Pharma Focus Asia - Issue 37

ISSUE 37

2019

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SUEZ WATER TECHNOLOGIES & SOLUTIONS

Enabling efficiency & compliance with Sievers TOC Analysers

Coaching Brand Strategy Important but difficult

Continuous Manufacturing The road ahead www.pharmafocusasia.com

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Foreword Continuous Manufacturing Is the pharma industry ready for a shift?

The pharmaceutical industry has for several decades been reliant on batch manufacturing, which dominated the blockbuster drug era. With profitability on the higher side, the need to innovate or consider new types of manufacturing wasn’t the need of the hour.

Things began to change in the post-blockbuster era as companies realised material costs during drug development increased significantly, while new drugs were required to be produced in smaller quantities. Increased costs, longer production timelines coupled with inherent risks associated with batch processing led companies to look for an efficient and cost-effective process.

Continuous manufacturing had been in use across other industries but early adoption of this process in the pharma industry saw light only in 2015. In 2015, Orkambi became the first US FDA-approved drug to be produced via continuous manufacturing and later approved by the FDA. Subsequently, three more drugs made their way into the market following continuous manufacturing.

Slowly, the industry appeared to be catching up on continuous manufacturing for drug development. Continuous manufacturing helps uninterrupted production, manufacturing or processing of materials and enables faster product development, decreasing operational costs while providing increased flexibility in manufacturing. According to FDA experts and leaders, continuous manufacturing will have a positive impact on the quality of drug as margin of effort could be minimal with little intervention in production process. With continuous manufacturing, a drug produced in a month under batch processing might probably be produced in a day.

Because the process is efficient and fast, it offers flexibility to produce drugs just-in-time based on market demand. This way companies would not need to worry about huge inventories to address surge in demand.

There are numerous players in the industry for which not all drugs developed would pass through clinical trial and successful production. As with any other change, transition to continuous manufacturing isn’t easy for the companies in this industry. A shift to a new manufacturing process involves huge investment and operational expenditure that could be unrealistic for a lot of companies, unless there’s a blockbuster drug with high market demand and requires continuous production.

In February 2019, the FDA issued a guidance ‘Quality Considerations for Continuous Manufacturing’, encouraging manufacturers to switch from batch to continuous production of drugs in order to improve consistency and mitigate the risk of shortage of drugs. The guidance indicates continuous manufacturing is recommended for solid oral drug products and small molecules and is certainly not applicable for biological products. Fast tracked drugs that undergo a quicker path to FDA approval and personalised medicine could be the trends to propel the need for continuous manufacturing, among other factors. Companies across industries are challenged to be flexible in manufacturing leveraging advanced technologies. Continuous manufacturing may probably not take over batch production as the de facto process in this industry, but it has the potential to play a bigger role in commercial manufacturing involving large-scale operations to meet changing market needs.

Prasanthi Sadhu Editor

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STRATEGY 06 Self-leadership in Developing Mental Capital

An essential approach for effective multicultural and multidimensional leadership

Andrew A Parsons, Business and Coach Psychologist Reciprocal Minds Limited

Sue Jackson, Master Executive Coach and Trainer Whitespace Coaching

COVER STORY

CONTENTS

14 Drug Regulations and Pharma Companies’ Plan of Compliance

Nanda Kumar Reddy Gollapalli, Assistant General Manager, Freyr

23 Promoting Regulatory Collaboration and Convergence in Asia

David Jefferys, Senior Vice President, Global Regulatory Healthcare Policy and Corporate Affairs, Eisai Europe and Chairman, Eisai Global Regulatory Council

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28 Coaching Brand Strategy

Important but difficult

SUEZ Water Technologies & Solutions Enabling efficiency & compliance with Sievers TOC Analysers

Brian D Smith, Principal Advisor, PragMedic

34 Is the Indian Pharma Industry as Black as it is Painted?

Dave Kremer, Senior Leader, SUEZ’s Water Technologies

Vikram Munshi, Founder, WhiteSpace Consulting & Capability Building

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40 Reshaping Pharmacovigilance

