cause-and-effect link to the performance dimensions is given. The enablers are thereby structured in three main categories, which contain each specific sub-categories. The maintenance and quality system is the first category of enablers, which focuses on practices that ensure process stability. For example, the question is asked whether housekeeping checklists are used in the lab.

The lab representatives have then five statements available for their multiplechoice answer. Those statements reach from “No housekeeping checklists are used”, over “Housekeeping checklists exist, but are adhered to unevenly”, up to “Regularly updated checklists exist and are consistently adhered to”. By choosing the statement that best fits the situation of the respective lab, an initial evaluation of the maturity of the implemented enablers is possible. The second category planning & steering system is focusing on elements that enable efficient operational processes such as the

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Marten Ritz is a postdoctoral researcher at the University of St.Gallen. At the Institute of Technology Management, he leads global collaboration projects to support pharmaceutical companies in developing KPI strategies and implementing quality metrics programs. His academic research focuses on aligning OPEX initiatives across manufacturing and QC lab in pharmaceutical production.

reduction of setup times or the layout optimisation of labs, as well as planning related instruments. The overall objective of this enabler category is to ensure that available resources are optimally used. Lastly, the management system incorporates culture related elements in the model that support an effective implementation of improvement actions and that effective management structures are in place. Based on the outcome of the precedent performance assessment, the enabler maturity analysis allows a systematic identification of improvement fields and the definition of corresponding improvement actions.

Since the St. Gallen OPEX research team has also long-lasting experience in benchmarking pharmaceutical production, several interconnections between the QC and manufacturing OPEX performance became apparent. With respect to the field of QC, the planning accuracy measured by the adherenceto-schedule (ATS) highly depends on the information flow along the entire value-chain, including manufacturing.

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

Only if sufficient information on production planning is provided, a reliant QC operations planning will become possible.

This is one of many examples that shows the importance of cross-departmental process management. Pushing OPEX activities in both fields in an aligned and holistic manner is most promising to achieve lasting improvements.

Outlook

Constantly growing competitive pressure forces pharmaceutical companies to continuously work on improvement of their operational processes. This holds for both, the field of manufacturing and QC. Following an integrated management approach, the objective in the future will be to further improve the companies’ processes end-to-end. Thereby, a major challenge is how to align individual processes across various departments and how to coordinate activities across the fields of QC and manufacturing.

Literature is available at www.pharmafocusasia.com

ENVIRONMENTAL AND SUSTAINABILITY REQUIREMENTS IN DRUG PROCUREMENT T Drug assessment is now progressively taking sustainability criteria into account alongside traditional cost-effectiveness, for their procurement, pricing, and reimbursement policies for pharmaceuticals. Many pharma companies have effectively incorporated innovative actions in their production, consumption, and supply chain to improve environmental and social sustainability practices, and to address the UN’s Sustainable Development Goals. In Europe, there is an increasing trend of the inclusion of environmental, social, and governance issues along with quality and pricing in the decision-making process specifically with respect to tenders and procurement.

Josep M Guiu, Director, Pharmacy and Medicines, Consortium of Health and Social Care of Catalonia; Adjunct Lecturer, Clinical Pharmacy and Pharmacotherapy, Faculty of Pharmacy and Food Sciences, University of Barcelona

o preserve a healthy environment and human well-being, there is a recognised need to move away from overconsumption, waste and ecological harm. Historical and current patterns of natural resource use are contributing towards negative impacts on human health and the environment. This is particularly evident in the global health supply chain, as the production of medicines, health products and equipment contain a high-level of an environmental and social trade-off impacts, and most notably in emerging markets.

Many products and materials that come into hospitals may be harmful to patients, staff, and those in the community. Some products may contain or release carcinogens, reproductive toxins, or other hazardous materials. Moreover, the healthcare supply

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chain contributes more than 70 per cent in greenhouse gas emissions. In addition, the healthcare sector is the second-largest user of energy and one of the largest users of water in large part due to goods and services purchased. Medicinal products and packaging are disposed after use, generating hazardous waste.

Healthcare organisations have the opportunity to minimise negative impacts resulting from their activity and to create positive, lasting impacts for their staff, patients, and community.

In this regard, several concepts emerge in the corporate social responsibility strategy of healthcare institutions where sustainable procurement policies is a crucial part of an action plan, all of them related and with a common objective, such as circular economy strategies, net zero carbon emissions, the impact of pharmaceuticals on the environment and on antimicrobial resistances or the reduction of the use of plastic in healthcare.

Accordingly, sustainable procurement seeks alternatives that minimise human health and environmental impacts to support community health.

The potential of green procurement as a policy instrument has been increasingly recognised, and over recent years there has been growing political commitment at national and international levels. It has been highlighted internationally by the Organisation for Economic Co-operation and Development (OECD) and was established as a policy instrument within the EU in 2004.

In Europe, the European Commission and several European countries have developed guidance in this area, in the form of national green public procurement criteria. Depending on the level of ambition of public procurement authorities, procurement criteria can be classified as "core" (focusing on the key areas of environmental performance of a product) or "comprehensive" (criteria take into account more aspects or higher

Figure 1: The United Nations Sustainable Development Goals

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levels of environmental performance and go further in supporting environmental and innovation goals). Both core and comprehensive criteria set the minimum performance levels that products must fulfil.

However, in the procurement of drugs and medical devices, sustainable procurement is commonly known as environmentally preferable purchasing, which involves social and economic aspects as well. In sustainable procurement, healthcare organisations meet their needs for supplies and services while generating benefits for the institution, society, and the economy while minimising damage to health and the environment.

Medicines account for 25 per cent of emissions within the healthcare systems. However, a small number of medicines account for a large portion of the emissions, and currently there is a significant focus on two such groups – anaesthetic gases (2 per cent of emissions) and inhalers (3 per cent of

RESEARCH & DEVELOPMENT

Social

Economic

Environmental

Figure 2: Three main dimensions of sustainable procurement

emissions) – where emissions occur at the ‘point of use’. The remaining 20 per cent of emissions are primarily found in the manufacturing and freight inherent in the supply chain.

The international framework is the United Nations Sustainable Development Goals, which provide a blueprint for prosperity for people and the planet. Sustainable procurement addresses goal 12 on responsible consumption and production. Health care spending represents 10 per cent of the GDP in the OECD countries and almost 18 per cent of the U.S. GDP by 2030. Responsible consumption minimises the use of natural resources and toxic materials as well as emissions of waste and pollutants over the life cycle of the service or product. Sustainable procurement can leverage this purchasing power to help meet the 2030 Agenda for Sustainable Development. Figure 1: In everyday practice, according to The United Nations Sustainable Development

Goals, sustainable procurement refers a broad concept, embracing three main dimensions: environmental, economic, and social.

Sustainable procurement of drugs and medical devices is commonly known as environmentally preferable purchasing, which also involves social and economic aspects.

Every product has an ‘environmental footprint’ because of the energy and material resources used in its manufacture and delivery, as well as in its ongoing use and disposal. Product waste and its potentially toxic properties can undermine human health and the health of ecosystems. Hospitals and healthcare organisations have a significant role to play in promoting health by purchasing products and services that mitigate their environmental and health impacts on patients, staff, and surrounding communities. Some products contain carcinogens or reproductive toxics, some have outsized carbon and water footprints, and many are designed for single use and are excessively packaged generating a staggering amount of waste.

Environmental considerations include reducing impacts on natural resources, air, and water; conserving energy; avoiding where possible chemicals of concern; and minimising end-of-use effects.

The economic aspect of sustainable procurement allows health systems to consider how their economic power can benefit all of society. For example, a health system can diversify supply chain vendors to promote economic wealth in underserved communities.

Economic considerations include not only the purchase price of a good or service but also the total cost of ownership. Sustainability makes economic sense not only because it reduces inequalities across the value chain, but also because it supports financial sustainability. Valuebased drug procurement approach helps minimise costs, resources, and reduce inefficiencies.

The social dimension of procurement is concerned with the health and wellbeing of people while ensuring all partners in a supply chain uphold basic human rights in their employment and workplace practices. These rights are expressed in the International Labour Organization’s fundamental conventions and create a baseline for minimum standards in safe and healthy workplaces. Tools such as supplier codes of conduct help commu-

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nicate expectations on human rights to suppliers. Figure 2: In this regard, sustainable procurement is preventative medicine that supports a high-performance healing environment, attracts new opportunities, models leadership values to communities, patients and employees, and can save money to healthcare organisations.

Embedding sustainability in drug procurement processes

The ultimate goal of bringing in sustainability into procurement is ensuring that a healthcare organisation makes more sustainable choices more often.

It is necessary not only to identify the sustainability criteria, but also to establish a necessary dialogue together between healthcare procurement organisations with drug suppliers and manufacturers. Defining the basis of the sustainability criteria can help both healthcare organisations and suppliers to use and fulfil these new requirements.

On the other hand, using a common set of criteria shared by other healthcare organisations tells suppliers there is a business case to produce sustainable products to meet market demand. It also guides suppliers on key issues in order to respond to requests for proposal or tenders with accurate data.

For procurers, using third-party labels and sustainability certifications can be an agile strategy to introduce sustainability criteria into procurement.

Third-party labels are often voluntary initiatives demonstrating the environmental and sustainable qualities of products. Although many focus exclusively on environmental impacts, an increasing number include ethical and social standards that relate to decent working conditions, worker health and safety, and fair market return on labour. The International Standards Organization (ISO) classifies voluntary labelling into three types. However, ISO type I ecolabels are the strongest for procurement purposes because they consider all adverse environmental impacts of a

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product throughout its life cycle and are awarded only after an independent process of verification.

