Pharma Focus Asia - Issue 40

ISSUE 40

2020

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Exploring the Role of Ultra-pure Gelatins and Collagens in Biomedical Applications Tanja Vervust Global Director, Biomedical Rousselot

Working Together, Apart Strategic planning processes must adapt to the new normal of social distancing A Decade of Reinforcing Business Integrity Making Asia-Pacific better prepared for COVID-19 www.pharmafocusasia.com

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Foreword Pharma in the Post-COVID Era Going digital We live in the digital era but one would have never imagined a world with little or significantly lesser in-person interaction. COVID-19 has consumed numerous lives, crippled economies and left millions in distress. The past few months showed how social life ceased to exist, with lockdowns across countries. Slowly but certainly, the world is trying to overcome the challenges posed by the crisis, adhering to healthcare guidelines. Social distancing became the order of the day as businesses, despite being negatively impacted by the virus, began focusing their efforts on employee safety and well-being thus embracing the new norm to keep the virus at bay.

This issue features an article in which Brian D Smith, Principal Advisor, PragMedic discusses the visible and invisible parts of the strategy process, how they are influenced by social distancing and how firms can adapt their strategy process to be effective even when their strategists can’t sit across the same table.

The novel corona virus has significantly impacted the way both pharma and healthcare sectors operate. The pharma industry is presented with the challenge of fast-tracking product development for a vaccine by utilising their production capabilities to the fullest extent. Healthcare organisations, meanwhile, have been relentlessly focused on treating patients and saving lives.

The COVID-19 pandemic has in a way accelerated the use of technology and digital solutions in pharma and healthcare sectors. From a collaboration standpoint, pharma companies have been forced to change the way they engage with healthcare providers. Pharma companies have begun to take the digital route in conducting their businesses, be it tele-consultations with healthcare professionals or increase in online pharmacies.

In-person meetings are a thing of past as leadership and strategic meetings have gone virtual now.

The traditional in-person engagement model is being replaced as major conferences and industry events are going digital to bring stakeholders together virtually.

COVID-19 has indeed brought about a significant change in consumption and we are starting to witness a fundamental shift in consumer behaviour with increased focus on health and well-being. This has prompted a change in strategic thinking for pharma companies. Adapting to this change isn’t going to be easy for companies. Companies have now been focused on streamlining their processes to be faster and more efficient. A latest Deloitte survey indicates biopharma companies lay focus on research & development and digital transformation as priorities while gearing up to address challenges resulting from cyber security issues.

As Sun Tzu, Chinese general, military strategist, writer, and philosopher once said… ‘In the midst of chaos, there’s also opportunity’, the COVID-19 pandemic has shown the world there exist opportunities amid the risk and uncertainty created by the crisis.

Digital technologies are here to stay. Investments in digital platforms and channels will help companies gain deeper insights to better execute their strategies. It is imperative for businesses to remain resilient through the pandemic, adapt to changing market needs and demands to thrive in the marketplace.

Prasanthi Sadhu Editor

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CONTENTS COVER STORY

STRATEGY 06 Crucial Decision-making in Drug Development for COVID-19

Modelling and simulation guides

Thomas Kerbusch, Chief Growth Officer, Certara

12 A Decade of Reinforcing Business Integrity

Making Asia-Pacific better prepared for COVID-19

Thomas Cueni, International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Director General and Co-Chair of the APEC Biopharmaceutical Working Group on Ethics

17 Working Together, Apart

Strategic planning processes must adapt to the new normal of social distancing

Brian D Smith, Principal Advisor, PragMedic

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Exploring the Role of Ultrapure Gelatins and Collagens in Biomedical Applications Tanja Vervust, Global Director, Biomedical, Rousselot

RESEARCH & DEVELOPMENT 28 Digital Solutions in Drug Development

Regulations to enable safe, effective, and high-quality solutions

MANUFACTURING

Anurag S Rathore, Professor, Department of Chemical Engineering, Indian Institute of Technology

Nikita Saxena, Research Associate, Indian Institute of Technology

Shrishaila Patil, Vice President, Statistical Programing, Navitas Data Sciences, a part of Navitas Life Sciences (a TAKE Solutions Enterprise)

CLINICAL TRIALS 34 Patient-Centric Clinical Trials

How language and tech are re-shaping clinical trials today?

44 Integrated Continuous Biomanufacturing

48 Human Vaccine Candidates Discovery and Development on Non-Animal Systems

An adoption with meaningful repercussions

S Dravida, CEO, Transcell Oncologics

Nimita Limaye, SVP, Strategic Partnerships and Medical Writing CSOFT Health Sciences

38 Double-blinding Capsules for Clinical Trials

How over-encapsulation can help tackle bias?

Steve Rode, Manager Business Development, Capsules and Health Ingredients, Lonza

Hideyasu Fujiwara, Business Development Manager, Lonza Capsules and Health Ingredients

41 The Importance of Principal Investigator Training

Lisa Dyment, Senior Director, Site Collaborations, PPD

Leanne Heaton-Sims, Senior Manager, Enterprise Learning, PPD Rita Bragadesto, Principal Learning Specialist, PPD

INFORMATION TECHNOLOGY 52 The Digitalisation of The Crystallisation Process

A holistic control strategy in Pharma 4.0

Kiran A Ramisetty, Diarmuid Costello, Sean Costello, Luke Kiernan, Gareth Clarke Innopharma Technology Limited

57 Artificial Intelligence in Pharmacy Practice

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ISSUE 40 - 2020

Josep M Guiu Segura, Dr Pharmacy department, Catalan Health and Social Care Consortium

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Advisory Board

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

EDITORIAL TEAM Debi Jones Grace Jones ART DIRECTOR M Abdul Hannan

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

PRODUCT MANAGER Jeff Kenney

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

SENIOR PRODUCT ASSOCIATES David Nelson Peter Thomas Sussane Vincent

Frank Jaeger Regional Sales Manager, AbbVie, US

PRODUCT ASSOCIATES John Milton

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

CIRCULATION TEAM Naveen M Sam Smith SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam

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

Laurence Flint Pediatrician and Independent Consultant Greater New York City

HEAD-OPERATIONS S V Nageswara Rao

A member of

In Association with

Confederation of Indian Industry

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

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

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Crucial Decision-making in Drug Development for COVID-19 Modelling and simulation guides

As COVID-19 shutters schools and businesses, stresses hospital systems, and threatens patients’ lives, modelling and simulation is guiding crucial decision-making on the frontlines in the development of drugs and vaccines to battle this pandemic. It is being used to track viral outbreaks, show how preventive measures are helping flatten the curve, determine appropriate doses for on-market drugs being tested off-label against COVID-19, and compare the effectiveness of rapidly emerging therapeutics. Now, it is also helping to select the best vaccines for deployment against the disease.

Thomas Kerbusch, Chief Growth Officer, Certara

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odelling and simulation has been growing rapidly in impact and is now actively used by biopharmaceutical companies worldwide for drug development and regulatory agencies for review and approval. It aims to integrate information from diverse data sources to help decrease uncertainty and lower failure rates, and develop information that cannot or would not be generated experimentally. Almost all novel drugs use these technologies for drug development.

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Medical researchers worldwide are employing modelling and simulation to determine which on-market drugs, drug combinations and vaccines may be safe and effective against SARS-CoV-2, the virus responsible for COVID-19.

Treating Different Disease States

COVID-19 involves three disease stages.

When a person first gets infected, the virus is actively replicating. At that stage, the goal is to inhibit replication, so viral replication inhibitors are used to supplement the person’s own immune response. Repurposed antivirals, which are already approved and on-market for another indication, are currently being employed to treat this initial disease state.

But new, more tailored drugs are being investigated too.

In the second stage of the disease, the viral replication results in respiratory epithelial cell death and local pulmonary inflammation. At this second stage, a person may start to experience significant respiratory problems, such as Acute Respiratory Distress Syndrome (ARDS), requiring supplemental oxygen and potentially a ventilator.

In the final stage, there is a systemic overreaction of their immune system, known as a “cytokine storm.” This overreaction weakens the body’s physical barriers, causing the virus to go deeper into the tissue, starting to affect organs like the lungs and brain and impact the blood clotting system.

COVID-19 is difficult to manage, because the effectiveness of viral inhibition treatment is highly dependent on timing of infection and initial viral load.

Sophisticated computer models of antiviral drug exposure, including combinations, and its effect on individual virological response have been built. Disease progression is also incorporated into these models to ensure that the right drug is administered with the right dose and right time.

vaccine in a small number of people in a Phase 1 trial to see if it is safe. Then, it is tested on a larger group of people in Phase 2 to see if it is safe and generates an immune response. After that, it goes into a large Phase 3 trial to see if it actually works in preventing subjects from getting the disease.

While safety is extremely important, it is not the only important factor. If the dose level (vaccine strength and adjuvant selection and dose) and regimen (number of vaccine inoculations) are optimised based solely on safety considerations, a vaccine may be developed that's not sufficiently efficacious.

By using model-based approaches to predict expected safety and efficacy, optimal vaccine candidates can be identified the first time and accelerate the development process.

On July 6, the World Health Organization reported that there were 149 candidate vaccines under evaluation for COVID-19. Several of them entered large-scale clinical trials in July.

It is anticipated that more than one COVID-19 vaccine will be selected.

The number of doses needed is so large that production limitations will effectively require there to be several safe and effective vaccines.

Accelerating Development with Advanced Quantitative Approaches

Model-based meta-analysis (MBMA) approaches can be used to extrapolate from the correlate of protection as measured in preclinical assays and predict what the clinical immune response is likely to be. Summary clinical trial data can then be employed to compare efficacy between different repurposed drugs. It will also soon be possible to compare different vaccines to determine which provide superior efficacy. MBMA is ideally suited to make these comparisons across a wide range of differently designed clinical trials, patient populations and countries.

Another cutting-edge approach involves adapting a quantitative systems pharmacology (QSP) model for immunological response to COVID-19 applications. This unique QSP immunology model was originally developed to determine unwanted immunogenicity by predicting whether an administration of a specific monoclonal antibody is expected to trigger unwanted immunological responses defined by an antibody-antibody reaction. However, this QSP model is now being repurposed to predict the desired immunological response of a vaccine. Mediated by the

Developing the Best Vaccines

The traditional approach to vaccine development is to first test the candidate

Photo of the COVID-19 Pharmacology Resource Center at www.covidpharmacology.com

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Photo of the compound screening dashboard in the COVID-19 Pharmacology Resource Center. The compound screening dashboard has a heatmap where you can select compounds of interest and then the heatmap shows which ones rate high and low on proof of hope for COVID-19, based on key metrics such as Cmax/EC50 and Cminss/EC50.

same immune system components, the QSP model can predict if a vaccine will provide sufficient and lasting immune protection. This allows researchers to predict, based on the vaccine’s antigen profile, what level of immune response it will generate, and not just the extent but also the duration of the immune response.

This type of modelling and simulation also helps to determine whether people will need to be inoculated once or twice, require initial boosting, or if the immune response will persist or wear off.

Improving Clinical Trials

There were 1,676 COVID-19 clinical trials underway globally as of July 6, according to Cytel’s Global Coronavirus COVID-19 Clinical Trial Tracker. They are all competing for resources – patients, staff or funding – leading to concerns that some of the studies will be underpowered and unable to produce meaningful, statistically significant results.

Modelling and simulation has been used to support more than a dozen COVID-19 programs, with trial design, dose optimisation, and stage-gate decisions. Larger studies have also been created in which many smaller trials can be included. This ensures that the same

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high level of rigorous study conduct is applied across all trials and their data can be pooled, making their results much more powerful from an interpretation perspective.

QSP and physiologically-based pharmacokinetic (PBPK) modelling are being used to help select drugs for inclusion in trials based on their mechanism of action. QSP enables the drug’s mechanism of action to be figured out and allow researchers to determine whether it will be beneficial in the active treatment of COVID-19, either by inhibiting the virological response or modulating the immune response. PBPK modelling allows researchers to figure out whether the drug gets to the site of action.

One recent example of this is ivermectin. For any drug to be therapeutic, enough of the drug needs to get into the cell to be efficacious and still be safe.

It was reported that ivermectin inhibits the replication of SARS-CoV-2 in cell culture. But how does this translate into safety and efficacy in humans? A PBPK model was used to study virtual patients and determine the relative potency levels of the drug in the body. It predicted that the right level of exposure of ivermectin will most likely not occur in cells to be efficacious without compromising safety.

Comparative Effectiveness to Identify Winner Vaccines

A COVID-19 Clinical Outcomes Database has been developed for drugs that show activity against SARS-CoV-2. It uses public clinical trial and observational study information. It already includes data on repurposed drugs, and it is being expanded daily with new trials and studies reading out. Vaccine trial data will also be added as they become available.

These clinical outcome databases include pooled information across trials, drugs, mechanisms of action and trial designs, and then MBMA is used to make inferences from all the data. This pooled MBMA approach allows trials to be combined that use different methodologies and patient populations. It enables a model to be built that includes patients at different stages of the disease.

From a modelling perspective, the Clinical Outcomes Database functions similarly to a registry trial. Instead of pooling dozens of trials, it pools hundreds of trials across all the relevant drugs. Different drugs are used in the same data pool and estimates are made of the impact of disease status, patient characteristics and trial designs on the outcome of treatments. Then by accounting for those differences in patients and

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Image shows the CQ simulator visualisation from the COVID-19 Pharmacology Resource Center.

trial designs, it allows apples to apples comparisons to be made, resulting in the comparative effectiveness of different drug treatments.

The impact of a treatment on COVID-19 is based on the stage of disease progression. The power for detecting and estimating those effects is

improved by pooling all that information.

Then, we can start asking critical questions: When is the right time to dose?

What is the right dose? Which drugs work best on which patient population? Which trial design provides the best response in those populations?

Analogously for vaccines, there are questions around comparative effectiveness and making sure that we learn quickly which are the likely winners from the initial response trials.

Insights from this Clinical Outcomes Database will be provided in the COVID19 Pharmacology Resource Center. We developed the Center with support from the COVID-19 Therapeutics Accelerator to foster global collaboration, share best practices, and facilitate COVID-19 candidate drug development.

Shifting to Combination Therapies

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Regulatory and Deployment Strategies to Expand Access

A pharmacology to payer (P2P) model, which incorporates both epidemiological and health economic data, is being used to translate comparative effectiveness into real-world scenarios for COVID19 drugs and vaccines.

Deployment models can help to determine who should be treated first with the new vaccines. Do you start with healthcare workers on the frontlines?

Then the elderly because they're affected the most, starting in elderly care homes where we're seeing the most flare-ups?

We can use epidemiological models to start describing the herd immunity that we need. Unfortunately, herd immunity is currently very low in most countries, running anywhere from 2 per cent to 4 per cent. Based on past experience, it will probably need to be approximately 60 per cent. Then, when the replication rate of the virus decreases, the infection risk goes down within the population.

Another consideration is how to navigate regulatory pathways to accelerate approval of COVID-19 therapeutics and vaccines. Modelling and simulation has been used to successfully fast-track drug approvals for orphan diseases and areas of high, unmet medical need, such as immuno-oncology. That expertise can be applied to COVID-19. Regulatory science and strategy expert teams that have successfully presented novel approaches, communicating the risk/ benefit profiles of new drugs, repurposed drugs and vaccines to regulators will have the requisite experience to meet that challenge.

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Supporting Disrupted Trials and Programmes

COVID-19 is having a disruptive effect on clinical studies in other indications.

Most trials for non-life-threatening conditions were put on hold or slowed down either because staff needed to provide clinical care for COVID-19 patients or the health risks of bringing patients in for follow-up appointments were too great.

Experienced regulatory teams can help their clients communicate the extent and impact of any trial disruptions to regulatory authorities. Then they work on mitigation solutions that help them get back on track. Modelling can also help disrupted trials recover their statistical power if patient attrition leaves them with incomplete data.

One of modelling’s strengths is that it looks across the population for the entire time course, whereas a classical statistical analysis looks at one time point and makes a comparison between two groups of patients. If a patient’s last visit data is missing because they dropped out of the study, we can make a reasonable prediction of what that last visit would have looked like based on their previous visits using a model.

Pharmacological models of drug response allow us to integrate data across time. We can borrow statistical strength across the time course to predict the

AUTHOR BIO

required to treat it. Our models allow us to look at the combined effects of different drugs and the impact of temporal administration. They allow us to suggest at which point in the disease progression one drug should be given, and when to switch to another, for optimal patient benefit, which can then be further evaluated in pre-clinical and clinical studies.

clinical endpoint. Therefore, we can still model the data even if data are missing.

Working Together

COVID-19 is a global problem that requires a global solution. Fortunately, modelling and simulation has already been adopted by global regulatory agencies, including the US Food and Drug Administration (FDA), European Medicines Authority (EMA), Japan’s Pharmaceuticals and Medical Devices Agency, China’s National Medical Products Administration, and the Australian Therapeutic Goods Agency.

The Asia-Pacific (APAC) pharmaceutical market is growing rapidly and by 2023, it will be larger than the European market. While Japan has the most established pharmaceutical industry, those in Greater China and South Korea are growing quickly, and their biopharmaceutical companies are now expanding beyond their domestic markets and eyeing international markets, using modern, innovative R&D pipelines. As a result, they have begun applying methodologies, such as modelling and simulation, which are required components in new drug applications to the FDA and EMA. APAC’s expanding involvement in global drug development and increasing adoption of modelling and simulation, could not have come at a better time, because COVID-19 demands that we all work together with scientific and quantitative approaches to produce the best drugs and vaccines to protect us all against this disease.

References are available at www.pharmafocusasia.com

Thomas Kerbusch is Chief Growth Officer at Certara, overseeing executive client relationships and integrated software and service offerings in growth markets, including APAC. Kerbusch joined Certara in 2015, initially leading EU consulting services and later serving as Divisional President.

Prior to that, he had a 15-year track record of successfully developing new drugs while leading and working with teams of researchers at Merck/ MSD, Schering-Plough, Organon and Pfizer.

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A Decade of Reinforcing Business Integrity Making Asia-Pacific better prepared for COVID-19

Over the last decade the Asia-Pacific has seen an unprecedented shift in the adoption and implementation of high-standard ethical business conduct across its healthcare enterprises, including in the biopharmaceutical sector. This positive uptake of integrity had positioned the region to better prepare for, and now to I hope to recover from, the current pandemic.