ISOP ISRAEL experience

Irene R Fermont, ISOP ISRAEL- IFC

RESEARCH & DEVELOPMENT 48 Medicines Management and Drug Delivery

Unique challenges in older age

Muhammad Suleman Khan, Diamantina Institute, The University of Queensland, Translational Research Institute

Michael Roberts, Professor, Therapeutics and Pharmaceuticals. NHMRC Senior Principal Research Fellow, Therapeutics Research Centre, School of Pharmacy and Medical Sciences, University of South Australia and University of Queensland

CLINICAL TRIALS 54 Barriers Preventing Clinical Trial Software Development

From transforming the design and execution

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Steve Galen, Global Head, Clinical Division Navitas Life Sciences, a TAKE Solutions Enterprise

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MANUFACTURING 60 Continuous Manufacturing

The road ahead

Kieran O’Connor, Senior Research and Development Chemist SK biotek

INFORMATION TECHNOLOGY 68 Pharma Supply Chain Intelligence

IT focus

Adam Tetz, Director, Worldwide Marketing, Pelican BioThermal

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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 Austin Paul Jessie Vincent 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

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

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

Laurence Flint Pediatrician and Independent Consultant Greater New York City

In Association with

A member of Confederation of Indian Industry

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

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

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

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

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STRATEGY

Self-leadership in Developing Mental Capital An essential approach for effective multicultural and multidimensional leadership The ability to adapt creates advantage. Agile processes are required to meet business goals. To facilitate this, Leaders need resources and skills to flex thinking and behaviours to match their current reality. This ‘mental capital’ is enabled through self-leadership: personal insights and ways to enhance relationships through 5key factors.

Andrew A Parsons, Business and Coach Psychologist, Reciprocal Minds Limited Sue Jackson, Master Executive Coach and Trainer, Whitespace Coaching

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L

eading in today’s culturally diverse workplaces with multidimensional processes and stakeholders requires individuals to adapt to new environments, learn new skills and manage a range of stresses and strains between the interface of professional and personal life.

Leaders may find themselves catapulted into new environments such as taking a senior role and having to move to a different country or culture. Alternatively, their career may

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STRATEGY

develop more organically with time to assimilate roles and develop skills over a longer period of time. Either approach requires the individual to transition to a new role and situation effectively. In the world of performance management systems this no doubt means with no detriment to ’the numbers’ or the measures of success.

Mental Capital

Mental capital is the sum total of all the resources we have available in any situation. These include inherent characteristics, such as our genetic personality traits and predispositions, and also the skills and experience we acquire through our lives to manage our life course and situation. The big five personality traits of conscientiousness, neuroticism, extraversion, agreeableness and openness to experience all impact our behaviours and therefore how we operate as leaders. In addition, the skills and abilities we have learnt through our lives support the development of core leadership competencies and the ability and degree of flexibility as leaders.

Psychological capital has been identified by Luthans and colleagues as being the ‘individuals positive psychological state of development’ with key measurable elements of confidence (self-efficacy), hope (motivation and adaptability of approaches), resilience (ability to grow from negative events ‘bounce back’) and optimism (the beliefs that you can positively impact events or the environment).

Our mental capital can also both increase and decrease depending on the situations we find ourselves in. As leaders it is therefore important to continually develop our mental capital to address the situations we encounter. To understand the complexities of maintaining and enhancing mental capital we have created some case studies from our own professional experience of leading business units and teams within the Biopharmaceutical Industry and supporting leaders make transitions in roles and expectations. We therefore offer 3 hypothetical situations to outline 8

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THE LEADERSHIP AND PERSONAL CHALLENGE SCENARIO 1: A female leader has been working in a global manufacturing

role for several years. Her initial career was at a local operating level within Asia. Her natural talent, enthusiasm and conscientiousness meant she was fast tracked within the multinational organisation she worked for and was recruited for senior strategic roles in several countries in Europe and North America. After 10 years she is returning to Asia, but not to her own country, to take the site leadership role at a manufacturing site that has recently received a warning letter from the US Food & Drug Administration (FDA). Processes within the site are not working effectively and there are concerns about the integrity of data being generated.

