Pharma Focus Asia - Issue 49

SHASHIBHUSHAN JOGANI Managing Director SGS India

Glocalisation in Pharma Facilitating the industry growth

A recent Strategy & report suggests that the “winners” in emerging pharma markets will know how to best balance their global competencies with tailored approaches for local markets.

The pandemic made medicine accessibility challenging worldwide. High levels of drug consumption and limited local pharmaceutical manufacturing have highlighted opportunities for pharma companies.

Glocalisation gained prominence as pharmaceutical companies decentralised their R&D and production activi ties with a focus on exploring and developing products for the local markets by establishing facilities in many locations across the globe.

Growing demand for advanced medicines in emerging economies, drug manufacturers aiming to reduce costs and the growing challenges with clinical trial recruitment in mature markets drove the globalisation of pharma. A few key factors that facilitated globalisation for pharma companies are US/EU marketing authorisation (MA) acqui sition, dossier and technology transfer, new formulations with US and EU regulatory compliance, local pharma ceutical manufacturing plant acquisition etc. However, a surge in M&A activity in the Asian pharma industry also contributed to the significant growth of the industry in the region. In developing countries, globalisation resulted in a decrease in exportation and domestic production, with an increase in importation of pharmaceuticals and a rise in prices and expenditures.

Meanwhile, continued growth of the industry with increased demand, with the development and commer cialisation of antibodies and next-generation medicines, such as antibody-drug conjugates and cell and gene therapies have led to increase in number of trials. This rising demand of populations in clinical trials has been easily handled with the glocalisation of the market. Glocalisation will also continue to be driven in part by

governments, non-governmental organisations (NGOs) and local entrepreneurs.

Increased outsourcing strategies by Clinical Research Organisations have demanded the global companies to explore local markets that have talent, resources and facilities. Many APIs found in generic and even branded small molecule drugs are now produced in China, India and other emerging markets, and biosimilars are increas ingly produced across the world.

In making global companies more effective competi tors, glocalisation should be in practice focussing the local markets as well. The advent of technology solu tions in the areas such as automation, Blockchain, AI, ML and Advanced Analytics, IoT are playing a key role in streamlining operations, enhancing manufacturing, improving production processes for the pharma industry.

The latest issue covers an article title ‘The Glocalisation Challenge’, where the author Brian D Smith, Principal Advisor, PragMedic talks about the promise of glocalisa tion and its challenges. He also tells that when a busi ness is global but its markets are local, it imperative for companies to glocalise. We will cover a series of articles on this topic in the forthcoming issues and as always I believe you will find this edition insightful.

Prasanthi Sadhu Editor

Advisory Board

Alessio Piccoli

Lead

Sales and Business Development Activities for Europe Aragen Life Science

Andri Kusandri

Market Access and Government & Public Affairs Director Merck Indonesia

Brian D Smith

Principal Advisor PragMedic

Gervasius Samosir

Partner, YCP Solidiance, Indonesia

Hassan Mostafa Mohamed

Chairman & Chief Executive Office ReyadaPro

Imelda Leslie Vargas Regional Quality Assurance Director Zuellig Pharma

Neil J Campbell Chairman, CEO and Founder Celios Corporation, USA

Nicoleta Grecu Director

Pharmacovigilance Clinical Quality Assurance Clover Biopharmaceuticals

Nigel Cryer FRSC

Global Corporate Quality Audit Head, Sanofi Pasteur

Pramod Kashid

Senior Director, Clinical Trial Management Medpace

Quang Bui

Deputy Director at ANDA Vietnam Group, Vietnam

Tamara Miller

Senior Vice President, Product Development, Actinogen Medical Limited

EDITOR

Prasanthi Sadhu

EDITORIAL TEAM

Grace Jones Harry Callum 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

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THE GLOCALISATION CHALLENGE

This article introduces the concept of glocalisation and describes why it is has become the essential strategic capability. It will contrast the increasingly global nature of the pharma market, both supply and demands sides, with the continuing importance of locally-specific market conditions, such as market access, competitive environment, healthcare systems and market segments.

The implications of this 'local needs in a global market' situation is that firms need to develop superior capabilities in "glocalisation" (the adaptation of a core, global strategy to local market conditions). The article will use examples to illustrate shortcomings in firms' current glocalisation capabilities and outline a three-part approach to improving these, thus setting up the rest of the series.

Brian D Smith, Principal Advisor, PragMedic

The pharmaceutical industry has changed dramatically since I first stood at a laboratory bench in the 1970s. Then, drug markets outside of “the west” were considered insignificant and competition from those developing markets was inconsequential. But today I live in a hugely different world, in which no company can ignore the opportunities and threats presented by what is a truly global pharmaceutical industry.

But the globalisation of our industry has created a dilemma. Our competi tors and customers are global but our markets remain intensely local. Biology defies borders, but the same is not true for regulation, competitors, health

care systems, reimbursement systems, cultural preferences and many other market factors that remain essentially local. This 'global but local’ nature of our market means that the challenge is to keep the scale and scope advantages of a global strategy without sacrificing the competitive advantage that comes from tailoring to local needs and wants. This is the glocalisation challenge.

This article, the first in a series of four, will help you to understand the challenges and promise of glocalisation and why many life science firms fail to glocalise. It will introduce the practices that enable the best firms to succeed at being simultaneously global and local.

In subsequent articles, I will expand on those best practices based on my decades of research into our evolving industry.

Why Globalise?

The pharmaceutical industry has been an international industry since first German and Swiss, and later British and American, companies evolved into the modern industry in the late 19th, early 20th century. Even in their earliest days, firms like Merck, Bayer, Roche, Pfizer and others were quick to sell their innovative products outside of their home markets. But for more than a century, pharmaceu ticals remained an international rather than global industry, with the vast

When your business is global but your markets are local, you must glocalise.

majority of both supply and demand being concentrated in the North America, Western Europe and a handful of other westernised countries. It wasn’t until so called “Globalisation 3.0” began in 1989 that our industry spread out from these countries to a significant degree.

Since then, the rate of globalisation has been an indication of its benefits. By and large, the high fixed and low variable costs of inventing and making medicines means that profitability is closely correlated to volume. This makes a global market much more attractive than a national or regional one. That demand-side pull is amplified by supply side push. Both developed and emerg

ing economies want the high-value jobs and export revenue that pharmaceuti cal companies create and, consequently, favour the sector in their industrial poli cies. Together, these two forces make it less of a question of 'Why globalise?’ and more an issue of 'Can we afford not to?’ Today, even the smallest pharmaceuti cal companies aspire to exploit global markets.

The Glocalisation Challenge

The inescapable logic of globalisation is powerful but it doesn’t change the irrefutable individuality of local markets. Some of this uniqueness is obvious and gradually eroding. For example, leading

edge clinical practice tends to converge onto international standards. Increasingly, imitation and consolidation are making pharmaceutical distribution channels more similar between countries. And the internet is gradually erasing what were marked differences in how prescribers access information. Against this trend for global homogenisation, important, market-shaping differences persist. This is especially true in the less obvious charac teristics of national markets. For example, the world is a still a very heterogenous place when it comes to attitudes to sexual health. Similarly, only a narrow stretch of sea separates the pill-loving British from the suppository-accepting French. And in many countries, especially in Asia Pacific, traditional medicine is still a direct competitor to modern pharma ceuticals. On balance, homogenisation and persistent heterogeneity combine to mean that each national market retains its predilections, strong preferences that create the opportunity for marketers to win customer preference and competitive advantage. And it is this combination of market similarities and dissimilari ties that creates the need to glocalise, to execute global strategy in a way that meets local needs.

Naïve Glocalisation

The need to glocalise has been recog nised by pharmaceutical companies as long as they have tried to globalize. I have studied, in detail, their glocalisation processes, both explicit and implicit and found that almost all companies follow a three-step method. But I’ve also found that the effectiveness of this three-stage process varies greatly. Most companies find it results in only a weak form of glocalisation, with little local competitive advantage. Only a few companies have found the secret to fully effective threestep glocalisation. If you want to avoid the mistakes of the former, it pays to consider their somewhat naïve approach. (Figure 1)

The first step in glocalisation is to decide which countries to focus on.

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The naïve, but most common, approach is to base this on market size. So most companies will buy market research data and allocate resources (and expect returns) in proportion to, for example, popula tion and disease prevalence. Some more sophisticated companies might overlay this data with the sales of comparator products to estimate the proportion of the market that is available to them. Even with good data and sophisticated analy sis, this approach to resource allocation is ineffective. Mostly, this is because it assumes market attractiveness is only a function of market size, but this approach is also flawed in the way it assumes that every national market is homogenous and equally winnable. When I do 'postmortem’ examinations of failed glocali sation strategies, this naïve approach to resource allocation is a big part of the problem.

The second step of glocalisation is tailoring the value proposition to the targeted markets. This has two elements. The first is to address tangible local requirements, such as regulatory approval and language issues. Almost all firms do this well, usually aided by local experts. But the second element — addressing intangible local requirements such as cultural issues and local practice — is rarely executed so well. It is usually left in the hands of local affiliate marketers who are given little latitude to adapt the global

TARGETING

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Figure 2: Astute Glocalisation

strategy. Even subtle changes to targeting and positioning are constrained, either by headquarters’ edict or by lack of local resources. In one example I observed, the local affiliate was not given the resources to generate HEOR data against a locally important comparator, even though that was vitally important to the local payers. Mostly, tailoring weaknesses have their origins in HQ’s simplistic defini tion of market segmentation. Clinically defined segments are easy to translate across markets but they often miss the nuances of non-clinical, intensely local, needs. This naïve, reductionist approach to describing market structure is another major reason that glocalisation fails.

The third step of glocalisation is learning, the creation of knowledge about what works and the sharing of that knowledge between countries. Large, global companies spend a lot of effort on this but they rarely get a good return on that effort. Through internal confer ences other methods that are supposed to share best practice, they encourage local marketers to exchange experiences. This often has the veneer of success when marketers pick up on the clever ideas of their colleagues. But when I’m asked to follow up on this knowledge sharing, I find that success is only superficial. In practice, good but mundane ideas are often rejected whilst bad but glamor ous ideas are evangelised. The underlying

TAILORING

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LEARNING

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reason for this is the sharing channels are often designed without any scien tific understanding of how knowledge management works. In any case, when the approach to glocalisation is naïve, it’s the learning element that is often an expensive failure.

Astute Glocalisation

The contrast between naïve glocalisation processes, as described above, and the more astute processes used by the most effective companies is striking but subtle. Both naïve and astute processes follow the same three step process but they differ significantly in how that process is executed. (Figure 2)

In astute glocalisation, the decisions about how to allocate resource between countries allow for the reality that country attractiveness is multifactorial. It consid ers not only obvious factors like how big a market is but also country’s influence on each other. Resource allocation also considers how easy or difficult it is to win in each country. Together, this amounts to an approach that is less about prioritis ing countries and more like managing a portfolio of countries. Details of this method will be discussed in article two of this series.

Once resources are allocated, the astute process for tailoring the value prop osition is also quite different from the naïve process. It is designed to address the

LEARNING

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needs of payers, patients and prescribers and, importantly, not only their obvious needs but also their intangible motiva tors. This leads to the construction of an extended, augmented value proposition built around the needs of a well-defined target segment. Details of how this is done in practice will be the subject of article 3 in this series.

The learning step of glocalisation, which is such an expensive failure in the naïve process, is much more deliberate in the astute approach. It involves defining what needs to be learned and then design ing an appropriate combination of induc tive, deductive and abductive processes to create and share that new knowledge. This is a knowledge management, rather than an idea sharing, methodology and the techniques used for this will be discussed in article four in this series.

Meeting the Challenge

If, like almost all pharmaceutical companies, you accept the benefits of globalisation and the realities of local

market individuality, then you must also recognise the reality of the glocalisation challenge. If you do, then you probably follow the three step process of allocating resources to markets, tailoring to markets’ needs and inter-market learning. And if you find your glocalisation has not effectively combined global strategy with

Professor Brian D Smith works at the University of Hertfordshire, UK, and Bocconi University, Italy and researches the evolution of business models and competitive strategy in the global life sciences industry. He has published over 300 papers, articles and books. www.pragmedic.com

Advantages:

local advantage then you, like many of the companies I have studied, may be being using a naïve glocalisation process. If you have come to that realisation, then you will be interested in knowing how astute companies meet the glocalisation challenge. If so, I am sure will enjoy the next three articles in this series. Optimization of operating times Increase

AUTHOR BIO

NEW WORKING MODELS WITH PHARMA

The 21st century pharmaceutical and biotech sector has come a long way from its heritages in 19th century pharmacy, with differentiated contract testing services business models. Traditional contract research testing services that follow the outsourcing model offer low-cost options to pharma that come with advantages and disadvantages. With New Approach Methodologies (NAM) being developed and encouraged by the FDA and CDER, there is a new business process and markets emerging parallel to outsourcing models. These new business processes impregnated with robotic process automation through artificial intelligence (AI) and machine learning (ML) tools, framework is forecast to build the bandwidth to create a new working equation with pharma industry. NeuroSAFE is one such breakthrough (NAM) with the power to democratise the safety and efficacy testing of pharma and biopharmaceuticals from R&D stage till manufacturing.

Traditional operating style

Over the last three decades pharma companies have increasingly relied on outsourced research to minimise costs, and incorporate new science relating directly to the better understanding of biology. The outsourcing trend led first to smaller, service-oriented companies taking up portions of early pre-clinical research contractually. These contract research organisations (CROs) arose in silos based on disparate skills employed along the complex drug developmental process. CROs specialising in chemis try provided services for synthetic and medicinal chemistry, whereas those with expertise in biology, separately, provided services in cell biology and animal studies. These pre-clinical CROs generated data for the investigational new drug (IND) application dossiers submitted by pharma clients, to the FDA, for commencement of human clinical trials. Clinical trials are conducted by another set of service providers that specialise in human stud ies. Today CROs conduct almost all of the R&D that leads to pharma product approvals.

Subhadra Dravida, Founder CEO, Transcell Oncologics Vasanthi Dasari, Scientific Officer and experimentalist, Transcell Oncologics

Over the last decade or so the CRO industry has been driven by acquisitions to amalgamate skills to (i) improve financials, (ii) assuage client concerns of having to deal with too many vendors, and (iii) play a seminal role in intellectual property generation to ask for risk-sharing rewards that are multiples above the cost-plus models associated with plain vanilla silo services. Even more recently, acquisitions in the space show a clear key trend, CROs are acquiring their peers for innovation, not just expanding top-lines or geographies. Testament to this is the fact that valuations of innovation-led acquisitions were almost double the rest over the past five years.

A closer look shows that the intellectual property (IP) is primarily gener ated in early pre-clinical stages of drug development. Importantly, a lot of this IP emerges from cell-biology research, relating to biochemical pathways, genes and proteins as drug targets. Later animal studies serve to help validate early hypotheses. But it is of note that animals is not where IP is generated. Animal studies are, however, integral to drug discovery as they allow testing at an organ ism level, and FDA approval is unthinkable without these. But now there is an emerging paradox: failures during human trials are mostly due to data from animal studies not translating to humans! Disease and drug response mecha nisms at the genetic level are different in animals. The rise of animal models with humanised diseased parameters have helped translatability but the overall failure rates are still >75 per cent for drugs under development, (albeit with better rates for biologics). Exacerbating the ‘non-translatability’ problem is the recent movement against animal research. In the Cosmetics sector, for example, a European commission has banned the use of animals altogether. Even for the pharma sector animal-research capacities are strained, due to which costs have nearly tripled over the last decade.

‘Inaccurate animal science’ and ‘animal rights’ is driving cell-biology efforts (both academic and commercial) to come up with solutions that are better indi cators of experimental drug performance. Leading cell-biology service providers today are not only providing better mechanistic details to understand safety and efficacy profiles, the bleeding-edge now is human cell systems. The cream of the crop here are companies that deal with human induced pluripotent stem cells (HiPSCs) that bring totally next generation benefits to the assay system. It is interesting to note that leading CROs like Charles River Laboratories started as an animal supplier to the pharma industry in the 1940s and went on to acquire Hemacare in 2021 for access to stem cells, cells, tissue like in vitro systems yielding human relevant readouts.

In parallel, information technology, AI/ML are also making significant strides in drug discovery, crunching big and voluminous data that is spewed all along the process of drug discovery. In the pre-clinical stages combining IT with human cell biology is creating realistic models for safety and efficacy testing akin to human systems. Moreover with the massive computing power available now, testing and modelling is done in a high throughput manner saving time and cost while increasing accuracy of insights that are relevant for human biology.

New Approach Methodologies Concept – Brewing New World Order

Even the FDA which is typically not concerned with approval of pre-clinical protocols is now recommending the use of NAM, which include cell biology methods that are more scientifically accurate. White papers from FDA and CDER encourage the global industry to embrace surrogate human in vitro pre-clinical models to improve the predictability of clinical outcomes. In line with this, international organisations including ICH, ICCVAM (NIH),

and OECD have outlined the principles of 3R (Replacement, Reduction and Refinement) framework for performing more humane animal research or do away with animal research completely. Current thinking from opinion lead ers and multilateral institutions are strong signals for the imminent shift to “non-animal”methods through the use of NAMs. Current literature describe NAMs using micro-physiological systems (MPS) like organ-on-a-chip, tissue-on-a-chip, organotypic cultures like co-cultures, 3D organoids, in vitro/ in silico toxicity prediction tools, quan titative structure activity relationship (QSAR) computer-based models for toxicity testing. Wide-ranging develop ments of MPS models using human cells have been developed to improve toxic ity and efficacy prediction in humans, and are understandably explored for use in both pre-clinical and drug develop ment stages.

An example of a well-used NAM in vitro method utilising HiPSC is CiPA (Comprehensive in vitro Pro Arrhythmia) assay to predict risks associated with drugs on ion channels. The readouts of CiPA paradigm help profile the risk of candi date drugs before clinical trials are under taken. Other assays like ALI (in vitro air liquid interface) cell culture model for studying structure and function of organs (including lung, intestine, kidney, lung, and liver) have been developed and validated for commercial applications.