Thomas Cueni, International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Director General and Co-Chair of the APEC Biopharmaceutical Working Group on Ethics

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he Asia-Pacific (APAC) region is no stranger to confronting and defeating disease outbreaks.

From SARS and Avian influenza to MERS and H1N1, the region’s economies have demonstrated remarkable resilience and with each new occurrence found themselves better prepared to confront the challenge. The global health emergency and ensuing economic crisis brought about from COVID-19 represents a far greater trial and one that will have ramifications to regional growth and development for years to

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come. I am proud to say that today, perhaps more than any moment over the past century, the patient-focused mission of the global biopharmaceutical industry is resolute in a common cause: leaning into science to safely treat and vaccinate against COVID-19. Never before in my lifetime have I seen such collective action, including with and between Asia-Pacific nations, and it gives me tremendous hope that we will defeat the virus. It is also once in a lifetime opportunity to showcase how integrity and trust are central to these endeavours. Luckily, we are not starting from scratch – both on the innovation needed to fight this coronavirus and the need for ethics to ensure that we are trusted in our endeavours.

What many may not realise is that over the last decade, APAC has seen an unprecedented shift in the adoption and implementation of high-standard ethical business conduct across its healthcare enterprises, including in the biopharmaceutical sector. This positive uptake of integrity had positioned the region to better prepare for, and now to I hope to recover from, the current pandemic. Substantial investments have been made across the APAC to bolster best practices from the moment a new medicine is imagined through to when it is received by those who need it. As the premier forum for facilitating economic growth, cooperation, trade and investment in the region, the APEC (Asia-Pacific Economic Cooperation) forum has shown great leadership in setting up the world’s largest publicprivate partnership to strengthen ethical business practices.

A decade of work

From 2012-2019, as a result of the Business Ethics for APEC SMEs Initiative,industry associations of both innovative and generic medicine manufacturers and distributors have extended through the increased number of codes of ethics high standard ethical business practices to over 10,000 enterprises of

every size across the Asia-Pacific, including in seven Asian economies where they previously did not exist. The APEC ethical principles for the biopharmaceutical sector detail strong practices, including measures for enterprises to preserve integrity and legitimate intent while upholding independence and accountability.

As my colleague Sabrina Chan, Senior Executive Director of the Hong Kong Association of the Pharmaceutical Industry (HKAPI), who has been actively involved in the APEC Business Ethics for SME Forum over the past decade, it is no mean feat to get everybody onboard. She has told that “it is a tough mentoring work, but one that yields a lot of satisfaction when approached by new organisations on how to review their code of ethics to align with ever-evolving societal expectations in terms of doing what is right”.

Such efforts pay off. In the last two years alone, Australia, China, Japan, the Philippines, and Vietnam have pioneered ground-breaking consensus agreements for ethical collaboration to align ethical standards across nearly 200 peak public and private healthcare bodies representing thousands of companies and healthcare providers as well as millions of patients. There is no doubt that these collective successes strengthen the region’s resilience and agility to confront the current crisis.

As an industry, we applaud our member associations and experts who have played an integral part in achieving these results. And let there be no doubt – this goal post moves constantly, especially for an industry like the biopharmaceutical industry that has a huge and vast impact on people’s lives.

In Australian, my colleagues at Medicines Australia have made pioneering strides in bringing others along for the benefit of patients. Medicines Australia has been a foundation collaborator in the development of the Australian Consensus Framework for Ethical Collaboration1. This has been jointly signed by over 50 peak healthrelated bodies in Australia and has become the most wide-ranging consensus framework in the region. Elizabeth de Somer, the Medicines Australia CEO, who has shown outstanding leadership in this field, says “it’s wonderful to see so many organisations co-operate to clearly articulate how the work they do together will always put the best interests of patients first and foremost”.

Standing the test – COVID-19 is creating a heightening risk of unethical behaviour

Nearly all of these agreements have been activated to reinforce integrity during 1 https://medicinesaustralia.com.au/media-release/mawelcomes-the-australian-consensus-framework/

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the pandemic and many companies and associations are working together to prepare for the aftermath in ways that would have been impossible just a few years ago.

According to the APEC forum, economic activity in APAC has been at a near standstill as economies implemented stringent measures to contain the pandemic, including travel bans, quarantines, lockdowns, and social distancing measures to curb the spread of COVID-19. Healthcare systems are under enormous pressure and are grappling with acute shortages of medical supplies and equipment as well as inadequate numbers of hospital beds and isolation units22. At the same time, there is an outbreak of disinformation and misinformation about COVID-19, ranging from fake cures, false claims and harmful health advice. Likewise, there are heightened concerns that organised networks and bad-acting opportunists are waiting to exploit this period of uncertainty and trade illegitimate or non-compliant products.

2 https://www.apec.org/Publications/2020/04/APEC-inthe-Epicentre-of-COVID-19

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The pandemic is putting everyone to the test. Actors across healthcare systems are confronted with an unprecedented demand in products or resource reallocation, trying to respond to a set of new challenges while trying to preserve and maintain patient trust. COVID-19 is creating a heightened risk of unethical behaviour, which organisations must resist.

In times of uncertainty, integrity becomes a differentiator. Frontrunners in integrity will distinguish themselves as never before, and those who remain behind are likely to be held accountable after the crisis has passed for breaking trust or failing to act according to societal expectations.

Ethical collaboration in the biopharmaceutical industry on a global stage

The biopharmaceutical industry is unlike any other, as it researches, develops, and distributes products that prolong and save lives. Trust is the sector’s life-blood.

There is great hope placed in science and in the biopharmaceutical’s industry

efforts to find a solution that allows the world to “return to normal”. As the biopharmaceutical industry is at the heart of developing tests, treatments and vaccines and getting them to billions of people around the world, integrity and trust has taken a global stage. I am proud to say that from the first days of the COVID-19 pandemic, the industry has been united in its response, acting with urgency and integrity. As a critical participant in the global healthcare ecosystem, we are bringing the full force of our scientific and medical expertise to address the coronavirus pandemic around the world. Society needs to know it can count on the biopharmaceutical industry. We have a responsibility to work tirelessly and rapidly to tap into the industry’s innovation capabilities to bring solutions. Today, hundreds of treatments and vaccines candidates are being tested in record time, inching the world closer to the much-awaited return. Not all will succeed, but with multiple shots on goal, I am confident that science will prevail.

Industry leaders have been clear that we must demonstrate to the world that

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it can count on our innovation, our commitment, our courage, our resilience and above all, our integrity to win this fight. We at IFPMA have found that our recently launched Ethos has been indispensable in helping provide the necessary framework to anchor ethical decision-making, where no specific rules could have previously been anticipated.

As we continue what looks to be a long ride, the need for shaping our actions around the concept of Ethos has never been clearer. As Rady Johnson, chair of the IFPMA Ethics and Business Integrity Committee has conveyed at the beginning of the pandemic, “with the core values of trust, care, fairness, respect and honesty, our Ethos provides the framework to ensure that even in times of crisis, we act with integrity.

With our Ethos front-and-centre, the integrity of the decisions and actions we make while navigating this crisis is assured”. The Ethos is a principles-

driven approach that will continue to guide IFPMA members’ conduct as they adapt to the evolving COVID-19 operating environment. We hope it can serve as a guide for other industries and for APAC economies to consult during these uncertain times, as it very much has done in the past. The IFPMA Code of Practice has been a building block for the APEC ethical principles for the biopharmaceutical sector.

Collaboration and coordination, embedded by strong ethical values, have been the foundation of the biopharmaceutical industry’s response throughout this crisis. It has become apparent that efforts to keep borders and trade open need to be coordinated, as well as to ensure integrity in the supply chain and distribution of legitimate, high-quality medical products. Biopharmaceutical leaders have been working with governments and relevant authorities to ensure continuity of manufactur-

ing and availability of product supply.

Global pharmaceutical supply chains are incredibly complex, with multiple manufacturing, testing and distribution sites – and an issue at any one of them can lead to delays in supplying essential treatments. The list of disruptions can become extremely long, and much less predictable than for the supply chains of other commercial goods. But there are safeguards in place and good practices, with compliance officers and experts doing their due diligence. The global supply chain has stood the test.

Keeping patients and healthcare workers safe

During the COVID-19 pandemic, biopharmaceutical companies proactively interrupted face-to-face interactions between their representatives and physicians, in order to protect patients, healthcare professionals, and their own employees, and have replaced in-office

High Containment Isolator for Micronization

))

1

This isolator reaches a Containment Performance Target (CPT) of 50ng/m3 and can host different sizes of jet mills to micronize down to a few microns.

2 The machine is fully automated with a centralized control system and HMI touchscreen panels.

3 For large production batches

all the 9 chambers are in use. For pilot batches, only a few chambers are used to minimize cost of operation and cleaning.

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

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patients and healthcare professionals trust that we are doing things in the right way and that we will live up to that, whatever the political pressures are. Indeed, we need to go as fast as we can but as safe as we must. We are working at record speed to condense the time from lab to bed side, but never at the expense of patient safety. We are doing so by working smarter and more collaboratively across the healthcare ecosystem and with regulators as to do things differently would mean risking to undermine trust in vaccines and treatments for COVID-19.

In sum, this industry is motived by integrity at the core of its mission and the Asia-Pacific region serves a central role in this global cause. As an example, I would like to mention the APEC SME Leaders in Ethics and Integrity Program (LEIP) to help biopharmaceutical industry associations equip leaders of their SME members with resources and a valued network to reinforce a culture of integrity within their enterprise. Using a “tone-at-the-top” approach, the mission is to integrate ethics principles into daily business practices of every SME that develops, manufactures, markets, or distributes any pharmaceutical and/or biologic product. This year the Initiative is launching pilots of the LEIP in the United States and China.

AUTHOR BIO

visits and face-to-face congresses with online platforms, virtual meetings and other forms of meetings, such as webinars. Maintaining dialogue and scientific exchange with the medical community is critical to inform physicians about new possible treatments, alternative treatment protocols, product supply or safety and efficacy data. This meaningful engagement is even more critical during the pandemic, as physicians contend with the many medical questions of how the virus could affect their patients’ existing treatments and at the same time need to remain informed about general scientific information and treatment options.

On 28 May, in close collaboration with 15 member associations across the APAC region, the IFPMA issued new guidance on ethical considerations for resuming in-person interactions with healthcare professionals after COVID19 . Keeping our HCPs safe and considering adequate protocols is important, like Francisco Tranquilino, member of the Pharmaceutical and Healthcare Association of the Philippines (PHAP) and a medical doctor himself attested.

New industry practices are also being assessed as I write this text that would uphold ethical business conduct and our patient-focused mission in an increasingly digitized world.

Not only does the sector owe these efforts to the patients and healthcare professionals who rely on our medicines, but ethical business conduct is crucial to the biopharmaceutical industry’s ability to innovate.

Without trust and business integrity, collaboration ceases. Without collaboration, there is no innovation and no end in sight for COVID-19. As we engage to support businesses and the healthcare ecosystem to uphold integrity and ethical standards, we must also be active in communicating what we are doing and letting others help us do things right. As one of the principles of our Ethos, “accountability” is the key to building trust. It is important that

Building back better, on strengthened ethics guidance

The pandemic is drawing significant attention to several of the world’s largest Collective Action initiatives that are reinforcing ethical business conduct in healthcare, such as the Business Ethics for APEC SMEs Initiative.

While these successes over the past decade are worth touting and have better prepared the APAC region amidst the current pandemic, the gains made through the APEC initiative cannot be taken for granted. Far more is needed to build upon the ethical advances that have been realised, especially as APEC economies turn to a sustainable and inclusive recovery from COVID-19. Health systems will face new challenges and ethical dilemmas, expected and unexpected, born through emerging technologies, supply chain evolution, and even higher expectations from society. Constantly evolving and incomplete evidence on new and repurposed therapies poses ethical challenges somewhat unique to this time in history as healthcare providers struggle to keep up with daily developments and manufacturers and biopharmaceutical representatives try and figure out how and when to scale production and increase promotion. Will most economies and businesses return to the pre-crisis status quo or will best practices emerge and be universally adopted? While it may be difficult to predict, we must set the course already and raise the bar even higher. This requires building back better than before, pursuing ambitious, forward-looking goals with strengthened ethics guidance. Long after the crisis has ended, society will see and applaud this integrity.

Thomas Cueni is Director General of International Federation of Pharmaceutical Manufacturers (IFPMA), the global association of research-based pharmaceutical companies and associations.

IFPMA has official relations with the United Nations contributing industry expertise towards great global health progress. Mr. Cueni serves as Industry Co-Chair of the APEC Biopharmaceutical Working Group on Ethics.

STRATEGY

WORKING TOGETHER, APART Strategic planning processes must adapt to the new normal of social distancing Making strategy is usually a highly social process, involving the sharing of ideas and discussion between cross functional teams. And even though technology allows us to talk and share documents across distance, social distancing – either because of COVID or because of geographically-spread teams, can hinder that essential human interaction and make strategy processes less effective.

In this article, the author discusses the visible and invisible parts of the strategy process, how they are influenced by social distancing and how firms can adapt their strategy process to be effective even when their strategists can’t sit across the same table.

Brian D Smith, Principal Advisor, PragMedic

R

ight now, all over the world, cross-functional teams in pharma, biotech, medtech and other life science companies are working on their strategic plans. Large or small, companies usually follow this annual ritual. But 2020 is a very unusual year. Traditional planning processes, punctuated by face to face meetings and presentations to audiences, have been replaced by socially-distanced strategising, where all interaction is necessarily remote. This is a big change, not like anything we’ve

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seen before and, unlike most changes in how we work, it has been a sudden change.

For someone like me, who uses Darwinian science to understand how the life sciences industry evolves, this abrupt shift to socially distanced strategising raises two fascinating questions.

First, does working at a distance make a difference to strategic planning? Secondly, if it does, how should we adapt to this new normal? In this article, I’ll answer those questions, but I’ll begin with a real-world view of how strategy is made.

How strategy making really works

Strategy making processes are like the human face, everyone is unique. Every life science company has its own process, its own terminology and its own systems.

But just as every face has eyes, a nose, a mouth and a chin, every strategic planning process has four essential features (see figure 1). They all start with some kind of sensemaking step, in which we translate information about the market into the knowledge and insights we need to make strategic decisions. Next comes the strategising step, in which we make resource allocation decisions about where and how to create value in the market place. Then comes the implementation step, when we break down the high-level decisions into smaller actions that will be implemented by medical, marketing, market access and other functions.

Finally, we take the measuring step, when we schedule all those actions and set up metrics about how much we’ll spend and what outcomes we expect. You will probably recognise these four steps in your own strategy process even though, like any face, its details are unique to your firm.

But my 20 years of working in pharma and medtech, followed by 20 years of academic research into the industry, has taught me that this four-stage process is only half the story. In the real world, there is another part of the process that is never written down and rarely discussed. I call this the shadow strategy

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1. The Visible Strategy Process SENSEMAKING

STRATEGISING

Translating data into insights for strategising

Making choices about where and how we will create value

MEASURING

IMPLEMENTING

Scheduling actions and setting metrics about spending and outcomes

Breaking down strategic decisions into functional activity

process, because it lies, barely perceptible, beneath these four visible steps (see figure 2). Beneath the sensemaking step, we make untested assumptions about what we already know and what we need to know. In knowledge-based industries such as ours, these assumptions are very important because they shape how we create and use knowledge.

Beneath the strategising step, we tacitly agree what a strong strategy looks like and how it differs from a weak strategy.

That’s important because it determines which strategy is chosen. Beneath the implementation step, we implicitly set and accept expectations about what each function can do and should do.

Those expectations determine the way that functions cooperate or conflict with each other. And beneath the measuring step, we reach unspoken agreements about how fast we can move and how effective we can be. Those unspoken agreements determine what we count as success or failure and therefore what

we change in the next planning cycle.

Experienced strategists recognise that, in the real world, this shadow strategy process goes on beneath the explicit planning process. Importantly, the shadow strategy process isn’t documented and it doesn’t happen in meetings. It mostly happens over coffee, in corridors, or when travelling together. It is an informal complement to the formal process, analogous to an adjuvant to a vaccine.

What social distancing does

The strategy teams I study differ in how effective they are at creating strong strategies. They also vary in how physically close the strategy team is because, even before COVID-19, some teams work in the same office and some are spread around the world. By comparing what goes on in each of these four categories of strategy teams, I can draw some interesting conclusions, as shown in figure 3.

These findings lead to four important conclusions. Firstly, both the visible and

2. The Shadow Strategy Process

SENSEMAKING

STRATEGISING

IMPLEMENTING

MEASURING

Untested assumptions made about what we already know and what we need to know.

Tacit consensus formed about the differences between strong and weak strategy

Implicit expectations set about what each function can and should do

Unspoken agreements reached about how fast we can move and how effective we can be

STRATEGY

3. Lessons from Strategy Teams Ineffective and together Visible process works well but shadow process hindered by intraorganisational conflict

Effective and together Both visible and shadow processes work well

Four kinds of strategy teams Effective and distanced Visible process works well and shadow process enabled by change in strategy process

shadow processes are needed to make strong strategy. This makes sense since the processes work together, like hardware and software. Secondly, physical distance has little impact on the visible strategy process. This is because the visible process centres on sharing documents and technology doesn’t care if you do this between desks or between continents. Thirdly, physical distance has a significant impact on the shadow process. This is a new finding but it isn’t surprising. The shadow process happens during informal social interactions and it is these that are curtailed by remote

Ineffective and distanced Visible process works well but shadow process hindered by reduced communication effectiveness

working. Fourth, some firms have found ways of protecting the shadow process against the negative effects of social distancing. This is a new finding and obviously one that is worth looking at more closely.

Working together when apart

From those pharma and medtech firms that make the shadow process work, despite social distancing, we can learn two things: what they do and how they do it.

What they do is to make the shadow process outcomes visible and explicit by

asking very specific questions. In particular, they ask a set of questions at each of the four stages of the strategy process, questions that are designed to provoke thought and to surface unspoken ideas.

At the sensemaking step, team members are asked structured questions to identify the different forms of knowledge they need to make strategy, what elements of that knowledge they already have and to prioritise their knowledge gaps. In a physically close team, this usually happens unconsciously as part of the social process. But in a socially distanced team, that unconscious socialisation is reduced, so the process has to be made more deliberate and conscious by asking carefully designed questions.

Figure 4 shows an example template I developed from observations of good sensemaking practice.