How pharma is implementing environmentally friendly processes

The pharmaceutical industry’s approach to circular economy builds on experience in sustainability, although the limitations, especially on speed of transition, from operating in a highly regulated industry. Due to the drug regulatory approval process, it is sometimes challenging to innovate in manufacturing processes or supply post-approval. The determination to move to a circular economy may also promote greater resource efficiency, create a more competitive economy, and reduce pollutants, but it needs to consider wider influences on the pharma industry activities, for example, on use of secondary materials in manufacturing.

Circular economy (‘circularity’) in the drug manufacturing process is based on a business model in which the manufacturer intends to maximise the lifetime of resources across value chains and reduce unnecessary waste and minimise environmental impacts, like climate change.

Figure: 3 Manufacturing of pharmaceutical ingredients and products are strictly regulated to secure patient safety and quality through the principles and guidelines for Good Manufacturing Practice (GMP).

This apply irrespective of where the ingredient or product is manufactured.

The environmental regulations governing manufacturing of products and APIs are, however, in general regional, national, or local. As the pharmaceutical industry is global, this consequently implies that environmental regulations in countries of manufacturing varies.

Figure 3: Pharmaceutical initiatives across the value chain are innovating in environmental responsibility Source: EFPIA

RESEARCH & DEVELOPMENT

CRITERIA

SCOPE

LEVEL

Information on location of: Pharmaceutical formulation API production for medicinal products

Country or countries of manufacturing

Advanced

Information about the production facility in which: pharmaceutical formulation takes place APIs are manufactured for medicinal products

Name and address of production facilities

Spearhead

Available environmental information for medicinal products

Products that are covered by EMA guidelines

Core

Available environmental information for medicinal products

Products that are not covered

by EMA guidelines

Spearhead

Risk management procedures for environmental API emissions during the manufacture of medicinal products

Own operations and subcontractors

Core

Implemented procedures for identifying and managing risks related to emissions of API

Requirements under the labour conventions

Own operations and subcontractors

Core

Effective risk management regarding worker rights

Sustainable supply chains

Operations and supply chain

Advanced

Risk management covering human rights, labour rights, environmental protection, and anti-corruption

Increase transparency and traceability to allow identification and prioritisation of environmental and social risks, as well as of follow-up efforts

Environmental information obtained and publicly available.

Information must at least include details on persistence, bioaccumulation toxicity and environmental risk, compiled in accordance with the latest EMA guideline, FASS guideline or other equivalent publicly available model

Overview of sustainability criteria for pharmaceuticals

Sustainable procurement should be lined up with the health organisation's sustainable responsibility goals, as well as with procurement priorities on drug selection and the formulary management, cost savings or patient safety.

AUTHOR BIO

Environmental aspects may be included for pharmaceuticals procured as a healthcare policy, which can contribute to the development of environmental harmonised standards in drug manufacturing.

In December 2019, the European Green Deal for the EU and its citizens was launched, which aims to “making Europe climate neutral by 2050, boosting the economy through green technology, creating sustainable industry and transport, cutting pollution”.

The Green Deal includes elements and initiatives that will or can have an influence on the environmental impacts along the pharmaceutical value chain, including climate impacts and emissions of APIs, as well as on the different identified applications to drive improvement along the chain, such as procurement.

PURPOSE

Supplier engaging in sustainability can be undertaken with more powerful impact through procurement criteria.

Engagement starts up communicating sustainable procurement strategy to suppliers and inviting them to work to achieve the organisation goals.

Sustainability value and benefits can also be tackled by a group procurement organisation (GPO), which have

Josep M Guiu is the Director of Pharmacy and Medicines at the Consortium of Health and Social Care of Catalonia and adjunct lecturer of Clinical Pharmacy and Pharmacotherapy at the Faculty of Pharmacy and Food Sciences of the University of Barcelona, Spain. He is also currently Secretary of the Catalan Society of Clinical Pharmacy and Vice-president for the Euro region of the Hospital Pharmacy Section of the International Pharmaceutical Federation.

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a significant role in advocating for sustainable procurement. Most GPOs have councils or committees that make recommendations and decisions on contracts. GPOs may also develop the elements of a sustainable procurement program, identify high-impact procurement opportunities, make recommendations on criteria, and support purchasing decisions to hospitals and healthcare organisations.

Assessing sustainable products and services available on the market that meet the primary function and technical requirements is also an action to be carried out by healthcare purchasers. This assess will have to consider misleading claims, ‘greenwashing,’ or harmful product substitutions.

Sustainability criteria consist of formulated requirements, together with motives for the requirements and suggestions for how to verify them.

Examples of environmental criteria elements considered in drug tenders for

drug procurement by the Consortium of Health and Social Care of Catalonia (Spain) are Environmental management, Ecodesign, Packaging (plastics and paper/ cardboard), Recyclable containers, Need for refrigeration, Emissions in the delivery and distribution of medicines and Waste management.

Sustainability criteria can be formulated as special contract terms or award criteria, and could be defined on three levels (Table 2): a. Core level covers basic requirements focused on reducing most of the environmental/sustainability impact that is associated with the specific product area, which are more ambitious than applicable legislation b. Advanced level goes beyond basic requirements. They may require more efforts in follow-up and verification for procurers c. Spearhead level represents the best available alternatives in the market in terms of environmental and other sustain-

ability aspects. They may require more specialised competence and efforts in work with follow-up and verification.

Procurement criteria are, however, voluntary for the contracting authorities to use. The implementation is made by the contracting entity who decides which criteria to include in the specific procurement situation depending on available information, resources, and ambitions.

In 2019, the EU presented a Strategic Approach to Pharmaceuticals in the Environment, which cover all stages of the life cycle of pharmaceuticals where improvements can be made. Although pharmaceutical policies have a higher impact on the development of a greener pharmacy, it should not be undertaken the deeper impact that decisions at the hospital level can have, as in the end, a critical decision-making point about medicines in the purchasing process.

References are available at www.pharmafocusasia.com

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Drug Development in the Technology Era Legal Considerations for Computer-Assisted Drug Design Computer-aided drug design seeks to accelerate drug development and increase success rates, while reducing costs. With more sophisticated bespoke programs being developed, relying on advanced AI technology, we pause to consider some of the potential legal and commercial issues which might arise, including IP ownership, remuneration strategies and liability.

Lydia Torne, Partner, Simmons & Simmons LLP Samuel Wilson, Trainee Solicitor, Simmons & Simmons LLP

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ith the cost of developing a new pharmaceutical product currently hovering around US$ 944m to US$2,826m1 and taking approximately ten2 years from product inception to approval, the pharmaceutical industry is understandably keen to identify ways to reduce these metrics. To this end, the industry has begun exploring computer-aided drug design (CADD) with a view to accelerate drug development and increase the success rate of products in development.

What is CADD? CADD can be broadly described as the use of software algorithms in drug discovery to identify and/or develop a potential lead drug candidate. For example, using software to review and assess a small molecule library against a defined target to identify potential “hits”. Other CADD software focuses on “molecular docking” (e.g. software which predicts both the binding affinity between ligand and protein and the structure of protein–ligand complex) to develop product candidates. Using software to predict characteristics of the product, e.g. predicting the absorption, distribution, metabolism, excretion, and toxicity properties of the product candidate thereby allowing scientists to better understand the product’s safety and 1 Source: Front. Med article 2 Source: paper from 2021 RPDI industry report

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efficacy profile before it ever reaches a trial subject. There is even the possibility of pure in silico trials, using a CADD drug product and “testing” this against data sets for theoretical clinical trial subjects.

Below we consider some of the legal implications of using CADD under licence: is the provider of the CADD software (the CADD Developer) also a co-developer of the resulting product?; how should the CADD Developer be remunerated for the use of its technology?; and how should liability be apportioned?

1. CADD provider as co-developer

If CADD software is material to the discovery and/or development of a new pharmaceutical product is there an argument that the CADD Developer should, or (in some cases of artificial intelligencedriven CADD software) the software itself, be recognised as a co-inventor of the resulting drug product? Further, if the software itself could be considered an inventor for patenting purposes - who should then own such a patent?

These issues have already begun to be considered by various courts, most significantly in Thaler v. Comptroller General of Patents Trade Marks and Designs3. Dr Thaler invented DABUS, an AI "creativity machine" designed to create novel inventions. Dr Thaler attempted to include DABUS as the inventor on a number of patent applications. In the UK, both the High Court and the Court of Appeal4 held that an "inventor" under English law must be a natural person and therefore DABUS could not be an inventor. The same outcome was found in similar applications at the European Patent Office (EPO) and the US Patent and Trademark Office (USPTO). However, in Australia, the Federal Court held that DABUS was capable of being an inventor under Australian patent laws.

These differences stem from the fact 3 Thaler v. Comptroller General of Patents Trade Marks and Designs [2021] EWCA Civ 1374 4 Ibid

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that in each jurisdiction it will be a matter of statutory interpretation as to whether AI software can be an inventor, not whether it should be5. This has prompted governments to question whether AI software should be an inventor. For example, the UK government recently performed a consultation on AI's impact on intellectual property law, the responses to which indicated that most respondents believe that AI should not own intellectual property rights. There was also a consensus (although less clear cut) that the current system could be a barrier to innovating using AI (such as CADD). This is because many respondents felt that it would be logical for the AI owner to be a co-owner of any patent for an AI-assisted invention, i.e. the CADD Developer, should have a claim as co-owner of any patent which claims an invention that the CADD software helped create.

The UK government has also queried6 whether AI-devised inventions should be protected through a new form of protection (rather than patents).

In view of the rapidly changing landscape, pharmaceutical companies using CADD software should ensure that their licence terms make clear that any inventions and intellectual property rights resulting from the use of CADD software is solely owned by the pharmaceutical company and include appropriate assignment provisions. It may also be prudent to ensure that the pharmaceutical company can obtain assistance from the CADD Developer, if needed, with the filing, prosecution, defence or enforcement of any patent covering the invention resulting from use of the CADD software.