Indian CROs: A Historical Perspective

The ~25-year old Indian CRO indus try has done well by achieving US$1.8 billion in revenues in 2021, while grow ing at double digits over the last decade. However, the performance is mostly attributable to chemistry services. Indian CROs are predominantly offspring of the traditional Indian pharma indus try or Indian corporate conglomerates, both financially and expertise-wise. Consequently, the industry is steeped in chemistry skills but less so for biol

ogy. Chemistry skills, stemming from the reverse-engineering culture of tradi tional generics industry, have been well exploited for early research, providing services for synthetic and medicinal chemistry, and also later for large scale manufacturing, where CDMO services have come of age and form significant portions of CRO revenues. However, due to the chemistry-laden heritage, the Indian CRO industry has made only modest strides in biology services. In at least one case a top-10 pharma major, Eli Lilly cancelled an ongoing research services contract with an India CRO, and shifted to Pharmaron in China for access to better biology skills.

More recently (for less than a decade) Indian CROs are incorporating biology services through both organic and inor ganic routes. Examples of this include GVK Biosciences acquiring Aragen in 2015, and Intox in 2021. The latter was acquired for the expressed purpose of incorporating animal toxicology services. But even these are mostly geared towards “non-human” cell biology or CDMO-type large scale biologics manufacturing, and not so much innovation and new discov ery (intellectual property). To reinforce this take the example of the leading global CRO, Charles River Laboratories, that has played an equal part in the innovation of 70 per cent of the drugs approved by its pharma clients over the last 5 years. In line with this leading international CROs (CRL, Wu-Xi, Pharmaron, Eurofins) are all evolving not only from an increased focus on cell biology but also through embracing human cell biology.

Introducing NAM concept in Safety and Potency Testing Offered as a Solution

Non-clinical safety and potency test ing on human MPS models is a reality to practice at industrial scale when digital tools and robotic process automation complement the in vitro system devel oped. One of the best features of this model is its seamless integration into the user’s workflow. The other advantages like user’s data privacy, access to human MPS based robust testing methodologies

integrated in the process to implement in R&D, pre-clinical, clinical and manu facturing stages are totally revolutionary.

Vaccine neurovirulence is a real safety concern of all the vaccines produced for neurotrophic viruses (eg: Polio, Covid19, HIV, Yellow fever, Mumps, Measles) with history of mishaps associated with qualified vaccines in the immunised population. Monkey Neurovirulence Test (MNVT) is the gold standard method practiced for over 50 years to test neurovirulence. Likewise, Human data are generally not available for IND’s neurotoxicity profile, but when they are they take precedence over animal test results.

References are available at www.pharmafocusasia.com

suba.dravida@tran-scell.com.

AUTHOR BIO

Vasanthi Dasari PhD, Scientific Officer and experimentalist @Transcell Oncologics with 12+ years of research leadership background.

Subhadra Dravida PhD, Founder CEO Transcell Oncologics that has Transtoxbio (transtoxbio.com) as a dedicated vertical with next gen workstation solutions in offering Safety Efficacy Testing as a Solution to the global pharma, biopharma industry.

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Technological and Regulatory Changes in Pharmacovigilance

Oracle’s safety management systems

1. Regulatory compliance and pharmacovigilance are undergoing a constant barrage of changes, which Pharma businesses can constantly cope with. How prepared is Oracle to cope with the change? Please share your experiences if any.

Maintaining regulatory compliance in a global marketplace is increasingly challenging as wellestablished regulators and regional local regulators increase their digital capabilities and expectations of Marketing Authorization Holders (MAHs). Oracle has a regulatory intelligence team that tracks global regulations and shares updates within our Safety Consortium, Regulations, and Audits Working Group. Compliance updates are released regularly, with adoption eased by the move from on-premise installations to SaaS cloud.

2. Recent years have seen

novel treatments that require specific pharmacovigilance monitoring, frequently following fasttrack approval. Can you tell us about the difficulties and potential growth in this area?

Over time, pharmacovigilance has become more intense – data about adverse events are collected more quickly, more cases are filed, and more questions are being asked about the data that is collected. In fact, according to market intelligence provider IDC, safety

caseloads are increasing by an average of 30 to 50 per cent a year1, so pharmacovigilance teams are looking for ways to process cases more quickly and efficiently. Automation and AI are key in this endeavor.

One recent successful automation deployment was seen in the rapid development of the COVID19 vaccines and therapeutics. With more than 10.4 million verified users and 150 million anonymous health records, the v-safeSM health checker created by Oracle and the CDC helps healthcare professionals

Yashi Kant, Vice President, Health Sciences, Asia Pacific, Oracle Corporation

1 * IDC MarketScape: Worldwide Life Science Drug Safety Services 2019–2020 Vendor Assessment — Building for Innovation

an increase in the marketing of

better understand how people respond to different vaccines—including common adverse effects— and make recommendations based on people’s responses.

The wide-scale adoption of the v-safe platform makes it one of the largest real-world patient data- gathering platforms in the world for a single therapeutic area. The data captured through v-safeSM has been instrumental in building the evidence base to support the safety and efficacy of the mRNA COVID-19 vaccine in pregnant women (who were not part of the original clinical trials) and other vulnerable populations. The data was also critical in securing formal FDA approval for the Pfizer-BioNTech COVID19 vaccine and subsequent booster shots.

Monitoring for new safety signals, which is information on a new or known side effect that may be caused by a medicine, is also challenging for these rapidly adopted new therapies and vaccines. We recently published new research on signal detection of the mRNA COVID-19 vaccine data which demonstrates the capabilities of Oracle Empirica Signal to identify potential signals earlier than historical methods.

Argus is a leading SaaS solution for processing, analysing, and reporting adverse event cases originating from pre/post-market drugs, biologics, vaccines, devices, and combination products. Its built-in automation, integration, and usability capabilities reduce manual tasks and maximise efficiency.

Argus can scale from supporting start-up companies with a handful of clinical candidates up through the largest biopharma companies with thousands of products marketed in a hundred or more countries. We are constantly monitoring for changes in global PV regulations and issuing compliance updates as needed.

No. In fact, with so many new ways to report adverse events, companies today have access to more data on drug safety than ever before. As adverse events arise, it’s critical to have a system in place that can provide fast, high-quality insights at scale to drive the company—and industry—forward. An automated approach allows human experts to focus on the critical cases, so existing resources are used most effectively even as the overall volume of data increases.

5.

current hot topics in the healthcare and life sciences sector are data and AI. How prepared is the pharmaceutical industry for digital transformation concerning drug safety? How is Oracle planning to face uncertainties?

Historically, the pharmaceutical industry has been slow to adopt new innovations, but the pandemic necessitated an acceleration of the adoption of digital technology, including new tools for automating safety case processing.

Key to this transformation understands how tools can be more efficient and effective, both in crunching data and enabling staff to focus on different areas of their jobs that allow them to be more creative and innovative. By applying machine learning and data science approaches, companies can automate mundane, repetitive tasks and quickly gain new information and insights about patients and therapies from the abundance of data.

Focusing on adverse event case intake, AI can be applied to a wide range of data types such as forms with a defined structure to images. It is also possible to extract and analyse data from unstructured sources like journal articles or emails. Once the documents have been automatically structured and processed, they can be separated into ‘routine’ cases that can be handled entirely by software, and ‘high-priority’ cases that require a closer review by safety specialists.

The insights provided by AI also enable safety evaluators to make more informed observations, for example, with new techniques such as neural signal detection, multimodal signal detection, and predictive signal detection.

Oracle Empirica is a leading solution for detecting, analysing, and managing safety signals originating in pre- and post-market drugs, biologics, vaccines, devices, and combination products. The platform provides users with a powerful data-mining engine with algorithms that offer flexible signal-management analytics with rich visualisations. With Empirica, pharmaceutical companies can help ensure they are always in compliance with EU GVP Module IX and CIOMS VII. Oracle continually researches, develops,

3. Could you tell our readers about a few of Oracle Argus' special features?

4. Are regulatory service providers' claims about the potential for AI to revolutionise processes overstated?

The

6. Please give us a brief overview of Oracle Health Sciences Empirica Signal and its significance. With such technological platforms, how do you monitor product safety?

and advances state-of-the-art data-mining algorithms and statistical techniques used in Empirica solutions.

8. Where does Oracle excel, and what novelties would you like to create going forward for the market for drug safety?

Today, medicinal product safety teams are under enormous pressure to control ever-increasing caseloads, new sources of signal detection data, and changing regulations—all with flat budgets and resources. Cloud-based platforms such as Oracle Argus and Oracle Empirica, coupled with standardisation, have helped lower costs through faster and easier implementations and upgrades. Through the delivery of technology solutions, we are an enabler to allow our customers to process and convert data into information and insights to drive improved patient safety.

9. What potential future business obstacles can pharmaceutical businesses face that Oracle is best equipped to handle?

One of the biggest challenges pharma faces is managing the massive amounts of patient data – and sources of data -- that are available today. There is more data available now than could have ever been imagined nearly a century ago when the first safety protocols were put into effect. Data can show us which patients should be prescribed certain drugs, which drugs are helping people, and which are not.

To process this vast and growing amount of data we will soon see technology used to move beyond augmenting human work to touchless case processing. Oracle Argus can help in this process, including assisting with automating all aspects of the safety process, from intake to report generation. While the touchless approach has not been fully adopted yet, there are certain aspects of safety case processing that are currently more suitable for greater degrees of touchless automation. For example, products that have been in the market for a considerable amount of time and are well understood naturally require less human intervention because the safety profiles are well-known.

As various system capabilities improve over time, more widespread use of touchless processing will become more feasible. Given that, companies can begin to plan for a touchless case processing system. The key is to adopt a stepwise approach, implementing and validating each automation area

one at a time, to eventually build an end-to-end automated process with confidence.

10. Where do you look for your company's future?

As we look forward to a new era of pharmacovigilance, cloud and AI technology have provided an opportunity for continued innovation and a way to bring new drug treatments to market faster and serve more people – safely. With so much data – and the technology to analyse it available today – there is no doubt we are evolving from the manual processes used in the early days of drug safety to an era of precision pharmacovigilance – a personalised approach to drug safety that will help maximise the reach of new drugs and minimise the number of adverse events people experience.

11. Any other comments?

While the pharmacovigilance process has traditionally been seen as a cost center, it’s now become a foundational component for any organisation. The information that is gleaned from safety processes is used to achieve the fundamental goal of drug safety –to reduce the risk of adverse events by informing doctors of potential side effects that were previously unknown so they can protect their patients who need the drugs.

Yashi holds a Bachelor’s Degree in Engineering and a Post Graduate

in Business Management. He has been involved in the IT industry since 1987, working in Sales & Marketing, Business Development, Support and General Management positions. As Vice President, Sales, he is responsible for delivering transformational solutions enabling Pharma, Biotech and CROs to drive innovation and bring drugs rapidly to market to cure disease. As Regional head of the world’s leading Clinical Development & Drug Safety solutions provider, Yashi is passionate about accelerating drug development and research by leveraging the power of modern technologies.

AUTHOR BIO

Diploma

DISTRIBUTED LEADERSHIP AND DECISION-MAKING

The benefits in a multicultural context

Innovation in R&D requires both leadership and effective decision-making at the edges of our current understanding. Despite the advances in translational sciences, overall success rates are still low. In this article, we outline approaches to how decisions can be aligned across organisational and cultural boundaries, adapting to new information as it emerges.

Kennedy, Organisation Development Practitioner Andrew A Parsons, Experienced Leader, Life Science industry

Navigating the complex challenges of bringing new medicines to the marketplace requires both leader ship and effective decision-making. New tech nologies and the development of translational sciences have created many new opportunities. However, the overall success rates are still low.

In this article we explore different approaches to decision-making and high light the benefits of a distributed approach to support decision-making across organi sational and cultural boundaries. We look at the structure of decision-making bodies throughout the process of bringing a new medicine to market, highlighting the dynamic nature of leadership and decision-making at the different stages of development. All of this is overlaid with the impact of the individual on the decisions taken.

Sherril

Support for Effective Decisionmaking

In 2004, the FDA emphasised the importance of using translational science to understand the relationships between pharmacological action and clinical util ity, safety and their potential as surro gate endpoints. In a recent analysis of the clinical development success rates from 2006-2015 in over 7000 projects, those that utilised patient selection biomarkers had a 3-fold better likeli hood of approval from Phase 1 stud ies (1). Even in these cases, the overall success from phase 1 is still significantly less than evens. The sobering conclu sion is that within the 9 years of focus on translational approaches, the most likely outcome of a drug discovery project is failure. However, there are areas to consider to help make appro priate decisions.

Technologies

Artificial intelligence (AI) and advanced machine learning techniques are becom ing more popular and a number of companies use these approaches as a core business platform. The scope of activities ranges from de novo design to clinical trials and patient selection (2,3). Significant reductions in cost and cycle time are becoming evident with AI based approaches and it is likely they will become an invaluable resource (3). The advances made over the last decade have supported decisionmaking in the pharmaceutical industry. However, other system effects have a consequence on the overall success rate of programs.

Collaboration

Developing a novel medicine requires working with a number of interrelated and distinct professional perspectives. Different medicine modalities such as chemical, biological or non-molecular entities have to be researched and evalu ated with assessment of the likelihood of them being effective and safe. They need to be manufactured to specific control

standards, gain access to appropriate markets and distributed to where they are needed.

It is perhaps not surprising that collaboration between these professional approaches improves success. For exam ple, a study of drug discovery projects between 1991 and 2015 in leading US Academic Institutions demonstrated that collaboration with Industry resulted in higher probability of success, especially at the later stages of development (4). The ability to work effectively within an academic and industrial collabora tion requires effort and skill from both partners.

A collaboration framework of 14 key principles has been developed to support an enabling environment to improve collaboration (5).

Collaboration Principles for Academic Institutions (5)

1. Understand different types of rela tionship to select an appropriate one

2. Identify Stakeholders

3. Understand the “why” and identify motivations

4. Identify and Appoint suitable people and involve leadership

5. Ensure basic partnership characteristics eg legal agreement, framework, roles

and resources

6. Establish Communication

7. Strengthen dissemination strategies

8. Address the IP

9. Adopt Policies to encourage collabo ration

10. Adopt strategy to encourage collabo ration

11. Focus on social capital resources eg building trust, common understand ing and effective knowledge sharing

12. Set up rewards and incentives

13. Active management of the collabo ration

14. Utilise alumni associations to develop long-term relationships with former students

Elements of these have applicability for non-academic institutions. Perhaps one area to exemplify further is that of decision-making. Within the bio-pharma industry, multi-stakeholder collabora tions often materialise through venture capital backed biotech companies that realise the value of academic innovation.

Biotech companies and related entre preneur networks provide the vehicle for these collaboration principles. As the companies validate their technology and grow, many potential collaborations are identified, often attracting new partners.

The “what” we need to do and “why” we need to do it are often the focus for collaborative agreements. This outlines motivations and rewards associated with a variety of activities or tasks. With a high level of complexity and uncertainty in the development of new medicines, develop ing a framework for “how” decisions are made will be beneficial for all parties, especially in a multicultural context. Differences in cultural contexts such as individualism or collectivism can be managed effectively with clarity on “how” decisions will be made.

A Focus on how we make the Decision

Clear roles in decision-making are impor tant in all businesses. Many decision tools are available and a useful model outlined in 2006 in HBR magazine (6) suggests

Distributed decision-making is a dynamic process that involves the right people at the right level, at the right time with the right authority to lead the decisionmaking process.

decisions involve various members of a team that provide input of data and a suggested course of action, agreement on the recommendation with input on vari ous trade-offs before one person decides. The decision maker has several useful attributes including “good business judge ment, grasp of relevant trade-offs, bias for action and a keen awareness of the organi sation that will execute the decision”. This approach can be used to transform the performance of organisations at the team and/or organisational level.

However, within the complex, multistakeholder environment of a drug discov ery programme the holistic and systemic nature of the business activities can be easily lost by breaking down decisions to a single decision maker. We offer an alternative approach, distributed decisionmaking that provides an opportunity to maintain alignment through various collaboration partners.

For the purposes of this article, we define distributed decision-making as a dynamic process that involves the right people at the right level, at the right time with the right authority to lead the deci

sion-making process. Fundamental to its success is the recognition and facilitation of the interdependencies between peers across the network of decision makers.

Figure 1 outlines the complex rela tionship between partners involved in the development of a new medicine from the perspective of a biopharmaceutical organi sations; they may have many collabora tions with smaller partners with a range of programs of activity across all stages of the drug discovery cycle.(Figure 1)

Irrespective of the stage of the activity, the overall goals of these organisations need close alignment to ensure delivery against objectives.

The Biotech board will include Executive, Non-Executive members and the primary investors. The overarching purpose and value proposition to satisfy the unmet need of customers and patients will be aligned through the various part ners via a vehicle, often termed the joint steering committee (JSC). Typically, this is a decision-making body for all elements of each collaboration. It must align with the objectives of the Pharma Partner and their board. The activities

of each Project will depend on a range of contractors, research, manufacturing and clinical partners, internal or exter nal to the large company. As projects advance, there will also be Government and Regulatory considerations to align activities.

Representation on the JSC is for members of the Biotech and Pharma Organisation. Decision-making maybe by consensus or by vote (democratic) with escalation procedures in the case of non-agreement. One approach would be to have a 2-step process, the first step being mutual resolution provided by the appropriate CEO/Head of R&D and where necessary the second step of going to arbitration.

There are a number of enablers and disablers for decision-making

• Stimulation and motivation for devel opment of the task and partnership

• The ability to gain support across a spectrum of interested parties

• Organisational and Individual resources and demands

Good decisions are not vested in any one person. While command and

Figure 1: Decision Making Systems: The relationship between decision making between collaborators

control may have a place, effective deci sion-making will be dynamic involving a range of people, each of whom is able to offer a different perspective. This is most apparent when undertaking a major project that involves a range of disciplines, organisations and cultures.

Decision responsibility will be dynamic reflecting the stage and impact of the project.

The Biotech Board and Primary Investors will agree the purpose of the assignment and the involvement of others to secure that outcome.

The Biotech Project Board will have primary responsibility for the integrity of the project and for maintaining the agreed purpose and standards adopted by each subsidiary Steering Committee.

Each subsidiary Steering Committee will have oversight for their contribution and will manage the various decisionmaking groups ensuring that the right bodies and individuals are involved at the right time for the appropriate purpose.

Routine monitoring will be required to ensure that decisions taken by each

of the Steering Committees to ensure they are aligned with the agreed remit and outcome.

Regular feedback will identify required modifications to the assign ment whilst resisting mission creep.

At each level of decision-making

Ultimate responsibility: Which body or individual role has ultimate respon sibility for the decision? It is the role not the current occupant that carries this responsibility.