At the strategising step, team members are asked structured questions about how likely the strategy is to meet its objectives. In a physically close team, this testing and revision of the strategy happens during the back and forth of discussion. But in in a socially distanced team, there is less opportunity for that conversational process, so it has to be enabled by asking the questions that lie

4. Sensemaking questions Questions to test our assumptions about what we know and what we need to know 1) Where is our knowledge superior to rivals?

Procedural knowledge

Causal knowledge

(i.e. How something happens)

(i.e. Why something happens) 1)

e.g. Current attitude of prescribers towards the use of digital health in respiratory

e.g. How primary care prescribers are influenced by secondary care physicians and KOLs

e.g. What causes prescribers to comply with or disobey local formulary guidelines

e.g. Patient pathway in asthma

e.g. How local formulary decisions regarding respiratory therapies are made

e.g. What causes patients to “stall” or “leak out” of patient pathway

e.g. Current prescriber Mode of Action preferences

e.g. How brand switching decisions are made in the case of uncontrolled asthma patients

e.g. What causes clinically identical patients to be prescribed different brands

Declarative knowledge (i.e. What something is)

(i.e. What knowledge might form the basis for competitive advantage?)

2) Where is our knowledge equivalent to rivals? (i.e. What knowledge is sufficient to operate but provides no competitive advantage?)

3) Where is our knowledge inferior to rivals? (i.e. What knowledge might it be necessary to build?)

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5. Strategising questions Questions to build a consensus about what is a strong strategy

Strategic option 1

Strategic option 2

(e.g. Broad Positioning Option)

(e.g. Narrow Positioning Option)

1) Are our target segments valid?

e.g. Target segments are patient disease categories and relatively heterogenous in needs and behaviours

e.g. Target segments are patient-payerprescriber contexts and relatively homogenous in needs and behaviours

e.g. Proposition is limited to clinical benefits and leaves non-clinical needs unaddressed

e.g. Proposition addresses clinical, economic and emotive needs of all three stakeholders

e.g. Choice of segment and proposition is based only on limited evaluation of product features

e.g. Choice of segment and proposition leverages strengths and mitigates weaknesses, both product and non-product

e.g. Target segment and proposition substantially similar to that of rivals

e.g. Both target segment and proposition substantially different to that of rivals

e.g. Choice of target and proposition assumes past market conditions remain largely unchanged

e.g. Choice of target and proposition anticipates and allows for significant market change

(i.e. are they homogenous, distinct, accessible and viable?)

2) Are our propositions strong? (i.e. to what extent do they meet the target segment needs?)

3) Is our strategy aligned to the market? (i.e. does it align strengths to opportunities and mitigate threats against weaknesses?)

4) Is our strategy differentiated? (i.e. to what extent does it differ from that of rivals? )

5) Is our strategy future facing? (i.e. to what extent does it anticipate change in the market?)

6. Implementing questions Questions to make explicit what each function can and should do 1) Is the programme congruent to the strategy?

Programme 1

Programme 2

Programme 3

Programme 4

(i.e.g. Sales team)

(e.g. Marcomms)

(e.g. Market access)

(e.g. Medical)

e.g. Sale team activity not sufficiently focused

e.g. Marcomms programme tightly focused on segment and proposition

e.g. Market access activity aligned at national but not local level

e.g. Medical activity conflicts with value proposition

e.g. Sales team activity contains full set of activities across all stakeholders

e.g. Marcomms programme lacks KOL enablement activity

e.g. Market access activity fails to enable local budget impact illustrations

e.g. Medical activity contains full range of activities

e.g. Timing of sales programmes not coherent with timing of other programmes

e.g. Sales support material not aligned with medical CME programme

e.g. HEOR evidence not integrated into marcomms and medical programmes

e.g. Medical programme not synchronised with marcomms and sales programmes

e.g. Sales team resources sufficient only for more tightly focused programmes

e.g. Marcomms resources to support peri-launch activity unlikely to achieve initial awareness goals

e.g. Market access resources not phased to match marketpreparation stage

e.g. Medical programme in line with allocated resources and goals.

(i.e. does it align to choice of target segments and value propositions?)

2) Is the programme complete? (i.e. does it include all necessary activities)

3) Is the programme coherent with other programmes? (i.e. does it reinforce and not conflict with other programmes)

4) Is the programme consistent with goals and resources? (i.e. is it achievable with allocated resources and proportionate to goals)

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7. Measuring questions Questions to make transparent what we need to measure and why that is useful 1) What lag indicators do we need to measure?

Unit of analysis 1

Unit of analysis 2

Unit of analysis 3

(e.g. Geographical)

(e.g. Product)

(e.g. Segment)

e.g. SGA costs by country and business unit

e.g. Profit lines by product line and SKU

e.g. Share by market segment

e.g. Granting of access by local payers at territory level

e.g. Adoption milestones (discussion, trial, growth) by product category

e.g. Differential uptake rates by market segment

e.g. Differential uptake by geography

e.g. Product mix and usage patterns

e.g. Perceived positioning by market segments

e.g. Profit lines by geographical territory

e.g. Promotional expenditure by product group

e.g. Sales team time allocation by market segment

(i.e. How will we know, at necessary granularity, if we have succeeded or failed?)

2) What lead indicators do we need to measure? (i.e. How will we know, in a timely manner, if we need to make course corrections?)

3) What learning indicators do we need to measure? (i.e. How will we improve critical assumptions for the next planning cycle?)

4) What resource allocation indicators do we need to measure? (i.e. How will we know our expenditure is within plan?)

underneath those conversations. Figure 5 shows an example template I developed from these observations of strategising by effective teams.

At the implementation step, team members are asked structured questions about how their tactical programmes fit with the strategy, with available resources and with each other. In a physically close team, this integration between functions takes place by repeated reiteration of tactics as gaps and conflicts become clear.

But in a socially distanced team, those iterations are reduced. So they have to be made more effective by asking questions that illuminate gaps and conflicts. Figure 6 shows an example template I developed from observing teams that do this well.

At the measuring step, team members are asked structured questions about what they want to measure and why they want to measure those things. In a physically close team, scheduling and designing of metrics evolves as the team ask each other questions during lots of informal encounters. But in a socially distanced team, those informal encounters are

limited so that questioning has to be formalised by asking questions that make clear what the metrics are for. Figure 7 shows an example template I developed from these seeing teams develop effective sets of metrics.

Evolution or extinction

The best cross functional teams in pharma and medtech can make strong strategy even when forced to be socially distanced. They do this by asking structured questions at each stage, questions that force the shadow strategy process out into the open. These questions are not simply the “comment on this document” questions so common in the visible

process. They are carefully designed to force reflection. It is this thinking that makes what is normally an informal social process happen even when that informal socialising is impossible.

Readers might ask if they really need to change their strategy process. Isn’t it complicated enough already? When I ask effective pharma and medtech companies that question, they respond with another: Our world has changed: why would you expect our strategy process to stay the same? These exemplary companies know that, in a changing world, it is those most capable of change that survive. They are evolving their strategy process to fit the new normal of social distancing because they know that the alternative to evolution is extinction.

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

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MEDICAL FAIR ASIA (9-11 DECEMBER 2020) Equip your business with future-ready solutions MEDICAL FAIR ASIA 2020 will be held from 9-11 December at Marina Bay Sands Show highlights include the Community Care Pavilion and Start-up Park Industry-led conferences and forums will be held alongside the 3-day exhibition

S

trengthening its position as the region’s leading medical and healthcare exhibition, the 13th edition of MEDICAL FAIR ASIA is scheduled to take place from 9-11 December 2020 and will bring together a comprehensive range of equipment, technology and supplies for the hospital, diagnostic, pharmaceutical, medical and rehabilitation sectors; providing a one-stop marketplace to showcase the latest innovations and technologies.

Mirroring industry trends and global statistics, which point to Asia’s rapidly ageing population, and the increasing demand for digital healthcare brought about by the COVID-19 pandemic, healthcare for the aged and technological innovations in the healthcare economy will be key themes at MEDICAL FAIR ASIA 2020.

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Highlights at MEDICAL FAIR ASIA 2020: Community Care Pavilion focused on rehabilitation and prevention

The Asia-Pacific region is undergoing profound and rapid population changes. All countries in Asia and the Pacific are in the process of ageing at an unprecedented pace, for instance a quarter of Asia’s population will be aged 60 years of age by 2050, while almost 50 percent of Singaporeans will be aged 65 years or older by the same time. Against this fast changing demographic, making a comeback with an enhanced focus on rehabilitative equipment, products and solu-

tions, particularly for the aged, is the Community Care Pavilion—a comprehensive platform featuring a wide-ranging suite of geriatric-related products and preventive healthcare solutions, as well as rehabilitative equipment, physiotherapy solutions, orthopaedic devices, new robotic technology for mobility, assistive technology, to smart fabrics and wearable technology.

Start-Up Park for innovative maturing healthcare start-ups The Start-Up Park will once again provide a dedicated platform for innovative, maturing healthcare and medical start-up companies looking to find business partners, network and meet industry professionals. The Start-Up Park will play a significant role as an enabler of the entrepreneurial ecosystem that encourages medical and health innovation in Singapore, bringing together thought leaders and stakeholders who will share start-up experiences and best practices.

The Start-Up Podium®, a specially curated programme including a series of fireside chats and panel discussions will also cover trending topics such as the Progress of Healthcare and Life Sciences during the pandemic, How the pandemic changed the use of Blockchain, AI & Cloud in healthcare.

Thought leadership and knowledgesharing programmes Interdisciplinary seminars covering relevant industry topics and trends will be held along side MEDICAL FAIR ASIA 2020 MEDICAL FAIR ASIA MEDICINE + SPORTS CONFERENCE | 9 December Returning for the third instalment, the 1-day conference will bring together regional as well as international, leading sports medicine and sports science experts, physiotherapists, professional athletes, sports techies and visionaries for an interdisciplinary dialogue on innovative approaches in prevention, training, regeneration and rehabilitation.

2nd ‘Paradigm Shifts in Healthcare’ Symposium – Prehabilitation & Pandemic Management in Community Health | 10 & 11 December After the resounding reception of Paradigm Shifts in Healthcare Symposium in 2018, the second edition will continue this successful streak and continue discus-

sions on ways to overcome challenges as healthcare models move beyond hospitals to communities.

Over two half-days, this symposium will focus on how communities can help prepare and enhance an individual’s functional capacity for better surgical outcomes even when surgery is not imminent or not immediately possible in the case of a pandemic.

OS+H Asia 2020 to be held alongside MEDICAL FAIR ASIA 2020 OS+H Asia 2020, the 12th Occupational Safety and Health Exhibition for Asia, will be strategically co-located with MEDICAL FAIR ASIA in December.

With a renewed focus on Safety, Security and Health at work, as well as a spotlight on Pandemic Management at the Workplace, the exhibition will showcase the latest technologies, innovative solutions, services and applications for the occupational safety and health industry. The synergistic showcase of MEDICAL FAIR ASIA and OS+H Asia will help tackle new challenges that have surfaced through the recent global pandemic and create a safer and healthier environment in the transition into the new normal.

With economies on the mend, MEDICAL FAIR ASIA 2020 is the ideal one-stop international sourcing and networking platform that offers a diverse range of business opportunities for exhibitors and visitors in the Southeast Asian market.

For pre-registration and more information on the exhibition, please go to www.medicalfair-asia.com.

Advertorial www.pharmafocusasia.com

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Exploring the Role of Ultra-pure Gelatins and Collagens in Biomedical Applications Tanja Vervust, Global Director, Biomedical, Rousselot

G

elatin’s legacy as a trusted excipient that complies with the highest international safety standards and regulations is well-established across the pharma industry, with the ingredient’s potential for biomedical applications also increasingly recognised worldwide. Its natural origin, cell-adhesive structure, high biocompatibility and biodegradability, as well as low immunogenicity, have made it an attractive material for biomedical solutions in a range of areas including regenerative medicine, drug screening and development, parenteral applications and hemostats.

Standard gelatins, however, do not comply with the purity requirements for most biomaterials. Pyrogens, including endotoxins, are common contaminants naturally found in native collagen, gelatin’s raw material, so extra purification steps need to be included in the production process to produce ultra-pure gelatins.

Endotoxins, which induce fever when released into the bloodstream, are a component of the exterior cell wall of Gram-negative bacteria. While they do not directly harm tissue, they can initiate mild to severe immune responses, as they act as an indicator for the presence of bacteria. Endotoxins can also trigger other cell types like stem cells and endothelial cells. In fact, any cell type containing the toll-like receptor-4 is sensitive to these molecules and has the potential to be affected in some way.

Depending on the concentration and exposure time, endotoxins can negatively impact cellular activity in terms of growth, morphology, differentiation, inflammation and protein expression even at very low levels (<100ng/ml). This means the biomedical application could fail or even endanger patient health.

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To minimise these risks, biomedical manufacturers are increasingly turning to highly purified gelatin solutions. We have recently spoken to Tanja Vervust, Global Director Biomedical at Rousselot, to find out more about the current and future use of ultra-pure gelatins and collagens in the biomedical industry.

Figure 1: Structure of an endotoxin

1. In what form are gelatins and collagens used in biomedical applications?

In its native form, collagen is one of the most abundant structural proteins in all connective tissues in the human body. Treated with hydrolysis and purification procedures, it can be processed into ultra-pure gelatin and hydrolysed collagen (or hydrolyzed gelatin) solutions for markets such as regenerative medicine, parenteral formulations and hemostats.

Cost-effective and readily available ultra-pure gelatins and collagens are, for example, an ideal choice for tissue engineering as they can build tissue scaffolds to simulate a native tissue environment without activating the immune system.

In stem and endothelial cells specifically, using low-pyrogen gelatin as a biomaterial for scaffolds helps to minimise the risks of both immunogenicity and potentially tumorigenicity of the transplanted hydrogel. Ultra-pure gelatins can even act as a mechanical barrier for implanted organs, against a rejection of the immune system.

In addition, highly biocompatible, purified pharmaceutical gelatin helps provide drug protection, offers superior drug loading rates, and great flexibility in the control of drug release. It helps stabilise vaccines and other formulations and minimises side reactions while ensuring patient safety.

Thanks to gelatinâ&#x20AC;&#x2122;s foaming functionalities, ultra-pure gelatin can be designed to absorb more than 40 times its own weight and is widely accepted as an ideal material to control blood flow through hemostatic applications, mainly in the form of sponges, strips, powder or nanofibers.

2. What are the benefits of using X-PureÂŽ ultra-pure gelatins and collagens in biomedical applications?

Our portfolio of X-Pure gelatins and collagens offers manufacturers the purity needed to create effective biomedical applications that ensure patient safety.

Ir TANJA VERVUST holds a Master of Science in Bioscience Engineering. She has over 25 years of experience at Rousselot where she held different positions such as Process Development Manager, Production Manager, Quality Manager and since 2011 Global Quality Director for Rousselot. In January 2018, she became Global Director Biomedical at Rousselot.

The FDA has imposed restrictions on endotoxin content for a number of medical applications, including 2.15 EU (or 0.06 EU ml-1) for devices exposed to the central nervous system via cerebrospinal fluid, and 20 EU (or 0.5 EU ml-1) for peripheral applications that can be reached by the cardiovascular and lymphatic systems. The European Pharmacopoeia, as well as its US and Japanese counterparts, also request compliance to endotoxin limits for parenteral administered pharmaceuticals. Endotoxin limits for injectables have to be determined in relation to the body weight and have conventionally been set to 0.2 EU kg-1 if introduced into the spinal canal and 5 EU kg-1 if injected elsewhere.

Rousselotâ&#x20AC;&#x2122;s patented endotoxin removal process overcomes the limitations of other approaches that change the composition of gelatin or cause new impurities. Our customisable platform also allows to engineer any type of pharmaceutical and medical gelatin with different purity ranges at any scale, facilitating customisation to your needs while providing unparalleled consistency and purity. This makes X-Pure the most advanced range of ultra-pure gelatins and collagens (10EU/g) for biomedical applications across regenerative medicine, parenteral formulations and hemostats.

Our X-Pure range is deemed Generally Recognized as Safe (GRAS) by the US FDA and compliant with the US, EU, Japanese Pharmacopeias.

X-Pure can promote tissue regeneration in high-risk surgeries and cell-laden treatments in low-risk surgeries, while also supporting the healing process of deep uninfected wounds. In novel www.pharmafocusasia.com

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stem cell therapies, X-Pure increases cell growth and the viability of cell culturing and transport.

X-Pure’s potential in endotoxin-sensitive cell cultures was highlighted by a study carried out in collaboration with Ghent University1. A comparison on the viability of immune cells (THP-s) in a 10 per cent X-Pure gelatin solution versus standard hydrogels showed a significantly improved cell survival in X-Pure after 3 days of culture. This study highlights the potential of X-Pure as a valid and improved solution for endotoxin-sensitive cell cultures, as it also represents a solution to the batch to batch variation and the overload of growth factors associated with some other hydrogels.

Interestingly, gelatin hydrogels devoid from endotoxins can also be used for storage or transport of endotoxin-sensitive cells, as they significantly improve their survival.

Preliminary results of a study carried out in collaboration with Ghent University showed that the addition of 10 per cent X-Pure gelatin to the medium significantly improved viability of endothelial cells after 3 days of storage at 4°C, even in absence of serum, and was significantly better compared to non-purified gelatin. It also aids the sustained or site-specific delivery of drugs, particularly in cancer therapy and orthopedic implants, and is an exceptionally safe gelatin solution for in-body hemostatic use.

1. Unpublished Rousselot study

Figure 2: The clinical potential of GelMA based biomaterials is huge. Depicted here is GelMA at work to control heart bleeding from cardiac penetration wounds (see Hong et al. 2019). GelMA excels as a bioglue because of its very strong adhesion to wet and mobile tissues.

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High-quality and fully traceable, the X-Pure range is especially well-suited for applications that require frequent or highquantity administration in contact with cardiovascular or neural systems, as well as end-products that reside in the body for an extended period of time. Beyond this, Rousselot’s ultra-pure X-Pure gelatins and collagens can be used in combination with sensitive active ingredients like live cells, where impurities could impact the effectiveness, durability and/or viability of the application.

3. You have recently launched a new gelatin methacryloyl, X-Pure® GelMA. Could you tell us a bit more about this product?

A polymerisable hydrogel material derived from gelatin, Gelatin Methacryloyl (GelMA) is an ultra-pure solution that is functionalised via photo-crosslinking and therefore holds great potential for the creation of tunable biological environments for culturing various eukaryotic cells at body temperature.