2. Remuneration for the software provider

Software developers usually seek a licence fee structure, perhaps per user, for a licence to use their software programmes.

However, in the case of CADD soft5 Notably, the UK, EU, China, Japan and Korea all currently require a natural person to be an inventor.

6 UK Government second consultation on Artificial Intelligence and IP: copyright and patents

ware a CADD Developer may seek an alternative remuneration structure e.g. if the resulting CADD drug product is highly successful and/or if the CADD software is developed specifically for a particular client.

If the software (or an element of it) has been developed or adapted specifically for that pharmaceutical company, then the CADD Developer may seek additional remuneration given: (a) the additional expenditure it has incurred (e.g. on staffing costs) to develop the specific program; and (b) the potential market advantage afforded to the client as a result of having access to a particular software model which its competitors do not (or at least do not yet have access to). This remuneration might be structured by way of an additional one-off sum and/or milestones payable if/when the CADD software achieves certain stages of development.

Similarly, the CADD Developer might request a royalty or further milestones payments if a CADD drug product is ultimately authorised and successfully sold. This may seem like overreaching, particularly given the still extensive and costly input required from a pharmaceutical company to develop the drug product. But, a CADD Developer might argue that it is entitled to a share of the significant cost savings which its software offers. In such cases, a pharmaceutical company might consider: (i) a very small, capped, royalty; (ii) commercial milestone payments tied to (high) sales volumes; or (iii) developmental milestones tied to the software producing a certain output at various stages of use and/or the developmental success of the resulting product. Other conditions might be attached to such payments, for example, a requirement to demonstrate that use of the CADD software has resulted in costs savings of a certain amount or above.

If CADD software uses machine learning, and therefore is automatically learning and improving as a result of using the pharmaceutical company’s data, a pharmaceutical company might argue

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that the CADD Developer’s ownership of such improvements is sufficient compensation (beyond any basic licence fee).

3. Liability for the resulting product

If a CADD Developer argues that its software is sufficiently material to the development of a drug product that it should receive greater remuneration, consideration should be given to what proportion of liability the CADD Developer will bear if the product is subsequently defective.

The potential for the CADD Developer to be liable under a statutory strict liability defective product regime is low. Under the Consumer Protection Act 1987, a consumer may seek indemnification of his/her personal injuries from the “producer”7 of a product, if he/she proves that: (i) the product is defective; and (ii) the damage they suffered is causally linked to such defect. In such circumstances, a CADD Developer is unlikely to constitute a “producer” of the drug product.

Similarly, a negligence claim is likely to be brought against the pharmaceutical company alone (with no visibility of any CADD provider). In any event, it would be difficult to demonstrate that the legal requirements for a negligence claim (a duty of care was owed to the individual, a breach of that duty occurred

AUTHOR BIO

7 Section 1 of the Consumer Protection Act 1987 broadly defines a “producer” as someone acting in a professional capacity manufacturing a product, producing raw materials, or manufacturing a component part of the product.

Lydia Torne is a Partner at international law firm Simmons & Simmons LLP. Lydia specialises in life sciences’ licensing transactions including, research, development and commercialisation agreements for early stage, pre-clinical and clinical assets, and related collaboration and consortia arrangements.

Lydia has a particular focus on biotechnology assets and digital health.

and resulting in loss for the claimant) exist between the CADD Developer and injured person8.

A CADD Developer might also resist contractual indemnification for the drug product given that the pharmaceutical company (at this time at least) would still be required to perform extensive further development and testing of any drug product designed using a software programme. Consequently, liability is often disclaimed on the basis that details of the designed product are provided “as is” and are not guaranteed to result in a successful drug product. Even indemnification for the designed drug product infringing a third party’s intellectual property rights might be resisted on the basis that the pharmaceutical company should (and would) perform freedom to operate analysis.

In view of the above, if the pharmaceutical company bears most (if not all) liability for the product, it has good grounds for refusing any additional or significant remuneration to the CADD Developer.

Notwithstanding the above difficulties, the CADD Developer should be asked to provide contractual indemnification for issues relating to the CADD programme being used and any third party data used as part of its modelling, 8 Notably, the use “black box” AI might also break any chain of causation between the CADD Developer and the individual.

such as third party infringement or misuse of data claims.

Notably, for AI-based CADD software, new regulation may be forthcoming.

In April 2021, the EU published its draft Regulation on AI9. As currently drafted, this regulation would apply to providers, users, importers and distributors of AI systems with a wide territorial reach.

The draft AI Regulation prohibits certain AI uses, as well as imposing additional obligations in respect of "high-risk AI systems" including increased record keeping, oversight, governance and reporting measures. Currently, CADD programs are neither prohibited, nor do they constitute a “high-risk AI system” (unlike AI driven medical devices). However, as the use of AI-driven CADD software increases, this may change. Under the draft AI Regulation, non-compliance can result in significant financial penalties of up to 2 per cent, 4 per cent or 6 per cent of worldwide annual turnover depending on the nature of the infraction. Notably, the UK (and other jurisdictions) are also considering introducing their own legislation in respect of the use of AI-driven software. CADD Developers and pharmaceutical company users should, therefore, continue to monitor whether the development and use of AI-driven CADD software is likely to trigger additional regulatory obligations.

9 Draft EU Regulation on AI

Samuel is a trainee solicitor in the intellectual property team at Simmons & Simmons LLP. He has a degree in biochemistry from the University of York and experienced the use of CADD in the course of his masters programme

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EXECUTIVES SPECIAL ISSUE 4 8 AUGUST 2022

Special issue is designed to focus on a theme or a sector trend. This issue is aimed at facilitating the industry leaders share perspectives and insights with our readers on key issues impacting and influencing the industry. The issue would also cover a few articles on trending topics in the pharma industry.

If interested in contributing, please reach out to prasanthi@ochre-media.com or gracejones@ochre-media.com

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Current Trends in Pharmacogenomics that will shape Clinical Trials The increased relevance of pharmacogenomics in explaining individual differences in drug responses is evident in the market’s projected growth to $9,346.8 million by 2031. The CRISPR Cas-9 gene editing, computer assisted structural simulation and DNA reactivity technology provide key insights for informed trial design, especially in Oncology studies where both germ line and acquired mutations play a role.

Ayaaz Hussain Khan, Global Head – Generics, Navitas Life Sciences

Gene variations and pharmacogenomics

Variations in genes that code for specific enzymes, drug targets, or even transporters have been shown to be associated with drug toxicity and may be used for identifying likely responses to drug products. An understanding of such variations that are present from birth, or germline variations, are inherited and are used as biomarkers to understand the pharmacokinetics of drugs. The increased relevance of pharmacogenomics in explaining individual differences in drug responses is evident in the market’s projected growth from nearly US$ 5,000 million in 2020 to US$ 9,346.8 million by 2031 at a CAGR of 5.71 per cent.

Inter-individual differences in drug response

T

he complete human genome was published in March 2022, heralding a new era in pharmacogenomics, advancing genome analysis, and unlocking value additions in precision medicine. It received a considerable impetus in the global market when former US President,

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Barrack Obama, announced the Precision Medicine Initiative in 2015. According to a McKinsey report, the precision medicine market is set to touch US$ 140 billion by 2026, with the growing demand bringing to the fore the need to conduct pharmacogenomics studies, adding new dimensions to clinical trials.

There are inter-individual differences in the response to drugs that are multifactorial and difficult to predict, but are partly associated with inherited genetic variations. Variations in genes associated with absorption, distribution, metabolism, and excretion (ADME) have been found to be associated with a drug’s pharmacokinetics (PKs) and pharmacodynamics (PDs), affecting various aspects of drug outcome. Gene variations are also associated with drug dosing, toxicity, the extent of effect, and even drug resistance and hypersensitivity.

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Evolving genetic testing landscape

The genetic testing and genomic services ecosystem is rapidly evolving, with the main drivers being advances in technology, improved utilisation of genetic information, and better delivery of information. Tiered single-gene methods and multigene panels have given way to genome-wide sequencing, and genome or exome sequencing, increasing the potential for faster genetic testing services.

Such advances have improved the clinical use of genetic information, or pharmacogenomics, for the past 15 years. This wide-ranging field of study utilises the information present in DNA variants to identify people who may be hypersensitive to certain drugs.

Changing the Clinical Trial Landscape

Germline variations that are known to affect the pharmacodynamics and pharmacokinetics of a drug are estimated to explain 20-40 per cent of the variation in drug response. In order to study the effect and the likely therapy, however, the conduct of randomised clinical trials

is a little more complicated when it is a pharmacogenomic study.

Pharmacogenetic trials that are prospective compare a standard arm with a pharmacogenetic guided arm.

Such studies are generally singleblinded, and the study participant is unaware of the arm that they are a part of. However, the clinical investigator is aware, and there are certain challenges in implementing medications. For example, there are multiple clinical genotyping panels that are available to support the prescription of antidepressants, however, only five pharmacogenetic trials for antidepressants were randomised, all the others were single-blinded studies.

Another aspect of prospective pharmacogenetic trials is that there is a need for a large sample size, as the effect of the gene variants may be modest, so there may be difficulties encountered in patient recruitment for the study.

Certain other factors that could affect such trials include the absence of ethnic diversity, clinical and environmental confounders as well as logistical considerations like the delivery of therapeutics, the tracking of adverse events manually, and compliance from

patients. Such issues may be overcome by the incorporation of recent innovations that could shape the conduct of pharmacogenomic clinical trials.

Digital health technologies

The use of digital devices has been shown to significantly improve the conduct of pharmacogenomic clinical trials. The use of wearable devices is already common in many clinical trials, where user activity is tracked by the device to capture digital biomarkers and associated outcomes like walking, sleeping, or even collecting electrocardiograms. In psychiatry pharmacogenomic studies, episodes of anxiety have been monitored using such wearable devices.