SCENARIO 2: A physician has been supporting patients with a rare and

potentially fatal condition for several years. Her passion for the care of these individuals and the research she initiated has been the spark for academics and biotechnologists to develop potentially life-saving gene modulation-based technologies that has resulted in two competing products in different Biotech companies. Early R&D has progressed well with both approaches and there is a pressing need to evaluate these approaches in humans. She has been involved as a consultant for both companies who want her to become the principal investigator for a trial of their agents. She has participated in minor trials previously and this will be her first experience as Principal.

SCENARIO 3: Following a re-structuring of commercial operations within

a multinational corporation, a new business unit has been formed of several countries across the Middle East and Asia. A new leader has been appointed to become the manager of the whole business unit and several general manager roles have been created at the country level.A commercial director has been identified to take his first general Manager role in a country that has been perceived to be under performing for some time. There was acknowledgment of the impact of political uncertainty within the country and the loss of several team members on its commercial performance. However, expectations are high for a rapid change in the ‘numbers’. some key approaches needed by leaders to develop their mental resources to adapt to these situations.

Common Themes

These scenarios present a challenge to the leader in question. Each individual will need to adapt their personal and professional lives to meet the challenge that has been offered. Each role provides a significant opportunity for them to develop their careers and themselves, it is likely they are highly motivated to be successful in these moves and have support of the organisation to create change. They will be likely to have professional support from their respec-

tive multinational organisations. Two of the roles requires the individual to move to a different geographical location, one in which they may find the culture slightly different from what they have experienced previously. All roles have clear time pressures associated with success.

In Scenario 1, to correct and introduce remediation of internal processes, in Scenario 2, to develop a safe clinical environment for evaluation of a new investigative product, and in Scenario 3, managing stakeholder expectations whilst creating a high performing commercial team. In all scenarios there would be an expectation to show progress within a matter of months.

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STRATEGY

The Role of Mental Capital – Focus on ‘how’ as well as the ‘what’

In each of these time pressured roles, there is often a focus for individuals on what they need to do or achieve. Attention on ‘what needs to be done’ can potentially shrink the focus of the leader onto important tasks alone and creates a risk of them supervising the work of others, as opposed to creating an environment where people are aligned to common goals and are energised and engaged in activities that create them i.e. the ‘how’.

The ‘how’ is an essential question of leadership. It is about creating the right environment for people to work at their best. However, it is not about letting people do what they want as appropriate governance and process measures will need to be put in place for compliance issues. This is an important aspect for all the scenarios.

The first element for leaders in creating the ‘how’ is to develop their own mental capital. The Foresight project investigating how to develop mental capital and wellbeing through our life identified five core elements that maintain subjective wellbeing and performance.

The five elements are: • Physical activity • Taking Notice (Mindfully) • Learning • Developing (meaningful) connections and relationships • Giving (being generous) These apply to all the individuals in these scenarios.

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According to Neck and Houghton, self-leadership can be thought of as the ability to influence oneself to establish selfdirection and self-motivation to perform from a perspective of intrinsic value.

Developing mental capital can therefore enable leaders to acquire additional skills to adapt and perform effectively in whatever challenge is presented to them.

Physical Activity

Taking time to be active is an important element of personal health. Not only does it enable leaders to ‘re-set’ by putting their attention to something that is not work-related, it also develops their fitness and resilience. Keeping active for periods of the day supports individuals to meet the challenge of leadership effectively.

Taking time to go for a walk or taking the stairs instead of the lift can provide enough activity to allow the physiology to re-set and face workplace demands in a more resourced state.

Taking notice (mindfully)

Our attention can easily become narrowed when we focus on immediate tasks. This can result in us missing the bigger picture. Within each of the above scenarios there is a time sensitive pressure that all the leaders will experience.

Developing the skills of taking notice or putting your attention to where you focus allows us to stay in the moment.

Mindfulness guided meditation exercises can be useful to build this skill. However, mindfulness can also be practiced in an informal way, integrated into everyday

life e.g. driving, walking and preparing for meetings.