Crucial commitment: Which bodies or individual roles must be genuinely committed to the decisions reached? Without this commitment they will be able to undermine the decisions taken.

Vital contribution: Which indi vidual roles have a responsibility to contribute essential information so that well informed decisions can be taken? These contributors will be unable to veto the decisions taken but can desta bilise the process by withholding or distorting their information.

Decision impact: Which roles will be affected by decisions taken and must be made aware of those decisions.

Those involved in the decisionmaking process will change over time. Clarity around the roles of those involved in the process will avoid confu sion and unnecessary competition and conflict.

The differing decision perspectives

Distributed leadership and decision responsibility will change over time and incorporate a range of perspec tives. Figure 2 details the spectrum and boundaries reflecting the needs of the decisions required. Each spectrum should be viewed as independent of the others.

Starting with the Response Imperative, a question to consider is “does the response need to be immedi ate, based on our current experience?” or is it more “remote, based on the application of our knowledge?”

Other perspectives to consider are the focus of the response, the authority

Figure 2: Perspectives to explore the dimensions of the decision to be made

Use

Grow

Rise

Generate

Gain

Connect

needed for decision-making, considera tion of the source of information and how knowledge is applied.

This approach also identifies the urgency and the organisational level of response. The next consideration, is the individuals involved in making the decision.

The impact of the individual Decisions-makers require the essential tech nical knowledge and skills. It is no longer appropriate to involve a person because of their status or the fact that they have time on their hands. Those with the necessary knowledge, skills and experience are the people who can make the greatest contri bution.

But over and above this is the impact of the individual. Each person has a unique thinking pattern that means they will concentrate on different aspects of the decision-making process.

• Some will be focused on gathering information and seeing different ways of approaching an end point. We refer to this as Researching

• Some will focus on determining what is to be done, what is important, and will weigh the pros and cons. We refer to this as Intending

• Some will focus on implementation, the timing and consequences of action. This we refer to as Committing

If those involved in the decision-making process are focused on different stages, they will be less likely to reach a decision where there is a common understanding and where there is genuine commitment to implementation of the decisions taken.

A further complication is the fact that each person will have their own interaction needs at each of these three stages.

• Some will think by talking so will embrace any opportunity to share their thinking. They may be sharing broad ideas or issuing an instruction; it is not always easy to tell

• Some will think privately and will only contribute when they feel there is something worth contributing. As a consequence, they may deprive the decision-making group of an important contribution.

Neither is right or wrong; both have their strengths and weaknesses. The important thing is to recognise these patterns and to accommodate them in a way that makes decision-making as comprehensive and effective as possible.

Senior Leaders may also consider the development of the enablers of decisionmaking skills as an important part of the learning and development of both the individual and the organisation.

Benefits of a distributed approach

Shared responsibility for decisions increases ownership and is better able to maintain the focus on the overall purpose of the assignment.

No one person has the knowledge, skills, experience and ability to fully understand the trade-offs to be made; a decision that builds on the strengths of all those involved will be a more rounded and sustainable decision.

Identifying the roles and relationships will prevent decisions being taken on autopilot; assumptions will be challenged and a common platform agreed.

Thinking in terms of roles and respon sibilities rather than named individuals will encourage objective and no-judge mental decisions and avoid the blame game.

Working in this way allows for greater agility and an ability to respond deliver under pressure without feeling under personal attack.

Conclusion

We have defined distributed decisionmaking as a dynamic process that involves the right people at the right level, at the right time with the right authority to lead the decision-making process. Fundamental to its success is the recognition and facili tation of the interdependencies between peers across the network of decision makers.

Maintaining alignment of purpose, process and people across a major multicultural project is complex and difficult.

The risks associated with such assign ments can be reduced by introducing the

monitoring and feedback routines to maintain an unerring focus on purpose and outcome that is robust and involves all players.

Risk is also reduced by understand ing the dynamic nature of key decisionmakers and the contributions essential to secure success.

The overarching Steering Committee does not know all the answers, but has a responsibility to facilitate a decisionmaking process that secures ownership and genuine commitment to implementation of the decisions taken.

References are available at www.pharmafocusasia.com

AUTHOR BIO

Sherril Kennedy PhD is a reputed organisation development consultant, specialising in the characterisation and analysis of human decision-making. She works with Boards and senior Executives to highlight, define and eliminate dysfunctional decision-group behaviours, embedding sustainable, scalable processes to ensure the success of an organisation or business into the future.

Andrew A Parsons CWP is an experienced leader in the life science industry with a track record of innovation in medicines and business processes. He was the head of migraine and stroke research and VP Preclinical Drug Discovery (CEEDD) in GSK, working multiculturally with a range of partner organisations.

Accelerating Next Generation Vaccine and Therapy Research and Unlocking Deeper Analytical Insights

To empower scientists, researchers and laboratory professionals in Asia’s pharmaceutical industry on their journeys to deliver next generation vaccine and therapy, Thermo Fisher Scientific has announced new instruments, workflows, software, and industry collaborations.

As the biopharmaceutical industry continues to push the boundaries of science, Thermo Fisher Scientific is continuing to advocate for the use of new technologies, workflows, and stronger industry collaborations.

Among the newest innovations are those focused on improving each of the critical steps in an end-to-end mass spectrometry workflow. These innovations include new analytical instruments, consumables, workflows, and software solutions that enable leading-edge biological research that spans the molecular spectrum—from targeted and small molecule quantitation and advancements in high-throughput quantitative proteomics and bio-molecular characterisation to a revolution in intuitive, AI-driven software.

All of these are aimed at empowering scientists, researchers, and laboratory professionals to generate new analytical insights and accelerate next-generation vaccine and therapy development.

Enabling Next Generation Therapies

Professionals in proteomics and biopharmaceutical laboratories who are working in drug discovery and R&D applications need to unlock the ability to clearly decipher complex mixtures of large molecules with simultaneous charge detection for analysis of previously unmeasurable analytes.

As such, Thermo Fisher has added a new Thermo Scientific Direct Mass Technology mode for its Thermo Scientific Q Exactive UHMR Hybrid QuadrupoleOrbitrap mass spectrometers that lets manufacturers analyse the characteristics of biotherapeutics in greater detail throughout development. This development will enable laboratory professionals to improve material quantitation and accelerate biopharma development.

This is because the Direct Mass Technology mode augments the UHMR Hybrid QuadrupoleOrbitrap mass spectrometers with charge detection

KAPIL KHULLAR, Senior Director, Growth Strategies and Application Excellence for Chromatography and Mass Spectrometry solutions, Asia Pacific and Japan, Thermo Fisher Scientific

The Thermo Scientific™ AccelerOme™ automated sample preparation platform with the Thermo Scientific™ AccelerOme™ sample preparation kit

capabilities, allowing direct mass determination of hundreds to thousands of individual ions in a single spectrum. As a result, laboratories can measure mass for complex heterogeneous mixtures of multiple charged components, unlocking new and rich insights into proteoforms, biotherapeutics and next-generation drug modalities.

For proteomics researchers, the Thermo Scientific AccelerOme Automated Sample Preparation Platform improves reproducibility in sample prep, a longstanding bottleneck preventing wider use in biomarker discovery for disease detection and research into new therapies.

Very simply put, the AccelerOme Automated Sample Preparation Platform eliminates the need for labour-intensive, manual sample preparation for LC-MS analysis, including the associated method development and reagent sourcing. Automated sample preparation also overcomes the challenge of maintaining reproducibility with manual

methodologies, and the new platform’s pre-built validated methods and kit format reagents further reduce any risk of user error.

A new Thermo Scientific µPAC Neo HPLC Column improves column-to-column reproducibility within proteomics and biopharmaceutical research applications as part of an end-to-end liquid chromatography-mass spectrometry (LC-MS) workflow. This further simplifies complex bottom-up proteomics analyses, enabling wider use in the discovery and detection of cancer and other disease biomarkers, and the development of new therapies and vaccines ranging from COVID to cancer and rare diseases.

Essentially, the µPAC Neo HPLC column provides proteomics and biopharmaceutical research laboratories with a new micro-pillar array column as part of an end-to-end LC-MS workflow that will simplify complex bottom-up proteomics analyses, complete with a detailed startup protocol. This helps

users accelerate their experimental setup with the reassurance of high-level performance across every component of the workflow.

Unlocking Deeper Analytical Insights

Scientists in biopharmaceutical, proteomics, and small molecule settings can enable more comprehensive analysis of their data with the latest software updates. New features enable researchers to extract more information from their new and existing data, streamline data interpretation, and standardise reporting with increased ease of use.

The new cloud-based Thermo Scientific Ardia platform integrates data across multiple chromatography and mass spectrometry instruments, letting biopharmaceutical and proteomics scientists share previously siloed data, simplifying analyses and unlocking deeper insights into new diagnostics and therapies that could reach the point of care sooner.

New Thermo Scientific BioPharma Finder 5.1 software uses advanced algorithms to improve biotherapeutic characterisation, an increasing priority as industry and regulators build stricter quality controls into the production of complex new biotherapies and vaccines.

For proteomic scientists, Thermo Scientific Proteome Discoverer 3.0 software interprets data from Thermo Scientific Orbitrap mass spectrometers and applies artificial intelligence (AI), giving researchers a faster method to identify and analyse billions of possible protein interactions in humans, insights that accelerate discovery and development of next-generation drugs and vaccines.

Lastly, for forensic toxicologists, clinical research toxicologists, employee drug testing facilities and wellness organisations, expanding the Thermo Scientific Tox Explorer Collection onto the Thermo Scientific Orbitrap Exploris Mass Spectrometer platform, provides an all-in-one LC-MS toxicology solution to solve complex analytical challenges and increase laboratory productivity.

Cross Industry Collaboration

Thermo Fisher has entered a relationship with TransMIT GmbH Center for Mass Spectrometric Developments to promote a mass spectrometry imaging (MSI) platform for spatial multi-omics applications in pharmaceutical and clinical laboratories.

TransMIT will combine its proprietary scanning microprobe matrix-assisted laser desorption/ ionisation (SMALDI) MSI and 3D-surface MSI technology with the exceptional high resolution accurate mass (HRAM) power of Thermo Scientific Orbitrap MS instrumentation.

TransMIT’s AP-SMALDI5 AF ion source coupled with Orbitrap MS technology enables spatial distribution mapping of a variety of molecules such as biomarkers, metabolites, peptides or enzymatically digested proteins by their molecular masses. This approach can be applied to omics applications such as metabolomics, lipidomics, proteomics, glycomics and to pharmaco-kinetic studies in a variety of tissues.

For more information, please visit: www.thermofisher.com/accelerome

AUTHOR BIO Kapil Khullar is Senior Director, Growth Strategies and Application Excellence, Chromatography and Mass Spectrometry in Asia Pacific and Japan, Thermo Fisher Scientific. A veteran of 25 years in the analytical science industry, Dr. Khullar attained his PhD in analytical chemistry from the Indian Institute of Technology Delhi.

SGS HEALTH SCIENCE

Integrated solutions for quality and compliance

As a leader in the Testing, Inspection and Certification (TIC) industry, SGS aims to increase cooperation and agility across its global network to leverage competencies. SGS India Managing Director – Shashibhushan Jogani, talks about SGS’s strategic focus on the Health Science industry, how its key investments in India will make the latest new-age technology available to native pharma companies and help to reduce cost for customers and result in faster turn-around time.

How does SGS look at India as a potential market for health science services and its capabilities to support the health science industry?

India is a major hub for manufacturing and exports of pharmaceutical prod ucts. These extend from APIs, drug intermediates to finished products. The Indian pharmaceutical industry has been consistently delivering a YoY growth over the past decade. The salient factors behind this boom in exports for India are price competitive ness as well as quality. As per the latest industry reports, nearly 60 per cent of the world’s vaccines and 20 per cent of generic medicines are manufactured from India. India also ranks at third posi tion worldwide for Pharma production by volume and 14th by value. (Source: Ministry of Commerce & Industry). This clearly establishes that the Indian phar maceutical industry is a key contribu tor which is defining and shaping the global arena.

Shashibhushan Jogani, Managing Director, SGS India

Our Health Science services can add significant value with specialist services extending from exploratory development, testing, regulatory support, safety studies and clinical research, to commercial QC and post-market testing. Delivered with high accuracy, integrity and scientific rigour, these solutions are supported by state-ofthe-art laboratories, and a rich pool of local as well as global expertise that give us the confidence to meet the vast requirements of this industry. Pharmaceutical products are strictly guided by regulations which are a combination of legal, administrative, and technical measures that governments across the world take to ensure the safety, efficacy, and quality of medicines, as well as the relevance and accuracy of product information. Our regulatory support services offer a huge benefit to clients by helping them to navigate through these complex regulations and to comply with local and international standards and therefore increased market access.

How does SGS stay on top of fast changing pharmaceutical market requirements and the complex regulatory environment?

Our team focuses on increasing the cooperation and agility across our global network. This is helping us to leverage the vast pool of expertise and competence that is available across our entire network and successfully meet the versatile require ments posed by our clients. It also helps us to keep abreast of changing dynamics of the industry as well as the regulatory landscape.

What are the advanced solutions and features that SGS has introduced to emerge as a leader in the TIC industry?

SGS has been consistently leading the TIC industry with integrated solutions to address various customer requirements, help customers to meet stringent standards

SHASHIBHUSHAN JOGANI was appointed as the Managing Director of SGS India including the sub-region of Bangladesh and Sri Lanka in June 2021. Prior to this appointment, Shashi was leading the SGS Indonesia operations as Managing Director. In a career spanning 20 years at SGS Group, he has held various executive roles within the company, including Indonesia Country Business Manager, India Business Director for Systems and Services Certification (now Knowledge) as well as Head of Strategic Transformation for the South-East Asia Pacific region. Shashi joined SGS in 2003 as a Business Controller for SGS India before assuming numerous key leadership roles across the company.

along their supply chain and improve the quality of life in society by assuring the quality, safety, sustainability and security in the health, wellness, and nutrition industries.

Our vision is to become the most digital company in the TIC industry. As part of this process, we have acceler ated our Digital & Innovation strategy to create new products and services, improve customer experience and auto mate our operations. We are leverag ing new transformational technologies like artificial intelligence (AI), robotics and applying automations, through several new digital platforms to improve our efficiencies, deliver operational excellence and continuously improve customer experience. Our focus on use of advanced technologies also benefits on various compliance aspects which eventually help our clients in accelerat ing product development and go-tomarket of new drugs and formulations for patients.

Recently, we have made two signifi cant and strategic investments in India. These are:

1. Advanced Analytics (AA) laboratory within our Navi Mumbai campus.

2. An Advanced Centre of Testing (ACT) within our Chennai laboratory. These two capability enhancements provide us a clear edge over the exist ing technologies that are available in the market.

The Advanced Analytics laboratory is equipped with new generation infra structure for performing Extractable & Leachable (E&L) studies, assessment of Nitrosamines, Genotoxic impurities etc. in pharmaceutical materials.

The Advanced Centre of Testing in Chennai takes quality testing to the next level with solutions like Digital Sensory Analysis using the electro sensing devices like the electronicnose(e-nose) and electronic-tongue (e-tongue) which provide unbiased, accurate and repeatable measure ments, allowing identification and clas sification of aroma mixtures and taste.

These advanced digital sensory meth ods help to improve the palatability of oral solutions to make them acceptable to patients. It also reduces the potential safety risk to trained human sensory panels due to exposure to harmful agents and cuts back huge expenses for organisation to recruit, train and maintain taste panelists. Applications of these tools in the pharmaceutical industry plays a key role in measur ing and comparing the taste-masking efficiency of formulations produced with different masking techniques, offodour investigations, development of placebos for blinded clinical testing, sensory features ageing overtime, comparing the taste of test medicines or generic products with benchmarked products etc.

What is your outlook for the next 5 years and your plans for future growth and investments in health science?

We are very optimistic and excited about the growth of the health sciences industry in India and plan to accel erate our investments in India within this sector. Our focus is to align our services and scale with that of the industry, especially in the Biologics and Biopharmaceutical arena.

We not only plan to invest in new technologies and equipment, but also

to leverage the technologies, platforms and quality systems that are already established at our network labs in US, EU to cater to the needs of our clients and the industry in India as well as the region. The integrated drug develop ment and testing facilities that we plan to set up will drastically reduce the dependency that Indian biopharma companies have at present, on Contract Research Organisations (CRO’s) in US and EU. These new facilities would be capable of meeting our client require ments and facilitate faster product development and go-to-market. Another important area that we are working to expand our footprint is the testing of medical devices.

Our outlook for the next few years is to accelerate our focus and invest ments into strategic industry segments within health sciences and leverage the competence across our global network to deliver these services and excellence to our clients. Agility within the global network is something we are strongly focusing upon. We are also making significant investment in our employ ees, new technologies and platforms to improve customer experience and automate our operations. These strategic actions and investments would help us to secure a strong customer base and a healthy, organic top-line growth that reinforces our leadership position in the TIC industry.

Maintaining a Drug’s Bioavailability and Masking Taste with Microencapsulation

Microencapsulation possesses numerous advantages for many pharmaceutical applications: it's an effective means of converting a liquid to a solid, it provides taste masking, and it ensures controlled release capabilities. But partnering with a CDMO that possesses microencapsulation experience and expertise is integral to the product’s ultimate clinical and commercial success.

Today’s formulation challenges are as diverse as they are demanding–from increasingly insoluble new chemical entities (NCEs) to highly bitter drugs, to increased regulatory emphasis on patient acceptance–arriving at a final dosage form that has commercial potential is a more complex proposition than ever.

Microencapsulation, the process by which particles are co-formulated with a polymer or other excipients to improve palatability, modify release rate or enhance bioavailability, possesses a number of advantages for many pharmaceutical applications. An effective means of converting a liquid to a solid, taste masking a bitter active pharmaceutical ingredient (API), or ensuring controlled release, microencapsulation offers the encapsulated drug protection from environmental factors, flexibility in dosage form, and an array of other benefits.

There are several technologies available for microencapsulating drugs. Finding a contract development and manufacturing organisation (CDMO) possessing the experience and expertise necessary to optimise a drug’s efficacy and manufacturing during formulation is integral to the product’s ultimate clinical and commercial success. To do so requires companies to understand not only

their own molecule, but the distinctions between technologies and among potential manufacturing partners, as well as the financial and therapeutic pitfalls often associated with unoptimised processes.