Over the past five years, gelatin methacryloyl (GelMA)-based biomaterials have increasingly moved into the spotlight and are widely used in various biomedical research applications, including bioadhesive, drug, gene and growth factor delivery, tissue engineering and biologyon-a-chip. Many of these concepts are now being translated into the clinic, making GelMA biomaterials an indispensable asset for medical innovation. Standard GelMA products, however, often carry high and variable levels of soluble impurities originating from either the raw material or the chemical synthesis process. The presence of these impurities such as endotoxins and MA residues are detrimental for in-body use and can also affect the success of in vitro applications.

To help biomedical manufacturers create high-quality, safe products, we have recently launched X-Pure GelMA, the first GMP-ready range of gelatin methacryloyl biomaterials suitable for preclinical and clinical applications, including

RESEARCH & DEVELOPMENT

3D bioprinting, tissue engineering and regenerative medicine. Once gelatin has been obtained via hydrolysis, Rousselot’s unique purification process performs a two-stage routine, which results in GelMA solutions with ultra-low levels of pyrogens and residual methacrylic acid. This, combined with the full and validated traceability of Rousselot’s raw materials, guarantees an excellent safety profile, and consistent batch-to-batch quality and mechanical properties that ensure reliable results and shorter lead times to the clinic.

The X-Pure GelMA production process is also scalable, meaning that variables can be changed to create solutions that are tailored to their specific purpose.

4. Are there any biomedical applications where purified gelatins are needed that you would like to highlight?

Tissue engineering is one of the most fascinating and trendsetting strategies for regenerative medicine. Its aim is to replace, repair or reconstruct injured tissue or organs with engineered functional tissue, biological implants and cell based multi-organ models attracting great attention for clinical, diagnostic and pharmaceutical research.

Within tissue engineering strategies, 3D bioprinting has been promoted as a state of the art tissue engineering technology, used to fabricate biomimetic scaffolds that are structurally and functionally relevant. 3D bioprinted scaffolds can support lineage-specific differentiation, intercellular communication between cells and their environment, and development into microstructures, such as capillaries, epithelia or organoids, meaning that it offers a great technological platform for reconstructing hierarchical tissue structures with full cellular functionality within the construct.

The 3D bioprinting process combines biomaterials with living cells to generate precisely controlled 3D cell models and tissue constructs.

Figure 3: Impurity levels of commercially available GelMA grades and Rousselot X-Pure GelMA (pellets after centrifugation of 1-ml of 8% w:w solutions).

X-Pure GelMA comes with ultra-low levels of impurities.

By optimally combining multiple cell types, growth factors and biomaterial compositions, highly complex and fully functional tissue constructs can be generated through self-organisation and maturation. In this process, the selection of a suitable biomaterial is of critical importance.

They should not only be biocompatible, but also have high water binding capacity and sufficient porosity to provide nutrient diffusion and cell migration. Additionally, mechanical properties such as stiffness and geometry have a great impact on cellular functions.

Gelatin’s versatility can represent a great advantage in bioprinting to obtain biocompatible cell laden constructs with high structural resolution and shape.

However, to create bioprinted hydrogels with a good mechanical stability at physiological temperatures, gelatin needs to be crosslinked.

High gelatin purity is essential to secure proper cellular characteristics and functionalities in the engineered tissue that will ultimately be transplanted into the body to restore the damaged tissue / reduce the risk of tissue rejection.

5. Rousselot is well-known in the pharmaceutical industry for its gelatin as an excipient for capsules and soft gels. Why are you now moving into the biomedical sector?

Rousselot has been exploring the collagen molecule for over 125 years and knows its seemingly endless functionalities inside out. As the biomedical market evolves and new applications emerge, this space offers an exciting opportunity for companies with strong research and innovation capabilities like ours to further expand our expertise in the collagen market and help push the industry forward. This is why we have decided to do our part to advance biomedical science by delivering highquality, ultra-pure gelatin and collagen solutions that meet the demands of the biomedical market today and in years to come.

To find out more about Rousselot’s X-Pure range of ultra-pure gelatins and collagens for biomedical applications, visit www.rousselot.com/biomedical or contact: biomedical@rousselot.com

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DIGITAL SOLUTIONS IN DRUG DEVELOPMENT Regulations to enable safe, effective, and high-quality solutions

From mobile medical apps and fitness trackers, to software that supports clinical decisions doctors make every day, digital technology has been driving a revolution in healthcare. As we are learning to live the virtual new normal in COVID-19 era, adoption of digital solutions has witnessed further acceleration. To keep pace with this promising innovation, the regulators must modernize its approach to regulation. Question to ask ourselves is “How to ensure high-quality, safe and effective digital health products”.

This article highlights changing Regulatory landscape (European/FDA Guidelines) for enabling Safe, effective, high-Quality & trustworthy AI/Digital solutions in Pharma.

Shrishaila Patil, Vice President, Statistical Programing, Navitas Data Sciences, a part of Navitas Life Sciences (a TAKE Solutions Enterprise)

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F

rom mobile medical apps and fitness trackers, to software that supports the clinical decisions that doctors make every day, digital technology has been driving a revolution in healthcare. As we learn to live in the new normal, forced by the COVID-19 pandemic, adoption of digital solutions has witnessed further acceleration.

To keep pace with this promising innovation, regulators must modernise their approach to regulation.

The question is “How can we ensure high-quality, safe, and effective digital health products”.

This article focuses on the changing Regulatory landscape (European and FDA Guidelines) for enabling safe, effective, high-quality and trustworthy Artificial Intelligence (AI) and Digital solutions in Pharma.

With COVID-19 acting as a catalyst, just what is changing?

In the past few years, many innovations and novel approaches across Clinical Trial processes have been witnessed.

RESEARCH & DEVELOPMENT

To a degree, COVID-19 has acted as a catalyst to some of these great innovations and adaptations.

Real World Data (RWD)/Evidence

• To leverage diverse data sources and analytics tools to enhance study design and protocol optimisation, capturing clinical trial data more efficiently.

• To make healthcare data both tangible and manageable using novel data analytics to extract insights, to aid a better understanding of disease. RWD can come from several sources, for example: • Electronic Health Records (EHRs) • Claims and billing activities • Product and disease registries • Patient-generated data, including in home-use settings • Data gathered from other sources that can inform on health status, such as mobile devices

Digital Data collection methodologies: Mobile Technology, Wearables, ePRO, eCOA, etc.

• To empower robust data capture, whether reported by the patient or by leveraging novel sensors. For example, we have seen the Apple Heart Study with Stanford Medicine with over 400,000 people participating to identify irregular heart rhythms.

Conventional Clinical Trials to Virtual Trial designs

• To Improve patient recruitment, retention, and real-time access to data for improved Quality • Sponsors need to ensure that vendors have enough industry, technological, and regulatory expertise to create a virtual trial environment • Training is required for both the personnel and patients involved in the

trial in order to understand the tools used • A hybrid model can improve the patient experience while, at the same time, giving sponsors a low risk jumping off point to familiarise themselves with the virtual trial environment Routine monitoring to Risk-based and centralised monitoring

• An improved and efficient approach to Clinical Trial conduct, with better oversight by moving away from 100 per cent source data verification. ICH E6 (R2) has really encouraged this approach • Real-time remote monitoring facilitating decentralised healthcare Digiceuticals or Digital Therapeutics • Digital therapeutics are evidence-based therapeutic interventions driven by highquality software programs to prevent, manage, or treat a medical disorder or disease. Some examples include:

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Total Product Lifecycle Approach of the Software Precertification Program

Figure 1

• FDA Approved Bluestar® Phone App (from Company Welldoc) for managing diabetes and is the only FDA cleared and reimbursable Software as a Medical Device that works with a patient’s existing device.

• FDA Approved reSET to help those with opioid use disorder Personalised Medicine

• Making sense of genomic data and personalised adaptive treatment, dosing plans for each patient • Medical treatment tailored and adaptable to the patient based on their predicted response or risk of disease Leveraging Big Data, Robotic Process Automation, Artificial Intelligence, Machine Learning, Deep Learning, and Natural Language Processing

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• Using technologies to unlock valuable new insights from the rich and diverse data available What we need to know is how this technological transformation impacts: • Patients • Study/Protocol Design • Regulatory Compliance • Data Quality • Investigators • Pharma Companies • CROs • Biometrics Process/CDM functionality • Scientific/Technical/Data Standards As a core part of clinical trial teams, each of us will have a significant role to play as we experience this exciting time of transformation.

We need to have a new mindset and adapt our SOPs, processes, and approach accordingly in order to accommodate these changes to the way that Clinical

Trials are conducted, Data is captured, analysed, and reported.

As we adapt, we need to continue to safeguard Data Integrity, Quality, and Security by ensuring compliance to changing requirements from Global regulatory bodies.

US FDA - Key Guidelines and Initiatives:

The 21st Century Cures Act (Cures Act), signed into law on December 13, 2016, is designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently.

As of today, more than 30 AI algorithms have been approved by the US FDA including those for the detection of diabetic retinopathy, stroke, brain haemorrhage, and atrial fibrillation.

RESEARCH & DEVELOPMENT

The FDA released its Digital Health Innovation Action Plan in 2017 clarifying the FDA’s role in advancing safe and effective digital health technologies and addressing Key provisions of 21st Century Cures Act. The FDA released its Policy for Device Software Functions and Mobile Applicationsi in 2019. This guidance explains how the Agency plans to regulate software that aids Clinical decision support (CDS), including software that utilises machine-learning-based algorithms.

The FDA is to focus regulatory oversight on higher-risk software functions, such as those used for more serious or critical health circumstances as well as Software that utilises machine-learning based algorithms, where the user might not readily understand the program’s

‘logic and inputs’ without further explanation Software Precertification (Pre-Cert) Pilot Program:

The Software Pre-Cert Pilot Program will help inform the development of a future regulatory model. This model will provide more streamlined and efficient regulatory oversight of software-based medical devices developed by manufacturers who have demonstrated a robust culture of quality and organisational excellence, and who are committed to monitoring real-world performance of their products once they reach the market.

The goal of the program is to have tailored, pragmatic, and least burdensome regulatory oversight that assesses organisations (both large and small) to establish trust that they have a culture

of quality and organisational excellence such that they can develop high-quality Software as a Medical Device (SaMD) products Figure 1.

The FDA's Total Product Life Cycle (TPLC) approach enables the evaluation and monitoring of a software product from its pre-market development to post market performance, along with the continued demonstration of the organisation's excellence: • Excellence Appraisal • Review Determination • Streamlined Review • Real-world Performance Achieving FDA Approval

FDA Approval Status could be put at risk after each update or new iteration for AI-powered therapeutic/diagnostic tools. For example: Security Updates,

Overlay of FDA's TPLC approach on AI-ML workflow

Figure 2

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adding new features or functionalities, or updating an algorithm, etc. Planning to take a version-based approach to the FDA approval process might be good idea. In this approach, a new version of software is created each time the software's internal ML algorithm(s) are trained by new set of data, with each new version being subjected to independent FDA approval.

FDA's TPLC approach on AI/ML workflow:

The highly iterative, autonomous, and adaptive nature of these tools requires a new, TPLC regulatory approach that facilitates a rapid cycle of product improvement and allows these devices to continually improve, while prov Figure 2.

To fully realise the power of AI/ML learning algorithms, while enabling continuous improvement of their performance and limiting degradations, the FDA’s proposed TPLC approach is based on the following general principles that balance the benefits and risks, and provide access to safe and effective AI/ML-based SaMD: • Establish clear expectations on quality systems and Good ML Practices (GMLP) • Conduct a pre-market review for those SaMD • Expect manufacturers to monitor the AI/ML device and incorporate a risk management approach in development, validation, and execution of the algorithm changes (SaMD Pre-Specifications and Algorithm Change Protocol) • Enable increased transparency to users and the FDA using post-market real-world performance reporting for maintaining continued assurance of both safety and effectiveness.

European Commission on Artificial Intelligence: EU has adopted a three-step Approach as described below.

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Addressing the AI Black Box Issue:

As of today, more than 30 AI algorithms have been approved by the US FDA including those for the detection of diabetic retinopathy, stroke, brain haemorrhage, and atrial fibrillation.

not decrease, limit or misguide autonomy • Robustness and Safety: AI should be secure, reliable, and robust enough to deal with errors or inconsistencies during all life cycle phases of AI systems • Privacy and Data governance: Citizens should have full control of their own data. Data should not be used to harm or discriminate against them.

• Transparency • Diversity, non-discrimination, and fairness • Societal and environmental well-being: AI systems should be used to enhance positive social change, enhance sustainability, and ecological responsibility • Accountability for AI Systems and their Outcomes: Mechanisms should be put in place to ensure responsibility and accountability for AI systems and their outcomes 2. European AI Alliance:

• Large-scale pilot with partners involving a wide range of stakeholders for feedback • Members of AI high-level expert group will help present and explain the guidelines to relevant stakeholders in Member states

1. Setting out requirements for achieving trustworthy AI

3. Building international consensus for human-centric AI

• Human Agency and Oversight: AI systems should enable equitable societies by supporting fundamental rights, and

• Play an active role in international discussions and initiatives

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• Can users understand the root cause of the negative outcome in AI solutions?

• Can users identify the training data or ML paradigm that led to AI application’s specific action?

• Incorrect Training Data can lead to misdiagnosis and/or an incorrect treatment recommendation. As a result, Clinical adoption is slow and there is a lack of trust from Patients.

• At this stage, AI can help provide data for better decision making (AI will not be fully replacing decision making processes). AI software developers will have to demonstrate to Clinicians that, with this tool, they can do a better job.

Formalised AI Use cases by American College of Radiology (ACR) Data Science Institute (DSI)

• To increase utilisation of AI adoption in Medical Imaging, the American College of Radiology (ACR) Data Science Institute (DSI) started releasing formalised use cases for how AI tools can be reliably used.

• Use cases empower AI developers to produce algorithms that are clinically relevant, ethical, and effective.

• The use cases are designed to guarantee that algorithms are applied to address clinical questions and allow for quality assessment measures that demonstrate compliance with legal, regulatory, and ethical measures.

• At present, ACR DSI has use cases for breast imaging, cardiology, musculoskeletal, neurology, oncology, paediatrics, and thoracic.

Approved AI solution in Pharma: A Case Study

IDx-DR is an AI diagnostic system that autonomously analyses images of the retina for signs of diabetic retinopathy.

This is the first ever autonomous AI system cleared by FDA (announced on 11 April 2018) that provides screening/ diagnostic decision without the need for a clinician to interpret the image or results.

RESEARCH & DEVELOPMENT

AUTHOR BIO

This device is a software program that uses an AI Algorithm to analyse images of the eye taken with a retinal camera called a Topcon NW400. Once the Doctor uploads the digital images of the patient’s retina to a cloud server on which IDx-DR software is installed, the software provides doctors with one of two results: • More than mild diabetic retinopathy detected; refer to eye care professionals

• Negative for more than mild diabetic retinopathy; rescreen in 12 months Conclusion:

With ongoing Global health concerns and the current COVID-19 pandemic situation, we need to identify and encourage forward-looking ideas, facilitate innovations, and bring them to life in order to cultivate ideas into potential solutions for our customers and, most importantly,

Shrishaila has done Masters in Biotechnology from Bangalore University & has more than 15 years of experience across Drug Development. He is currently working as Vice President at Navitas Data Sciences, heading the Statistical Programming department, India. He is also working as CDISC Volunteer and PhUSE India Membership officer. He has authored an International book ‘FDA Clinical Outcome assessments and CDISC QRS supplements’ under ‘Clinical disciplines’ category with LAMBERT Academic Publishing group. He has exposure to various Analytical tools like SAS (Base and Advance Certified), R, PYTHON and CDMS Tools like Inform (EDC), Medidata Rave (EDC), Clintrial and Oracle Clinical LSH. He is a passionate Speaker & active in most of the conferences in the industry. His hobbies are Reading, playing Table tennis etc.

save the lives of patients in need.

We must ensure both Patient Safety and Data Integrity when dealing with Technology.

Working professionals need to understand the changing landscape, Data sources, and Metadata, to ensure Data Quality during its processing and be able to upskill themselves to manage new technologies and tasks.

Global Regulatory bodies are actively encouraging the implementation of technology for faster drug development and are introducing Key Guidance documents and Initiatives.

Sponsors and vendors need to think innovatively in terms of their Study designs and executions plan and incorporate technology driven elements. Only then can we develop innovations beyond the current boundaries.

References are available at www.pharmafocusasia.com

We take responsibility for everything we do. Our service employees make sure you get the support you need.

Straightforward, quick and right there with you – ranging from support during product innovations and commissioning to after-sales service. Our portfolio continues to grow - and helps take you further!

Syntegon. Formerly Bosch Packaging Technology. syntegon.com/numbers

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PATIENT-CENTRIC CLINICAL TRIALS

How language and tech are re-shaping clinical trials today?

This article elaborates upon the meaning of ‘patientcentricity’, and touches upon industry trends, evolving regulations and organisational strategies to develop a ‘Patient Focused Drug Development’ strategy, and the best practices and metrics used to define success.

While technology has clearly been a game-changer in enabling a ‘patient-centric’ approach, with trials shifting focus from the site to the patient’s home, the industry is grappling with the need to ensure the ‘patient-connect’. This article discusses different strategies for driving patient-centric clinical trials, including the importance of listening to the patients needs and engaging with the patient in the right way..

Nimita Limaye, SVP, Strategic Partnerships and Medical Writing, CSOFT Health Sciences

S

o, we’re spending US$2.6 billion on bringing a new drug to the market (FDA News, 2014) and we’re spending about a dozen years to do so. That is a lot of time and money spent! For whom are we doing all this, again? The patient, yes, of course! But are we really listening to the patient’s voice and addressing the patient’s needs? The right to self-determination is the consequence of a free society. Yet is the patient a passive recipient of healthcare decisions made by the investigator and the sponsor, or can patients be active participants and participate in the decision-making process and improve their own clinical outcomes? A report published by The

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Economist Intelligence Unit (commissioned by PAREXEL) demonstrated that the patient-centric approach resulted in not only doubling the number of patients being recruited, but recruitment took half the time. In addition, the drug was 19 per cent more likely to be launched in these trials. Surprisingly enough, only 5.2 per cent of phase II-III trials followed this approach (EIU, 2018).

The industry is waking up, albeit a little late, to the need to drive patientcentric clinical trials. The ‘Chief Patient Officer’ is a new term that has come into existence as the industry adapts to the ever-evolving model of clinical trials and pharma companies are now taking

measures to engage actively with patients.