This way, the leaders in our examples may be able to structure these activities into their day. Developing and engaging these skills in pressurised situations will enable leaders to use these skills when needed. Simple grounding and breathing exercises such as bringing your attention to your breath for one minute or using biofeedback (for example, HeartMath) can provide the space to clear your head and develop the skill of being more present and available in the moment.

The awareness and ability to notice what you are feeling while maintaining a focus on your goals and an ability to flex develops leadership presence which enables improved individual and team performance. Developing these skills so that they become integrated mental resources will help to ensure that in pressurised situations, leaders will be able to draw on these skills and behaviours when needed.

Learning

Leaders need to keep learning to develop.

Learning new activities and behaviours to stay active and keep in the moment provides a platform for life-long learning.

However, the leaders in these scenarios also have immediate challenges to address.

In Scenario 1, learning about the new culture and existing processes will help her focus on the issues it is necessary to address. Gaining awareness of the need to train in regulatory requirements would also broaden the scope of what is necessary for her in this leadership role.

In Scenario 2, the leader not only needs to learn about her new responsibilities and accountabilities she also needs to develop her leadership style as a PI. Developing her soft skills in line with her new accountabilities as a leader, physician, researcher and study manager will be time well spent as she takes on the role of PI. In Scenario 3, learning about each of the main brands in the portfolio will no-doubt be essential to focus activities of the team.

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STRATEGY

In all 3 scenarios the ability of the leader to learn about themselves and their knowledge gaps to focus their learning needs is a key aspect of mental capital development for leaders. Self-reflection is a really helpful way of doing this effectively. Transferring the discipline of continuous improvement reviews from ‘what’ has happened to ‘how’ we have led the team and managed the situation provides fuel for further growth and development. All leaders will need to develop trust within the team to enable a real focus on their resources and ways to negotiate or manage the barriers to obtaining their objectives.

As leaders become more aware of their own patterns, beliefs and values it enables them to better relate to themselves and others. This is an important aspect of trust.

Develop Meaningful Relationships

Leadership capital develops meaningful professional relationships at work. These relationships are important as they build the foundations of trust within the team and organisation. Balancing the complex interplay between personal and professional lives also is an essential element of leadership capital. Taking time to build in physical activities in the workplace also provides permission for others to do the same. Taking notice of the efforts of those around you provides an opportunity to build a positive relationship where both the leader and the team member create meaning and purpose from the interaction. This can be readily demonstrated as an alignment of goals and the development of that all-important trust in the team. It also provides an opportunity to assess if there is fundamental misalignment and differences in values or perspective between the organisational demands and team members.

In Scenario 1, this will be an important aspect of determining the motives behind any issues with compliance. The prospect of fraudulent or illegal actions of team members, for example, will require action to show that the consequences of such behaviour would not be tolerated.

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Leaders may find themselves catapulted into new environments such as taking a senior role and having to move to a different country or culture.

Giving time for the development of others beyond the immediate objectives shows that the aims are long term and not just a single transaction. Human interactions are found to be more cooperative when it is clear there are multiple transactions over a long term and therefore an interest in the development of the team over the longer term provides benefits all round.

Conclusion: The Self-leadership Accountability

Giving (with compassion)

Giving can often be seen as incompatible with the commercial environment.

However, it is also part of an organisation’s social responsibility and an opportunity for them to “give back” to society.

It is also an important aspect of leadership capital. However, it must be given with compassion and with no strings attached.

The leader who gives time to others in the team can really support the close alignment of objectives. It can help others learn, it builds stronger teams especially when the focus is on the development of the team and the leader themselves.

Being seen as someone who is continually developing and learning new skills and processes creates an environment where this becomes the norm. It is likely that this will not happen overnight, but a continued focus on the development of self and team will enable sustainable results.

Developing mental capital allows leaders to adapt to the situations in which they find themselves. There is accountability to their teams, stakeholders and themselves to continually develop their resources to ensure sustainable and compliant performance and enhance wellbeing.