The Factors that Affect a Drug’s Efficacy

For oral drug formulations, there are three primary characteristics pharmaceutical companies must consider in their development paradigm to optimise a drug’s efficacy: solubility, permeability, and bioavailability. Arguably the single most important measure of a drug’s efficacy is its bioavailability, or the amount of unchanged drug which reaches systemic circulation. There are a number of physicochemical factors which impact bioavailability, including a drug’s solubility, its hydrophobicity, and its pKa. There are also various external factors, including whether a patient has consumed food, the relative health of a patient’s gastrointestinal tract, and whether a formulation has been tampered with prior to administration.

The reasons for poor bioavailability are equally diverse. They can include poor solubility, degradation in the gastrointestinal tract, interactions with food, insufficient time to ensure absorption, drug efflux pumps such as p-glycoprotein, hepatic first-pass

Nathan Dormer, Director of Drug Product Development, Adare Pharma Solutions

metabolisation, and other factors. Addressing these requires a comprehensive approach to formulation, one that considers physical modifications to the size of the molecule, carriers that optimise dispersion, chemical modifications to the pH or salt content of the drug, and other methodologies.

There are several technologies that have been employed to enhance the solubility, dissolution, and bioavailability of drugs, as well as to improve their taste and overall palatability. These technologies include those which reduce the size of particles, an important first step in improving the control, stability, appearance, efficacy, and manufacturing of a drug. The most commonly-utilised technique to reduce particle size, micronisation, which can reduce API to a micrometer or, in some cases, nanometer size. This improves the solubility of poorly soluble APIs by increasing the particle surface area-to-volume ratio, accelerating the rate of dissolution. Considering the complexity of bioavailability, however, micronisation and other solubility-enhancing techniques can have a limited impact if the final dosage forms do not also exhibit uniform disintegration and performance. Simply stated, all facets of the product must be designed for consistent disintegration and dissolution.

The Solutions that Ensure a Drug’s Efficacy

Adare, a global technology-driven specialty CDMO providing product development through commercial manufacturing expertise, focuses on oral dosage forms for the pharmaceutical, animal health, and OTC markets, and utilises propriety technology platforms for taste masking and customised drug release. Adare’s Optim m® technology is a melt-spray-congeal process that offers a wide range of modified release options in a powder format, allowing the such powder to mirror an extended-release tablet’s performance. Optim m-produced powder is compatible with many other dosage forms, including liquid suspensions, dispersible tablets, chewable tablets, and granular multi-dose devices.

The primary advantage Optim m offers when compared to other similar technologies is in the uniformity of the particles it produces. Adare’s Precision Particle Fabrication® technology enables particle uniformity with precision engineering, allowing for tighter control of release kinetics, and is the under-pinning technology for Optim m and Strat m TM (a long-acting injectable application).

While there are a handful of melt-spray technologies on the market for microencapsulation, many of them are incapable of producing particles uniformly in size; even small variations in particle size can have implications for the final dosage form’s release rate and potency.

Inconsistency in particle size can lead to content uniformity issues, which sometimes necessitates manufacturing modifications. For instance, during a coating process, if substrate particles are not uniform, a specific coating duration will result in different levels of coating for particles of varying sizes, with differing release rates or taste-masking, which can affect homogeneity of performance within a dose or from dose-to-dose. To address this problem, many manufacturers need to sieve their intermediate particles to create a more consistent particle size. This comes at a literal cost: as much as 30 per cent of what has been produced is subsequently discarded.

Adare’s Microcaps® technology is another example of a microencapsulation technology that can customise a drug’s release profile, provide taste masking, or combine otherwise incompatible APIs. With Microcaps technology, the raw API is directly coated with a thin layer of polymer. This does create a wider size distribution than that achievable with Optim m technology but enables a much higher drug loading on a weight basis. Moreover, Microcaps is an ideal choice for tastemasking high-dose applications, whereas Optimum has more flexibility in taste-masking and extendedrelease for moderate-to-low dose therapeutics. Like Optimum, drugs formulated using the Microcaps technology can be compounded into an array of dosage forms, including powders, dry syrups, orally disintegrating tablets, and Adare’s Parvulet dosage form, which mimics the texture of soft foods such as

yogurt to increase swallowability for certain patient populations.

Microcaps and Optim m represent just two of Adare’s solutions for improving a drug’s efficacy and palatability. With a range of barriers and coatings, taste modifiers and suppressants, and API and API solubility modifiers, Adare’s portfolio of dosage form technologies is one of the most comprehensive in the world. These technologies, coupled with a long-standing focus on patient compliance, have positioned Adare as a leader in formulation for specific populations. Adare’s expertise also extends to pediatric formulations, which is a critical consideration for virtually all therapeutics.

By partnering with a CDMO like Adare, companies can identify a format that is the best fit for their drug and target patient population, thereby meeting increasingly stringent regulatory standards and, ultimately, improving patient outcomes through better patient adherence. If microencapsulation is the best choice for your drug, Adare has a portfolio of manufacturing approaches to get the job done.

AUTHOR BIO

Nathan Dormer is the Director of Drug Product Development at Adare Pharma Solutions in Lenexa, KS. Dr. Dormer is a pharmaceutical scientist and bioengineer with over a decade of experience developing microsphere- based solid oral and parenteral/ implantable dosage forms, with an emphasis on controlled release and other innovative formulation concepts.

Safety De-risking Approaches for Advanced Modalities

The continued rise in the number of biologics and advanced therapies in development has required the biopharmaceutical industry to adopt different strategies to de-risk these products compared to more traditional small molecules. This article will examine the technologies and platforms available and how they can best be applied.

Peter Gaskin, MTOPRA: Senior Director, Scientific Advisory Services, Charles River Laboratories Pramila Singh, DABT: Senior Principal, Scientific Advisory Services, Charles River Laboratories

Screening strategies for small mole cules have evolved over decades to pan through thousands of mole cules in silico and in high-throughput in vitro assays using the smallest possible amount of compound at minimal cost. As companies move increasingly to biolog ics and advanced therapies, the safety liabilities are changed, and the approaches and technologies required to de-risk the products change too. The applied tech nologies depend on several aspects includ ing stage of development, availability and

final formulation of test item, class of therapeutic, pharmacological target and mode of action. We discuss some of the more commonly used and useful screen ing technologies and explain how they work together to de-risk the development and safety of advanced therapies.

In silico assessments

In silico tools to aid the safety screen ing of therapeutics have been available for a long time. The Derek system that identifies and has helped to catalogue

structure-activity relationships was originally set up in the 1980s based on structural alerts for carcinogenic and noncarcinogenic potential (Ashby 1985). The system proved successful in predicting the mutagenic risk of small molecule drugs and has now expanded to consider the safety of predicted metabolites as well as parent molecules.

Whilst the Derek and related systems have proven invaluable to screen small molecules, the system is not applicable to biological therapeutics and advanced

therapies. However, the success of Derek and other systems has led to widespread acceptance and adoption of in silico risk assessment approaches.

For gene therapies, the use of large and continuously evolving data bases containing specific gene and protein sequences found in different species(e.g.BLAST, MegaBLAST and blastp)has proven indispensable for developing analytical methods, identifying potential off-target binding, detecting or verifying interspecies target specificities and transcript mapping across mamma lian genomes.

In silico assessments are routinely used in the development of biological therapeutics to assess sites of possible post-translational modification and chem ical stability. It is now possible to screen a library of over one-hundred billion fully human antibodies, computation ally optimised in silico for therapeutic

developability with complementaritydetermining regions sourced and incorpo rated at specific frequencies for maximum library diversity.

Use of these tools early in discovery helps to remove undesirable characteristics such as the risk of protein aggregation and immunogenicity from biologi cal lead molecules. The approach also allows developers to conduct in silicoguided engineering of epitope sequences to reduce the immunogenicity of their preferred lead candidates.

Gene editing

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) gene editing, and related gene editing tech niques, have the potential to produce advanced therapies that radically alter disease progression and patient outcomes. This technology provides the possibility to edit out faulty genes and replace them

with functioning copies of the normal gene.

Engineered CRISPR systems contain two components: a guide RNA and a CRISPR-associated endonuclease (Cas protein). The guide RNA is a short synthetic RNA composed of a sequence necessary for binding to the Cas protein and a modifiable spacer sequence of approximately 20 nucleotides that defines the genomic target to be modified. When designing a CRISPR Cas9 editing system the genomic target of the Cas protein can be changed by simply changing the target sequence present in the guide RNA, making it incredibly quick to engineer and widely applicable to a broad range of diseases. The system will edit where guided by the guide RNA, so if the guide RNA sequence is not sufficiently specific, or is inaccurate, it is possible that the system will edit the wrong gene, with potentially devastating consequences.

In silico assessments of all potential hybridisation targets of any guide RNA are therefore critical in the design of guide RNAs to ensure that the correct gene is edited and that no off-target or unintended editing occurs. Establishing a rigorous and early validation protocol for new therapeutic candidates based on gene editing technologies is a prudent de-risking strategy.

Next Generation Sequencing (NGS) and Proteomics

For nucleic acid-based therapeutics the combination of next generation sequenc ing (NGS) to sequence the whole genome and in silico evaluation is used to de-risk guide RNAs used for therapeutic gene editing tools, such as CRISPR-Cas9. As discussed above, in silico assessments help to predict and eliminate potential modi fications leading to off-target effects, and it is NGS that is used to confirm that the editing proceeds as planned.

NGS is also applicable to target deconvolution and mechanism of

action/mechanism of toxicity studies. When utilising NGS it is important to ensure that the data can be generated and processed in a meaningful way. This means that NGS is most powerful when coupled with a robust bioinformatics workflow and software, a pathways biol ogy platform and deep expertise in data interpretation.

NGS is increasingly finding useful applications in proteomics. Researchers are using tools like CITE-Seq (cellular indexing of transcriptomes and epitopes by sequencing) and REAP-Seq (RNA expression and protein sequencing assay) among other techniques to understand mechanisms of disease by evaluating rela tionships between RNA transcripts and proteins in healthy and diseased cells, which will lead to the identification of specific therapeutic targets and even tually to innovation of highly targeted therapies.

Therapeutic mechanisms work ing through gene silencing or protein degradation, such as Proteolysis Targeting

Chimera (PROTAC) and RNA interfer ence (RNAi) biotechnology products, can lead to unintentional alterations in levels of endogenous proteins. In vitro off-target binding and activity assays appropriately used for small molecules are not suitable for these modali ties. For this reason, new proteomic methods have been developed for the assessment of secondary pharmacology effects. One such proteomic platform has been developed using human cell lines to establish a prioritised panel of nearly 3000 proteins, which has been referred to as the “selected off-target proteome” as described in Liu et al., 2021.These researchers also demon strated how they further refined the human proteome panel to produce a modifiable and expandable platform for identifying potentially adverse off-target or secondary pharmacology effects.

RNAScope

Use of RNAScope has become increas ingly prevalent in development of novel

gene therapies, allowing visualisation of transgene expression in situ. The tech nique utilises RNA in situ hybridisation (ISH) to allow the visualisation of single RNA molecules within individual cells. It is perhaps most commonly used with formalin fixed paraffin-embedded tissue from in vivo studies, but it can also be used to elucidate mechanisms of action and relevant biomarkers of safety in vitro. As an illustration, researchers have used RNAScope on non-adherent cells such as cytospin samples of patient-derived PBMCs (Chan et al. 2018), and to char acterise neuronal cell culture models of chemotherapy-induced peripheral neuropathy (Eldridge et al 2021). The technique can also be used for visualising the expression of target(s) across multiple tissues even where there is limited avail ability of reliable antibodies. The use of RNAScope greatly enhances the ability to decisively determine transgene deliv ery and link localisation to the expected therapeutic benefits of gene therapy products using precision analytical tools.

Microarray technologies

Microarray technology, such as the Retrogenix cell microarray system enables users to quickly screen ligands including viruses and CAR-T cells for binding to thousands of proteins expressed on the surface of human cells. The proteins have relevant post-translational modifications and are naturally folded. Platforms are designed to include plasma membrane monomers, but also heterodimers. Secreted proteins have also been included by tethering to the matrix. The system can be run with either fixed or unfixed cells.

Thousands of full-length human plasma membrane and tethered secreted proteins are spotted onto microarray slides. Human cells grown over the top become reverse-transfected resulting in cell surface expression of each respective protein at distinct slide locations. The test molecule or cell is applied, and specific binding analysed and confirmed using an appropriate detection system. Detection methods include immunofluorescent labels/tags or radio label.

With broad coverage, such systems enable the detection of even low affin ity interactions with a high degree of specificity and sensitivity. This informa tion can be generated early in the design process to ensure target interaction, but critically target specificity, minimising the risk of off-target effects. As part of a CAR-x discovery program microarrays are used to screen the antigen recognition element initially and subsequently the whole engineered CAR-T or CAR-NK cell product to provide confirmation that binding to the target and off-target bind ing has not been inadvertently altered during the cell engineering and produc tion process.

Cell-based assays

Cell-based systems lend themselves to higher throughput as compared to organ on a chip and are being more widely used for de-risking of advanced therapies.

Different virus serotypes and viral capsid variants are known to have differ ent patterns of tissue tropism and anti genic properties. Chemical modification of capsids by adding receptor-binding moieties can enhance tropism. Also, by chemically masking the original receptor-binding moieties, the capsid can be shielded from neutralising anti bodies that can inhibit effective distribu tion of gene therapies into their target tissues. Some of these approaches are described in Castle et al (Castle et al 2016). One of the earliest examples of modifying adeno-associated virus (AAV) tropism successfully by capsid engineering used the insertion of short peptides into the surface of the AAV capsid to confer affinity for a receptor expressed on the target cell (Yang et al 1998). Primary cells are regularly employed during this development process to screen new capsid constructs for improved tropism to the target cell. These in vitro screening studies ensure, not only that efficiency of transgene expression is increased to improve effi cacy, but the safety risk of the therapy is reduced as the target cell population is more selectively targeted.

iPSC-derived cell lines have many similarities to normal human cells in terms of the way in which they respond to test items. By reprogramming the cells to become more differentiated and phenotypically neuronal or myocyte in characteristic, they become much better models to assess the individual cell type susceptibility to pharmacological action or toxic insult.

iPSCs from patients offer a further possible advantage as they hold the prom ise of producing neuronal or other cell lines with characteristics of patients with a wide range of diseases. These represent excellent models for screening the activ ity of many types of therapies. Patient iPSC-derived cell lines incorporate the weaknesses and susceptibilities of these patients own neuronal cells, making them excellent models to assess the compara tive safety of new therapies in patients with particular diseases compared with healthy individuals.

Artificial intelligence

Artificial intelligence (AI) is now a powerful tool which can be applied to significantly improve the safety de-risking process early in discovery, with AI-driven pipelines of biotechs expanding at a very fast rate. Data from screening studies with DNA-encoded libraries together with high throughput in silico data are screened through AI-enabled computa tional platforms. These platforms lever

age a wide range of in vitro and in vivo models and along with computational predictive models to help identify targets, predicting ‘druggable’ characteristics and target selectivity of molecules from a vast space. In terms of safety, AI can also be used to predict potential interactions and by leveraging publicly available data or proprietary databases can predict poten tial on- and off-target safety liabilities. A major advantage of AI systems is that they include an active learning loop, referred to as machine learning, which helps to improve the accuracy of predic tion and to identify advanceable lead series or candidate molecules leading to a very high success rate, which improves as more data is gathered. Critically AI can also be used to screen billions of molecules virtually, reducing costs and resource requirements and improving the discovery process by more efficient use of molecular biology, public and private databases and other resources.

In Conclusion

We have discussed some of the approaches that comprise an arsenal of powerful tools for de-risking novel biotherapeutics and advanced therapies. Often used in combi nation, the application of these tools in early development of advanced modalities can lead to even more effective, more selective and safer treatments for patients. References are available at www.pharmafocusasia.com

Peter Gaskin has over 30 years’ experience in the discovery and development of pharmaceuticals, biopharmaceuticals and advanced therapies. With expertise in toxicology, pharmacology, pharmacokinetics, and pharmacodynamics, he has a proven track record of designing early derisking strategies and for successfully transitioning drug candidates from research into development and to market.

Pramila Singh is an expert in the nonclinical development of pharmaceuticals, biologics, and advanced therapies. She advises on discovery safety screening and has worked with US government research on disease models of allergic asthma and cell signalling and in global industry positions managing safety testing and evaluation teams.

3d Tumor Models copy

AUTHOR BIO

THE SCIENCE OF ALIGNMENT

The ‘Ultimate’ objective

The concept of alignment for partnering and/ or collaborating to advance like-minded research appears, on the surface, evident to most individuals working in the scientific community. However, beneath this obvious axiom is a level of complexity that too often creates a show-stopping conundrum, wherein perceived individual needs outweigh or overshadow the common good sought from pursuing the partnership or collaboration. The key to resolving this conundrum is proper alignment of stakeholders and resources.

Shawnmarie Mayrand-Chung, Immunologist

Do more, better, and faster research! Scientific researchers have always generally acknowledged the importance of collaboration and sharing of scientific findings to advance scientific innovation. Whether at the level of discovery, development or product testing, the common motivation among stakeholders involved in such activity, be it academic, government, industry, or private researchers, is to minimise cost and time while maximising scientific expertise and outcomes. This ‘win-win’ mentality across research groups provides the backbone for a collaborative advancement whereby additional incentives are provided to

Finding ways to bring the scientific community together more frequently and easily to solve larger goals that go beyond the interests of the individual participants would be not only beneficial but essential if we wish to effectively tackle the increasingly complex sustainability goals facing the world.

one or more stakeholders groups. The benefits of research partnerships and collaborations in the life sciences have been demonstrated by the successes of public-private partnerships (PPPs) such as The Biomarker Consortium (BC), Accelerating Medicines Partnership (AMP) and The Critical Path Institute (CPI). Although the success of these PPPs can be largely attributed to their pre-competitive nature and/or opensource design, the value of the partnership itself should not be undervalued. In addition to achieving their individual scientific research goals, these PPPs serve as positive examples of how different stakeholders can align to reach concurrently a common objective.