Other interesting devices that have been used in pharmacogenomic trials include a device to measure blood pressure as well as anticoagulation levels for pharmacogenetic trials focused on cardiac therapy. There are specially designed apps that can be used on smartwatches like SmokeBeat, which detects how many times an individual carries out hand-tomouth gestures. An effective app that can be used to understand the association of gene variants with smoking cessation.

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CRISPR-based gene editing

A significant step forward in pharmacogenomics is the use of clustered regularly interspaced short palindromic repeats (CRISPR) based gene editing that allows pharmacogenomic screening of lab-grown cells in different flasks. Such innovative strategies allow scientists to identify genomic changes that influence the clinical effects of a drug.

The information can then be used to check clinical trial participants for the presence of certain gene variations associated with altering the activity of certain drugs. This will help in improving the trial design, improving safety and efficacy, and providing specific solutions.

This technology is currently being used in cancer research, but with improvements in technology, it can be used to provide insights into other medical conditions as well.

Pharmacogenomics in COVID-19 therapy

Pharmacogenomic biomarkers have provided a lot of tangible and intangible benefits. The tangible benefits have been the discovery of new COVID-19 medications while the intangible benefits have been the strategic insights gained that have helped broaden the understanding of the fight against COVID-19.

One of the many genetic variants associated with varied response to COVID-19 is the ACE2 gene variant.

Angiotensin-converting enzyme 2 (ACE2) has been shown to be the receptor for entry of the SARS-CoV-2 Coronavirus.

The ACE2 enzyme leads to the degradation of the angiotensin II, which facilitates the entry of the virus. Recent studies have shown a possible association between ACE gene variants and severity of COVID-19 outcomes, highlighting a likely genetic contribution.

As a result, pharmacogenomics is expected to provide key insights into therapeutic innovation for COVID19, especially as new COVID-19 waves are expected. Such insights will help immensely in contributing toward drug

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According to a McKinsey report, the precision medicine market is set to touch US$ 140 billion by 2026, with the growing demand bringing to the fore the need to conduct pharmacogenomics studies, adding new dimensions to clinical trials.

discovery, as well as being a decisive factor in the design of clinical studies.

Phenomics 2.0

A new and emerging field of phenomics 2.0 shows promise, aiding in real-time drug-related outcomes for association analysis based on pharmacogenomics.

Phenomics is expected to provide a deeper understanding of phenotypes by capturing the living architecture of disease progression with digital dynamics.

Internet of pharmaceutical things (IoPT)

The concept of the Internet of Pharmaceutical Things (IoPT) aligns experience innovation with process innovation to ascertain a wide range of phenotypes specific for innovative COVID-19 medicines. There are potential applications of this innovative system in pharmacy services, for comprehensive drug response to COVID-19.

There are a number of preventive and therapeutic applications that can be developed for clinical, pharmacy, and health practices using pharmacogenomics.

Pharma companies have, for a long time,

depended on a manual workforce and siloed environments, however, successful partnerships have aided in innovations that greatly support the growth of the industry.

Innovations that spearhead pharmacogenomics

A global pharmaceutical company partnered with a major software company to develop a tech-enabled house called ‘Parkinson’s House’. Multiple sensors are placed in the house to analyse and monitor the movements of patients to aid in supporting their condition, revolutionising both support and care. In another instance, a global clinical research organisation utilises OneClinical to reduce the time in mapping highly complex studies by up to 50 per cent, coupled with a 60 per cent improvement in cycle time to develop an initial Interface for the data warehouse, and a 30 per cent cost reduction.

Precision medicine in oncology saw progress with the OncologyCloud platform that has been designed to combine Electronic-Medical-Record (EMR), claims billing, longitudinal clinical data, as well as analytics for nearly two million patients with active cancer. This helps support targeted therapy, for example, for individuals with epidermal-growthfactor-receptor (EGFR) and the anaplastic-lymphoma-kinase (ALK) mutations.

Such innovations will help in speeding the development of tailor-made therapies, while adhering to all data privacy regulations. There is an increased pace of innovation in utilising the EMR, with multiple stakeholders supporting personalised medicine by actively linking EMR with genomic medicine. To safeguard data, there are stringent regulations like the General Data Protection Regulation (GDPR) in Europe and the Health Insurance Portability and Accountability Act (HIPAA) in the United States.

Advanced analytics in pharmacogenomics

Advanced analytics are leveraged for

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the development of highly precise drug therapy, especially for rare diseases. Such technology solutions aid the gathering of data from multiple sources, translating the information into easily assimilable insights that companies use to understand individual behaviour.

Real world evidence

AUTHOR BIO

Real world evidence (RWE) is being employed in innovative ways using the analytics capabilities that are available. RWE has been used extensively to understand patient behavior but is now being leveraged to help move

precision medicine from a detailed understanding to enabling predictive approaches.

Effective use of RWE in oncology clinical trials is in the synthetic control arms. Such arms aid in overcoming challenges posed in patient recruitment in randomized clinical trials, as well as in combating ethical issues faced when supporting placebo arms.

Regulatory authorities also favor RWE, with approval provided in certain instances. For example, the information provided by RWE was utilized to expand the label for IBRANCE, a prescription

Ayaaz Hussain Khan is an authority in BA/BE domain of generic drug industry. He brings with him a rich experience of conducting over 1000 Bioavailability/Bioequivalence studies. He has been a gold medalist in his academics and completed his M. Pharm in Pharmaceutics from Birla Institute of Technology & Science, Ranchi. He further pursued and earned PhD in Pharmaceutical Medicine with specialization in Clinical Pharmacokinetics from Jamia Hamdard University, New Delhi.

medicine, to include male breast cancer by the US Food and Drug Administration (FDA) in 2019. The drug is used as a treatment for breast cancer patients who test negative for human epidermal growth factor receptor 2 (HER2) and positive for hormone receptors. This cancer is extremely rare among men, and such RWE-based approvals will aid in the ability to bring life-saving medicines to people who most need them quickly.

Pharmacogenomics- Shaping the Future of Medicine via Efficient Clinical Trials

In conclusion, Pharmacogenomics is undoubtedly poised for greater acceptance and relevance with pragmatic clinical trial design required to tap into advancements in DNA technology and digital health solutions to harness the big data from genomics. This will help revolutionise care and provide highly targeted medical therapy. Supported by efficient clinical trials, pharmacogenomics will help in shaping the future of medicine.

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NEXTGENERATION CELL CULTURE MEDIA AND FEEDS SYSTEMS A multi-faceted approach for optimising monoclonal antibody manufacturing productivity Choosing an optimal cell culture media that can be seamlessly integrated into recombinant protein production workflows is essential for successful bioproduction.

This article will examine some of the key attributes that manufacturers should look for when choosing a suitable medium for their process. It will cover areas such as the availbility of alternative formats and the need for supplementation, as well as highlight the importance of investigating how the media has been designed. Through this, it will spotlight how next-generation techniques including multi-omics analysis and bioinformatics modelling are being used to design highly optimized off-the-shelf media options.

Paul Gulde, Manager, Multi-Omics Research and Development, Thermo Fisher Scientific Chad Schwartz, Senior Global Product Manager, Thermo Fisher Scientific

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S

ince the 1980s, monoclonal antibody (mAb) therapies have been a growing part of modern medicine’s toolbox of biopharmaceuticals with no sign of this progress slowing down.

The recent success of mAb therapeutics against SARS-CoV-2 has demonstrated the potential of this technology to treat infectious diseases and prevent serious illness in vulnerable individuals and has contributed to a growing demand for these therapies.

To support this demand, there is no doubt that there will be significant pressure on mAb manufacturers to improve the output of their processes. Although mAb manufacturing workflows using Chinese hamster ovary (CHO) cells are well established, achieving improved output will still require process optimisations. It will be critical that productivity improvements are achieved without compromising on end-product quality or economic feasibility. In particular,

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choosing the optimal cell culture media and feeds system will be essential.

Nutrients, growth factors, and hormones provided by cell culture media and feeds directly influence both cell growth and mAb product titres and quality—crucial factors in determining overall process productivity.

In response to the need for improved productivity, three key areas of media and feed development have seen significant advancements in recent years: performance, process efficiency, and risk reduction. Taken together, these improvements have the potential to significantly enhance mAb production. It is important for mAb manufacturers to appreciate these latest developments and understand how they can leverage them to optimise their workflow. This is imperative regardless of whether they are designing their own custom medium formulation, using a catalogue option, or combining both by customising an off-the-shelf option.

A multi-omics approach to media development

One of the key drivers of innovation in

In response to the need for improved productivity, three key areas of media and feed development have seen significant advancements in recent years: performance, process efficiency, and risk reduction.

media development is the use of multiomics approaches for media design and optimisation. Specifically, the use of metabolomics and proteomics, which refer to the molecular characterisation of cell metabolites and proteins, respectively.

Traditionally, media development and optimisation has been conducted using a technique known as spent media analy-

sis. This technique compares the levels of different media components before, during, and after cell growth to identify how they are being used by the cells. An iterative, empirical approach can then be used to establish which components are driving productivity and how their relative quantities can be refined to develop an optimal formulation. This analysis allows major metabolites such as amino acids and vitamins to be measured and informs developers which molecules are being taken up or secreted by cells. As a result, spent media analysis has been a powerful tool in the media developer’s arsenal.

Multi-omics analysis builds on this strong foundation by providing even greater levels of detail and increasing the number of molecules that can be studied. By enabling the identification of specific proteins, proteomics enables the specific intracellular pathways that are being activated and inactivated to be recognised. This information can then be combined with metabolomics to assess how specific metabolites are flowing through these pathways. Overall, this

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only producing maximal product titres, but also mAbs with the correct quality attributes. Secondly, by preventing the disfunction and apoptosis of cells, it can limit the impurities released in the culture, preventing further cell damage and simplifying downstream purification.