The skills of self-leadership provide the ability to influence personal and professional development, to take the time to focus on the ‘how’ and to learn and grow are essential in our fast-paced and uncertain business environments. It is more than self-regulation or self-control, it is providing the internal motivation and ways of thinking to take the time to develop. In our experience of supporting and challenging individuals in this process, the benefits of self-leadership become manifest both professionally and personally.

References are available at www.pharmafocusasia.com

AUTHOR BIO

Andrew A Parsons is former VP and Head of Preclinical Drug Discovery, External R&D, GSK. He now works as a Business and Coach Psychologist.

Sue Jackson is a Master Executive Coach and Trainer.

STRATEGY

DRUG REGULATIONS AND PHARMA COMPANIES’ PLAN OF COMPLIANCE The Primary function of any pharmaceutical organisation is to protect end-user’s health and well-being by discovering and developing innovative medicinal products. Hence, they are subject to rigorous regulatory scrutiny to ensure safety and efficacy of the products. But, at times, they may find it difficult to keep pace with the evolving regulations, digital transformations, and developmental costs to stay ahead of the competition. This article throws light on what kind of difficulties they may face en-route, and how should they sustain compliance hurdles to reach the markets.

Nanda Kumar Reddy Gollapalli, Assistant General Manager, Freyr

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STRATEGY

T

he Pharmaceutical industry has been growing in parallel to human evolution. Either inventing path breaking medicines for some of the incurable diseases or eradicating the viral threats from their roots; the industry has put in enormous efforts for the safety of humankind. In the last two decades, the industry has seen

a new shift only to improve the efficiency and effectiveness of the medicinal production. In a way to be flexible and qualitative while benefitting the patients, the industry has been mainly focussing on bringing out the new classes of drugs and new-age technologies such as gene therapy, stem cells, nano-medicine, new drug delivery systems, etc. Standing with the industry’s growth, the global health authorities, too, endorsing the patients’ safety, have been coming up with new drug approval systems, compliance best practices, and procedures. In this scenario of 3600 evolution, how should companies design their plan of compliance? What should be their main focus is what we are going to cover in the following sections.

It is widely known that it takes an average of 14 years and 350 million dollars for a pharmaceutical company to get a new drug from a laboratory to the market. As each phase of these 14 years is completely regulated, companies should carefully plan the entire drug life cycle, right from the patent application, marketing approval, post-market sustenance and amendments to the patent expiration. In addition, they must consider phase-wise drug regulations to withstand global competition.

Phase-wise Regulatory Outlook

Health authorities control every stage of the drug development procedure including post-approval and the marketing stages as well. For the benefit of their assessment, evaluation, validation, and review procedures they mandate

manufacturers to follow certain guidelines and best practices right from research to approval to commercialisation to postmarket amendments as depicted below.

Let’s discuss these phase-wise regulations and procedures in detail.

Preclinical Testing

New drug development starts with the pre-clinical stage where pharmaceutical companies examine thousands of compounds to find a therapeutic value targeting a specific disease.

The preclinical studies have to be conducted by following the Good Laboratory Practices (GLP) as suggested by respective health authorities.

The principles of GLP govern the planning, performance, monitoring, recording, reporting, and archiving of preclinical studies. In this phase, the drug undergoes trials (in vitro, and in vivo) on laboratory animals to evaluate metabolism (pharmacodynamics [PD] and pharmacokinetics [PK]), safety, toxicity, dosage, and efficacy. Companies are obliged to show enough evidence to the respective health authority in the form of an Investigational New Drug (IND) application for the drug’s chemistry, manufacturing, and controls (CMC) to assure the identity, strength, quality, and purity of the drug.

Out of various compounds subjected to testing, if any of the drug compounds show promising results, only then can a company file an IND application.

If safety concerns arise in the IND review, the health authorities can

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Clinical Development Strategy

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Submission in Other Markets

Renewal Submissions

Product Reclassification

Product Withdrawal

Figure 1: The above picture depicts various Regulatory activities involved in the drug development process

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STRATEGY

place the application on partial or full clinical holds. Often, such a case might be a disaster for companies striving to move forward to conduct their clinical trials.