Bristol-Myers Squibb, for example, is soliciting patient inputs on their protocols, that include, among other things, the inclusion and exclusion criteria; and Ipsen Biopharmaceuticals seeks patient’s inputs from the start of the clinical trial set up and has adapted protocols based on patient’s inputs (Round and Williams, 2018). Merck has attempted to enhance patient retention by having at-home sample collection kits to minimise the patient burden. It is conducting conversations with subject matter experts to enhance its cultural competency and develop outreach tools. It is also monitoring enrolment data by ethnicity to enhance patient diversity and has focused on enhancing minority and ethnic representation (African Americans, for example, represent less than 5 percent of the clinical trial population) (Nissen and Geday, 2019).

With a similar objective in mind, Janssen conducted trials like GRACE (Gender, Race and Clinical Experience) and LOTUS, using social media, imagery and educational materials, and arranged for transport and chose sites so as to optimise inclusion.

In addition to recruitment, patient retention is of prime importance.

With one-third of patients dropping out of clinical trials, companies are investing in diverse initiatives to enhance patient retention. Janssen Pharmaceuticals has gathered feed-

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back from over 1,700 trial patients in 19 countries to better understand patients needs and has launched Health Caring Conversations for Clinical Research, to drive science-based patientcentred conversations. It has also integrated concepts such as telemedicine, ‘Direct-to-Patient’ (DTP) shipment of drugs, collection of samples from patient’s homes and the use of platform solutions and wearables to take trials to the patient’s home (Levine, 2019). In fact, it is running two virtual clinical trials. The Heartline Study, which is the largest randomised trial on heart disease in history, which will run for three years on 150,000 patients, all above 65, uses the Apple Watch ECG application and the Apple’s iPhone Health app (Hale 2020). The CHIEF-HF is the first virtual trial to evaluate a new indication for Invokana (canagiflozin – a drug earlier approved to treat diabetic kidney disease). The trial which is to be conducted on 1900 patients leverages an innovative mobile clinical trial platform, and wearables and will assess the quality of life and track physical activity of people with heart failure with

or without type 2 diabetes. It follows a patient-centric approach and will not only take the trial to patient’s homes, but will also return patient’s their own data to help them understand how treatment and lifestyle choices affect their health. (Janssen, 2019).

Sanofi conducted a fully virtual phase IV clinical trial, VERKKO, using a wireless glucose meter to monitor diabetes, using things like e-consenting, and successfully recruited 60 patients (average age 56) via Facebook. More importantly, the patient satisfaction score was 4.52 out of 5, demonstrating the success of this patient-centric approach (Limaye R et al, 2018). Sanofi has also worked with patient advisors, standing-in as subject matter experts, representing patient groups. Leveraging their input at an early stage, has helped Sanofi design trials focused around the day-to-day lives of patients, and decrease the number of patient visits and significantly bring down the number of protocol amendments as well (ACRP, 2016).

In a patient-centric approach towards oncology clinical trials, Pfizer launched the Living with Cancer initiative, which

includes the LivingWith™ app which assists people manage their lives track how they’re feeling, and communicate with loved ones.As a part of the Pfizer Oncology Together program, Pfizer arranges for dedicated ‘Care Champions’ with a social-work background to deal with a lot of procedural, emotional, logistical and financial complexities. Pfizer also runs a patient gratitude program to acknowledge patients’ contributions.

(Schmeltz, 2018). The FDA’s Oncology Center of Excellence (OCE) launched an initiative called Project Patient Voice to create a publicly available information bank describing patient-reported symptoms from cancer trials for marketed treatments and Astra Zeneca became the first company to participate in this initiative contributing patient data from its ongoing AURA3 trial for locally advanced or metastatic non-small cell lung cancer (Ray, 2020).

Some of the important aspects of designing a patient-centric clinical trial include: • Obtaining patient’s inputs into the Target Product Profile (TPP), the blueprint of the product label

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• Obtaining patient’s inputs into protocol design – ‘crowd-sourcing’ of protocols, to find out what works best for patients, from patients. Transparency Life Sciences has developed a platform ‘Protocol Builder’, which enables patients and physicians to share their inputs in the protocol development process and this platform is being used to develop trials for irritable bowel disease, Parkinson's disease, and multiple sclerosis (Carlson, 2014). It is believed that the most successful trials of the future will be designed by patients • Obtaining patients insights at all stages along the patient journey from TPP to product label • Identifying end-points that are important to patients – establish meaningful benefit to patients. Patients know what matters to them – what makes a difference to their lives. This has been highlighted in the U.S. Food and Drug Administration’s (FDA’s) Guidance for Industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (Dec ‘09). ICH E8 (R1) (May 2019)also stresses upon the importance of obtaining patient input in the design, planning and conduct of clinical trials • Recognising that it’s not only about quantitative research: qualitative research also matters. Personal interviews, focus groups, etc help better understand the patient’s point of view • Ensure that content validation of Patient-Reported Outcomes (PROs) is based on patient’s inputs. PROs are questionnaires which obtain the patients point of view on the impact of the treatment on their symptoms, their quality of life, treatment satisfaction, or the impact of the treatment on their daily life • Understanding ‘what is the most burdensome aspect of the disease?’

• Ensuring that the most relevant ‘current’ needs of the patient are being addressed as patients’ needs are also evolving • Conducting ‘mock’ trials. Running a ‘day in the life of a patient’. Putting

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A report published

by The Economist Intelligence Unit (commissioned

by PAREXEL) demonstrated that the patient-centric approach resulted in not only double the number of patients being recruited, but in recruitment taking half the time.

yourself in the patient’s shoes – and figuring out whether you like what you are experiencing. If you perform UAT for a software application before launching it to ensure that end-user’s requirements are being met, shouldn’t we be doing the same for patients?

• Enhancing patient education.

Knowledge drives empowerment – leads to better decision making. This allows patients to have a better control over their health and also improved adherence • Use the right level of health literacy.

The Patient Protection and Affordable Care Act of 2010, Title V, defines Health Literacy as ‘the degree to which an individual has the capacity to obtain, communicate, process, and understand basic health information and services to make appropriate health decisions.’ It is recommended that health information should be communicated in lay language so that an 11 – 13-year old (6th – 8th) grade literacy level) cab understand it.

Microsoft Word’s Flesch-Kincaid grading scale recommends a readability score (reading ease) of 60 – 80. This is impacted by the length of the words and sentences used and by the percentage of passive sentences used. Short, sweet and simple is the way to go! All medical jargon should be avoided and scien-

tific terms should be broken down into simple, lay language. The active tense is recommended. Images and pictograms if used, should be simple. Only relevant information should be included and it should be contextual • Ensuring that you are communicating with the patient in the right language, at the right time, using culturally sensitive communication • Facilitating logistical needs - with 70 per cent of patients staying more than 2 hours from the trial site, it can be challenging for a patient to participate in a clinical trial. Traveling to a site would be even more difficult for patient’s that are aged, frail, are children, or have infants.

Arranging for a concierge to help with travel to the site or managing day care costs can make a lot of difference.

• Partnering with patient advocacy groups and establishing patient alumni networks and patient communities to obtain deeper insights and greater engagement • Establish increased transparency by sharing aggregate trial results • Developing patient-friendly websites • Creating a digital health strategy to listen to the patients’ voice • Conducting virtual clinical trials – enhancing access to clinical trials.

Providing the patient with the comfort of participating from home • Empathy is a very big piece of this. AI driven customised text-messaging, that can respond to patient’s needs.

While many companies are implementing novel ‘patient-centric’ strategies, there is still some ambiguity in defining the right measures of success to determine the efficacy of the implementation strategy. In a survey conducted by Deloitte across pharma, medtech and patient advocacy / disease research organisations, it was found that challenges still exist in establishing the performance of a ‘patientcentric’ model (Myers et al, 2020).

Some short-term Return on Investment (RoI) metrics that are used to measure the success of a patient centric approach include:

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Higher patient satisfaction scores Improved recruitment and retention Faster Trials Fewer protocol amendments Greater brand loyalty.

The viewing lens is changing – the patient is finally finding a voice – the patient perspective is actually being obtained from the patient – not from the provider or payer, nor from the regulator or the sponsor. The consumerisation of care and higher levels of patient education has encouraged the development of a patient-centric approach (Robinson, 2014). A very interesting difference in patient vs physician perspective has been shared by John Bridges, a professor at Johns Hopkins University, who brought to light striking differences between the patient’s and the physician’s perspective. He highlighted that in patients with schizophrenia, patients prioritise improved satisfaction, independence, physical health, activities of daily living, and work capacity, as against decreased psychotic symptoms, improved self-confidence, improved capacity for communication and emotion, and decreased mistrust and hostility, which were prioritised by physicians (Myers et al, 2020).

The FDA has been a catalyst of change driving Patient-Focused Drug Development (PFDD) and is developing 4 guidances on how sponsors can obtain comprehensive patient input, how they can identify what is important to patients, the methods for developing fitfor-purpose clinical outcome assessments (COAs) and how these COAs can be incorporated into regulatory decision making (FDA, June 2020). The main objective of PFDD is to assess how to better incorporate the patient’s voice in drug development and evaluation.

The FDA has organised several patient listening sessions in collaboration with NORD (The National Organization for Rare Disorders), which have been helpful in obtaining the patients perspectives, both in terms of the impact of the treatment on a day-today basis, as

well as the long-term impact. There are also FDA led and externally led PFDD meetings and the FDA’s Patient Representative Program (PRP), in which Patient Representatives provide direct input to inform the Agency's decisionmaking (FDA, August, 2019).The Patient Engagement Collaborative (PEC), a joint initiative of CTTI (The Clinical Trial Transformation Initiative) and the FDA involves meetings of the FDA with 16 diverse representatives from the patient to achieve more meaningful patient engagement in drug development and regulatory decision making (December 2018).

In a survey conducted by CTTI in 2017 on 193 patients in the US across four therapeutic areas, that 90 per cent were willing to use alternate modes of communication with a trial doctor instead of in-person visits and 76 per cent indicated that they would prefer to participate in a mobile trial instead of a traditional trial and thought that the data would be more accurate. Many were also very willing to use mobile apps, wearables devices and patches, bodilyfluid diagnostic devices, and ingestible sensors (Perry et al, 2019). Thus, technology is not only being increasingly accepted by patients, but is becoming a way of life for them.

Digital therapeutics are taking patient centricity to the next level.

The FDA approved the Prescription Digital Therapeutics (PDTs) reSET-O® for Substance Use Disorder, reSET-O®, for Opioid Use Disorder and Somryst™. reSET-O for the treatment of for the treatment of chronic insomnia, resulting in Pear Therapeutics winning the 2020 MEDTECH Breakthrough Award For

Digital Health Innovation (May 2020).

The FDA recently approved a video game called EndeavorRx, developed by Akili Interactive Labs to treat ADHD. This has become the first video game to be approved by the FDA as a digital therapeutic (Nield, 2020).

Yet patient’s still want the personal touch and don’t want to participate in a trial in a vacuum (Stoecker, 2019). To make it even more personal is Mabu, Catalia Health’s AI enabled robot which helps treat patient’s with chronic illnesses.

It uses AI to learn about each patient through daily conversations, provides feedback to the patient and shares data with the healthcare provider as well (Winn, 2019).

Laura Holmes Haddad, cancer survivor, who shared her journey at the DIA Annual Conference 2020, highlighted three things that drive patient centricity: • Acknowledging the patient behind the number • Easing the economic burden on patients • Educating the provider.

She emphasised that though the trial sponsor and the patient are inextricably linked, at the nucleus of this relationship, humanity is the core.It’s really simple isn’t it – keeping the patient in the centre – or is it?There has been a paradigm shift. The focus has shifted from the healthcare practitioner to the patient.

Patients are indeed uniquely positioned to inform drug development. We need to understand their language, to hear what they are saying – and be sensitive to their needs. To quote Dr. Eric Topol, ‘The Patient Will See You Now!’ The world today is truly becoming ‘patient-centric’.

References are available at www.pharmafocusasia.com

AUTHOR BIO

• • • • •

Nimita Limaye has over two decades of life sciences leadership experience and serves as the SVP, Strategic Partnerships & Medical Writing at CSOFT Health Sciences. She is a strategic business leader with a strong understanding of the drug development industry, with rich cross-cultural experience working across the US, Europe and Asia.

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Double-blinding Capsules for Clinical Trials

How over-encapsulation can help tackle bias?

During the preparation of clinical studies, the method for visually blinding dosage forms is a vital consideration. While many blinding options are available to sponsors, overencapsulation remains the most popular for many reasons, including better accessibility, efficacy, ease, shorter development time and cost.

However, over-encapsulation involves a number of individual operations that can create a variety of complex situations if not managed effectively. From capsule colour and size selection to having a well-trained team dedicated to the manufacturing process, it is vital that companies take the time to make sure each part of the process is managed properly to curtail problems and provide an effective blind in the study..

Steve Rode, Manager Business Development, Capsules and Health Ingredients, Lonza Hideyasu Fujiwara, Business Development Manager, Lonza Capsules and Health Ingredients

C

apsules are tried, tested and trusted, but that is not to say that the method is simple or without innovation. Formulation considerations and patient-centricity have driven significant innovation by some businesses in the market. With the development of Hydroxypropyl Methylcellulose (HPMC) polymers, sponsors and manufacturers now have access to a capsule that is vegetarian and vegan-friendly and has a broader range of applications across different disease indications.

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Capsules and Health Ingredients business division and Hideyasu Fujiwara, Ph.D., Business Development Manager, Lonza Capsules and Health Ingredients, Japan discusses the importance of capsule selection and process considerations for providing an effective blind as well as how HPMC-based capsules can further the use of capsules in clinical trials.

Factors for effective blinding

Clinical studies are performed to evaluate the efficacy and safety of a trial drug in relation to a marketed comparator

product or a placebo. When blinding a drug product, the goal for investigators is relatively simple: to prevent patientsâ&#x20AC;&#x2122; ability to identify the blinded product.In a double-blinded trial, this goal is extended to include the trial staff. The design of the clinical study and characteristics of comparators, as well as advantages and disadvantages for each blinding approach, must be explored to determine the best blinding option.

For clinical conditions in which exposure to the drug at the right time is a critical determinant of efficacy, and encapsulation is being used as a blinding

CLINICAL TRIALS

method, it is strongly suggested that both the investigational and the reference drug are encapsulated to provide an effective blind. This will negate any questioning of the validity of the study’s results relating to the blinding method and ensure that appropriate comparisons and conclusions can be drawn without reproach.

For sponsors and their manufacturing partners, this can be challenging as they need to ensure that: • The blinded product is no more challenging to dose the patient than comparators or placebos; • The blinded drug product is expected to show the equivalent efficacy to the investigational medicinal product (IMP) or the commercial dosage form; • There is no risk of additional side effects; and • Resources/cost required for manufacture, blinding, qualification, release and stability are tightly controlled.

Over-encapsulation remains the most widely used method of blinding as it can deliver on all these fronts and is invariably the simplest technique to implement.

When done correctly, over-encapsulation has no impact on the trial drug product’s stability or efficacy– meaning it requires little additional process development and analytical work– while offering the flexibility to blind a wide range of oral dosage forms.

Once the decision has been taken to over-encapsulate, it is important to select the appropriate components that will be needed and to plan ahead to curtail problems that could occur once the patient receives the supplies. This includes common challenges such as managing the ‘shadowing’ effect, where the dosage form is visible through the shell of the capsule, providing a consistent weight and feel, as well as selecting an appropriate inactive backfill present in the dosage form that prevents ‘rattling’, or achieve a uniform rattle.

Size

The size of a capsule will be heavily influenced by two things – the size and shape

HPMC-based capsules offer a range of development benefits that complement traditional hard-gelatine capsules.

The introduction of these polymers increases accessibility to capsules for sponsors and gives them greater flexibility and product compatibility when selecting their dosage format. of the IMP and comparators and the potential to impact patient compliance.

The first step is to determine what size capsule shell is needed to properly blind each unit – remembering that uniformity is key so the difference in size between comparators and IMPs will have to be effectively managed. Although it is not completely necessary, it is recommended that the unit that is being encapsulated does not protrude above the body of the capsule shell when inserted. If the unit does not “sit” properly inside the body shell it may become necessary to backfill the capsule in a manner that will produce a considerable amount of waste.

If tablets are to be broken, it is critical that all of the tablet fragments are collected and accurately placed into each associated capsule shell.If all the fragments are not collected, the final dose of the blinded tablet could be altered. In addition, in some markets, regulators do not recommend breaking tablets to fit them inside capsules for blinded clinical trials, as there are questions raised around the impact this could have on drug efficacy and safety. For example, in the late 1990s, under newly modified regulations, tablets could only be broken if they had been designed with a score and the developer had specifically conducted studies around the potential impact of the broken tablet.

Study populations are also a vital consideration, as child and geriatric populations may have difficulty swallowing larger capsules. Capsule size is also an important factor where dysphagia, which is usually associated with Central Nervous System (CNS) indications, is a symptom of the disease or the restricts the ability to apply pressure using the tongue.

Selection of backfill material

Backfilling may be required to eliminate the rattle of a unit inside the capsule shell so that the patient is not able to determine the dose inside the capsule. If the rattle is not eliminated, the patient could possibly identify what is in the capsule, which could affect the clinical outcome or break the blind. In some cases, backfill may not be required as both the placebo or comparator and the active doses contain over-encapsulated units with similar rattle.

Where backfill is required, it is recommended to choose an excipient that is present in the dosage form being blinded.

Dissolution profiles and stability work may need to be conducted to verify that the material selected does not affect the pharmacokinetic profile.

The most commonly used excipients for backfilling are Microcrystalline Cellulose and Lactose Monohydrate.

These materials are used both independently of one another, as well as combined in a blend. In some cases, research has shown that the combination of the two may improve the dissolution results, meaning excipients for backfilling can affect the dissolution of the product1.

Depending on the grade of the material chosen, a lubricant, usually Magnesium Stearate, present at less than 0.5 per cent, is added as part of the backfill formulation. Not all grades of these two materials require such lubrication and the choice of adding the Magnesium Stearate is usually based on its presence in the formulation of the unit being encapsulated.

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The colour of the capsule is an extremely important detail that requires much consideration. It is not only critical to choose a colour and opacity that will completely hide the enclosed unit and prevent shadowing, but to consider colour-effect associations.