For the last two decades, we have seen a proliferation of scientific research part nerships, and an expansion of collabo ration. The drivers for these partner ships include the need for: proprietary tools, leveraging of scientific expertise and knowledge, and access to data or samples, for example. Traditionalstructured partnerships have for the most part been conservative in their design, being narrowly crafted and with a finite endpoint. In such partnerships, each stakeholder participates in a shared research effort chiefly to advance each participant’s individual benefit. Finding ways to bring the scientific community together more frequently and easily to solve larger goals that go beyond the inter ests of the individual participants would be not only beneficial but essential if we wish to effectively tackle the increasingly complex sustainability goals facing the

world, such as hunger, health and wellbeing, affordable and clean energy, and climate control.

The conundrum

The scientific research community has long suffered from the tendency to work in silos, whereby ideas, data and discoveries are held confidentially by the research organisation. In some cases, even within the same research organisa tion, there is a propensity to keep such information from being shared broadly within that organisation. Regardless of the stakeholder group – e.g. government, academia, industry, private organisa tions (not-for-profit or for profit), the historical tendency has been to “hold close” these pieces of information or risk missing an opportunity for publi cation and/or funding. This inherent fear that personal opportunities may be lost by sharing information, be it data or scientific knowledge, has played a major role in the inefficiency of medi cal research and the unaffordability of medical device and drugs. Although the potential promise of scientific alignment, intellectually, makes sense to most researchers as most recently demonstrated by the heroic efforts to develop COVID-19 vaccines, the reluc tancy to work collaboratively remains pervasive in the scientific community. The reality is that stakeholders are not always able to either successfully come together for numerous reasons, includ ing failure to identify amongst potential stakeholder partners suitable comple mentary resources held by others and

mis-matching needs of stakeholders. Even when they can match up needs, they may not be able to successfully work together to achieve the desired outcome. The inability to align these factors ulti mately results in missed opportunities and inefficient and more costly research.

The Science of Alignment: Making research collaborations work

Although the last two decades have shown that it is possible to achieve a “win-win” through PPPs and research collaborations, generating more such opportunities for scientific research to be done more effi ciently, effectively, and affordably remains unfulfilled. There are several key elements required to achieve the alignment needed for a successful scientific partnership or collaboration. In addition to reaching the ultimate shared outcome, it is also critical that all stakeholders reach their individual desired benefits. For both the overarching and specific individually desired outcomes to be achieved, there are core aspects of the formation of the partnership or collaboration that must be considered and realised. Importantly, the relationship amongst stakeholders must be structured and memorialised in a concrete way. The hallmarks of a successful relationship also include the following steps:

1. Identify prospective partners with resources that complementarily align with the sources brought by the other prospective partners.

2. Cross-check that the needs of the prospective partners align with the expected outcome(s) of the partner ship/collaboration to ensure adequate incentives exist for the participants to fully contribute the expected resources toward the partnership/collaboration; and

3. Once suitable partners are identified, align stakeholders to reach agreement on clear policies and robust procedures to carefully define and document the engagement.

By following these steps, the benefits include:

· Transparency – building trust to assure cooperation and full participation in the collaboration

Confidentiality – protecting stake holder intellectual property interests Accountability – assuring appropriate governance

The Stakeholders: Know and understand your partner’s needs

A critical part of assuring a successful partnership or collaboration is to appreci ate what each stakeholder (1) brings to the table and (2) needs to take away from the table. This entails understanding your partners and aligning on both the primary shared benefit(s) – e.g. “the sweet spot”, and all secondary benefits that accrue to individual shareholders. Secondary

While the ‘common good’ is easy to identify, and the benefit of sharing cost, time and resources easy to understand, appreciating the specific expectations that have driven a stakeholder to want to enter a partnership or collaboration is much more challenging. More often than not, stakeholders fail to take into account all the factors and needs that their future partners must achieve and/ or consider before agreeing to collabo rate. This is particularly true in the life sciences where many of the traditional barriers still exist. Some of the factors and needs of each type of stakeholder is described below:

Academia: Historically, academic researchers and entities have not focused on the commercialisation of their scien

desire to be a supporting element of the commercialisation – they also expect to be involved and compensated accord ingly for this stage of development. The academia-government relationship has traditionally been one of ‘money-matters’. Because much of academic research is funded by government entities the publish or perish’ mentality plays a strong role. Government-funded research is often also supplemented by private funding – which is again dependent on the researcher being able to demonstrate value in their respective field of research.

Government: The benefits for governments to support PPPs is probably the easiest to appreciate as their mandate is to use their resources to advance science for improving the health of society. More specifically, by participating in PPPs in science, technology, and innovation (STI) they are poised to (1) be more responsive and proactive in developing policies that support the rapid advancements in science, technology, and innovation and (2) address urgent social and global

challenges, such as future pandemics or other health crisis. Governments can use PPPs to mitigate risk of failures, reap the benefits of cost-sharing, and harvest useful insights regarding how to plan for future societal challenges and crisis.

Industry: Collaboration with indus try stakeholders affords academic scien tists money and access to tools and inno vative technology, which are not always available. In return, industry gains access to cutting edge scientific knowledge and early innovations. Additionally, industry-academia partnerships can lead to the development of new markets, as well as helping to solve global health problems, such as developing COVID19 vaccines. While these research part nerships are often fruitful, partnering with industry can often be viewed as undesirable for reasons surrounding conflict of interest. This is especially true for companies that fall within the definition of a ‘prohibited source’ by government entities. The optics of work ing alongside a company that has been deemed to have or perceived to have motives that are contrary or misaligned to those of the public health officials, whether grounded in proof or not, can be a deterrent to academic researchers and or non-profit organisations. The need to consider both actual and optical conflict of interest is thus a must when considering a partnership with industry.

Not-for-profit and non-government organisations (NFP & NGOs): These stakeholders hold an important posi tion in the formation of PPPs because of their ability to serve as a neutral entity among government, industry, and academic stakeholders. Because both industry and academic institutions (that are receiving government funds) must respect their status as a poten tial ‘prohibited source’ for government engagement, a neutral entity is often used to prevent conflict of interests. NFP & NGOs can also bring together unlikely partners, i.e. multiple industry partners, by creating a unique collabo ration structure that protects all needs

of all individual stakeholders. NP & NGOs can align stakeholder groups with like-minded interests in ways to harness the valuable outputs of collabo ration, while simultaneously protecting against far reaching policies such as anti trust policies.

Policies & Procedures – Defining the bright yellow lines

It has been demonstrated that without clear policies and robust procedures to create ‘checks & balances’, all scien tific partnerships, collaborations and alliance run a very high risk of failure. Furthermore, even when the bedrock of such engagements is carefully defined and documented there is often missed opportunity. This is particularly true when different stakeholder groups are working together – e.g. academia and industry, government, and industry, nonprofit and academia.

It is essential that that all research collaborations establish the following policies and procedures to ensure that that all stakeholders are aligned with these key aspects of the collaboration.

• Conflict of Interest Policy

• Confidentiality Policy

• Publication Policy

• Intellectual Property Policy

• Data Sharing Policy

• Anti trust Policy & Guidelines (if one or more of the stakeholders are from industry)

• Grant Award Policy & Guidelines (if awarding funds is part of the collabo ration)

When there is misalignment of one or more if these elements, the entire collabo rative entity is in jeopardy of failure.

The Future of Scientific Collaboration – Broader tangible benefits

During this time of heightened aware ness about the importance of taking steps towards a sustainable future to protect the planet and to protect humanity’s future, we should take stock of the applicability of the principles and factors discussed

here as integral element to fostering partnerships and collaboration in sectors beyond just scientific research. Many of the shortcomings and failures of partner ships and collaborations outside scientific research can be traced to many of the same issued discussed here. This article will hopefully provoke an even deeper consideration of how stakeholders, in general, currently engage with each other, and foster dialogue around whether improved stakeholder alignment could support advancing the environmental, social, and governance (ESG) principles that have become increasingly important to today’s society.

These principles discussed here for the successful formation and execution of scientific collaboration holds the potential to catalyse addressing broader societal challenges, including for example, within just the life sciences sector, protecting human rights in the supply chain, envi ronmental sustainability, improved drug access, and better and more affordable drug pricing. Thinking beyond just the purely research aspects of innovating new medicines, stakeholders will need to consider collaborative new models that agilely tackle the significant and increasingly complex global challenges confronting the world today.

Mayrand-Chung, a PhD-trained Immunologist who also holds a J.D. specialising in intellectual property and negotiations. She held director-level positions within government, industry, non-profit organisations, and academia. Her expertise and passion is in the areas of stakeholder alignment, strategic partnerships and collaborations, regulatory and health policy, scientific engagement, and innovation.

AUTHOR BIO

START WITH Y

A case for better pandemic preparedness

In both an Australian and a global context, there is a pressing need to consider a rebalance and increased investment in preparedness planning for pandemics and other significant national emergencies, rather than the current heavy focus on response and recovery.

While COVID-19 is not yet behind us, there has never been a better time to consider the meaning of national resil ience and to prepare for the next threat.

It’s almost universally agreed—in respect of pandemic preparedness—that there will be a . Monkeypox, while not a pandemic, has been formally proscribed as a public health emergency by the

World Health Organization (WHO). If COVID has been the wake-up call the world needed to shatter its compla cency about a so-called Disease X, then how are we ensuring that we’ll be better prepared for Disease Y?

Working in the defence and national security sector exposes you to a lot of jargon. The military is infamous for its acronyms and often accused of having a language all of its own.

One of those terms that I’ve taken to heart is the idea of system-of-systems challenges. These are wickedly complex scenarios for which a truly comprehen sive view of capability development is needed. The Australian Defence Force describes this with terms like fundamental inputs to capability, a recognition that an enormous range of enablers and other factors must be considered—and are

Leigh Farrell, Lead, Health Security Systems Australia (HSSA)

critical to success to deliver an effect such as pandemic preparedness—in addition to the acquired commercial ‘product’ or equipment solution.

It’s no surprise that these wick edly complex problems such as global pandemics require system-of-systems solutions, but this is where we see cracks starting to appear in relation to resilience and disaster response. While we see inno vative work on elements of those systems, there is too often a lack of situational awareness of one system as it relates to another system. Planning in one system is developed often independently from that in other another system. One exam ple might be assumptions made about the capacity and capability of Defence to contribute to hazard management or humanitarian assistance missions, from the point of view of civilian first responder agencies. Another might be data collected in one system or agency that is not shared (either in time or at all) with other nodes of the system.

In the solutions space, key players across the sector (governments, industry and researchers) need to come together

to create collective early warning systems that take account of multiple inputs— disease surveillance, epidemiological test ing, open source intelligence and industry capability analysis among them—rather than focusing on any one dimension of the solution.

There is also more work needed on the macro health security implica tions and macro-economic cost consid erations of national response planning. Creating pull factors for innovation is one example. Australia is very good at some elements of innovation, but not so much, I would contend, in innova tive policies around agile procurement and policy settings. Where supply chain vulnerabilities are evident, the steps to remedy those are slow and an appetite for transformational ideas is wanting. The potential to implement and fully leverage public-private partnerships, similar to Operation Warp Speed in the US, is yet to be fully explored. Special economic zones are another example of a transformative idea with big potential to drive innovation and build sustainable industry capacity.

Coordination across state and federal jurisdictions and with the industrial sector is occurring and some agility is evident, so to look in the rear vision mirror and say “everything we’ve done before was rubbish” would be simplistic at best. We should acknowledge those elements of the system, the muscle that has been exercised and is building nicely, while also committing to doing better in other areas.

In thinking about the prevention and preparedness elements of the Prevention, Preparation, Response, Recovery (PPRR) risk weighted model, it’s hard not to conclude that more balanced invest ment is needed. Australia’s Productivity Commission has reported that 97 per cent of funding allocated for natural disasters is spent in the response and recovery phases, and only 3 per cent in the preparedness and prevention phases.

In assessing the gaps in PPRR plan ning for particular threats, it is clear that a multi-faceted approach is required to align our PPRR plans with global best practice. Investment also has to be balanced in respect of not putting all of our eggs in one basket. It was already known, but is now even clearer from global experience, that the world could not simply vaccinate our way out of the pandemic. Of course, vaccines and thera peutics are important tools for managing infectious diseases and pandemics but it’s important that we use all the tools at our disposal and develop system-of-systems approaches. This includes considerations like PPE, modelling and simulation, deci sion support tools, medical devices and surveillance.

We are also learning hard lessons about the fallacy of the ‘one bug, one drug’ mindset. Focused attention and priority needs to be given to the devel opment of platform technologies and developing broad-acting, threat-agnostic countermeasures against families of bacte rial and viral pathogens. In seeking to catalyse research and development activi ties, further attention is needed to setting more precise strategic requirements rather

There is a compelling and urgent need to rethink, and rebalance, our approach to preparedness planning for pandemic threats and other man-made or naturally occurring disasters, writes Leigh Farrell.

than more general guidance on areas of interest.

With COVID-19 we saw innovation in the regulatory system where master protocols were adopted for clinical trials, for example, and this allowed a pooling of the data globally, in turn leading to more rapid approval for these vaccines. Anticipatory work on master protocols and streamlined emergency use authori sations is one area where an investment in preparedness and prevention could reap substantial dividends.

We need more sophisticated simula tion, modelling and decision support tools – as well as advanced measurement technologies and access to expertise in foresighting – to understand what we are dealing with, on a domestic and inter national scale. Recovery and response strategies need to be comprehensively stress-tested in both desktop and field exercises involving all relevant respond ing agencies.

As part of its CBR Sensing System Program, the Health Security Systems Australia (HSSA) division of Australia’s DMTC Limited is investing in projects focused on the development of sensing technologies that alert the wearer to chemical and biological threats, allow ing more time for interventions such as medical countermeasures, and supporting rapid operational decision making. We are also working on hazard-prediction models that could provide time-critical information to decision-makers. Fasterthan-real-time urban wind and plume transport models hold the potential to revolutionise atmospheric transport and dispersion modelling and simula tion tools that are used to predict the spread of airborne hazards in urban environments.

In our own backyard, surveys have consistently shown that Australia’s medi cal technology and health innovation system has A-class components but, by comparison, only C-class connectors and wiring. These judgements are useful inputs to discussions about priorities and actions that can be taken to address

gaps in both capacity and capability. Surveys, however, are only limited in their scope and value. They are static snapshots and what is needed, in their place, is a dynamic and evolving picture of the landscape.

Working with stakeholders across the Australian Government, my division is taking important first steps towards this envisioned outcome for Australia by developing a national health security database. With unknown but anticipated threats ahead of us, a database like this will identify health security sector capa bility and supply chain resilience, which will inform both policy development and targeted investment.

To draw on another bit of Defence jargon that I think is most relevant here, the Australian Army often talks about the challenge of being “ready now and future ready”. Lashing these two horizons together is an acknowledgement of a dynamic and constantly evolving threat landscape, and the need for a balanced view when it comes to priority setting, investment decisions and policy frame works. Achieving one of the twin aims at the expense of the other is simply not an option. It requires a culture and decision-making mindset that keeps

pace with change rather than lagging behind it.

Conclusion

Whether for natural disasters or pandem ics, experts agree that there is little time to sit and ‘admire the problem’. The resources and investment needed to tackle these problems are finite, and contested, which focuses attention on selecting the most relevant research and investing in proposed solutions that show the most potential. The capacity for thinking beyond borders is also sorely needed. Horizon scanning is critical to identify and implement best practice, and to stay ahead of the curve.

References are available at www.pharmafocusasia.com

support from a whole-of-government agency group, since 2016. The division’s work extends beyond medical countermeasures to include other areas such as modelling and simulation, and sensing systems.

Leigh Farrell is an experienced senior executive having held senior global roles in the biotech and pharmaceutical industries. He currently Head Health Security Systems Australia (HSSA), a newly-formed division of Australia’s DMTC Limited. HSSA operates within DMTC’s program management structure and focuses on the protection of military and civilian personnel against chemical, biological and radiological threats, and emerging diseases. Its work is built around the success of a Medical Countermeasures program that DMTC has led in Australia, with

AUTHOR BIO

The Personalised Healthcare Revolution is Underway…

What are the implications for the Life Sciences industry?

In 1998, Genentech received regulatory approval for Herceptin, a monoclonal antibody targeting HER2 positive breast cancer, marking the beginning of the modern personalised healthcare revolution. What made Herceptin different? It was the first adjuvant therapy targeted at a subset of a population that was identified using molecular diagnostics to ensure that only patients who could benefit from the treatment would receive the treatment. Today, use of companion diagnostics and targeted therapies is widespread,

and healthcare providers are beginning to leverage molecular residual disease (MRD) diagnostics to adapt and tailor each patient’s treatment in pursuit of curing disease. The personalised healthcare revolution has arrived, and the life sciences industry needs to adapt by accelerating new product introduction and technology transfer for manufacturing facilities, enabling contextualised real-time data capture, and developing integration and operations analysis tools that enable real-time release for GMP products.

FROM

Diagnostics are regulated as a function of statistical repeatability and reproducibility studies.

Treatment protocols are a function of populationbased studies, dependent upon study participant selection using population-based diagnostics.

Treatment efficacy is limited by variations within clinical study populations.

Manufacturers are incentivized to produce large batches based on population-derived demand forecasts.

Therapeutics are centrally produced and distributed globally.

TO

Precision, patient-specific diagnostics are regulated as a function of controlled processes

Treatment protocols are a function of precision diagnostic generated bioinformatics leading to patient-specific courses of treatment.

Treatment efficacy is not limited to confidence intervals that are constrained by variations within the population; treatment that leads to cure is an expectation for all patients.

Manufacturers are incentivized to minimize batch sizes in favor of real-time production.

Manufacturing supply chains are flexible, with localized production capabilities to deliver specific therapeutics as close to real-time as possible.

Christian Berg, Life Sciences Solutions Architect Consultant, Emerson

The Life Sciences Industry is Rapidly Evolving to Cure Disease

Personalised healthcare is characterised by providing a unique, empirically informed treatment regimen for each patient, based on each individual patient’s expressed disease characteristics and how the patient’s disease responds to treatment.

Personalized Healthcare Overview

Patient is grouped with cohort based on traditional diagnostics. Disease profile is isolated using precision molecular bioinformatics to tailor and modify treatment until patient is cured. Treatment is not solely a function of therapeutics; it is a function of patient-specific treatment response as well.