Standing with the industry’s growth, the global health authorities, too, endorsing the patients’ safety, have been coming up with new drug approval systems, compliance best practices, and procedures.

Clinical Trials

The objective of clinical trials is to evaluate the safety and efficacy of medicinal product(s) in humans.

Clinical trials involve four phases and each phase must comply with regional requirements as well as GCP as per the respective health authorities’ guidelines.

The purpose of GCP is to ensure that all clinical trials adhere to ethical and scientific standards to protect the rights, safety, and well-being of trial participants as well as the reliability and credibility of trial results. GCP is also concerned with the data integrity.

Clinical trials held in the first three phases are conducted to collect safety and efficacy information to support the licensing application and phase IV is conducted post-marketing i.e., once the product reaches the market. The phasewise details are as follows.

Phase I: Phase I clinical trials aim to find the best dose of a new drug with fewer side effects. These trials include initial single-dose studies, doseescalation, and short-term repeated-dose studies. The goal of Phase I clinical trials is to determine what the drug’s most frequent side effects are and, often, how it is metabolised and excreted. If the drug is found to be safe enough, it is appropriate for further testing.

Phase II: Phase II clinical trials are considered as exploratory trials (as in this phase further assessment of drug safety is evaluated). Clinical pharmacology studies are also included in this category.

Good Laboratory Practices (GLP)

GOOD CLINICAL PRACTICES (GCP)

Across Preclinical Testing

Across Clinical Testing

Figure 2: GxPs To Be Followed – Across the Product Lifecycle

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Phase II trials begin only if Phase I trials don’t reveal unacceptable toxicity.

The drug, if found to show positive results is then considered for Phase III testing. At the end of phase II clinical trials, the manufacturer will have to discuss and update the health authorities regarding the development process, and the protocols for phase III clinical trials, which is the most extensive and expensive process of drug development.

Phase III: Phase III clinical trials or confirmatory trials are conducted to obtain additional information about the drug’s effectiveness and safety to assess the benefit versus risk of the drug. If approved by the health authority, the trail data can then be utilised for drug labelling process.

During the clinical trial stage, improper study design, cost computability, timeline, and lack of knowledge of pharmacovigilance may affect the company’s plan of compliance.

Apart from these, companies must also

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GOOD DOCUMENTATION PRACTICES (GDOCP) Across Product Lifecycle

review and check the accuracy of all submission materials in comparison with guidance documents from the Regulatory agency and safety topics from the International Conference on Harmonization (ICH).

Across the clinical trial life cycle, different types of data are generated, which has to be accurately reported to address specific research questions.

Companies use this data to submit detailed Clinical Study Reports (CSRs), which forms the basis for marketing applications. Inaccurate or incomplete data may impact the product approvals.

Therefore, maintaining data integrity is a mandatory requirement throughout the drug development process.

Manufacturers are also obliged to follow Good Documentation Practice (GDocP), which applies to the creation, maintenance, and retention of documents.

Approvals

Once the phase III clinical trials are completed, and if the data demonstrate the safety and effectiveness of the drug, the manufacturer will have to compile the trial data to file a NDA or a Biologics License Application (BLA) depending on the type of the product.

NDA or BLA usually comprises all the data, related to nonclinical and clinical testing and manufacturing, which must be in accordance with the Regulatory requirements.

In addition, while filing the NDA or BLA, manufacturer should consider the preferred regional format for submission either paper or electronic.

Only once the Health authority approves the NDA or BLA, the manufacturer can commercialise the drug in their jurisdiction. If there are any deficiencies

GOOD MANUFACTURING PRACTICES (GMP) & GOOD DISTRIBUTION PRACTICES (GDP) Across Product Lifecycle

GOOD VIGILANCE PRACTICES (GVP) Post Market Authorization

STRATEGY

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(major/minor) found in the data submitted, and the data provided with respect to safety, efficacy, CMC and labelling information is found to be inadequate, the health authority may reject the application and would ask for necessary clarifications.