The ideal colour is one that does not show any shadowing or air pockets due to the backfill, or allow for the encapsulated tablet or capsule to be seen.

Ideally capsules for over-encapsulation are generally opaque capsules in nature and are usually not the same colour or shade as the unit being blinded, but rather slightly darker or more opaque in colour.

It is vital that the colour dyes and pigments used in the colour formulation are accepted wherever the study is being conducted. Many countries have restrictions on particular colours which need to be researched prior to selection.As regulatory rulings of various countries are constantly open to review and change, it is recommended that decisions regarding daily intake limits be made with advice from relevant regulatory experts.

Colour psychology is also an important factor when it comes to customer preferences and should be considered.

It can also play a significant role in patient adherence and there is evidence it can alter therapeutic effect in some indications2.

HPMC

HPMC-based capsules show great potential in becoming a viable alternative to gelatine-based formulations, where required. They are often preferred in clinical trials, and for many investigational New Drug Substances (NDSs)3, because they have the added flexibility to accommodate a vast array of drug products and formulations.

With potent NDSs under development, challenges deploying APIs in gelatine-based capsules are contributing to a shift towards the use of HPMCbased capsules. Issues with cross-linking

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reactions can lead to dissolution delay, difficulty containing hydroscopic APIs and mechanical stability.

Benefits of HPMC as a base material include the following: • Offers lower moisture content, which helps stabilise formulations and mitigates the challenges associated with APIs and excipients that are incompatible with gelatine.

• Polymers can withstand a wider range of temperature variation and fluctuation in storage and transit, meaning there is less chance for brittleness or breakage when compared to traditional gelatinebased capsules.

• HPMC is also non-ionic, enabling pH independent drug release, which can lead to more consistent bioavailability of the drug product. It has also been shown that advanced HPMC capsules without a gelling agent can provide improved and parallel dissolution performance compared to other HPMC capsules with a gelling agent4.

Customer preferences and perceptions

Provenance is becoming more important and there is increasing consumer demand for products free from any animal proteins and with colours and ingredients derived solely from natural sources.

Gelatine-based capsules offer traditional benefits and are supported with data to prove compatibility, but they do not meet clean-label requirements.

Developers of therapeutics of all kinds are responding to emerging social and cultural trends, forging a path for innovative clean-label products in the form HPMC-based capsules compatible with vegetarian and vegan lifestyles.

In summary

Over-encapsulation is one of the simplest solutions for blinding oral solid dosages in clinical trials. Its simplicity combined with high efficacy means it will continue to be the de facto blinding technique of choice wherever it is appropriate.

To deliver an effective blind and successful study, consideration must be given to the size, colour and material choice of the capsule as well as its compatibility with the IMP and comparator products - dissolution, diffusion and stability studies may be an essential element of selection in some instances.

HPMC-based capsules offer a range of development benefits that complement traditional hard-gelatine capsules. The introduction of these polymers increases accessibility to capsules for sponsors and gives them greater flexibility and product compatibility when selecting their dosage format.

Sponsors and clinical supply, manufacturing and service partners that understand and control every step of overencapsulation—from material selection to manufacture—will gain an efficient means for the integrity of their study and avoid bias.

Steve Rode is focused on supporting and growing the pipeline of new pharmaceutical and OTC products utilising Lonza’s diverse portfolio of capsule-based products and technologies.

With more than 31 years of industry experience, Steve has had the privilege of working with many top pharmaceutical and consumer healthcare companies in the development and launch of pivotal products

AUTHOR BIO

Colour

Hideyasu Fujiwara is supporting and growing the pipeline of new pharmaceutical and OTC products utilising Lonza’s diverse portfolio of capsule-based products and technologies. With more than 20 years of experience in the pharmaceutical industry, Hideyasu has had the privilege of working with many top Japanese pharmaceutical companies on a wide range of projects from early development stage to generic development.

CLINICAL TRIALS

THE IMPORTANCE OF PRINCIPAL INVESTIGATOR TRAINING M Many physicians and health care providers are intrigued by clinical research and seek out to become Principal Investigators (PI) without knowing what that role entails.

While future PIs may have advanced medical degrees and specialised training, they are often unfamiliar with what is involved in overseeing a clinical trial or the regulatory responsibilities that are needed for their role.

Lisa Dyment, Senior Director, Site Collaborations, PPD Leanne Heaton-Sims, Senior Manager, Enterprise Learning, PPD Rita Bragadesto, Principal Learning Specialist, PPD

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any physicians and healthcare providers are intrigued by clinical research and seek out to become Principal Investigators (PI) without knowing what that role entails. While future PIs may have advanced medical degrees and specialised training, they are often unfamiliar with what is involved in overseeing a clinical trial or the regulatory responsibilities that are needed for their role.

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to healthcare practitioners, enabling them to experience the many benefits of clinical research.

Offering flexible training delivery via virtual, face-to-face, or combined training sessions as needed allow PIs the opportunity to make trainings work with hectic schedules.

Given the importance of physicians in determining appropriate care options, it is imperative that the industry do more to educate and enable physicians to access clinical research trials for their patients. This article aims to share best training practices and explain why improving patient access to clinical trials starts at home by developing more physicians to become clinical research investigators.

PIs play an vital role clinical research.

They are responsible for all clinical research-related activities at their site and act as the bridge between the research and physician practice communities. PIs play an integral role in the conduct and management of the study. Unfortunately, there is a shortage of high-quality sites available for sponsors for certain indications and in certain parts of the world.

Approximately 50 per cent of principal investigators who participate in a clinical trial for the first time do not participate again 1, citing complexity of trials as the main reason, as well as lack of training and support, according to the Tufts Center for the Study of Drug Development’s analysis of data from the U.S. Food and Drug Administration2.

1. Gertz KA, Lamberti MJ. Global site landscape remains highly fragmented with variable performance. Tufts Center for the Study of Drug Development Impact Report. March/ April 2013;15 2. Wilkinson M, Getz K. Tufts CSDD Study Highlights: End-to-End Site Identification Through Start-up. April 2017

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The high PI turnover rate raises concerns, and some sponsors hesitate to use inexperienced PIs since they help determine the success of a study.

With experience often comes operational efficiencies in site selection, study start-up, enrolment, and data collection, among other things. These efficiencies help reduce trials costs and expedite timelines, which is why it is important to address the barriers that lead to “one-and-done” participation syndrome.

Barrier to participation

When surveyed, PIs cited lack of time, lack of resources, inadequate research experience, trial-specific issues, existing clinical management duties as reasons for not participating in clinical research3.

While participating in research, PIs are expected to recruit by discussing trial participation with his or her patient base and assist with the screening process. PIs will conduct study-specific visits and take part in regulatory and monitoring visits. In combination with these barriers, complex protocols can create undue stress. Much of this stress can be alleviated with practical, advanced clinical research training, coaching and support 3. Rahman, S., Majumder, M. A., Shaban, S. F., Rahman, N., Ahmed, M., Abdulrahman, K. B., & D'Souza, U. J. (2011). Physician participation in clinical research and trials: issues and approaches. Advances in medical education and practice, 2, 85–93. https://doi.org/10.2147/ AMEP.S14103

Benefits of taking part in clinical research

Adding high-performing research sites through adequate PI training broadens the pool of patients potentially eligible for trials and address the industry challenge of site and patient access for pharmaceutical and biotech companies developing promising new therapies.

Training more healthcare providers to conduct clinical research will give patients greater access to trials closer to home which makes trials more convenient and enables more patients to participate, including patients from traditionally underrepresented populations. This in turn enhances clinical trial diversity, making studies more representative of the real-world patient population and reducing failure rates.

Clinical research offers patients access to cutting-edge therapy, increased quality of care, closer medical attention, better follow-up, and continuity of care. If physicians with practices in rural areas participate in clinical research, their communities' benefit from expanded access to healthcare options. Physicians active in clinical research can expand their knowledge base and help develop medical innovations. Clinical research creates an additional revenue stream for sites, too. Research also helps hospitals and educational institutes with additional funding and grant capacity.

To increase participation, the research community needs to clearly outline the benefits of clinical research and potential to improve patient care. To make clinical research more accessible as well as encourage research culture, it is necessary to supply PIs the support they need to enhance their probability of being successful in taking part in clinical research. One way to do this is through advanced training tailored to the needs of the investigative site and staff and ongoing coaching designed

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Enabling PIs’ success

The first step in setting up PIs for success is to correctly train new-to-research sites the right way from the very beginning to provide quality data. Effective training drives repeat participation by physicians and healthcare providers in clinical trials by equipping them with the knowledge, skills, and desire to perform successfully.

A robust training programme can develop and upskill workforce capabilities across the clinical research industry, ease CRO burden by improving site capability to deliver quality outputs, promote career expansion and development, and bring clinical trials closer to the patients who need them. Training with spiral learning – an approach founded on the premise that students acquire a greater understanding of a subject each time the topic is met -- exposes learners to a wide variety of concepts and topics while deepening the complexity. Spiral progression, anchored by experiential based learning achieved through the real-life scenarios and interactive activities, builds confidence by providing real and practical experience.

Training should be detailed enough to address multiple learning styles and include the role specific ACRP (Association Clinical Research Professionals) core competencies for clinical site staff, aligned to the current Good Clinical Practices guidelines. To meet the demand of training needs, it is beneficial to implement a train-the-trainer approach. This will allow experienced clinical staff with an interest in training, to expand their area of focus, influence their own career development plan and boost motivation whilst sharing their expertise with the sites. The inclusion of multi-lingual staff in this approach provides opportunity for the training to be delivered in other languages, expanding the global reach and accessibility for PIs.

Training performed at crucial intervals between site qualification and activation, before the study, during the study and after the study provides a full continuum of support for learning. An easyto-use program that includes multiple tools and comprehensive training at each critical stage of the clinical trial process will increase engagement with healthcare providers. Offering flexible training delivery via virtual, face-to-face, or combined training sessions as needed allow PIs the opportunity to make trainings work with hectic schedules. User-friendly features such as an intuitive online interface to support the trainee, a learner community portal offering resources and tools, a learner forum and mobile gaming increase learner retention and encourage repeat site participation in trials.

Also, ongoing coaching in certain key areas like audits and inspections, study

protocol review, statistics or risk-based monitoring helps keep momentum and support.

Conclusion

Given the current clinical trial landscape, it is more important than ever to expand the pool of clinical research sites. The most effective method to do this is to engage these physicians in a robust, targeted, just-in-time training program that bridges the gap between medical practice and clinical research.

Ongoing support is also key to reinforce key concepts and knowledge throughout the life of the trial with user-friendly tools and process templates. By applying this methodology, using a program like PPD’s SiteCoach, hopefully we can increase repeat site participation and move away from the 'one and done’ pattern currently observed.

Lisa has been in the Strategic Site Collaborations group since January 2017. Her previous positions at PPD included roles in Project Management, Global Strategic Proposal Development and Strategic Feasibility. Lisa has worked in multiple therapeutic areas including neuroscience, respiratory, ophthalmology, cardiovascular and gastroenterology. She is a member of the Society for Clinical Research Sites (SCRS) and has been a regular panelist and presenter at SCRS annual conferences. Her current role at PPD involves global oversight of the Gen Med, IRD and Vaccine therapeutic areas for PPD Select. Lisa has been involved in the development of SiteCoach as a subject matter expert.

Rita joined PPD 12 years ago and is based in Lisbon, Portugal. She developed her career in Clinical Research on the Clinical Operations and Start-Up side, moving upwards as a CRA, then embracing her passion for Learning and Development as a Training Specialist. SiteCoach is the core of the her responsibilities since she was challenged to develop this Training Program in partnership with PPD’s Site Collaborations and Patient Centricity group.

AUTHOR BIO

to encourage repeat site participation.

Providing mentorship programmes and peer programmes helps build a support system amongst research physicians.

Leanne is a home-based employee located West of London in the UK and has been at PPD for over 13 years. Her focus over this time has involved EDC training, support of virtual environment training (PPD 3D) and delivery of GCP programs.

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INTEGRATED CONTINUOUS BIOMANUFACTURING Continuous manufacturing provides a new paradigm for biotherapeutics manufacturing. It has been shown to deliver high productivity (10-15X), lower cost of goods (by 50-75 per cent), and a more consistent product quality. This article highlights the key benefits of continuous processing for production of biotherapeutic products as well as the challenges that a practitioner is likely to face and solutions that are available today. It is emphasised that a centralised control platform for an integrated bioprocess is essential for real time data acquisition and on-line process control.

Anurag S Rathore, Professor, Department of Chemical Engineering, Indian Institute of Technology Nikita Saxena, Research Associate, Indian Institute of Technology

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atch manufacturing is the technology platform that is currently used for production of biopharmaceutical products. It involves step-by-step processing wherein one-unit operation must finish before commencement of the next operation. The mobility between the unit operations is slow as a result, affecting the overall productivity. In addition, the biopharmaceutical industry suffers from complexities related to scale-up, technology transfers, and batch to batch variability in product quality.

This has prompted interest amongst the manufacturers to migrate from batch to continuous processing. Perhaps the biggest motivator is the significant difference in productivity. While the automation for the shift requires investment in the initial stage however the long-term profitability aspects are compelling. Studies have demonstrated a reduction of 50-75 per cent in the cost of manufacturing due to 10-15X increase in productivity which

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results in significantly reduced footprint of the manufacturing facility along with reduced capital cost as well as improved use of consumables. In addition, the cost involved with the transportation of batches to lab for analysis is also reduced (Jungbauer & Hammerschmidt, 2017).

In the pharmaceutical industry, shifting to continuous manufacturing saved operating cost by 9 per cent to 44 per cent, capital expenditures by 20 per cent to 76 per cent and foot print reduction by 40 per cent to 90 per cent (Spencer et al. 2011).

Improved capacity utilisation of the production chain in achieving demand and supply requirements, improved implementation of complex recipes, elimination of transition times anda more consistent upkeep of the schedules are some of the advantages that continuous processing offers over batch manufacturing (Rathore et al. 2015) (Figure 1). In addition, the development of soft sensors (Figure 2) and process analytical tools

(PAT) are likely to further enhance control and consistency of product quality (Thakur et al. 2019, Zobel et al. 2017, Hebbi et al. 2019). Further, process automation reduces the need for manual interventions, thereby resulting in fewer human errors and minimum system disturbance. While the benefits of continuous processing are quite significant, the transition from batch to continuous is technically quite complex.

The concept of Quality by design (QbD) is quite aligned to what continuous manufacturing offers with respect to modernisation of production and improvement of consistency in product quality (Rathore & Winkle 2009).

The systematic, science and risk-based methodology that is adopted towards experimentation and knowledge generation ensures that the manufacturer utilizes robust control strategies. For a manufacturer to successfully run a continuous process, this knowledge base is essential

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Comparison of batch and continuous manufacturing

Figure 1

so as to maintain the process within its design space and ensure that the critical quality attributes (CQA) are consistently maintained (Rathore et al. 2018).

Challenges in implementing continuous manufacturing

Creating a continuous process platform is not merely connecting different unit operations in series. The manufacturing system consists of a number of parts whose assembling and calibration is an extensively time-consuming process.

At times, suitable technologies may be required to integrate unit operations for improving the process efficiency.

For example, it is becoming common practice to integrate the bioreactor with a cell retention device followed by continuous capture chromatography. Such an approach has been successfully demonstrated for high volume production of a monoclonal antibody (mAb) product as well as a low volume, less stable protein (rhEnzyme) (Warikoo et al. 2012). A recently reported invention is that of a continuous flow inverted reactor (CFIR)

which allows for performing any reactionbased unit operation (such as protein refolding and protein precipitation) in a continuous format (Kateja et al. 2016, Sharma et al. 2016).

The most significant challenge that a user faces in designing a continuous process is that of process control. Batch processing allows the user to take a sample at any process point and do the required analysis before initiating the next process step. Continuous process does not give this opportunity to the user and as a result if a robust control regimen is not put in place, continuous production cannot be realised. For an end to end integrated continuous manufacturing platform, developing an architecture is a challenge (Konstantin & Cooney 2015, Kateja et al. 2017, Kateja et al. 2018). One such example of an integrated architecture is use of a perfusion process in bioreactor combining alternating tangential flow systems (ATF), followed by two four column periodic counter current chromatography for capture, viral inactivation and two polishing steps (Godawat et al.

Illustration of soft sensor technology for control purpose

Figure 2

2015). This platform has been shown to offer better resin, buffer and equipment utilisation compared to the traditional processes. However, designing such a platform requires in-depth understanding of the process, the process equipment, as well as that of the product and its attributes. In addition, product recalls in batch manufacturing are easier than in continuous manufacturing as back tracing is relatively straightforward. This creates a need to maintain a quality control system that should be meticulously designed to

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Multi level control system â&#x20AC;&#x201C; a potential solution for the control related issues. Level 1 & 2 represent the greater process understanding and tight control over process parameters whereas lower level in the pyramid requires more regulatory oversights

Figure 3

minimise the odds. Significant amount of work is required to transform the concept of continuous processing into systematic industrial strategy.

Potential solution

One of the promising solutions is to develop a robust integrated bioprocess that is operated by a Distributed Control System (DCS) that can be single layer or multilayer control (Figure 3). A centralised platform for the automation of the bioprocess improves real time data acquisition and on-line process control.

For example, a computer implemented process control method has been adopted to control continuous production of biopharmaceuticals using proportional integral and derivative controller along with the fuzzy controllers (Patent EP3294856B1). Incorporation of surge tank/break tank increases the sampling points for the inline monitoring of the process parameters. This improves the operational feedback control strategy of the unit operations which includes

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clarification, chromatography, ultrafiltration, and depth filtration (Patent, US20140255994A1). Commonly, PAT tools that operate in real-time, such as spectroscopic techniques (UV, NIR, Raman) are ideal for performing real time process control. As stated before, the biggest challenge for continuous manufacturing is developing a flexible control system. The centralised control can take the various operating parameters as inputs for the different unit operations, such as flow rates, cycle times, pause times, and cleaning schedules to carry out the normal operation of the continuous train. A python layer with the userfriendly interface can be used for dynamic implementation of different recipes for individual unit operations depending on the task (normal steady-state operation/ deviated operation), molecules (different mAb/protein molecule characteristics) and feed conditions (high/low titer, high/low impurities/aggregates/charge variants). It also assists in dynamic process scheduling wherein intelligent decisions can be

enforced. For instance, using pressure/ turbidity sensor for scheduling cleaning cycles and filter switching (Thakur et al.