The focus of Emerson Life Sciences is to address digital technology challenges in order to enable the personalised healthcare revolution. These challenges include:

1. Accelerating new product introduction and technology transfer for manufacturing facilities.

2. Driving real-time, end-to-end data capture with query-able context.

3. Enabling real-time release for GMP products.

Streamline New Product Introduction and Tech Transfer

For the life sciences industry, New Product Introduction (NPI) and Tech Transfer (TT) have been characterised by detailed project management involving collection of process definition information, production line configuration, deployment of process definition information into process controls,

Technology Approach Needs to Adapt to Personalized Healthcare Challenges

FROM

Isolated databases

Digital stack of applications

Requests for proposals and supplier-driven deployment

Long lead-time for system implementation and integration

TO

Shared OT data core

Ecosystem of applications

Marketplace purchases and customer-driven deployment

Rapid, modular deployment of new functions

and validating that the facility functions as intended with respect to the product being introduced. This leads to resource-intensive and lengthy initiatives that inhibit delivery of novel, high-quality, life-saving treatments at reasonable cost. NPI and TT have both logical and physical requirements that need to be addressed to accelerate the personalised healthcare revolution.

Key to accelerating NPI and TT is having product and process definition information accessible from a single, shared source that spans the product lifecycle from product development to pilot-scale production to commercial production. Once product and process information has been consolidated into a shared platform, that information can be leveraged to determine facility fit and rapidly cascade the relevant process definition data to a receiving plant. Integrating and accelerating logical changeover is dependent upon receiving facilities having implemented local, parameterised control system configurations that align with equipment models shared between the enterprise process definition system and the plant process control system.

With product and process definitions consolidated, and equipment models aligned, one final NPI and TT challenge to overcome is rapid changeover and implementation of new equipment. We typically refer to this concept as ‘plug-n-play.’ Pragmatically, this requires standardisation of control system hardware components, interchangeable controller configuration packets, and electronic marshalling. In response to these challenges, equipment manufacturers have begun partnering with control system suppliers, like Emerson, in order to make ‘plug-n-play’ a reality for life sciences manufacturing.

As detailed product and process definition data gets consolidated into single-sources-of-truth, and physical manufacturing equipment standardises on ‘plug-n-play’ capable controllers, the time and effort to complete New Product Introduction and Tech Transfer will decrease in support of the needs of personalised healthcare manufacturing.

Move Beyond Electronic Batch Records with an OT Data Core

Electronic batch records (eBR) are widely adopted by the life sciences industry to minimise data entry errors, streamline compilation of production records, and enable review by exception to reduce time and effort required for product release. Manufacturing Execution System (MES) is a core

enabling technology for eBR, and it works in concert with Enterprise Resource Planning (ERP) and Process Control Systems (PCS) to orchestrate production activities, enforce controls, and capture relevant data. These systems have significantly improved operations management activities related to production records. Implementation of eBR is typically dependent upon complex integration of application suites across the digital landscape which leads to data replication, application-specific interfaces, and limited reporting and analysis capabilities.

Smaller batch sizes, more frequent product changeovers, increased traceability requirements, and shorter product lead times are exposing limitations of the traditional MES-based eBR approach. Implementing an Operations Technology (OT) Data Core as the single source of truth for execution data provides a new information management foundation upon which to build the next generation of process control and production records. The OT Data Core must not only meet regulatory data integrity requirements, it must also be able to facilitate platform-agnostic data sharing with query-able context.

The Data Core needs to be able to support many data types and data sources while providing context-driven storage and accessibility. This technology differs from traditional data historians which are typically dependent upon time, sequence (or series), and source identity (or instrument tag) for organisation and retrieval. OT information needs to be readily accessible by many systems and users with simple yet specific data identification to facilitate retrieval and usage.

To make the most of a Data Core, operations management activities need to be orchestrated by functionally specific applications that conform to Data Core context standards so that data can be published and shared across many users and use cases. A key consideration when developing and documenting manufacturing processes will be to understand which data inputs and outputs are shared across many platforms, use cases, or users. This data set represents the beginning definition of scope for the Data Core contents and informs user requirements for the Data Core. The OT Data Core facilitates pursuit of a ‘single-source of truth’ for execution data. Additionally, aligning functional applications to the Data Core enables flexibility and rapid scalability for the manufacturing digital ecosystem.

Reduce Lead Time with Real-Time Product Release

Addressing the final challenge to agile, patientfocused, manufacturing supply chains requires addressing a primary cause of long product leadtime, product release. GMP product release involves thorough evaluation of production records that include evidence of compliance to approved process standards, quality test results, and deviation investigations and responses, to name a few. Many of these elements are addressed by eBR systems that include Review by Exception (RbE) functionality, but there are components that exist outside of traditional eBR implementations that contribute to lead time and effort.

One of the contributors to extended lead times is resolution of process deviations. Realtime identification, investigation, and resolution of process exceptions can readily be implemented for existing eBR systems with RbE through adoption of exception-handling specific functionality that triggers an immediate response from operations managers and quality assurance when exceptions occur. Addressing deviations in real-time requires a technological component that is connected directly to the manufacturing process to identify the need for quality action and record associated investigation and remediation activities. It also requires a behavioral norm within the manufacturing organisation to immediately respond, investigate, and resolve investigations. Having this real-time deviation response functionality embedded into the eBR system can help drive the desired organisational behaviour.

BIO Christian has a passion for driving operational excellence and leveraging digital solutions to enable world class performance. He offers over 24 years of life sciences industry experience in automation, engineering, manufacturing, and process and systems transformation. Just prior to joining Emerson, he was Director of Manufacturing for oncology pilot plant operations at Invitae (formerly ArcherDX) where he implemented operations management standards and initiated digital transformation to enable Personalised Cancer Monitoring (PCM) production. Prior to Invitae, Christian held multiple operations management positions at Johnson & Johnson, Genentech, and Amgen.

Another contributor to extended lead times is off-line product quality testing. Spectral Process Analytical Technology (PAT) is a rapidly evolving solution to evaluating product quality as a function of physical properties that can be measured with in-line instrumentation. When integrated with a control loop, PAT can be used to optimise production performance, enforce product quality, and predict deviation conditions before they occur. Process development teams are actively pursuing means to measure and record product quality attributes in-line, and PAT is a promising option in pursuit of real-time quality control.

With process data being digitally captured, contextualised, and evaluated in real-time, implementing a holistic, real-time product release platform is becoming a greater possibility for more life sciences manufacturing organisation.

Meet the Needs of Personalised Healthcare

The personalised healthcare revolution gives us the tools necessary to end treatable disease caused deaths in our lifetime. In order to enable this exciting new approach, our technological focus needs to shift from viewing specific medical devices or therapeutics as the value object of our processes to viewing each patient’s healing as the ultimate value proposition of an integrated process. To do this, industry needs a more sophisticated digital toolset that addresses real-time contextualised data capture, rapid product and process introduction for manufacturing, and real-time release of GMP products.

AUTHOR

AUTOMATION ACCELERATORS IN DRUG DISCOVERY AND DEVELOPMENT

Digital transformation is paving way for improved efficiency and efficacy in pharmaceutical industry. With changing global business environment and shortage of resource dexterities — automation and digitisation have become key drivers for business growth, sustainability, and competitive differentiation. New technological advancements in quantum mechanics, machine learning and artificial intelligence are showing tremendous success in curtailing screening of compounds, and at same time bringing molecules faster to clinical assessment.

Drug discovery and development chevron illus trates various critical phases of progression to develop any molecule for human use. There is a pertinent desire to improve the cycle time to bring medicines as fast as possible for betterment of human health. Over the years, profound efforts were success fully accomplished in this direction. However, with the advancement of technologies in automation and robotics, there is a plausibility to enable pharmaceutical industry to further increase speed, reliability, preci sion and accuracy. These technologies can strengthen and enhance credibility of organisations to maintain stringent compliance, in conjunction and integrity, with operational brilliance.

Data analytics have been considered as a cornerstone and boon to develop robotics, automation, and artificial tools. With better knowledge and understanding of

Somesh Sharma, Head, Discovery Chemistry group, Aragan

processes and future requirements, the information can be explored to create a differentiated business propositions. Broadly, these tools can create value in disease prediction, diagnosis interpre tation, material supply projections for clinical trials, and improve patients expe rience, healthcare data management and precision robotic surgeries.

COVID-19 has significantly accel erated digital transformation in phar maceutical and healthcare industry. It is able to drive organisation on the path of innovation, dexterity, resilience, adaptabil ity and flexibility to improve production and logistics integration for healthcare business. With inherent cognizance of high research & development cost and extreme failures rates, pharmaceutical companies are focusing on alternative strategies to identify more efficient and accurate innovative paths to bring molecules faster to market.

Digitisation is not a buzz word, it is a perpetual journey towards excel lence, quality, and transparency. For success of digitisation implementa tion, an intuitive framework needs to be constituted with competitive and intelligent business landscape assess ment. It is noteworthy to mention that digitisation and automation always goes in parallel and brings different dimension to discovery and develop ment organisations. To accomplish and establish Pharm 4.0 targets, the digi tal technological elements need to be devised and incorporated for a sustain able& exponential growth.

1. Machine learning (ML) and arti ficial intelligence (AI) tools: Quantum mechanics and AI tools have taken a big leap in driving discovery initiatives and development processes. These instru ments are being used to address various challenging problems in pharmaceutical industry viz automation and optimisation of manufacturing processes, along with designing marketing and post-launch challenges.

ML tools will enable to analyse large amount of data for disease identification and diagnosis. AI technologies can assist

in identifying new chemical space to get novel compounds in shorter time with deep understanding and analysis of struc tural relationships, improve in-vivo analy sis with auto sample collection, report analysis and interpretation through BOT platforms. Convolution neural network platforms can help in predicting drugdrug interactions, an evolving technology in this field. Furthermore, web-based lab accelerator (WLA) tools allow scientists to work remotely for chemistry and biol ogy via robotic control platforms with user friendly interfaces.

2. Data analytics: Advanced analyti cal techniques are giving an edge to convert historical and real-time data accessible with pharma companies to create a knowledge-based repository for prediction, diagnosis, prescription, and safety assurance of participants. Recent progression in OMIC and data analy sis are providing new insights toPKPD interpretations.

3. Automation: It has different facets and applications based on the business requirements.

a. Supply chain: Digitisation has strength ened entire supply chain networking across the globe. It has become more predictable on raw material availability, supplies and cycle time. Integration of diverse vendor databases and their predictability in material supply, is a positive step on digitization of supply chain.

b. Blockchain: It has promising implica tions in supply chain management and healthcare for nurturing transparency, traceability, and minimising commu nication gap across various stakehold ers. It has also been explored to tackle menace of counterfeit and substandard medicines supply.

c. Packaging: Computerised tools play significant role in accurate dispens ing, sorting, labelling and distribution management. Quality control through computer vision becomes more accurate and precise.

d. Distance monitoring: Information tech nological platforms can bring instru ments closer to users and can help in proactive maintenance, real time check, recognise compliance issues, prevent human errors, and transform opera tions cleaner.

e. Robotic process automation (RPA): It streamlines repeated and mundane activities, for instance, recruitment process of patients and healthy volun teers for clinical trials. Improve compli ance with automatic document checks, monitoring and providing a succinct report.

4. Manufacturing: Robots are replac ing standard operations (blending, drying, milling, micronisation etc.) in manu facturing, and bringing operations safer, error free and reliable. There is a paradigm shift in manufacturing environment from batch to flow technologies to control health hazards, ascertain atom economy and manage waste generation. These all efforts are well supported by advance DoE tools to get the best reaction parameters for better conversions, yields and high purity materials.

There are few areas like digitisation of crystallisation needs extensive evaluation for delivering right quality of drug prod ucts. As an example, to achieve consist ent supply, it is important to overcome crystallisation hurdle of drug substances and establish a control process to get correct crystal morphs for therapeu tic use. Process analytical tool (FTIR) and Raman spectroscopy have become powerful tools to monitor and control

With the advancement of technologies in automation and robotics, there is a plausibility to enable pharmaceutical industry to further increase speed, reliability, precision and accuracy.

the solute-solvent interactions with real time spectral data. However, digitisation of crystallisation requires implementa tion of control strategies such as popula tion balance modelling, concentration feedback control, predictive and generic model control. The future of research is to integrate chemistry, mathematical models and crystallography tools.

5. The internet of things (IoT): This platform can be used at various stages of drug discovery and develop ment value chain. At discovery stage, organs-on-microchip technology is getting lot of prevalence for drug safety evaluation. Wearable devices with sensors provide real time health report of individuals for better prognosis of disease. Manufacturing facilities are utilising RFID and sensor technologies for predicting maintenance of machines, capturing work parameters, and building smart warehouses. For patient acces sibility, digestible microchips in pills have already been approved by FDA for drug usage and medication compliance.

6. Robots for precision drug delivery: A fascinating field of micro/nanorobots for targeted drug deliveries to hard-toreach areas is expanding tremendously. These robots can be controlled remotely to perform critical biochemical opera tions with minimum invasion.

7. Extended reality: Mixed real ity (MR), virtual reality (VR), and augmented reality (AR) is transforming organisation to visualise things like never before. For instance, XR reduces human dependencies through guided instruc tions, remote training and delivering critical information on timely basis. It can enable real-time location-agonistic interaction among research teams. In pharma industry, process validation and auditing can be executed with XR integrated platform with IoT data, and AI to ensure compliance in accordance with regulatory standards.

8. Real-world data (RWD) and real-world evidence (RWE): FDA uses RWD and RWE to monitor post market surveillance, appropriate regulatory deci

sions and develop new guidelines for future. The availability of real-world data through computers, mobile devices, wearables and other biosensors enabled by the Internet of Things (IoT), allows restructuring of pharma industry to develop new medical products and accelerate its approval process.

9. Digital therapeutics: Evidence based therapeutic interventions are getting tremendous tractions to prevent, manage, control and treat the behav ioural condition of any individual for better health outcomes. AI abridges the gap among doctors, patients, and hospi tal administrators by executing tasks at minimal cost and in less time.

10. Curative therapies: Cell and gene therapies are bringing a paradigm shift in disease management. Instead of taking a pill throughout the life, genetic approaches (like CRISPR technology) are being evaluated to cure diseases in time limited manner.

The workplace of future will auto mate monotonous tasks and encourage employees to focus on meaningful and complicated scientific challenges. Future labs will use cloud-based applications to enable integration, collaboration across sites, combine IoT, AI and AR to remotely support harmonised lab environment, and empower decisionmaking faster.

Generally, there is an apprehension that investment in automation might eliminate the human workers and replace their tasks with machines. In contrary, automation complements human skills and strengths to provide a competi tive advantage with more engaged and creative work force. Additionally, these advance technological platforms can encourage a conducive environment of nurturing, upskilling, reskilling, multi-skilling of existing talent pool, and help in attracting future talent for organisations.

For successful implementation of Pharm 4.0 technologies, organisations need to have right mindset, aspiration, vision, and agility. The proponents of

these techniques should explore inno vative tools that can stimulate differ entiation and immediate impact, have flexibility and modulatory to meet current and future requirements. Till now, these technologies have shown immense success and benefits on repeat or mundane activities but there is tremendous potential to expand its scope with fully integrated predictive AI modules.

Digital tools from connectivity to data analytics, robotics and automation, will ensure internal process optimisa tion, collaboration, improved employee performance, quality, compliance, and accelerate business agility. It can trans form organisation to lean structure, facilitate a robust cost management institution, foster innovation, and deliver an integrated ecosystem for business inclusiveness, diversity and expansions.

References are available at www.pharmafocusasia.com

Somesh Sharma has more than two decades of rich experience in synthetic and medicinal chemistry to support integrated drug discovery programs from concept to clinical. Currently, he heads Discovery Chemistry group at Aragan, and responsible for business growth, customer engagements & assimilating new technological platforms. Prior to joining Aragen, he has held various leadership roles at Jubilant Biosys, Nicholas Piramal and Ranbaxy Research Laboratories.

AUTHOR BIO

TARGETED MEDICINES USING NANOTECHNOLOGY The future of therapeutics

As oncology drugs continue to be limited by severe side-effects and poor efficacy, resistant chronic neurodegenerative conditions remain an area of therapeutics with a huge unmet clinical need. The future of therapeutics, therefore, lies in being able to deliver therapeutic synthetic molecules intact, protected, and transported in nanoparticles to target diseased organs.

Adedapo Adesokan, Director/Founder, PreciseMed, Glasgow

Traumatic events such as date rape, drowning or death of loved ones in accidents often neces sitate the use of antidepressants for a short treatment course. Unfortunately, many antidepressant use is plagued by antidepressant discontinuation syndrome (ADS). ADS is a common problem in patients following the interruption, dose reduction, or discontinuation of anti depressant drugs. Typical symptoms of antidepressant discontinuation syndrome include extreme insomnia, nausea, gait instability, sensory disturbances, dizzi ness, increased suicidal thoughts and hyperarousal. These symptoms can be disabling, long-lasting, limiting the use of some antidepressants.

To reduce the incidence of ADS, PreciseMed, an R&D pharmaceutical company based in the UK is experi menting with the use of nanotechnologydriven antidepressants in discontinuation syndrome animal models. The aim is to see whether such use alleviates ADS in the animals, and hopes to transfer the tech nology later to humans. From the vari ous classes of antidepressants, we selected choice examples and developed them in

appropriate nanoparticles to encapsu late them on and tested these on ADS animal models to see if nanoparticles as a delivery system, which implies a lesser bioequivalent dose compared to the free form of the drugs, reduces the incidence of ADS.

Among the different classes of anti depressants, SSRIs are the most widely prescribed type of antidepressants. For this study, we used in the study are Fluoxetine, Citalopram and Paroxetine as well as other classes of choice antidepres sants including serotonin-noradrenaline reuptake inhibitors (SNRIs) duloxetine, Noradrenaline and specific serotonergic antidepressants (NASSAs) mirtazapine. Others are Tricyclic antidepressants (TCAs) amitriptyline, serotonin antago nists and reuptake inhibitors (SARIs) trazodone and Monoamine oxidase inhib itors (MAOIs) phenelzine for analysis and ADS effect in an animal model.

Methodology

So far, we have loaded the antidepressants into noisomes (nanoparticles) and the prepared formulations were character ised by size, polydispersity index, surface charge, and drug encapsulation.