Marketing and Commercialisation:

Pharmacovigilance(PV) and Quality Monitoring

Once the drug is approved and released into the market, manufacturers will have 18

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to conduct post-marketing surveillance to evaluate the performance of the drug or to report any unwanted and dangerous reactions. This is also known as Pharmacovigilance (PV).

Like other stages, PV too has its significance in controlling the drug’s market position. Though the manufacturer’s core responsibility lies in developing and releasing a safe drug into the market, they also need to track the drug’s performance and its effect on end users once it is released. If any adverse reactions take place, they should shoulder the responsibility of confronting it. Health authorities globally especially of the U.S. and Europe take adverse reactions seriously and mandate the industry to follow Good Vigilance Practices (GVP)to track the drugs’ performance once they are out in the market. The purpose of GVP is to ensure that continuous safety monitoring activities take place and all appropriate actions are taken to reduce the associated risks.

AUTHOR BIO

Once the drug is approved, manufacturers need to submit marketing authorisation applications in every country as per their targeted market-entry list by following GMP. Compliance with GMP is necessary in obtaining a marketing authorisation. This is because the health authorities validate the quality of drug products by carefully monitoring drug manufacturers’ compliance with GMP regulations. The GMP regulations govern manufacturing facilities, methods, processing, controls, and packaging of a drug product to ensure the identity, strength, purity, and quality of a product is appropriate to its intended use.

Apart from aligning to the GMP, companies must also follow the Good Distribution Practices (GDP) to ensure that there is no alteration to the drug’s innate formulation and to its package elements during the distribution.

In case if the drug is already approved in one country and the targeted country considers accepting the available marketing authorisation, the process can be a little easy for manufacturers. If it is not the case, the level of scrutiny would be higher. Then manufacturers may face challenges in terms of compiling qualitative regionspecific clinical documentation, providing supplemental data during review stages if any deficiencies are figured out, and bridging evidence gaps, if any. En-route they may also have to consider targeted country’s assessment methods for marketing authorisation applications.

Hence, a manufacturer is expected to have a well-established PV system in place to monitor drugs’ safety cautiously and submit periodical reports about the benefit-risk profile of the drugs. In case of any discrepancy found in the post-marketing surveillance, there is a chance that health authorities may ask the manufacturer to withdraw the drug from the market. To avoid non-compliance and associated penalties, manufacturer must ensure that their PV systems are aligned to evolving regulations.

Though the phase-wise Regulatory outlook seems almost similar for many countries, there exist certain diversifications in obtaining approvals. Even if the procedures are different, the aim is mutual i.e. to protect the end user’s safety. To protect the same, the need of the hour is to harmonise the regulations, drug development, and approval procedures across the globe. Health Authorities should look upon a common global platform to govern and regulate the industry and bring in more centralised and commonly acceptable procedures.

This way, many innovative products can see the light of the day globally as soon as they are invented, and many unmet patient needs are addressed within the timelines. While Health Authorities should start working on centralised regulations, companies, with a unified view across development, approval, marketing and quality-monitoring stages, should build a robust plan of compliance i.e. to keep abreast of global standards and regulations and apply best compliance practices right from the first step (preclinical) to patent expiration.

Nanda Kumar Reddy is a 15+ years

experienced Regulatory Professional in handling end to end regulatory services for Regulatory Strategies, Registration and Life cycle management for Innovator and Generic Products to US FDA.

www.pharmafocusasia.com

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NEW LANDSCAPE FOR DRUGS STANDARDS Today’s pharmaceutical industry continues to be highly complex with significant developments or trends worldwide that impact Asia’s pharmaceutical industry. One of these includes drug recalls in developed countries.

Moving forward, how can Asia’s pharmaceutical industry and its stakeholders collaborate to make the world healthier, cleaner and safer for everyone?

Ian Smith, Vice President of Commercial Operations for Chromatography and Mass Spectrometry, Asia Pacific, Thermo Fisher Scientific

Over the last decade, governments have been focusing on making healthcare accessible, leading to a decrease in the prices of drugs. This “race to the bottom” has put the spotlight and pressure on the costs of drug production. Pharmaceutical companies are relooking at their processes and supply chains to find ways to be cheap and still keep up to speed with the regulations and competition in the market.