Another avenue of optimisation opened by next-generation media and feeds systems is improved consistency of mAb quality. As the critical quality attributes (CQAs) of mAbs—such as glycosylation profiles, charge variants and aggregates—directly affect their biological activity, achieving consistent and desirable quality is crucial to enable the manufacture of efficacious therapeutics. Furthermore, high levels of inconsistency can impact productivity, as mAbs that do not meet the required CQAs will need to be removed during downstream processing, reducing the overall process yield. Combined, these factors demonstrate the need to either choose or develop a media and feeds system that can optimise mAb quality. can enable developers to identify pathway bottlenecks that could impact productivity and design new experiments to resolve them. For example, in a process where the amino acid cysteine is being consumed at a much higher rate than it is used in the manufactured protein, multi-omics can be used to identify where exactly the cysteine is being used. Developers can then undertake further investigations to develop a strategy that can direct cysteine toward protein production instead to improve productivity.

Using this approach, media developers can not only accelerate the development of an optimised solution, but also potentially uncover new strategies that would not have been possible with spent media analysis alone. Crucially, as multiomics approaches are now being applied in the development of both catalogue and custom media and feeds systems, an appreciation of this technique is essential for all mAb manufacturers.

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Improving process performance

Simplifying manufacturing workflows

It is also important for mAb manufacturers to understand what key performance improvements are now attainable.

Previously, innovations in cell culture media and feeds have been mostly limited to increasing cell density and cell viability which, over time, has led to a plateau in the mAb titres achievable using CHO cells [2].

However, through the utilisation of multi-omics to design new media and feeds, progress has been made. For example, many next-generation media and feeds have the potential to increase specific productivity (QP) which can enable manufacturers to improve titres.

They can also prolong cell viability during long bioreactor runs. This is a particularly important feature for improving overall process productivity for two main reasons, first, it can extend the period of time when the cells are functioning optimally. This means they are not

Despite the clear importance of choosing a medium and feed combination that can maximise product titres and quality, it is vital to acknowledge that high performance alone is not the only indicator of a successful process. This is because overall productivity is a combination of both performance and process efficiency, with the latter becoming increasingly important as production volumes increase.

One area where innovation has helped dramatically improve process efficiency is the development of advanced media and feeds formats. When working at a commercial scale, the use of liquid format media is often unfeasible due to the cost, transportation and storage challenges associated with handling the large volumes of liquid required. Instead, many manufacturers purchase their media in a dry format which can be easily stored and reconstituted in-house when needed.

Although, it is essential to remember

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Reducing risk and avoiding delays

Another way manufacturers can reduce risk is by using animal–origin free (AOF) and chemically defined (CD) media and feeds. Use of AOF components can reduce the risk of adventitious agents and eliminate the need for additional lengthy qualification procedures. Furthermore, by providing a known formulation, CD media and feeds can increase process reproducibility, improving batch-tobatch product consistency in terms of both mAb titres and quality.

Beyond the formulation of the medium and feed themselves, there are also wider considerations around procurement that can reduce the risk of delays.

For example, working with a vendor that

can leverage a global redundant manufacturing network can make supply chains more robust and reduce the risk of supply disruption. In this scenario, it is vital to assess vendors’ site-to-site equivalency to validate lot-to-lot consistency. Finally, when leveraging an external media manufacturer to produce a custom formulation, ensuring that the vendor employs rigorous raw material qualification and offers supply chain transparency is crucial to help prevent lot-to-lot variability.

Optimising mAb manufacturing productivity

Given the significant progress that has been made in the development of nextgeneration cell culture solutions, it is no surprise that medium and feed selection can be a daunting process. Along with deciding whether to develop their own formulation or choose a catalogue option, mAb manufacturers also need to fully understand what key attributes to prioritise during the selection or design process. This is going to be essential to enable them to optimise their processes specifically for their target CHO cell clone and reach a level of productivity that can meet the demands of the growing mAb market. Most importantly, they will need to be able to maximise their titres and workflow efficiency while keeping their process economically viable.

AUTHOR BIO

that not all dry formats are equal. To maximise efficiency, advanced dry formats are available that have been designed to simplify reconstitution. Specifically, features such as improved dissolution and pH and osmolality pre-adjustment offer major benefits and can contribute to significant time savings when considered over the lifetime of the process.

Catalogue media and feeds supplied in these advanced formats have been carefully engineered to achieve equivalent performance to the liquid formulation, allowing for a more streamlined scale-up journey. However, this may not always be the case for custom formulations. As a result, manufacturers with the goal of developing their own formulation need to prioritise ensuring it is compatible with conversion into an advanced format.

Importantly, they need to do this from the beginning of the design process as late-stage redevelopment is often costly and can delay scale-up.

In addition to new formats, new catalogue feeds are also being designed to be integrated more easily into mAb manufacturing workflows. This includes the development of single-part feeds which, by eliminating the need to blend multiple components, can enable manufacturers to improve the efficiency of their workflow and reduce the risk of formulation errors.

Ultimately, to achieve this, manufacturers need to gain a wider awareness of what is now available and achievable within the industry. One straightforward way to gain this knowledge and embrace the future of mAb production, is by speaking to a trusted vendor. Whether they are looking for support in developing a custom formulation, or choosing the best catalogue solution for their process, drawing on the knowledge of professionals can prove invaluable. By leveraging an understanding of the past, present, and future of mAb manufacturing, they can provide a detailed insight into how an individual workflow can be optimised to achieve maximum productivity.

References

[1] Brand Essence Market Research (2022) Monoclonal Antibodies Market Size, Share & Trends Analysis Report By Source (Chimeric, Murine, Humanized, Human), By Indication (Autoimmune Disease, Inflammatory Disease, Infectious Disease, Cancer, Others), By End User (Research Institute, Hospital, Others) Based On Region, And Segment Forecasts, 2021 – 2027. Available at: https://brandessenceresearch.com/healthcare/monoclonalantibodies-market-size [2] Yao, G, Aron, K, Borys, M et al.

(2019) Metabolomics approach for increasing CHO cell specific productivity. Biochemical and Molecular Engineering XXI.

After graduating from the University at Buffalo with a PhD in Microbiology and Immunology, Paul joined Thermo Fisher Scientific. In his current role, he has been instrumental in the development of Thermo Fisher's multi-omics capabilities which have been utilised to support the development of the new Gibco™ Efficient-Pro™ medium and feed system.

After completion of his PhD at the University of Kentucky and a post-doctoral appointment at UC Davis, Chad has had professional stints across the bioprocessing industry. As a senior product manager at Thermo Fisher Scientific, Chad is responsible for the new Gibco™ Efficient-Pro™ medium and feed system and the customer-owned formulation product line.

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Ensuring Efficiency in Packaging Process should be a top Priority for Pharma Packaging Companies

Covid-19 drastically impacted the way pharma packaging functioned. The overnight entire supply chain was heavily fractured across the globe and at the same time demand for healthcare products skyrocketed due to panic amongst the public. There is no scope of mistake when it comes to packaging critical drugs, especially rubber stoppers. It is a test of all our compliances, quality and proficiency in producing critical components to protect drugs and maintain their safety and efficacy. We are now witnessing a robust change in the working environment with demand planning, Quality, Innovation, Supply chain as well as storage.

India is the new powerhouse of pharmaceutical packaging. It is time to increase capacity for quantity and quality production.

Siddharth Shah, Director, Bharat Rubber Works

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he pharmaceutical industry is one where decades of innovation lead to one new product, like a drug or vaccine. It’s common knowledge that the development of a critically vital drug or

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vaccine is a difficult process that requires years of development time and millions of dollars in research funds to complete.

Pharmaceutical manufacturers are faced with many obstacles once they've

formulated a new drug or vaccine. One of the obstacles is the packaging of these newly developed drugs. When it comes to packaging, there are several critical steps that go into ensuring that a product reaches the end-user in very good condition. Pharmaceutical manufacturers often have many options when it comes down to picking the correct type of packaging solutions that can protect their product to ensure uncompromised quality along with maximum safety and efficacy. A lot of the time, the success or failure is usually determined right at this stage. There are many factors that can be taken into account such as shelf life, homogeneity of drug formulations and composition, as well as patient safety and delivery control considering it may require controlled temperatures for efficacy.

The Repercussions of COVID-19 on the Pharmaceutical Packaging Industry

Starting with the outbreak of the COVID19 pandemic, the pharmaceutical packaging sector suffered a significant setback.

The supply chain was severely disrupted, and the rapid increase in demand posed difficulties for both manufacturers and packaging solution providers alike. An important problem was the inability to dispatch supplies during this period due to a lack of available global logistical facilities. Aside from that, supplementary industries to the pharmaceutical industry, such as the manufacture of packaging materials for pharmaceuticals, had not yet been placed under the purview of vital services. Slowly, but steadily, the

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industry was able to adapt and restore normalcy throughout the supply chain as a result of government policies and actions designed to transform these services into vital services. However, there were some important shifts during this period. COVID-19 paved the way for a more prominent localization approach, which had a significant impact on pharmaceutical packaging. As a result of the COVID-19 pandemic, Indian pharmaceutical packaging contractors got an opportunity to actively enter and compete in a growing global packaging market.

The Pharmaceutical Packaging Industry Has Undergone Significant Changes

Indian pharmaceutical manufacturing is third in volume, leading to an industry nickname of "The Pharmacy of the World." Supply chain constraints during the pandemic forced pharmaceutical manufacturers to seek out solutions with quicker turnaround times. Localization worked as a big push towards this change, transforming India into a world pharma packaging center. Domestic producers were also forced to seek effective pharmaceutical packaging solutions due to the pandemic, and they rapidly learned that the local pharma packaging industry was more than capable of satisfying local and global requirements for pharmaceutical packaging.The production and packaging of COVID-19 vaccine was a product that received significant attention from both Indian and international manufacturers, serving as validation for Indian pharmaceutical packaging companies at large. Thus, the fortunes of India's pharmaceutical packaging business changed substantially, for the better, in the last 24 months.