In the ongoing ADS study we created six animal groups and five treatment groups. Each treatment group has six mice for each of the eight antidepres sants-free drug forms, their nanoparticlesdriven form were delivered intraperito neally, intranasally and orally. There was a group treated with empty nanoparticles, a group treated with citalopram as posi tive control and the normal saline treated group as negative control. The animals were housed in 21o C on a 12 hours light/dark cycle in open-top cages for one week prior to commencement of treat ment to condition them to be depressed. Treatment was daily for 28 days and the discontinuation period where the five groups excluding the negative control group were administered with normal saline only was for three days. Anxiety was chosen as the focus discontinuation syndrome symptom for this study. The primary endpoint is to observe if there is

increased Anxiety in elevated pulse maze (EPM), open field test and tail suspen sion test following discontinuation of treatments and to see if its occurrence is worse in the comparator arm compared to treatment arms. Should this be the case, it would call for the clinical trial of nanoparticles-driven antidepressants in depressed patients in the future to see if loading such drugs in choice nano particles alleviate the disabling discon tinuation syndrome symptoms patients experience in real life.

The future of therapeutics

For CNS drugs, COVID-19 brought to prominence its peculiar symptoms such as anosmia and ageusia (loss of smell and taste). This potentially will lead to the exploiting the olfactory bulb and trigeminal nerve route to deliver the next generation drugs for treating chronic neurodegenerative diseases, neuropsy chiatry and incurable brain tumours. CNS drugs continue to be plagued by poor absorption as less than 5 per cent

bioavailability is where most CNS drugs stand at present. This is due to presence of tight junctions, the worrisome ABC drug transporters such as ABCB1(P-gp) and ABCG2 (BCRP) in the Blood-Brain Barrier (BBB) limiting CNS drugs uptake among other factors. Therefore, CNS chronic diseases therapeutics is largely an unmet clinical need space requiring novel approaches and medicines.

In line with this, our R&D company with collaborators have in the pipeline novel polymeric and nanoparticles-loaded actives as lead candidate next generation experimental therapies for Alzheimer dementia( AFXI-02), Parkinson’s disease (AFXI-03), incurable brain tumours like Gliomas, Medulloblastomas (AFXI-04, AFXI-05), depression and anxiety (AFXI06), developed largely as nose-to-brain formulation in “protected cargoes” to circumvent poor BBB absorption problems, ensure better tolerability and compliance for patients suffering from these chronic conditions.

Conclusion

UK over the last 6 years. He bagged his PhD training in Medicine and Therapeutics from Glasgow and Strathclyde University. Adedapo leads all preclinical drug development projects and clinical trial protocols for the repurposed and novel pharmaceutical agents Precisemed develops. He has vast research experience (>10 Publications, >5 Conference Abstracts, >7 oral/invited conference Presentations). Adesokan leads an Independent research group applying nano and microfabrication techniques in pharmaceutical drug delivery systems manufacturing for repurposed or novel synthetic medicines delivered in novel delivery systems in form of targeted therapeutics.

Developing excellent new medicines is not going to be enough in the future for optimal patient care. The use of nanoparticles and micro-needles will dominate the therapeutic discovery scene in the next 10-20 years follow ing the emergence of nanoparticlesdriven covid mRNA vaccines. The next-generation blockbuster drugs would have to be designed to be carried and protected in cargoes (nanoparti cles) intact to choice diseased targeted organs as the new standard in the future once we get more used to developing and using the targeted approach tech nologies. This would not only ensure improved efficacy, minimise off-target accumulation hence reducing toxicity, but also improve the safety profile of the next-generation blockbuster medi cines in addition to improving patient compliance. The mantra in the future of therapeutics is expected to be “deliv ering the right medicine to only the right organ in the right vehicle with the right precision”.

AUTHOR BIO

Adedapo Adesokan (MD/PhD) (Founder/ Director and Lead Scientist, PreciseMed): Dr Adesokan has worked in several NHS trusts across the

GeneTherapy

An emerging therapeutic approach

Gene therapies are promising treatment options for diseases that are considered untreatable. These therapies are designed by either of three methods, gene silencing, gene replacement, and gene editing to achieve the final therapy outcome. Although there are various methods to transfer the therapeutic gene into the target cells, viral vectors such as adeno-associated viruses (AAVs) seem to be the most preferred ones.

2

Gene therapy is a powerful therapeutic approach which relies on the modification or over-expression or suppression of gene expression. The conventional therapeutic approaches like use of small molecule inhibitors and biologics can't provide mitigation of genetic anomalies. Inherited genetic disorders involving mutation or deletion of genes may lead to defective metabolism, cell cycle, receptor-ligand interactions, protein synthesis and others. Hence, the unmet medical need in the area of genetic abnormalities is fulfilled by gene therapy. The past decade has seen great interest in the area of gene therapy with the approval of gene therapy based medicine Onpattro in 2018. In this edito rial we provide an overview of the widely used methods for gene transfer, challenges in gene therapy and the applications of gene therapy in medicine.

Methods of Gene Transfer

Gene therapy relies on the process of transferring engineered genes to the targeted cells. Gene transfer is a process that aims to induce the synthesis of desired protein by inserting copies of manipulated genes into the living cells. Various methods are employed to transfer the genes into the target cells, which can be listed as physical methods, chemical methods, and biological methods. Several factors influence the choice of employing one of these methods for gene transfer, which include ease of use, efficiency, cost, reproducibility, toxicity, and mechanism of delivery. Figure 1 summarises the commonly used methods of gene transfer.

Physical methods help genes to enter the cell by exerting physical force on the cell membrane, thereby increasing the permeability of the cell. This method carries a risk of injury to cells due to

the sheer physical force applied to it. Physical gene transfer methods include electroporation, biolistic, microinjection, laser, elevated temperature, ultrasound, and hydrodynamic applications.

Chemical methods help the genetic material to enter the cell by forming complexes. The chemical agents used in this method include calcium phosphate and diethylaminoethyl (DEAE)-dextran. These chemical compounds are mixed with DNA to form fine co-precipitates (complexes) which enter the cell through phagocytosis. Although this method is comparatively inexpensive, low trans fection efficiency is considered a major disadvantage.

Biological methods used for gene transfer employ either viral transfec tion vector carriers or non-viral trans fection vector carriers. Viral vectors can be adeno-associated viruses or lentivirus, whereas non-viral vectors include lipo plex and polyplex. Adenoviruses and lentivirus work differently, for instance, adenoviruses do not integrate within the host cell genome and have an episomal expression, whereas lentiviruses integrate inside the host genome which results in the formation of a stable and permanent expression of the gene and its products.

Sravan Kumar Pasumarthi1, Amit Khurana2*, Ralf Weiskirchen2*

1 The Business Research Company (TBRC ), India

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital

Although biological methods are highly effective there remain noticeable limita tions such as large-scale virus production, immunogenicity, toxicity, and insertion of mutagenesis (in the case of integrat ing viruses).

In addition to the three methods discussed, there are novel delivery systems for gene transfer, which include cationic lipid-mediated transfection, liposomes, polymers, virus-like particles, erythrocyte ghost, exosomes, and other nanoparti cles. Although some of these methods are considered better compared to the chemi cal methods in terms of efficiency, they cannot replace viral vectors. For instance, the transfection systems based on cationic lipid molecules are simple to synthesise and reliable but show disadvantages such as heterogeneity and structural instabil ity, toxicity, and inactivation in blood with a lack of targeted delivery. Similarly, liposomes are also better than chemical methods but are not relatively efficacious as viral vectors.

Barriers to Gene Delivery

Major barriers to gene delivery include barriers to ease of formulation and largescale production of vectors coupled with the stability and storage of these products. In addition to these, there are three main barriers such as degradation of free plasmid DNA in the circulation, targeted delivery and intracellular traf ficking, and efficient processing of gene delivery systems within the cell.

Free plasmid DNA is vulnerable to degradation within the circulation, cationic lips such as DOTAP (1,2-dioleoyl-3-trimethylammonium propane) and DOPE (dio-leoylphosphatidyle thanolamine) are employed to prevent DNA degradation. These cationic lips are used to encapsulate the plasmid and protect it from the enzymatic environ ment outside the cell.

Once the plasmid DNAs are protected from the circulatory environ ment, the next phase is to protect them from the extracellular matrix surrounding

the cell, as this environment limits the direct delivery of macromolecules inside the target cell. One of the main barriers to successful gene delivery is the release of DNA from the endo some before its degradation at the lysosomal level. Employing liposomes, cationic polymers polyethylenimine (PEI), and fusogenic lipids (such as DOPE, and cholesterol) are helpful for endosomal escape. For instance, Lipoplexes are employed to help the DNA escape from endosome through the fusion of liposome with the endo somal membrane.

Although the DNA is protected from circulation and extracellular matrix, there remains a challenge to transferring the genes from exog enous genetic material from the cell membrane to the nucleus. Most of the methods for enhancing nuclear import include exploitation of the cellular protein nuclear import machinery.

Figure 1: Methods of gene transfer. Different methods of gene transfer can be grouped into physical, chemical and biological methods. The figure is reproduced with permission from N. Sayed, P. Allawadhi, A. Khurana, V. Singh, U. Navik,

(2022) 120375

S.K. Pasumarthi, I. Khurana, A.K. Banothu, R. Weiskirchen, K.K. Bharani, Gene therapy: Comprehensive overview and therapeutic applications, Life sciences

Applications of Gene Therapy

Gene therapies have the potential to treat many disease conditions such as cancer, cardiovascular disorders, infec tious disease, and inherited disorders, among others. The success factors for gene therapy can be two-fold, being less prone to face problems of resistance, and being a permanent substitute for patients born with genetic disorders. Gene therapy has some serious side effects such as undesirable changes in the host body due to the risk of viral mutagenesis (when retrovirus and adenovirus are used as vectors).

Gene therapies are in clinical trials for various cancers such as lung cancer, prostate cancer, and melanoma. Currently, recombinant cancer vaccines are generated by using gene therapy. In this process, patients’ cancer cells (autologous) or already available cancer cell lines (allogenic) are harvested and allowed to grow in-vitro. Thereafter, the cells are modified by inserting one or more genes, which are mostly cytokine genes. These modified cells are further grown in-vitro, killed, and the released cellular components are assembled into a vaccine. There is a good clinical trial response using vaccine therapy for lung and prostate cancer. For instance, the GVAX vaccine reduces the time of progression of these diseases and also the tumor doubling time. Owing to the recent advance ments in gene therapy this may become a major therapy area for treating cancer in the coming future.

In addition to cancer, gene therapies are effective in treating heart illnesses. Sickness correction can be achieved by infusing a normal copy of a gene in place of a defective one to achieve disease correction. Viral vectors such as AAVs are considered safe as they do not cause any disease in human beings. Infectious diseases that are not controlled by traditional clinical methods are targets for gene therapies. The gene therapies should be designed to inhibit or express the action of the target genes or gene products which can

aid in the treatment. Neurodegenerative patients can achieve therapeutic benefits from gene therapies which can help in neurorestorative, neuroprotection, direct correction of pathogenic mechanism and symptom control. These applications for gene therapy are not exhaustive as the research for genes as therapeutic agents is being continued for many other conditions such as metabolic diseases.

Summary

Extensive research to develop novel gene therapies is in progress. The demand for such therapeutics is very high, due to their unique therapeutic benefit of healing the disease permanently from

the genetic level. However, challenges such as difficulty in production scaleup, and the need for high transfection efficiency with low toxicity need to be addressed to produce safe gene deliv ery systems. Clinical research for gene therapies for various disorders shows the promise that gene therapies can hold in the future as the understanding of critical aspects of fundamental molecu lar physiology and pathology are being advanced. Improvements made in gene therapy strategies will pave the way for the treatment of genetic maladies in the near future.

References are available at www.pharmafocusasia.com

Sravan Kumar is Lead Consultant in healthcare market research domain at The Business Research Company, India. He has more than 8 years of market research experience working in healthcare sector with notable experience in gene therapies, cell therapies, and vaccines. Sravan holds a master’s degree in Pharmaceutical Chemistry from the National Institute of Pharmaceutical Education and Research (NIPER), Mohali.

Ralf Weiskirchen was born in 1964 Bergisch Gladbach, North Rhine Westphalia (Germany). After his school education, he studied Biology and made his PhD at the University of Cologne (Germany). Thereafter, he worked as a Research Associate in the Institute of Biochemistry at the University of Innsbruck (Austria). Back in Germany he habilitated at the RWTH University Hospital Aachen and became a Professor assignment in 2007. Now he is the head of the Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC) in Aachen.

Amit Khurana is currently working as a DAAD-PRIME Fellow at the Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry at the RWTH University Hospital Aachen, Aachen, Germany. His research interests include exploring novel therapeutics for gastroenterological disorders, applications of advanced drug delivery carriers for emerging health problems. He has authored more than fifty research and review publications in reputed international journals, has contributed to more than 10 book chapters and has edited a book. He is recipient of multiple prestigious fellowships and awards like the EASL-Basic Science School Fellowship (2022), DAAD-PRIME Fellowship (2020), DSTDAAD Doctoral Fellowship (2017-19), DBT-CNPq Indo-Brazil Fellowship (2016-19), PC Dandiya Young Scientist Award of the Indian Pharmacological Society (2019), International Travel Award from ICMR (2016) and Merit Award from the Delhi Pharmacy Council (2009).

FUTURE OF OPEX IN PHARMA

What is the future of OPEX in Pharma? We look back at our series of publications in Pharma Focus Asia and provide an overview of how OPEX evolved in the industry during the past decades. Moreover, we suggest four propositions of future pathways of OPEX in Pharma.

In our previous articles we addressed several approaches and concepts which we either identified or devel oped to contribute to the advancement of the pharmaceutical industry. Thereby, we always used a combination of a research and practice driven perspective high lighting some key findings and patterns, which we have seen over the years. First, in our article The Link between Plant Performance & Maturity – Seeing the whole picture, we draw the attention to the fact that true performance cannot be measured with isolated metrics. Thus, we exposed the importance of jointly analysing performance together with the maturity of pharmaceutical manufacturing facilities. We further argue that on the one hand performance needs to be interpreted as an outcome measure related to effective ness and efficiency but on the other hand maturity needs to be considered to build capabilities that lead to achieving higher effectiveness and efficiency. In our second article, St.Gallen OPEX Benchmarking

for Pharmaceutical Manufacturing SitesMeasure yourself against the best but do it right, we further presented the St.Gallen OPEX Benchmarking as a solution to holistically assess a site’s performance. Since 2003, we provide insights to phar maceutical companies by locating them in their competitive landscape and allowing for meaningful comparison. Drawing on the world’s second largest pharmaceutical OPEX-databases with more than 400 sites, we help to identify areas of improvement and further contribute to enhance the pharmaceutical industry. In our third arti cle Benchmarking Pharmaceutical Quality Control Labs – Holistic assessment of Operational Excellence in Pharmaceutical Companies, we indicated that through the years more and more pharmaceuti cal companies have managed to extend OPEX and Lean-thinking beyond manu facturing. Nevertheless, we have identified that many pharmaceutical companies are still lagging behind when incorporating an end-to-end perspective. Especially

the critical position of Quality Control (QC) labs in the pharmaceutical value chain is often times still underestimated.

To address this gap, we developed the St.Gallen QC Lab Benchmarking, which takes into consideration the specifics of QC labs. With more than 130 pharma ceutical QC labs included in the St.Gallen QC Lab Benchmarking database, we apply a holistic perspective of performance and maturity to assess Productivity, Quality, Service and Cost as well as Enablers.

In our last article, Learn from your Metrics – Using Operational Data to Improve Operations in Pharmaceutical Manufacturing and QC Labs, we showed how St.Gallen’s holistic approach on meas uring performance allows companies to strategically define improvement initia tives that lead to stable and long-lasting enhancement of a company’s performance. Thus, we gave two distinct examples of improvement initiatives which were derived from St.Gallen benchmarking data. In this concluding article, we will

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

take a look at the history of OPEX in the pharmaceutical industry and present our interpretation of the future.

Evolution of operational excellence programmes in pharma Compared to other industries the pharmaceutical industry was a laggard in adapting an OPEX philosophy and striving for continuous improvement. OPEX developed in three major phases (see Figure 1). As of the late 1990s, there were no structured and carefully designed approaches for improving manufacturing processes during the pre-OPEX phase. Moreover, the industry was characterised by a culture of "no change”. During the second phase, OPEX gained momen tum and became a priority of Top Management and workforce (Friedli & Werani, 2013). This trend was not only a result of increased pressure on drug prices or the often-cited productivity crisis in pharmaceutical research & development, but was also mainly driven by regulators. Thus, it was the U.S. Food and Drug Administration (FDA) in 2002, which announced the pharmaceutical current good manufacturing practice (cGMP) for the 21st Century initiative. The FDA encouraged the pharmaceutical industry to adopt modern and innovative manu facturing technologies to improve quality, performance, and patient security (FDA, 2004). Thereby lean thinking and OPEX was not only considered a suitable instru ment to improve operations but also to

meet regulatory expectations (Friedli & Bellm, 2013). However, during that phase, the whole industry tried to copy successful practices from Volkswagen, BMW, Daimler and co with moderate success. Many companies initiated Six Sigma programmes and built extensive problem-solving capabilities, resulting in a wave of belt certifications. Yet, after certifications continued lasting improve ments remained limited. By trying to transfer OPEX practices to pharma ceutical production by just copying training programmes wasn't enough to get employee buy-in. That is why the focus on people and change manage ment constitute the third phase, the trans formation phase. Most pharmaceutical companies appear to be in this phase, as they have overcome initial beliefs that success could arise from copying training plans, methods and tools. For most of the companies we work with, their OPEX programmes have now a significant focus on soft skills and more human related practices (e.g., empowerment of workers, teamwork, management involvement, coaching). In one example, the company moved away from all the different tech nical tools but focused on the basics of standardisation, problem-solving, and coaching, all aiming at encouraging employees to continuously improve.

As we move forward, the "Integrated Operating System" phase is beginning to emerge. In this phase preventive and reactive OPEX will arise on the one hand

and on the other hand, all improvement initiatives will be aligned at the topmanagement level (Friedli & Werani, 2013). Few examples show early advance ments of OPEX programmes starting from the very top and comprising more than “just” production. (Figure 1)

Future pathways of operational excellence in pharma

To predict the “future” of operational excellence in Pharma, we suggest several propositions by looking at the past and how OPEX programmes evolved through out the industry. Our research projects and exchange groups give us nourish ground to see what will (or might) happen.