2020), using pressure sensor for scheduling chromatography column replacement, and using NIR for scheduling loading decisions in Protein A chromatography (Thakur et al. 2019). In addition, prediction made by model-based control can be used to check against real time operation of the process. For instance, product CQAs can be monitored during the bioreactor operation using Raman/ NIR and customised adjustments in the feed and feeding rate can be designed in perfusion systems. Three-way data flow between the model, unit operation and the PAT tool is helpful for achieving optimised performance for the wide range of operating conditions. In case of sufficient data, rule-based models can be implemented which are based on the experimental thresholds and provided different control logic based on the real time status of the different process parameters. However, due to the complexity of the unit operation, hybrid models (combination of empirical model and mechanistic model) for real time control are preferred over others. A provision can be made in the DCS to select the model from the stored library/historian in the real time.

The increased necessity in enhancing the process efficiency, productivity and the product quality has significantly increased interest in Statistical Process Control (SPC).It works on the theory of variation that combines time series analysis with the variable data history and aims to provide insight for a high level of performance. It has been seen that the control loops considered based on the empirical or mechanistic models are not enough to maintain the product quality in case of process uncertainties (Kroll et al. 2017). An effective online statistical process control strategy should be developed to handle the correlations between the input and output variables which are directly or indirectly affecting the product quality. The concept shifts

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A hypothetical centralized control system for a continuous process. Data flows from equipment to control system unit to operator workstation to unit operation equipmentâ&#x20AC;&#x2122;s via IOâ&#x20AC;&#x2122;s and ethernet network

Future perspective on continuous bioprocessing

The increasing interest in commercialisation of continuous manufacturing necessitates that the technical challenges that

arise need to be overcome. Despite the benefits of continuous processing, adoption is at a slow pace. Key concerns of the manufacturers include the risk of contamination and challenges associated with process control and increased operational complexity. We are confident that the biopharmaceutical industry will gradually adopt continuous processing

AUTHOR BIO

the focus from a fault detection-based strategy to a fault prevention-based strategy. Real time monitoring of the variables helps the operator to track the changes in the trend before the effect manifests itself in the product. Statistical tools like control charts, histograms, capability index can predict process variability and contribute to quality control. The approach can be implemented with the help of a centralised system where the data can be acquired and stored. Using the data historian large summation of the errors can be avoided and hypothesis can be formed related to the changes in the variables.

Anurag S Rathore is a Professor at the Department of Chemical Engineering, Indian Institute of Technology, Delhi, India.

He is also the Coordinator for the DBT COE for Biopharmaceutical Technology. Prior to joining IIT, he held management positions at Amgen Inc., Thousand Oaks, California, and Pfizer Corp., St. Louis, Missouri.

due to the significant benefits it offers with respect to increased productivity, reduced cost of manufacturing and improved consistency in product quality. Innovations in approaches taken for control of continuous processes will continue to be in spotlight.

References are available at www.pharmafocusasia.com

Nikita Saxena is Research Associate at Indian Institute of Technology Delhi.

She is an expert in process control. She is presently working on a major project that involves automation and digitisation of biopharma processes for continuous production of biopharmaceuticals.

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Human Vaccine Candidates Discovery and Development on Non-Animal Systems An adoption with meaningful repercussions The principles of Humane Experimental Technique has resulted in 3Rs concept: Replacement, Reduction and Refinement of animal tests. The number of animals used for both preclinical and quality control is thought to be reduced to zero if vaccines are better characterised while allowing testings by a set of in vitro methods rather than in vivo scenarios. The in vitro methods to detect safety related to potency of vaccines can employ alternative platforms like that of human derived cell/tissue based surrogate systems - The humane technique facilitating increased control of critical steps in production, relating safety with potency, international harmonisation and validation of test procedures S Dravida, CEO, Transcell Oncologics

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vaccine is traditionally a biological substance containing a harmless form of the causative organism that causes a particular disease. It is usually given to healthy population by injection, to prevent the contraction of the disease.

New age companies like Moderna have defied this definition of a vaccine to work on mRNA platforms where information from viral genomes is used to produce viral proteins from within a cell developing vaccine candidates.

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Vaccines are biological and formulations that boost the human bodyâ&#x20AC;&#x2122;s ability to fight against the targeted infectious diseases. The biological preparations fuel the recipientâ&#x20AC;&#x2122;s immune system stimulating to recognise targeted aspects of infectious organisms (bacteria and virus) as foreign; generate host reaction or response to regulate or completely eliminate them.

In addition to this, Vaccines evoke immunological memory of the targeted aspect, which provides protection against any

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future infection by the same or similar pathogen. Vaccines are generally created from inactivated or attenuated organisms; or sometimes derived from purified or recombinant subcomponents of these disease-causing organisms; providing antigens that can be incorporated into vaccines composed of peptides, proteins, and polysaccharides. The R&D advancements led to the new methods of indirectly introducing to the host immune system through recombinant DNA plasmids or chimeric virus vectors.

Inactivated vaccines are prepared through the use of heat or chemicals, whereas attenuated vaccines contain live, less virulent organisms. These vaccines are derived from live viruses that are cultured in the classified facilities under conditions that incapacitate their pathogenic properties. There is evidence with attenuated vaccines producing a durable immunological response on the other hand and thus are usually preferred for many classes of infectious agents.

Subcomponents of disease causing microorganisms also have been used as antigens in vaccine preparations. Toxoid vaccines, for example.

When various antigens are combined in making Vaccines, synergistic and inhibitory interactions are the expected outcomes with immunological response.

Responses to vaccines in the human body follow a complex but coordinated set of physiological and immune reactions that are controlled involving different cell types and biochemical intermediates.

Antibody and cell-mediated responses that occur following immunisation with vaccine are known to be significantly influenced by the type of components used in the vaccine product triggering adaptive humoural, cell mediated immune and innate immune responses.

An adjuvant is a pharmacological or immunological agent when added in the Vaccine formulation is known to improve the immune response of a vaccine.

Vaccine induced effectors of immunity are classically antibodies produced by B lymphocytes and cytotoxic CD8+ T

lymphocytes. The response to various antigens is affected by factors such as 1. dose, concentration of the antigen 2. quantity and nature of the adjuvant 3. time between inoculations and route of exposure. The schedule between injections of the vaccine is shown to be a key element of the immune response and varies with type of vaccines.

After the primary exposure, secondary exposures are usually mediated by specific populations of cells like plasma cells and memory B cells.

Immunisation is the process where a person is made resistant to an infectious disease by the administration of a vaccine as scheduled. The practice of immunisation dates back to hundreds of years with Buddhist monks drinking snake venom to confer immunity to snake bite and variolation which is smearing of a skin tear with cowpox to confer immunity to smallpox in 17th century China.

Edward Jenner, the father of vaccinology has set the beginning in 1796, when he inoculated a 13 year old-boy with vaccinia virus to demonstrate immunity to smallpox. Louis Pasteurâ&#x20AC;&#x2122;s experiments directed the development of live attenuated cholera vaccine and inactivated anthrax vaccine in humans in 1897 and 1904 respectively. Plague vaccine was invented in late 19th Century while bacterial vaccine developed Bacillis-Calmette-Guerin (BCG) is still in use today. In 1923, Alexander Glenny discovered a method to inactivate tetanus toxin and subsequently a vaccine against diphtheria was developed in 1926. Viral tissue culture methods that were researched till 1980s led to the introduction of the Salk, the inactivated polio vaccine and the Sabin, the live attenuated oral polio vaccine.

The advancements in Molecular genetics domain had aided in developing new vaccine delivery systems like viral vectors, DNA vaccines, topical formulations and new adjuvants in the development of more effective vaccines against pandemic influenza,

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cytomegalovirus, herpes simplex virus, respiratory virus, HIV, staphylococcal disease, streptococcal disease, shigella.

Vaccines production unlike a drug involves lengthy manufacturing and control processes while the quality controls represent 70 per cent of the manufacturing duration. Efficacious manufacturing of quality vaccines requires international standardisation with starting materials, production and quality control testing. It is a fact that it takes 12-36 months to manufacture a vaccine before it is arranged for distribution. All the components utilised in vaccine preparation, production processes, testing methods, reagents used have to comply with the standards set not just for the regulatory acceptance but for the real time application.

Vaccine identity, purity, sterility, potency and induced toxicity are some of the efficacy and safety related processes to comply from the research & development (R&D) stage till the batch wise release and distribution.

Safety Concerns

Vaccines are known to produce various adverse clinical effects like inflammation and pain at the site of injection, fatigue and febrile responses. These clinical signs may have their counterparts expressed in toxicity studies in animals, such as infiltration of inflammatory cells at the

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site of administration, decreased food consumption by the animal, loss of body weight, elevation in body temperature etc. These adverse effects along with the intensity reflect the activation of various components of the immune system that varies with specific nature of the vaccine antigen and adjuvant.

The disturbed inflammatory system with elicited cytokines and their entry into the bloodstream contributes to the expression of systemic manifestations of toxicity in clinical context while other physiological effects like altered arterial endothelial function are indicative of a systemic inflammatory response to the vaccine. More commonly, toxicities associated with vaccines stem from several factors involved in the inflammatory events in response to the administered antigen and/or adjuvant while excipients, preservatives, including antibiotics, that may be linked to these toxicities.

Vaccines given by intramuscular injection can cause lesions consisting infiltrations of inflammatory cells, neutrophils, heterophils, lymphocytes, macrophages, hemorrhage, myofiber degeneration, muscle necrosis, cysts. In some facets, these side effects appear to mimic the course of increased disease severity, or adverse events like with respiratory syncytial, dengue, and measles virus infections, pulmonary eosinophila, exaggerated memory Th2 response, unfavourable

T-cell responses, over reactive immune responses involving cytokines, interleukins. Another grave impending toxicity debated to be associated with vaccines is autoimmune disease involving complex molecular mimicry, epitope spreading, and autoimmune dysregulation.

Vaccine class like any other therapeutic candidates while being researched and developed are expected to be evaluated in preclinical stages for safety to be qualified for human infusion. Once a vaccine is approved after successful clinical trials, it continues to be tested in production and batch release as part of quality control for the following read outs as the composition has the disease causing pathogenic organism: Potency, Purity, Sterility FDA regulations for preclinical toxicology studies of vaccines require the components like antigens and adjuvants to also be tested for any adverse effects individually and in combination. There are five types of toxicology tests in addition to Potency test as part of regulatory submissions: 1. Single, repeat dose 2. Reproductive and developmental 3. Mutagenicity 4. Carcinogenicity 5. Safety pharmacology In 1955, some batches of polio vaccine given to the public confined live polio virus, even after passing required safety testing. This mishap, known as the Cutter Incident, resulted in many cases of paralysis in children. The Cutter Incident was an outlining moment in the history of vaccines, manufacturing and associated continuous safety evaluations during manufacturing and real time application from batches released for immunisation highlighting the need for other relevant safety specific nonanimal read outs. The abnormal toxicity test, Specific toxicity tests, Absence of toxicity, Irreversibility of toxicity, Test for pyrogens, extraneous agents are some of the essential evaluations that should be performed both in preclinical stages and during manufacturing batches. For certain types of vaccine,

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specialised toxicity studies are mandatory; for example, new, live attenuated virus vaccines that have either a theoretical or even an established probability for reversion of attenuation or neurotropic activity, virulence and neurovirulence studies are necessary for every batch manufactured.

Human Surrogate In vitro Systems for testing Vaccines

Vaccines are administered to healthy humans and demands for safety and efficacy are therefore very high. Non-clinical testing, which is a prerequisite to moving a candidate vaccine from the laboratory to the clinic includes all aspects of validations, product testing, immunogenicity studies and safety testing conducted prior to clinical testing of the product in clinical tests. The nonclinical evaluation of vaccines includes continued safety related toxicity measurements of the manufactured vaccines before release for distribution. Potential safety concerns include toxicity due to the active ingredients, excipients, reactions to impurities such as production substrates, and interactions between components of other vaccines administered simultaneously if at all.

Although, studies/tests designed to determine the ideal dose to induce an immune response in qualified animal models can provide valuable information on the immune response extrapolated to subjects in clinical trail, and for the wider population once marketed, it is recognised that there are limitations in animal testing including: â&#x20AC;˘ Susceptibility to infection by viruses, bacteria, other microorganisms are habitually highly specific. â&#x20AC;˘ The immune responses in an animal model, mainly at the elevated doses used for nonclinical testing, will not predict of what will occur in humans.

Since Vaccines are derived from living organisms which are distinguished from chemical pharmaceuticals due to their complex physical, chemical and molecular compositions, their characteristics vary from batch to batch. The

New age companies have defied the definition of a vaccine to work on mRNA platforms where information from viral genomes is used to produce viral proteins from within a cell developing vaccine candidates. details of processes by which the vaccine is produced and tested including the in-process and final product testing are the primary goals of the manufacturer.

Previously established concepts and methods of quality control were based on the distinctiveness of each individual batch of vaccine. The development and validation of alternative methods based on the principles of 3Rs for both potency and safety testing of vaccines to establish consistency in different batches was considered to be well thought at international forum. It was realised that few of the animal models in vaccine research and development are inevitable and irreplaceable, there are many in-vitro tests developed and established to evaluate Vaccine candidates induced toxicity profiles while being adopted for routine vaccine lot-release to overcome the major limitations with time taken to obtain scientific results. Use of virulent microorganisms or toxins in in-vivo assays poses a potential risk to those working in the laboratory like what would have happened with COVID-19 disaster.

Human surrogate system is an in vitro platform with human sourced primary progenitor cells based platforms as testing podium. Human surrogate cellular system involves growing human sourced cells in a culture dish, often with a supportive growth medium. They are known to offer a level of control that was not available if live animals had to be used, and can also support large-scale virus production. Some of the in vitro established tests like immunological specificity, immune activity and the potential for immune toxicity, antibody concentration, cellular immune responses (T-cell proliferation and cytokine quantification), functional antibody assays, titration assays, inherent and direct toxicity of the final formulation, toxicity associated with the pharmacodynamic activity of the candidate vaccine or its components, toxicity of contaminants and impurities are performed on cell based systems. Any cell based system is of great value if the source to harvest the relevant cellular components is human. Any cell source is relevant to build the human surrogate system in vitro suitable for throughput screening and to for reproducible, specific, selective read outs if the dependence is not on biopsied tissues. The only other alternative to biopsy is biological discards and the availability in abundance make them the preferred choice to source primary and valuable live cells to utilise in preparing human surrogate in vitro systems for testing Vaccine candidates and Vaccines.

Use of in vitro methods and if on human surrogate systems would have advantages in respect of their relevance, reliability, costs and moral acceptability in Vaccinology.

AUTHOR BIO

S Dravida is the Founder CEO of Transcell Oncologics, Hyderabad, India. She is a technocrat with track record of commercialising research driven findings to business opportunities through Transcell Oncologics.

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THE DIGITALISATION OF THE CRYSTALLISATION PROCESS A holistic control strategy in Pharma 4.0

Controlling the industrial crystallisation process poses a significant obstacle in the production of drugs and numerous other products. Digitisation of the crystallisation process now allows for radical change by increasing process automation to control overall crystallisation. The main pillars of Pharma 4.0 are process automation, improved control strategies, data visualisation, cloud edge storage, chemometrics, and mathematical modelling technologies. SmartCrys is a revolutionary integrated process control system that harnesses the mainstays of Pharma 4.0 with the combination of PAT tools in order to digitise the crystallisation process and achieve total process control.

Kiran A Ramisetty, Diarmuid Costello, Sean Costello, Luke Kiernan, Gareth Clarke Innopharma Technology Limited

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O

ne of the main issues faced by the pharmaceutical industry is ensuring reliable and timely access to secure, innovative, and economical medication. These issues are becoming more critical due to the world's growing but ageing population. Recent scientific developments in the healthcare market have given rise to targeted medicines that have now opened up new treat-

ment options for individuals according to their lifestyle and genetic makeup. These developments have led to a shift within the market towards the improvement of lower dosage and extremely powerful drug products. Ultimately, these trends are contributing to additional complexity being placed within the market.

Industry 4.0 is the latest industrial revolution that seeks to address many of

the problems industries are experiencing in the pursuit of enhancing the production and requirements for safer drugs.

The 4th industrial revolution centres around using advanced solutions like artificial intelligence, robotics, cloud information, and storage, as well as the Internet of Things (IoT), as seen in figure 1. Digitalisation of processes by incorporating the use of data analytics

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Basic principles of Industry 4.0.

and the secure storage of large amounts of data are among the highlights of the Industry 4.0. Figure1 Pharma 4.0 follows the key concepts of Industry 4.0 and aligns with basic GMP standards and regulatory constraints. Over the years, the pharmaceutical industry has adopted many industrial revolutionary changes and technologies that have improved the quality of production and led to ever more robust manufacturing. As such, Pharma 4.0 is another essential revolutionary concept that the pharmaceutical industry is beginning to embrace. Some industries are already inline with Pharma 4.0 and have applied continuous manufacturing as a novel strategy to overcome difficulties in batch processing. Many of the pharmaceutical unit operations, such as crystallisation, granulation, and tablet compression, can

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now be transformed by digitalisation.

These innovations are achieved by utilising advanced process control strategies brought about by recent technological advancements. Crystallisation is one of the most powerful techniques used to purify active pharmaceutical ingredient (API). In recent years, many pharmaceutical companies around the globe have already moved from batch to continuous crystallisation. Digitalisation of this process is achieved through rigorous and intelligent data analytics supported by Process Analytical Technology (PAT).

Implementation of Pharma 4.0 for such an important unit operation is therefore highly desirable.

Crystallisation

Control of the crystallisation process serves as a significant barrier in the production of drugs and numerous

other products. For efficient downstream operations (e.g., filtration and drying) and product effectiveness (e.g., bioavailability and tablet stability), the control of the Crystal Size Distribution (CSD) can be vitally important. Poor control of crystal shape and size can result in unacceptably long filtration and drying times, or perhaps additional processing steps, such as milling or even recrystallisation. Crystal purity and crystal shape are also crucial in determining the overall therapeutic effect of the end product. Controlling crystal shape and size can enable the optimisation of the dissolution rate, resulting in therapeutic benefits, while minimising the potential for side effects.

The essential driving force of the crystallisation process is supersaturation. Supersaturation occurs when a solution contains more dissolved material than would typically be dissolved by the solvent due to changes in the state of the solution brought about by varying its conditions. This can also be defined as the difference in the chemical potential of the supersaturated solution and the solid face of the seed crystal.