The Indian pharmaceutical packaging businesses provide solutions for a broader range of pharmaceutical products than merely the COVID-19 vaccines. In fact, what has been observed over the last few years is that the demand for non-COVIDrelated drugs has surged by a factor of 100%. This has ensured that the phar-

maceutical packaging industry has seen significant growth and demand, not just for COVID-19 related drug packaging but also for the other essential medications in constant demand. Given this reality, it's common to find an alliance between pharmaceutical producers and pharmaceutical packaging companies during all phases of development. Aside from that, the sector has gained a great deal of knowledge about operational strategy, particularly in the area of raw material procurement since it is vital for them to stay profitable and maintain the price point advantage.Through the use of smart supply chain management and realistic market forecasting, the sector is on track to grow at previously unheard-of rates.

Packaging of Critical Drugs: How Rubber Stoppers Play a Huge Role

Pharmaceutical packaging solutions in this field have a greater obligation to produce high-quality solutions because vaccines and other critical drugs have the potential to save millions of lives. Having said that, preserving these critical drugs and vaccine integrity across the supply chain can be difficult without the proper packaging solutions. There are two crucial components to consider when it comes to packaging these: the first is glass vials, which are all designed to have a very low moisture vapor transmission rate, and the second is rubber stoppers. During the pandemic, the producers of these vials

and stoppers were under enormous pressure to manufacture items in a timely and high-quality manner while adhering to strict quality standards. Stakes were high as there was no COVID-19 vaccine without the right packaging. The fact that Indian pharmaceutical packaging industry could ensure adequate and high-quality packaging solutions during the pandemic has further catapulted their image and importance in the global pharmaceutical space. This has helped them garner a good reputation, not just as the largest producers of pharmaceuticals but also as one of the largest providers of high-quality packaging solutions to the pharmaceutical industry worldwide.

Pharmaceutical Packaging as a Solution to Combat Counterfeiting

As a result of the pandemic, there were acute shortages of some important pharmaceuticals. As a result of the high demand for these drugs, many people were forced to purchase medicines from black market dealers who sold counterfeits that came in significantly lower quality than what they were substituting. Several counterfeits entered the market to fill this resulting supply gap and take undue advantage of the situation. This was a major source of concern for producers, merchants, end-users, and all other players in the ecosystem. Fortunately, modern communication methods, increased reliance on digital verification, as well as a

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Packaging That is Centered on the Customer is Essential.

India is gaining the much-needed recognition for its pharmaceutical packaging supplies capabilities and is growing considerably at the global level. Less than 40 percent of the country's businesses in this industry have reached a point where they are able to offer their customers products that are highly customizable. In today's world, customer-centricity is one of the most difficult aspects of any business to execute. Some companies emphasize giving their customers what they want, when they want it, and even how they want it. The same is true for pharmaceutical packaging businesses in India.

Building best-in-class customer experiences is vital since it is a discipline that has the potential to revolutionize entire sectors. Customers' needs are becoming increasingly important to the best-in-class 58

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organizations, which is allowing them to organize their businesses around them. By providing customers with simple, differentiated, safe and effective experiences, a company may unleash great value by increasing client loyalty while simultaneously lowering leakage and churn. Having said that, the Indian pharmaceutical packaging business is still in its growing phase when it comes to developing solutions.

A significant amount of emphasis is still placed on the fact that the majority of packaging companies in the domain are striving to make every packaging collateral as customer-centric as possible. It is fair to say that customer-centric packaging will be critical to the future success of the pharmaceutical sector, and as time goes on, more and more companies will begin to take this into consideration when designing their goods.

So, what is the future of the Indian Pharmaceutical Packaging Industry?

As previously said, pharmaceutical packaging is vital in ensuring access to pharmaceuticals and medicine, and in a country known as "The Pharmacy of the World," the local pharmaceutical packaging business plays an even more critical role than it did prior to the current crisis. As more pharmaceutical businesses rely on medications and medication produced in India, this presents a new set of constraints as well as opportunities for innovation. When developing devices for new pharmaceuticals, the pharmaceutical packaging industry must first satisfy a specified benchmark before moving on to the next step. This step is carried out

AUTHOR BIO

swift action by influential opinion leaders assisted in the fight against counterfeits.

There are many ways that a packaging solution provider can be proactive when it comes to tackling counterfeiting drugs or medication. By actively fighting against counterfeit drugs, manufacturers and suppliers of medicine will experience a much-needed reduction in black market trade and positively impact consumers' health and safety. In turn, fighting counterfeit drugs directly helps foster the pharmaceutical industry's growth.

Packaging is an essential part of fighting counterfeit drugs in the pharmaceutical industry because it can serve as both a way to identify and authenticate medications and a way to protect the medication itself. This problem of counterfeit medicines can be easily avoided by including pharmaceutical packaging solutions in the manufacturing process as early as possible. Packaging companies worldwide, including India, are actively developing trace and track technology solutions, which incorporate advanced blockchain technology to create an atmosphere of assurance, security, and trust for all stakeholders at all stages of the manufacturing and distribution processes.

to ensure the safety and preservation of the medication under various circumstances. This test should also be specific to the drug's identity and conform to worldwide and regional regulatory standards. Additional requirements include: Regular quality control inspections are required to guarantee that this system is not tampered with.

Additionally, the Consumer Product Safety Commission (CPSC) has established a set of guidelines that must be rigorously adhered to at all times. Today, there are very few things available on the market that are not packaged in a way that is child-resistant. This is particularly true in the case of medications. Product and packaging teams are also concentrating on ergonomic solutions that are efficient at the logistics end while also being more consumer-centric in their design.

All things considered, pharmaceutical packaging is an essential component of pharmaceutical supplies throughout the world. With more localization and manufacturing taking place within the country, the scope and quality of local pharmaceutical packaging are becoming increasingly important for sustained growth across the pharmaceutical industry.

No matter the type of medication, it’s crucial to make sure an appropriate pharmaceutical packaging is used to seal and maintain the safety, efficacy and quality of the medicines at all times. This is exactly why global pharmaceutical companies are eager to work with India's most reliable pharmaceutical packaging manufacturers and see what they offer as appropriate solutions to their pharmaceutical packaging conundrums.

A young stalwart of Bharat Rubber Works, Siddharth Shah has been the Director of the company since 2018. Mr. Shah joined Bharat Rubber Works after completing his bachelor’s in Banking and Wealth Management from the University College of Dublin in 2018. He has also completed his Diploma in Marketing from Kaplan. As the director of the company, Mr. Shah is responsible for overall growth and company operations. Since his arrival at the family-owned business, Mr. Shah has taken the company to another level, allowing Bharat Rubber Works to become a leading manufacturing solutions provider to the healthcare industry.

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THE USE OF CRYSTAL ENGINEERING TO EFFECTIVELY TARGET LUNG INFECTIONS

Crystal engineering offers novel solutions for the delivery of antimicrobials to treat lung infections. This approach is based on removing the need for carrier particles allowing larger doses of the drug to be delivered.

Hisham Al-Obaidi, Thermal analysis Lead, University of Reading

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ung infections, especially lower respiratory tract infections are one of the leading causes of transmissible deaths worldwide according the world health organisation. Majority of the patients who suffer from lower respiratory tract infections are colonised www.pharmafocusasia.com

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in their lungs by different bacteria, such as Staphylococcus aureus, Pseudomonas aeruginosa and Haemophilus influenza.

These infections tend to have a greater impact on patients who already have existing lung problems such as cystic fibrosis, chronic obstructive pulmonary disease (COPD) and bronchiectasis. These infections are also responsible for contributing to disease progression by prolonging the infection and inflammation that occurs.

Cystic fibrosis is a genetic condition that is caused by a mutation in the transmembrane conductance regulator gene. This gene is responsible for controlling the movement of salts and water between cells in the body. However, when impaired, the secretion of the salts — the chloride ion in particular — is reduced.

The effect of the gene mutation dehydrates the lung airway surface resulting in hypersecretion of thick mucus and reduced mucociliary clearance. This thick mucus and the reduced clearance can then form mucus plugs within the lungs, which creates an ideal environment for certain anaerobic bacteria, e.g.

Pseudomonas aeruginosa (P. aeruginosa), to safely grow. P. aeruginosa is the most common chronic lung infection that occurs in cystic fibrosis patients. This chronic infection is the main cause of mortality and morbidity in patients who suffer from cystic fibrosis.

P. aeruginosais a gram-negative bacterium that has adapted and become resistant to many antibiotics that are normally used to treat the infection.

The P. aeruginosa bacteriahas developed extended-spectrum-β-lactamase strains allowing it to form biofilms that are particularly difficult to treat with the current antibiotics available (Figure 1).

Biofilms are defined structures attached to the microorganism, providing an optimal environment for genetic material to be exchanged between cells and are enclosed in an extracellular polymeric substance matrix (EPS). The increased bacteria resistance to current antibiotics is driving the need to develop new and more effective antibiotic treatment to fight this infection.

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Figure 1: The typical viscous mucus environment in which P. aeruginosa mutates into the mucoid strain, establishing biofilms.

Why target the lungs directly?

There are several different antimicrobial agents that can be used to treat the P. aeruginosa infection, the most common antibiotic is ciprofloxacin (CFX).It is recommended that first line treatment for the P. aeruginosa infection is oral CFX monotherapy. CFX belongs to the second generation of fluoroquinolone antibiotic group and is classed as broad spectrum. It is known for having good, strong antibacterial effects against the P. aeruginosa biofilms. At present there are only two administration methods available for this antibiotic, oral and intravenous, both of which can result in severe gastrointestinal problems and arthropathy.