From static implementation to dynamic development – Moving beyond “just having one” As we outlined above, OPEX programmes in pharma did not just come about over night as they are. Over the years, their inherited nature has changed. This is not only true for the industry in general but also for specific companies. Take for example Toyota, the pioneer of lean. Its Toyota Production System was a result from years and decades of experiment ing and learning (Holweg, 2007). By acknowledging the dynamics of OPEX programmes, companies will understand that they are not “done” with the sole implementation of certain practices. That is, OPEX programmes are not binary –having one or not having one. Instead, companies need to look after them if they are still on track and check how the execution is going, over and over again (Liker, 2017). Hence, today’s OPEX programmes will most likely not be the same in the future. Yet, how much they differ remains an open question. The following propositions might, to some degree, impact the evolution of them.

From quality metrics to quality management maturity – Quality integration

FDA’s Quality Metrics initiative with its draft guidance (FDA, 2015) and revised draft guidance (FDA, 2016) has recently

Figure 1: Four phases of OPEX in Pharma (Gronauer et al., 2010)

gained new traction. A public docket open for feedback form industry and other stakeholders provides insights into the agency’s current thinking on report ing metrics to improve quality oversight (FDA, 2022). It moves away from solely asking for three metrics to suggest four broader reporting categories. In addi tion, the Office of Pharmaceutical Quality (OPQ) published a white paper on qual ity management maturity (OPQ, 2022). The agency perceives quality management maturity as “the state attained by having consistent, reliable, and robust business processes to achieve quality objectives and robust business and promote continual improvement.” (OPQ, 2022, p. 3) As regulators’ thinking goes far beyond sole compliance but aiming for a state in which improvements are the norm and not exception, OPEX is not the opponent but driver of it. That is, OPEX programmes and quality management systems that have in the past been viewed separately – are two sides of the same coin. The future should, and will, show more integration and alignment of both. Trends in deviations posing new improve ment projects, taking every single event as an opportunity for improvement instead of just closing it, aiming for excellence in quality control and assurance, are just a few examples.

From digital-driven to digital enhancing –Digitalisation integration

Another strong trend which we acknowl edge through the years when exchanging with the industry is an ongoing and nota ble rising interest in the field of digitalisa tion. Pharmaceutical companies have long since recognised the opportunities of digi talisation to enhance OPEX initiatives. Human error reduction, quicker decision making, fast and transparent information cascades, ownership reinforcement and clear boundaries are expected benefits just to mention a few expectations. We see that more and more pharmaceutical companies have understood the concepts of Lean and OPEX and thereby consist ently agree that digitalisation will neither

replace human decision making nor the people at the shopfloor. Additionally, we cannot see that there will be companies that intentionally try to digitise waste and bad processes just for the sake of digitalisation. However, a potential threat is still given as more and more compa nies currently develop their digitalisation roadmaps and heavily invest in the field. The central question here is and will be how to align digitalisation efforts and OPEX and how do companies have to organise for change to integrate digital with OPEX.

From site focus to across network coordination –Network perspective

For many years, OPEX programmes, their tools and improvements projects, have been perceived as a shopfloor-only topic. While it is arguably its origin, companies have moved beyond the shopfloor level up the organisational ladder. Several concepts are now applied to higher management levels and vertical integration increases. This in turn leads to OPEX programmes being more than just a toolbox which is adopted and adapted by sites. Instead, especially corporate OPEX teams are almost like network managers. They need to develop and align site individual roadmaps, monitor and track sites’ progress of implementation and decide on the right levers to pull as

sites have different circumstances and goals. Thereby, sites might even take different roles such as “teaching sites” for the deployment of OPEX programmes.

Summary and outlook

In this article, we summarised our series of publications in Pharma Focus Asia. OPEX, as a philosophy directing an organisation towards continuous improvement, should start with trans parency and understanding its current situation (Friedli & Bellm, 2013). Only with that, the right conclusions can be derived and decisions are not based on gut feelings anymore. Thus, benchmarking is an essential part of OPEX. Moreover, we outline several (not exhaustive) future pathways of OPEX in Pharma. The common notion of it is a broader and more integrated understanding of OPEX. The era of a cost-cutting-only, meant for shopfloor-only understanding is over. Many companies have taken the right path and successfully embarked on their OPEX journey. Other have or will fail eventually.

Our future research activities will verify (or invalidate) our propositions and also provide new ones – striving for advancing state-of-the-art operational excellence in Pharma.

Literature is available online at www.pharmafocusasia.com

AUTHOR BIO

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

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

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

Enabling Digital and Decentralised Solutions in Clinical Research Writing decentralised clinical trials into the protocol!

In recent years clinical research trial designs have gradually started to change from fully paper and brickand-mortar sites (traditional trials) to digital-enabled designs utilizing decentralized solutions, which allow participant visits to be conducted remotely, rather than designated brick-and-mortar sites. In this article, we will spend time on the importance of embedding digital and decentralized solutions during early trial development.

during the trial — enabled to make better decisions to the benefit of the participants. In addition, the data helped successfully identify strategies that significantly improve efficiency in future clinical trials.

In parallel with EDC, the clinical outcome assessments (COA) followed the same path of digital enablement, moving from paper COA to an elec tronic version (eCOA), whether it be electronic patient-reported outcomes (ePROs) or electronic clinician-reported outcomes (eClinROs).

In recent years, clinical research trial designs have started to change from fully paper and brick & mortar sites (traditional trials) to digital-enabled designs utilising decentralised solu tions, which allow participant visits to be conducted remotely with some visits on site (hybrid design) or all visit decentralised from designated brickand-mortar sites (fully remote/ virtual design).

Moving from paper case report forms (CRF) to electronic data capture (EDC) was possibly the first gigantic technology leap and the first true test of the industry’s ability to adapt and change. Data management departments across pharmaceutical companies and clinical research organisations (CRO) strengthened their core capabilities to align with the shift to EDC and the increased volume of data being captured,

collected, and curated. With the move to EDC, the clinical research associate (CRA) profile started to change from previously verifying all data on-site to reduced source data verification (SDV) with increasingly remote capabilities.

Sponsors, investigators, and study teams were — by collect ing and trending real-time data

Wearables have been the new kids on the block pre-pandemic both as part of standard of care, as well as in clinical research. That’s been driven by innovative approaches to manage and monitor diseases both on-site and in the tranquility of the participant’s own home — 24/7, if needed. With technology evolving rapidly these tech nological advances make endpoint data

Kamilla Posselt, Senior Director, Decentralised Clinical Trials Strategy, PPD Clinical Research Business, Thermo Fisher Scientific

collection in research much easier while reducing the participant’s discomfort of long on-site trial visits and travel time.

Clinical research technology plat forms have also emerged, providing participant-facing apps and websites where you can build in or interface with some or all the previously mentioned solutions, as well as expanding to other research-related activities such as virtual training, electronic informed consent form (eICF), participant recruitment, engagement, visit reminders and concierges, etc. Implementing these platforms, the individual participant is given an even more active role in their own research journey, as they are responsible to enter their own subjec tive data directly into the designated technology platforms. As with weara bles, the technology platforms enable study staff (both clinical site staff and research study teams) to access data in real time and monitor the well-being of the participant remotely.

The recent pandemic served as a significant catalyst to enable even more research tasks to fit in to a digital or decentralised solution. These activi ties likely would have progressed to a digital and decentralised layout over time as technology, legislation and industry acceptance underpin the change. Among these tasks, consenting to participate in clinical research was included in the “e-club” (e.g., eConsent/ eSignature, eCOA, etc.) across most countries. Adoption of televisits was equally promoted and implemented to overcome the logistics of missing visits during lockdowns in addition to supplementing with in-home or mobile visits performed by health care providers (HCP). Both consenting and televisits are a prolongation of standard of care innovations, as many countries already had implemented solutions and path ways for academic sites and general prac titioners to utilise these elements, and many countries already were engaging with HCPs in primary care, extending their patient treatment to take place at in-home settings.

Adoption of decentralised clinical trials (DCTs)

The PPD clinical research business of Thermo Fisher Scientific conducted a survey in 2021 among companies that outsource clinical research services or operations to CROs . The objectives of the study were to gain current insights into trends in the clinical trials market, including the changes in trials, partici pants and data driven by the impacts of the continuing COVID-19 pandemic. The data also covers the expansion of adoption of decentralised clinical trials (DCTs) during the pandemic and the likelihood of continuing to use those trial models going forward; the impor tance of different technologies, tools, and solutions; and ways that the efficiency and integrity of DCTs can be improved.

The research study was global in scope (n=100), with all respondents working in pharma/ biopharma with respond ents working in North America, Europe and Asia-Pacific. Nearly two-thirds of respondents (63 per cent) reported currently using digital and DCT options for their clinical research.

As the pandemic has slowed, we have seen most pharma companies do not anticipate reverting back to traditional methods of clinical research or scaling back on innovation. This assumption was further supported by the respondents revealing that they had seen a clear shift from pre-pandemic adoption levels of clinical trials sponsored by their organi sations. During the portion of the year studied in 2021, only 46 per cent were traditional, on-site trials, while 39 per cent were hybrid or digitally enabled and 15 per cent were fully decentralised/ virtual trials, a shift further enhanced when discussing trials planned for later in 2021 or 2022 (41 per cent, 42 per cent, 17 per cent, respectively).

The majority (58 per cent) believe they will continue using these new research models rather than revert to traditional models, and similar responses were given to a question about the future of specific trials in which hybrid or DCT strategies were implemented. The survey

participants selected “replacing paper clinical outcome assessments with digi tal ones” and “remote site visits/moni toring” as both the top DCT strategies they had implemented and as the most important of the offered strategies. The participants also ranked the importance of a range of attributes of DCT solutions and ways to improve or change those solutions and shared feedback they have received from sites, clinicians, and study participants. More than three quarters (78 per cent) reported feeling that DCTs produce data of the same (or higher) quality than traditional trials and a will ingness to be a first adopter for a new feature, product or platform introduced to support their trials.

Embedding digital and decentralised solutions in trial designs

A clinical research trial runs through defined sequential steps; starting with the development of the trial design and protocol followed by vendor selection and startup that includes trial design and tech nology setup and submissions. Approvals mark the end of submissions with the next steps being enrolment/recruitment, study maintenance and participant reten tion, through to database lock (DBL), statistical analysis and completing the clinical study report (CSR) and trial master file (TMF) closure. These steps may overlap each other, in addition to having multiple iterations These steps are the same regardless of trial phase and the curriculum of assessments you wish to add to the trial’s schedule of assessments/ events (SoA/SoE). The SoA/SoE can be refined and adjusted, adding, or remov ing assessments as necessary if the trial design answers the research questions.

The clinical trial begins with the end in mind. This means that the whole process is designed keeping the deliver able in view and documented in the trial protocol. As a clinical trial is designed to answer the research question, the vari ous trial functions partaking in the trial have their unique sub-processes in place designed to complete their functional

deliverables/scope of work with focus on participant safety, quality, timeline, resources, and cost. For example, the data management process is designed to deliver an error-free, valid, and statistically sound database. To meet this objective, they start their process early, even before the finalisation of the protocol.

Most errors in clinical trials are a result of poor planning. Statistical meth ods cannot rescue design flaws. Thus, careful planning with clear risk assessment and prudence is crucial. Issues in trial conduct and analysis should be antici pated during trial design and thought fully addressed.

When opting for a dynamic clinical trial design, implementing digital and decentralised solutions, layers of complex ity are being added throughout the trial steps that needs additional consideration, especially during the design phase, to ensure strong planning and successful implementation.

There is a misconception that it’s easy to add on any DCT component(s) post protocol development. Retrofitting DCT solutions was a necessity during the pandemic as there was no other choice to keep participants enrolled in clini cal trials. Now, it’s time for change. We should be incorporating flexibility for the use of DCT solutions at the design stage.

When you add digital and decentral ised components to your trial design, but still utilise the same approach to develop the protocol, setup and manage the trial, it can be compared to buying an electric bike, but still choosing to pedal uphill without using the bike’s motor to assist your peddling for a smoother, faster, and easier ride.

Bringing it together by design

With our survey results in mind, there is a clear appetite to continue evolving clinical research with implementation of digital and decentralised solutions. We are still in the early days, meaning that there is still a fair amount of learnings, change management required and limita tions originating from individual country regulations, as well as the capabilities of

the individual digital and decentralised providers.

Our survey metrics also identified that the vast majority of pharma compa nies (96 per cent) outsource operations or full clinical research to CROs. Most CROs have been first movers within the DCT space, understanding the necessity to engage with trial sponsors when imple menting DCT by connecting technology or decentralised service providers to the overarching trial management plan and timelines.

Engaging CROs during the proto col development phase — using their full-service know-how, from clinical, safety, DCT and data delivery — can bridge the gap between the end-to-end study delivery, weaving in all the trial elements, including digital and decen tralised solutions, and mapping out the full extended participant and data journey instead of having a piecemeal trial design layered on post-protocol development. Another benefit is having multiple services managed centrally. Without that central management and understanding of the various require ments of each digital and decentralised solution it can be difficult to build one encompassing trial management plan and timeline outlining all key deliverables, handoffs, predecessors, and successors between all trial services in scope. The risk then becomes the research questions not being answered appropriately.

Digital and decentralised considerations

There is a misconception that adding digital and decentralised solutions to a study is like adding EDC. To the contrary, there are many differences, with three key differentiators being: 1) EDC is not (yet) participant facing, making EDC a somewhat easier technology to imple ment, as it does not require translations per research country involved in the trial; 2) the EDC and the completion guide lines do not need (in most countries) to be added in the submission package/ or added in local language; and 3) authori ties approve of the EDC approach.

Furthermore, the EDC model has been well tested over the years with sites and study teams well trained and famil iar with the data capture and collection process, with dedicated data management, programmers, and statistician teams to configure the database and curate the data. Additionally, there are few EDC providers that share most of the market, meaning that both the industry as well as clinical research sites are well versed in their EDC layout, usage, and capabili ties thus making it easier to deploy on trials in terms of timelines, resources, compliance, and training as processes are well-known and predefined.

We have established that all partici pant-facing solutions need to be trans lated, addressed in the ICF and submit ted to the IRB/EC for its approval. What needs to be factored in when deploying a digital participant-facing platform/ app/website that may contain eCon sent, eCOA, connectivity to a wearable, visit notifications, televisits, IMP eDiary compliance and/or in-home visit eSource data is that they add substantial changes to and prolong the trial startup timelines. That is yet another reason to build in digital and decentralised strategies from the onset, because it allows you to map out what solutions are needed, allowed per country and how it is integrated with the other trial functions to ensure a seamless and early start of the trial setup.

Building a U.S. English digital partic ipant-facing platform (app/website) takes

Wearables have been the new kids on the block prepandemic both as part of standard of care, as well as in clinical research.

between six and 12 weeks depending on complexity from specification build, through user acceptance testing (UAT) to provision of final screenshots to IRB/ EC submission and approval. This time line does not include the Google Play (Android)/Apple App Store (iOS) submis sion and release duration, which can take an additional two to four weeks. If your trial has multiple countries/languages, additional time needs to be allocated to cover translation of the U.S. final version, IRB/EC submission and approval, and the extra timeline for the Google/Apple app stores. These translations impact the submissions packages as the latter need to be coordinated to include all participantfacing material.

In parallel with the digital platform (site facing platform/eSource, participantfacing app/website) being configured (with input from data management and statistician, medical, HCP and clinical trial management) work needs to be done in terms of understanding the data integrations and entries, assessing how the data obtained by site, HCP and participant will be captured, collected, curated and eventually what data is being transferred to the EDC, frequency, data cleaning and querying process.

There are many different DCT design variations and providers to select from, which requires a thorough discussion with experts within full-service trial delivery during the synopsis phase before locking in the trial budget and protocol. This ensures you plan the right SoA/SoE and assess both the participant, site and data journey as well as the participant, site and study team burden.

The following is not an exhaustive list, but offers some key digital and decen tralised considerations during protocol development to assess whether hybrid or fully virtual trial designs are feasible.

• Endpoints/trial assessments: Identify if any of the assessments are compat ible with a hybrid/fully remote model.

• Participant profile: Have a high-level understanding of their challenges and limitations that they go through in their life with the current or chronic

disease that they may have and identify if hybrid/fully remote is feasible for the participant.

• IMP: Assess if IMP is safe and stable to be shipped, stored, and adminis tered in a home setting and if it can be self-administered or needs to be administered by an HCP.

• Recruitment: Understanding the recruitment funnel is key, espe cially as we become more virtual. Understanding where the participants are going to come from and the typical catchment area for an individual site. Are recruitment engines and materials needed? Identify advocacy groups you may need to engage with to develop the best study design that supports the research question. Consider if the full remote trial design facilitates expected recruitment rate.

• Operational logistics: Understand if hybrid or fully remote trial designs can be operationalized in terms of country regulations as well as providers. Assess if the operational strategy improves recruitment and retention and results in a low burden not only to participants but also to sites. The sites’ ability to manage and navigate the DCT design needs to be considered and it must be easy for them to manage to prevent site resistance, especially if the DCT elements are being added as optional or at the PI’s discretion.

• Understand the data monitoring: If the data is stored in the cloud, does it lean toward remote SDV or remote SDR, by whom and is a change required in the profile performing data review (moving from CRA to CDA).

• Data: Understand the data flow, monitoring, architecture, and digital connectivity between the DCT solu tions. Assess if data trigger points and thresholds need to be established to help the investigator and medical teams monitor safety data. Understand the data privacy policies and data transfer/ storage in selected countries.

Adding DCTs can be a challenging endeavour, especially if not done right!

To summarise, most errors in clinical

trials are a result of poor planning. The lack of planning and strategising with a piecemeal DCT plug-and-play mental ity can result in increased trial budgets, missed deadlines, quality issues, scope creep, and poor adoption. As such, digital and decentralised solutions need to be designed to link with the full end-toend operational trial management team/ delivery.

In preparing for the trials of today and tomorrow, the timing of what, if, and how digital and decentralised solu tions are selected as part of the trial strategy should be determined as early as possible in the protocol development stage to minimise trial risks and errors. Early considerations need to be made to identify if, where, and how the vari ous trial assessments can be conducted in a more participant-centric approach, either on-site or remotely, as part of the trial concept/synopsis development and integrated into the final protocol.

AUTHOR BIO

Kamilla Posselt serves as senior director of decentralized clinical trials strategy for the PPD clinical research business of Thermo Fisher Scientific. In that role, she is responsible for developing digital and decentralised enabled trial strategies and innovations through a variety of different methodologies. She has more than 20 years of clinical research experience.

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