The generation of supersaturation utilising different techniques is the key process technology in crystallisation.

Supersaturation is usually created in crystallisers by cooling, evaporation, or by anti-solvent addition. Nucleation and growth are the processes involved in crystallisation; nucleation is the formation of clusters of solute molecules to nanometre-scale nuclei, and the growth process the increase in the size of the nuclei to micrometer-scale. Many critical quality attributes are important when considering crystallisation; for instance, CSD, crystal shape, and polymorphic form decide end-product qualityâ&#x20AC;&#x201D;as such, controlling crystallisation to obtain these desired quality attributes is the main challenge for the pharmaceutical industry. The substantial challenges in controlling crystallisation are kinetic parameter estimation, crystal breakage, agglomeration, and poor mixing.

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Crystallisation processes are complex and challenging, requiring the use of non-linear models to predict the outcome of the process. Mathematical modelling of crystallisation involves non-linear partial differential equations coupled with mass balance equations.

The population density of the crystals during the nucleation and growth process is unstable due to changes in the thermodynamic and kinetic behaviour of the system. These factors impact the number of crystals generated, dissolved, or grown to larger sizes spatially within the crystalliser. Critical process parameters involved in crystallisation control are cooling rate, antis-olvent addition rate, impeller speed, supersaturation, seed crystal size, crystal number, along with the crystalliser design. CSD defines the final product quality of crystals, with an arrow CSD targeted for improved downstream unit operations, such as filtration and drying. Targeting larger crystals(~200µm) with a narrow CSD improves the performance of filtration, drying, and vice versa. However, new advances like sono-crystallisation, supercritical anti-solvent crystallisation are targeting smaller crystal sizes (~30µm) with a narrow CSD that eliminates the need for downstream processes such as milling, while still achieving the desired product size.

Process Analytical Technologies (PAT)

Pharma 4.0 is unimaginable without the real-time process monitoring required to advance towards the digitalisation of the crystallisation process. PAT tools are essential in assessing the real-time change in chemistry between molecules.

As crystallisation is a multi-component system of solute-solvent molecules, in-situ monitoring spectroscopy techniques can be used to track the changes in chemistry between these components.

Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy enables the accurate measurement of the concentration of dissolved

Industry 4.0 is the latest industrial revolution that seeks to address many of the problems industries are experiencing in the pursuit of enhancing the production and requirements for safer drugs.

solute in a solvent for crystallisation processes without interference from the solid crystals in the slurry. In a twocomponent system of solute-solvent, FTIR can distinguish the solute peak in total spectra, which is highly useful in tracking the supersaturation profile of the solute. This profile can be altered using control strategies and by changing process parameters to precisely control crystal size and polymorphism while maintaining visibility of polymorph solubility Raman spectroscopy probes, simply called Raman probes, are another important PAT tool useful for monitoring the crystallisation process. Raman probes work by tracking the polymorphic changes in a solution-mediated transformation. Raman spectroscopy can show significant differences in spectra when substantial changes in polymorphism occur during the crystallisation process. One single Raman probe can also be used to detect spectroscopy for dry powder samples, as well as crystals suspended in a solvent. Unlike FTIR, Raman can detect spectral changes in both solvent and crystals within a slurry.

Another revolutionary particle tracking PAT tool is Focused Beam Reflectance Measurement (FBRM). This method is used to track changes in crystal size and crystal number via chord length distri-

bution measurement. FBRM has been a widely used technique for the past two decades as a means of understanding the crystallisation process. Real-time particle view technologies have also appeared to observe the changes in particle shape and size. These techniques are useful in observing crystal agglomeration and breakage, especially in the in-situ rotary stator milling process, where they are intended to reduce crystal size and create nucleation in-situ.

Strategies to control crystallisation

The digitalisation of the crystallisation process involves the implementation of automation control strategies as a first step in meeting one of the Pharma 4.0 objectives. Over the years, several control strategies have been implemented to control crystal size and its distribution by researchers. Their findings offer a key solution to controlling crystal size and the overall crystallisation process, leading to more robust operations and qualitative outcomes. Some of the highly valued control strategies are: • Population balance modelling 1. Method of Characteristics (MOC) 2. Method of Moments(MOM) • Concentration Feedback Control (CFC) and Direct Nucleation Control (DNC) • Model predictive control • Generic model control Population Balance Modelling (PBM) is the widely used method for predicting the final CSD. This requires preliminary experiments to generate the data required to estimate the parameters for nucleation and crystal growth, typically using PAT tools. This technique is also useful in predicting the final CSD of scale up studies -assuming identical conditions with laboratory experiments. PBM is the complex partial differential equation which can be solved using popular methods such as Method of Characteristics (MOC) and method of moments (MOM). There are multiple software programmes such as Dynochem, gCrystal available to

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carry out the mechanistic modelling of the crystallisation process. These programmes use population balance models that consist of complex equations for crystal nucleation, growth, agglomeration, and breakage.

The Concentration Feedback Control (CFC) strategy is an open-loop system and an extensively reported technique used to control the final CSD. This approach produces larger crystals with uniform CSD and less agglomeration.

Unless the PBM, CFC/DNC approaches are in-situ, process control strategies targeting the supersaturation are calculated directly from FTIR. CFC/DNC follows the basic principles of crystallisation to adjust crystal dissolution and nucleation via changes in temperature and anti-solvent addition. The targeted or set point value of supersaturation drives the temperature profile to match the set point values, which in turn automatically adjust the temperature to dissolve fine crystals to promote the growth of larger crystals. The DNC approach is dependent on maintaining the predetermined number of counts read from FBRM to lower the number of small-size crystals and increase the number of large-size crystals via temperature or anti-solvent addition changes.

Model predictive control(MPC)is a closed-loop system and utilises mass and energy balance equations and PBM to predict the behaviour of the crystallisation process. The difference between actual and predicted output values is minimised via relaying feedback signals to the controller. A predefined temperature profile can be accurately controlled in MPC compared to other techniques. Data from PAT tools is highly useful for accurate prediction using the MPC approach. Non-linear model prediction control, combined with non-linear moving horizon estimation, is the most recent advancement in using an MPC approach for controlling crystallisation precisely.

Generic Model Control (GMC) was derived for the control of any batch

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reactor. This model is dependent on PI controllers to control process parameters and for predicting the temperature profile in the crystallisation process.

This approach takes a long time to reach set point values compared to MPC. Conclusion

The future of the pharmaceutical industry is set to change with the advanced technologies brought forward by Pharma 4.0. Traditional industrial crystallisation processes present a challenge due

to limited process control and impact the efficient production of drugs and other products. Digitalisation of the crystallisation process with SmartCrys is a possible solution in overcoming the challenges faced by the pharmaceutical industry to date. The combination of PAT, various approaches in control strategy, as well as cloud data storage and manufacturing intelligence will prove to be extensively useful in monitoring and controlling, and digitising the crystallisation process.

AUTHOR BIO

Kiran Kumar Ramisetty is working as a crystallisation research fellow at Innopharma Technology. Previously, he worked as a postdoc at the University of Limerick in the area of process crystallisation control using advanced nucleation control technologies. He holds a Ph.D. in Chemical Engineering from the Institute of Chemical Technology, Mumbai.

Diarmuid Costello is currently a Sales Support Specialist at Innopharma Technology. Previously, he has worked as a Quality Engineer at Medtronic, Galway in the Process Validation department.

He has earned a BSc. Biotechnology from NUI Galway.

Sean Costello is the director for the technology group of Innopharma in the development of real-time non-contact imaging technologies for monitoring and control of processes in pharmaceutical, food and chemical industries. Prior to joining Innopharma, Dr Costello was Site Manager for Leica Biosystems Irelandand also the founder of SlidePath Ltd, a Digital Pathology company acquired by Genetix Plc.

Luke Kiernan is the director for technology services at Innopharmalabs, he has 25 years of experience in pharmaceutical industry working with Elan, Gerard Laboratories, BioAnalytical Laboratories, Wyeth & Pfizer. Luke has held various management roles in Validation, Technical Services, Process Development, Regulatory Affairs, Analytical Method Development, Quality Control and Quality Assurance.

Gareth Clarke has been Product Manager at Innopharma Technology for over three years. He obtained his PhD in Clinical Medicine from Trinity College Dublin, exploiting the near infrared transmission window of biological tissues for biomedical diagnostics using non-linear optical nanomaterials.

RESEARCH & DEVELOPMENT

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ARTIFICIAL INTELLIGENCE IN PHARMACY PRACTICE Artificial intelligence and machine learning-based technologies have the potential to transform healthcare by deriving new and important insights from the vast amount of data generated during the delivery of healthcare every day. The challenges for clinical pharmacy practice include discovering how to apply these technologies in ways that reveal new patterns in health data that make a real difference for patients.

Josep M Guiu Segura, Dr Pharmacy department, Catalan Health and Social Care Consortium

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rtificial Intelligence (AI) and machine learning-based technologies have the potential to transform healthcare because they offer new and important insights derived from

the vast amount of data generated during the delivery of healthcare every day. The capacity of AI to learn from real-world feedback and improve its performance makes this technology uniquely suited

as Software as a Medical Device (SaMD) and is responsible for it being a rapidly expanding area of research and development. Clinical pharmacy practice may undergo major change due to the implementation of this technology. The challenges facing clinical pharmacists include discovering how to apply AI technologies in ways that reveal new patterns in health data that make a real difference to clinical practice. AI is expected to assist healthcare professionals in enhancing patient experiences and health outcomes, augmenting the health of the population, reducing costs and improving the interventions that pharmacists and other providers instigate with patients. Thereby, the use of AI could help clinical staff to provide more informed medication-use decisions and improve outcomes.

However, healthcare professionals must ensure that there is evidence indicating that any new SaMD to be implemented and all AI implementations are safe and effective before they are put into use in practice. Whether or not a Health Technology Assessment (HTA) process is performed, pharmacists clearly play a critical role in helping to generate the evidence that is needed to inform decisions concerning how and when to implement AI on a widespread basis in routine clinical pharmacy practice.

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Not all software used in the healthcare settings is considered to be a medical device. However, depending on its functionality and intended purpose, software may fall within the European Union (EU) definition of a “medical device”. The EU and the United States both have their own criteria for identifying healthcare and medical devices, although both definitions are the result of a purpose-based approach. AI software properly classified as a medical device must comply with the rules that aim to ensure its safety and level of performance.

Given the capacity of AI to capture various forms of personal data, cybersecurity will also become very important to ensure the sustainability of this technology, including periodic reviews of the internal processes, to make sure it fulfils the requirements for the protection of privacy. In the EU, for example, the processing of personal data is governed by the General Data Protection Regulation (GDPR). Meanwhile, in the United States, regulatory issues may arise for AI developers based on the intended use of the product. Once a product is classified as a medical device, its class will define the regulatory requirements applicable for FDA clearance or approval.

Regardless of the classification of the product, however, AI developers will need to assess whether the HIPAA (Health Insurance Portability and Accountability Act) rules apply, as well as any design controls and postmanufacture auditing that also apply in terms of cybersecurity.

The traditional paradigm of medical device regulation was not designed for adaptive AI technologies, which have the potential to adapt and optimise device performance in real-time to continuously improve healthcare for patients .

Impact on the core responsibilities of pharmacy practice

Online pharmacy activities and telepharmacy lead to a new style of relation between patients, doctors and other healthcare professionals. New opportunities and threats will arise due to

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the disruption of the digital revolution, and these affect medication safety with a specific focus on what pharmacy can contribute in a rapidly changing healthcare sector. Moreover, the application of AI will also be advanced by assisting and monitoring patients and their needs in the absence of clinical professionals (i.e., chatbots).

Maybe the greatest potential for disruption from AI in clinical pharmacy will come from the discovery and application of patterns that matter in practice and can better inform pharmacist’s decisions and make a real difference to clinical practice.

While in the ambit of diagnosis AI will provide considerable assistance with very rich databases, in therapy (and particularly in drug therapy) schemes and alternatives will be hierarchised. Medical treatment decisions may see less of an impact on them because they have to be very close to the patient, but AI and robots will evolve too. However, maybe the greatest potential for disruption from AI in clinical pharmacy will come from the discovery and application of patterns that matter in practice and can better inform pharmacist’s decisions and make a real difference to clinical practice.

By using a large number of Electronic Health Record (EHR) data and AI to learn patterns concerning appropriate use of medication, software could become able to detect and alert to instances when a prescribed drug seems to deviate from its pattern of appropriate use. Moreover, AI could help in drug selection decisions, indicating, through automated classification, which patients would not be likely to experience particular adverse effects

from a specific drug.

Medication Therapy Management (MTM) and pharmacokinetic-guided dosing is standard practice in the clinical management of narrow therapeutic index drugs, and AI may eventually be used to help guide decisions on dosage in real time.

In recent years, clinical pharmacy practice has had to deal with the global problem of medicine shortages, which means taking inventory management decisions. Managing medicine shortages and ensuring continuity of supply can result in significant amounts of the time and attention of a clinical pharmacist being diverted from other important tasks in the provision of high quality, safe and efficacious care. AI could predict medication use in hospitals and health systems more accurately, as well as providing support for clinical decisions when exploring treatment alternatives if a drug is not available.

Polypharmacy is common in older adults and younger at-risk populations, and it increases the risk of adverse medical outcomes. The optimisation of the medicines clinical pharmacists deal with can provide a review of medications which thereby optimises cost-effectiveness and clinical use of medications, which when aligned with patient preferences should contribute to improved health outcomes. In this area, AI could provide new tools for understanding drug–drug interactions and associated mechanisms, as well as predicting alternative drugs for intended clinical use that avoid negative health effects.

The objective of pharmacovigilance is to detect, monitor, describe and prevent adverse drug events. AI is needed to analyse the large number of data collected through post-marketing studies, EMRs records and the Internet.

Clinical pharmacists have an opportunity to lead the expansion of AI into pharmacovigilance, using entirely new skill sets in this discipline.

In addition, AI may facilitate communication between healthcare

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of millions of molecular structures, the design and making of new molecules, predicting off-target effects and toxicity, predicting the right dose for experimental drugs, and developing cellular assays at a massive scale.

The work on developing AI algorithms to enable patients and care takers to take their healthcare into their own hands has lagged that for clinicians, pharmacists and health systems. Wearables and health apps can evolve from playing a passive role or recording patient data to giving standard advice to patients, from diagnosis to drug treatment adjustments.

Most common chronic conditions, such as hypertension, depression, and asthma could theoretically be managed with virtual coaching through AI devices such as chatbots. Crucially, if AI is going to make health professionals better at caring for patients, the datasets being used must be representative of the whole of society and not be biased in terms

AUTHOR BIO

professionals and patients by decreasing processing times, thereby increasing the quality of patient care. Many healthcare procedures have a costly bureaucratic burden, which digitalisation by itself has not reduced. Moreover, scheduling conflicts or overbooking is another important issue that AI can solve. AI could prioritise appointment scheduling based on the risk of readmission and overall severity of an illness with the aim of reducing readmissions.

With AI, data analysis becomes more attractive and pragmatic. Reviewing drug healthcare outcomes in the real world could require permanent analysis of the application of existing therapeutic options to approved indications or to a new disease. In drug repurposing, this is advantageous because the new drug which is already approved can go directly to phase II trials for a different indication without having to pass through phase I clinical trials and toxicology testing again.

While upstream from clinical practice, the progress of AI in the life sciences has been notably faster, with many peerreviewed publications. Drug discovery is being revamped through the use of AI at many levels, including sophisticated natural language processing searches of the biomedical literature, data mining

of sex, race, ethnicity, socioeconomic status, age, ability or geography. This need for representation is not only a data science issue, it is also an ethical one. In the absence of equal representation, discrimination and injustices have occurred.

However, although studies have demonstrated that AI can perform on a par with clinical experts in disease diagnosis, most of the tools involved have not been evaluated in controlled clinical studies to assess their effect on healthcare decisions and patient outcomes.

Inconsistent data quality and a lack of clarity with regard to the effective integration of AI into clinical workflows are significant issues that threaten its application. Whether AI will ultimately improve the quality of care at a reasonable cost remains an unanswered, but critical, question. Therefore, AI tools have to be implemented with caution.

Furthermore, not all challenges require AI solutions, as statistics and database research can often provide a perfect solution and may be easier and less expensive to implement.

While the application of AI in pharmacy practice faces several challenges, we should accept the fact that is needed.

Challenges such as new pharmaceutical policy initiatives, the regulation of data protection and cyber security, the debate on unusual accountability and responsibility issues, questions about the fiduciary relationship between patients, and medical AI-based devices could all be approached in such a way as to reflect the ethical standards that have guided other actors in healthcare and solutions should be held to those same standards.

References are available at www.pharmafocusasia.com

Josep M Guiu Segura is currently Head of pharmacotherapy planning and coordination at the Catalan Health and Social Care Consortium in Barcelona, Spain. He is also adjunct lecturer of Clinical Pharmacy and Pharmacotherapy at the Faculty of Pharmacy and Food Sciences of the University of Barcelona. Since 2018, he is Vice-president for the European Region of the Hospital Pharmacy Section of FIP.

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

STRATEGY BioGenes GmbH....................................................................................09 F. P. S. Food and Pharma Systems Srl...................................................15 Medical Fair Asia.......................................................................05, 22-23 Turkish Cargo..................................................................................... OBC

RESEARCH & DEVELO PMENT BioGenes GmbH....................................................................................09 F. P. S. Food and Pharma Systems Srl...................................................15 Lonza.................................................................................................. IBC SUEZ Water Technologies....................................................................IFC Syntegon...............................................................................................33

MANUFACTURING BioGenes GmbH....................................................................................09 F. P. S. Food and Pharma Systems Srl...................................................15 Lonza.................................................................................................. IBC SUEZ Water Technologies....................................................................IFC Syntegon...............................................................................................33 Valsteam ADCA Engineering.................................................................03

BioGenes GmbH....................................................................................09 www.biogenes.de F. P. S. Food and Pharma Systems Srl...................................................15 www.foodpharmasystems.com Lonza.................................................................................................. IBC http://pharma.lonza.com/ Medical Fair Asia.......................................................................05, 22-23 www.medicalfair-asia.com SUEZ Water Technologies....................................................................IFC www.suezwatertechnologies.com/sievers Syntegon...............................................................................................33 www.syntegon.com Valsteam ADCA Engineering.................................................................03 www.valsteam.com Turkish Cargo..................................................................................... OBC www.turkishcargo.com

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