The two CFX delivery methods available do not deliver high concentrations of the antibiotic to the lungs as most of the drug is lost systemically, resulting in systemic side effects. Developing a CFX inhalable version for pulmonary drug delivery is an area of great interest as it isnon-invasive. The lungs have a good blood supply and a thin alveolar-capillary membrane increasing the drug absorption and, therefore, increasing the effect at the active site. Delivering a drug via the lungs also avoids first pass metabolism that occurs within the liver for the current delivery methods. The lungs have low enzymatic activity resulting in less of the drug being metabolised before having its therapeutic effect. There will also be a quicker onset of action as the drug is

delivered directly to the active site. In addition, an inhalation method allows the drug to be dispensed as a powder form, which reduces the storage stability issues of CFX in its present form and improves the shelf life of the product.

Inhalers are small, portable and easy for the patient to use and should improve patient adherence when it comes to taking the medication.

Current treatments and the need for innovative drug delivery

Current inhalation products that are on the market tend to use a carrier to deliver the active pharmaceutical ingredient to the site of action, in this case the lungs. The carrier most commonly used is lactose and the common ratio of drug to lactose content is 1:30. This would mean only small quantities of the inhaled drug are reaching the site of action in the lungs meaning larger doses have to be administered to have the same effect.

Some inhaled antibiotics, such as tobramycin, aztreonam lysine and colistin, have already be trialled and tested for treating P. aeruginosa infections.

However, there are associated side-effects with these antibiotics when inhaled and they have not been very successful in eradicating the P. aeruginosa infection.

Tobramycin significantly reduced the P. aeruginosabacteria count, though as a side effect it resulted in a high number of patients experiencing adverse respiratory

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events. CFX has also been tested as an inhalation formulation by itself in the form of nanocrystal liposomes using the spray drying technique. This technique showed that the spray dried particles demonstrated greater dispersion of the drug throughout the lungs when tested using the cascade impactor. The findings identified that the drug, CFX, could be delivered to the site of action and have a greater effect treating the infection. It is hoped that this method of delivery will result in fewer side effects as less of the drug will enter the systemic circulation.

Even though inhaled CFX has shown to have reduced systemic side effects, still a large proportion of the drug is remaining in the oral cavity which needs to be addressed. Recent methods showed promising findings via spray drying technique to form the engineered microparticles that showed efficient deposition using Andersoncascade impactor. An advantage of using the spray drying technique is it produces homogeneous particles that are small, which are important factors when it comes to developing an inhaled formulation.

Crystal engineering to combat lung infections

The inherent problem with the evolving antimicrobial resistance must also be addressed using innovative methods to engineer the drug particles. There have been different studies showing that forming co-amorphous dispersions will lead to better efficacy. This type of dispersions eliminates the need for a carrier as the drug flow properties will be improved.

It also offers the benefit of combining the drug with another molecule (also known as co-former) that can possess antimicrobial properties. For example, via using physiological bile acids that are found in the intestine, where their main role is to aid the digestion of lipids, however some bile acids can also inhibit bacterial growth as well as acting as bactericidal. For example, deoxycholic acid is a secondary bile acid that has good, proven antimicrobial properties against

Crystal engineering represents a breakthrough in carrier-free technologies offering novel co-amorphous/ co-crystal based formulations without the use of bulky carriers.

two different strains of P. aeruginosa. A secondary bile acid is a primary acid that has undergone metabolism via bacteria flora in the colon. It is suggested that the antimicrobial properties of the bile acids are due to their hydrophobicity nature, this increases the affinity of the acids to the phospholipid bilayer that is present in the membrane of all bacteria cells, resulting in bacteria cell death. Forming co-amorphous effervescent particles is another method to enhance efficacy by which the effervescent effect will disrupt

the bacterial biofilms leading to enhanced antibacterial effect. The use of crystalline equivalents to co-amorphous dispersions (i.e. as co-crystals) can also be used similarly to enhance the properties. After the rejection of Bayer’s CFX DPI formulation due to concerns over antimicrobial resistance (AMR), particle engineering to be within larger end of the required 1-5 μm particle size range, deposition of CFX can be limited to impaction in the conducting zone, avoiding potential low dose systemic delivery of CFX and therefore the potential for further AMR development.

In summary, crystal engineering represents a breakthrough in carrier-free technologies. The preparation of dispersions by established methods such as spray drying is a straightforward process, offering novel co-amorphous/ co-crystal formulations without the use of bulky carriers. These formulationscan achieve excellent in vitro deposition performance to target the conducting zone where for example P. aeruginosa biofilms are most problematic to eradicate. Most importantly, the use of appropriate co-former can enable the formulation to have a potent, synergistic effect against bacterial biofilms. It is anticipated such formulations would be used with IV or oral antibiotics in the clinic which would fully eradicate biofilms from the respiratory zone of the lower respiratory tract, with the inhaled formulations targeting the conducting zone. Similarly, as the treatment of P. aeruginosa is becoming increasingly difficult with multidrug resistant strains and biofilms becoming more widespread, antibiotic treatment options are quickly becoming limited.

AUTHOR BIO Hisham Al-Obaidi is a lecturer in pharmacy and pharmaceutical sciences and the thermal analysis lead of the chemical analysis facility at the University of Reading. His recent research focused on the use of solid dispersions to target infections affecting the lungs.

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EXPERT TALK

Innovative Biotech Ecosystem in Singapore and Asia In this interview, Daphne Teo, CEO and Founder of NSG BioLabs, shares her insights and understanding of the innovative biotech ecosystem in Singapore and Asia. She elaborates on the opportunities for biotech startups and the kind of support they need to solve some of the biggest medical challenges of the 21st century.

Daphne Teo, CEO and Founder, NSG BioLabs

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EXPERT TALK

1. To begin with, can you tell us about yourself and your journey so far?

I was born in Singapore and from very early on had a deep love for science and physics, as I had a curiosity to understand the natural world and also to work on technical ways to address problems. This led me to pursue a bachelor’s degree in engineering at Purdue and a master’s degree in engineering at Stanford.

I made the jump from engineering to investment banking where I worked at HSBC and Goldman Sachs in Singapore and Hong Kong, as I wanted to understand the integral role of finance and capital in businesses seeking to build and commercialise products. Eventually, I returned to help the family real estate business in securing investment and developing real estate in various regions across Southeast Asia and North America.

After some successes and learnings outside of biotech, my fellow co-founders of Engine Biosciences and I developed novel concepts for drug discovery, including AI and bioengineering approaches, that led to the company.

With my science background, I thought it was quite apt, drawing from the technical and engineering training that I had in college.

Engine Biosciences gave me a first-hand, founder’s perspective of the challenges in setting up the must-have infrastructure for science. I was inspired to develop a solution for the general biotech ecosystem and help many founders in their fundamental issues, and I founded NSG BioLabs, a co-working laboratory and office space that aims to provide a conducive environment for biotech companies in Singapore to grow, scale and commercialise their operations. This has been a culmination of my

interests and educational background in science and engineering, as well as my experiences working in finance and real estate.

2. Speaking of biotech, how is Singapore supporting the growth and innovation within this space?

Singapore has had a multi-decade, longterm vision for building a world-class biomedical cluster. This is evidenced by the many billions of dollars invested in basic research at universities and research institutes, growing clinical infrastructure, funding many scholars to study overseas to further their studies in science and technology, drawing multinational pharmaceutical companies to the country, and directly providing capital to startups. I am heartened to see vocal support for the industry from the highest levels on down, and then to see follow-through with actions from the public sector in many meaningful ways.

Singapore has had a multi-decade, long-term vision for building a world-class biomedical cluster.

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3. What can be done to help young biotech companies in the region continue with their research and development and potentially scaling innovation?

Despite significant advances in the sector, biotech companies in Singapore continue to face challenges in their growth ambitions. Emerging biotech companies require conducive collaborative space, high-end laboratory equipment, expert guidance and community support to achieve breakthrough results. Recruiting and retaining key talent is critical for biotech companies, yet can be very difficult anywhere, especially in Asia where the biotech ecosystem is more nascent than in the US. Mentorship is also an important component in helping young biotech companies in Asia. Young or firsttime CEOs usually require guidance throughout their journey, so having great scientific and business advisors, access to key opinion leaders, strong investors and board directors is critical

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Recruiting and retaining key talent is critical for biotech companies, yet can be very difficult anywhere, especially in Asia where the biotech ecosystem is more nascent than in the US.

to their success. Connecting young companies to these experts can be invaluable as company leaders navigate the twists and turns of building great companies.

4. What do you consider to be the most significant areas of biotech and life sciences innovation right now?

Unfortunately, there are huge unmet needs around the world that lead to too many health issues and deaths.

Addressing cancer continues to be a major issue, which many companies are focusing on and making progress in, but it’s not enough. Central nervous system (CNS) disease continues to be a major issue, especially considering ageing populations, but the sector needs to make more progress.

There are also major opportunities for medical breakthroughs in inflammatory diseases. Finally, infectious diseases have been historically under-invested

in relative to the needs; COVID-19 has made people more alert to the issues, but we need to see more continued investment to address existing and future infectious diseases. The human, societal, and economic impact has proven to be tremendous and worth preparing for.

5.What kind of multistakeholder / regional collaboration can help Asia’s biotech industry grow faster?

Firstly, more focus on the region’s needs and supporting the burgeoning R&D ecosystems from large pharma companies would be very helpful. It is important for leaders to showcase the innovation and the opportunities in the region and inspire more activity and investment.

Secondly, regulators across the region could explore avenues to promote innovative R&D, including encouraging clinical trials in challenging diseases.

Thirdly, finding ways to compile population-level and patient data across the region, spanning the diversity and leveraging the large aggregate populations that exist, would be a huge driver of new R&D and products that are designed for the needs of the people in our region.

AUTHOR BIO

Singapore’s handling of the pandemic has been data-driven, sensitive to clinical considerations, and pragmatic. This has also helped to attract more biotechnology investments and innovative projects, including but not limited to nucleic acid, vaccine, and genetic medicine projects.

The country continues to be a strategic launch pad for businesses around the world looking to expand into new markets in the region. It also provides a reliable and stable business climate, rich talent base and a growing biotechnology industry for both well-established and young biotech companies to take advantage and potentially scale further.

Daphne Teo is the founder and CEO of NSG BioLabs, Singapore's largest and leading biotech coworking laboratory and office space.

INFORMATION TECHNOLOGY

A DIGITALISED FUTURE FOR PHARMACOVIGILANCE

The use of traditional paper-based case record forms (CRFs) are becoming a thing of the past as Contract research organisations (CROs) increasingly embrace digital transformation, enabling more accuracy and reliability of data, security in pharmacovigilance, collaboration, innovation, and speed of operations.

Bruce Palsulich, Vice President, Product Strategy, Oracle

P

harmacovigilance (PV) is increasingly taking its toll on life science organisations. According to EY research1, large pharmaceutical companies contend with an average of 700,000 adverse event 1 https://engineering.report/Resources/Whitepapers/30bb73a41332-4331-a84d-a2326a9469d9_Robotics-reshapingbiopharma.pdf

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(AE) cases each year, a number that IDC2 has found to be rapidly increasing by 30 to 50 per cent annually. The pandemic has exacerbated the situation, with the fast tracking of COVID-19 vaccines increasing AE caseloads to more than one million a year for some industry players.

Companies are under pressure to manage this increased case load effectively while still maintaining their current cost base. Data sources are proliferating, challenging safety teams to make sense out of the jumble of data points to produce valuable insights, while also satisfying divergent regulatory requirements for safety reporting – all of which contribute to increased cost for PV departments.

This means that safety teams need to be more efficient in managing their workloads. The question is, how?

A phased approach to introducing technologies such as artificial intelligence (AI) into the pharmacovigilance process can pay significant dividends.

Reshaping PV Processes for the Digital Age

What if pharmaceutical organisations could accurately forecast adverse events or quality compliance issues before they took place, or receive real-time feedback throughout the drug lifecycle directly from patients to eliminate lead times and delays?

To bring this into reality, pharmaceutical PV organisations need to move into a “digitalised future” where technology plays a key role in PV processes.

This includes automating and streamlining the information streams to reduce complexity, from case processing to reporting. Once automated, companies need to begin to look to artificial intelligence to add further value from their data.

By applying artificial intelligence (AI) and data science approaches, organisations can turn the overabundance of data from being a challenge to solve, into an opportunity. A well-designed, automated, AI-powered PV system can not only eliminate tedious and repeti2 https://www.idc.com/getdoc. jsp?containerId=US45863116

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tive tasks but also reduce human errors and analyse massive volumes of data efficiently. This can even empower teams with predictive signal detection capabilities with insights derived from integrating disparate big data sources.

Ultimately, this can enable specialists to make more informed observations and recommendations on product safety.

The Building Blocks of Digital PV

Pharmaceutical organisations, however, need to be cognisant that technology is not a solution unto itself. Success in digital PV should start with a foundation of both digital and operations transformation. To derive the most value from a digital approach to PV, teams will need to build complementary capabilities such as: • Having the right people in the right roles: New skills are essential to the next-generation PV team. In the typical PV department today, there’s a gap between the medical skills and technology skills of any given staffer.

Companies will need to invest in building the PV workforce of the future by upskilling and building cross-functional teams at both management and operational levels. While finding people who have both skillsets may not be easy in a time of a global talent shortage, this will be essential to making the most of the technology that’s on the horizon.

• Empowering patients: Patientcentricity has become a hallmark of not only high-quality health care, but also high-quality PV processes. A true patient-centric organisation means connecting with the patient throughout the entire lifecycle of the product, from trials to market. Patient involvement early in the trial design process can provide teams with invaluable feedback to identify required improvements, allowing for the development of new digital products that best meet patients’ needs under real-world use conditions.

• Collaboration – internally and externally: Breaking out of silos is sound advice for any function in any business today, but it’s doubly important to PV teams who have responsibility for something as important as patient safety. So, it’s important that safety works across functions inside the company in order to keep the patient at the centre. It’s also important to build external collaborations – within the industry to share best practices and build data resources; with regulators to help guide rules so they ultimately benefit the patient; and with technology companies and those in academia to help drive and shape change.

• Embracing a culture of innovation: To be able to integrate and use technology to its best potential means it is critical to foster the right culture to embrace innovation and be datacentric in your thinking. That is what will enable predictive safety, provide useful insights across the company, and increase efficiency. A next-generation, digitalised PV department is pioneering and able to drive change across the business.

INFORMATION TECHNOLOGY

Putting the above into practice will be essential to create the foundation for a next-generation PV department as the industry continues to move to a digitalised future.

DiagnoSearch – A Real World Example of Success

AUTHOR BIO

India-based DiagnoSearch, a full service contract research organisation (CRO) is increasingly benefiting from embracing digital transformation. The company’s services cover every aspect of clinical study – from phases 1 to 4 – including PV, clinical operations, data management, bio-statistics, central laboratory, and protocol and clinical study writing for pharmaceutical, biotech, and vaccine manufacturers.

“We used to rely on paper-based case record forms (CRFs) to record data and other information on each trial subject,” said Mandar Vaidya, vice president at DiagnoSearch. “Though its format is designed to allow for accurate input, presentation, verification, audit and inspection of the recorded data, using CRFs has become more challenging as our business grew.”

India-based DiagnoSearch has been in the business for 27 years, and has

since extended its geographical footprint in Australia, South Africa, Kenya, Uganda, Zambia, Gambia, and Mali.

“As our business continues to grow, so is the data that we have to handle and analyse. Delayed data entries, printing issues, human errors, and the like, which were associated with our old paper-based CRF system had to stop,” added Vaidya.

“We value our reputation and we offer high quality services based on the best science and technology of the day.”

DiagnoSearch now uses an integrated platform for all its clinical trials, including robust and time-tested database solutions that provide accuracy, reliability, and efficiency – from data collection to data integration, to analysis, to reporting.

Using cloud services also enables seamless budgeting that brings transparency to the business. All this has helped the company reduce project timelines and improve data quality, which increased overall productivity and business outcomes.

Likewise, DiagnoSearch’s customers continue to benefit from improved efficiencies, including shortened timeframe for starting up, conducting, and closing out every clinical trial study – and above all, accurate clinical trial results that help ensure drug safety.

The Future of PV

The shift to a digital-first economy continues to drive the need for digital transformation – essential to avoid being disrupted, and to remain competitive.

Pharmaceutical organisations that have yet to take the step toward digital transformation should now plan for and lay the groundwork for digital PV processes.

The key is to adopt a stepwise approach, including digitalisation and cloud adoption that will lay a robust foundation to support further technology adoption and business growth.

As capabilities evolve, a phased approach to introducing technologies such as AI into the pharmacovigilance process can pay significant dividends.

As organisations and safety teams become more comfortable with automation, they will gain the knowledge and confidence to increase and adjust autonomous workflows accordingly for optimal outcomes.

While challenges such as those pertaining to regulation will no doubt remain, organisations that begin the transformation processes now will benefit from technologies sooner, improving their safety management in a highly competitive business environment.

Bruce Palsulich is responsible for the strategic direction of the Oracle Health Sciences Safety Cloud – an integrated suite of the market-leading safety case management solution (Oracle Argus), and the market-leading safety signal management solution (Oracle Health Sciences Empirica), delivering unified end-to-end multivigilance throughout the entire lifecycle of medicinal products.

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STRATEGY

CLINICAL TRIALS

Medical Fair Asia...........................................................................09 MSC.............................................................................................IBC

B Medical Systems S.à r.l.............................................................42

Qatar Cargo................................................................................ IFC

ECOLAB............................................................................ 03, 10-12

Turkish Cargo............................................................................OBC

Quantys Clinical Pvt. Ltd...............................................................51

Valsteam ADCA Engineering........................................................05 MANUFACTURING RESEARCH & DEVELOPMENT B Medical Systems S.à r.l.............................................................42 ECOLAB............................................................................ 03, 10-12 F. P. S. Food and Pharma Systems Srl.........................................17 Quantys Clinical Pvt. Ltd...............................................................51

ECOLAB............................................................................ 03, 10-12 F. P. S. Food and Pharma Systems Srl.........................................17 Valsteam ADCA Engineering........................................................05

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

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

B Medical Systems S.à r.l.......................................................... 42 www.bmedicalsystems.com

Qatar Cargo............................................................................. IFC https://qrcargo.com

ECOLAB..........................................................................03, 10-12 www.ecolablifesciences.com Exyte......................................................................................26-30 www.exyte.net F. P. S. Food and Pharma Systems Srl...................................... 17 www.fps-pharma.com Medical Fair Asia........................................................................ 09 www.medicalfair-asia.com MSC.......................................................................................... IBC www.msc.com

Quantys Clinical Pvt. Ltd............................................................ 51 www.quantysclinical.com SGS.......................................................................................18-19 www.sgs.com Turkish Cargo......................................................................... OBC www.turkishcargo.com Valsteam ADCA Engineering..................................................... 05 www.valsteam.com

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THE WORLD'S NEW LOGISTICS CENTER THE NEW HOME OF TURKISH CARGO THAT FLIES TO THE MOST DESTINATIONS IN THE WORLD IS BECOMING THE NEW CENTER OF AIR CARGO LOGISTICS, CONNECTING CONTINENTS.

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