We speak with Mr. Ian Smith, Vice President of Commercial Operations for Chromatography and Mass Spectrometry for Thermo Fisher Scientific in Asia Pacific on the evolution of changes in the pharma landscape over the last 30 years. He talks about the significant trends worldwide that impact Asia’s pharmaceutical industry, with the latest focus 20

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Ian Smith is Vice President of Commercial Operations for Chromatography and Mass Spectrometry for Thermo Fisher Scientific in Asia Pacific. For 30 years, Ian has held various commercial and management roles for the company.

He has a Fellowship of the Institute of Biomedical Sciences.

being drug recalls in developed countries and discusses how Asia’s pharmaceutical industry and its stakeholders can collaborate to make the world healthier, cleaner and safer for everyone.

What is the landscape for today’s pharmaceutical industry?

Today’s pharma industry landscape is changing rapidly. Pharma makers need to look at increasing productivity while still delivering drugs that are effective, affordable and compliant with strict regulatory requirements.

The major pharma makers have been focusing on research and development (R&D) to deliver new drugs to the market that could be patented and bring in the revenue needed for growth. For instance, in 2018, the United States Food and Drug Administration (FDA) approved an all-time high of 59 new drug therapies. From 2011 to 2018, the FDA approved 309 drugs (an average of more than 38 per year) in the highest sustained productivity. So, we are looking at an industry that is growing and innovating.

However, the idea of innovation in the pharma landscape should not only be about breakthroughs or being ground-breaking. Innovation can be better focused on making things or processes easier, simpler, better and safer.

This type of innovation for simplicity, quality and safety involves a vital concept – the concept of connectivity, in particular, the connectivity between pharma manufacturers and their supply chains in today’s highly complex pharma industry.

This is an interesting concept. Can you share an example so as to give our readers a better idea of what this means?

An example of such connectivity is software integration in the form of Thermo Scientific™ Chromeleon™ Chromatography Data System (CDS). What we typically see is each laboratory using various brands of analytical instruments (be it for routine testing or for R&D). Imagine having a system like Chromeleon CDS where, regardless of the instrument you use, be it Thermo Fisher Scientific’s or any other brand of analytical instrument, all the information can still be integrated and accessed in one place. With its multi-vendor instrument control, Chromeleon CDS offers choice for pharma makers and stakeholders in their supply chain. Plus the ability to integrate to Laboratory Information Management Systems (LIMS) ensures a compliant, seamless flow of knowledge from the instrument to the business. This should be the type of innovation that the pharma industry strives towards as ultimately, connectivity and integration will enable innovation of better quality, safer and more effective drugs for patients.

Great example on innovation from a different perspective. Let’s go back to talking about the landscape for today’s pharma industry. Anything else you’d like to add?

Yes, let’s think about pharma growth on a worldwide scale. According to Statista, the forecast of pharma sector growth between 2017 and 2030 by country shows Asian nations such as India (growth at 232%), China (230%) and Indonesia (196%) in the top three markets of growth. In comparison, the pharma sector worldwide is expected to grow at just 160% during that period. So, we can see that Asia is a very fertile region in terms of growth.

Another important event in the pharma landscape is the expiration of patents for several drugs in the next few years. And we see the common trend in which, because of patent expirations, there will be downward pressure on the drug prices which will impact drug makers in the industry.

If we narrow the focus to Asia’s pharmaceutical industry, what would you say are the significant developments or trends that are impacting this industry today?

The aging population across the globe is a major concern. It has been estimated that there will be 2 billion people who are 60 years or older around the world by 2050. Such an increase in the elderly means that governments must find ways to meet

the increase in medical needs. As such, the world will need large quantities of drug treatments and the industry is expected to be US$1.2 trillion in size by 2024.

With the looming problem of an aging population, medicine prices need to decrease for health care to be affordable for the citizens. So the effect of low prices will impact drug makers and their investments into R&D – for instance, should they focus on breakthroughs to develop drugs that they can patent for higher profits or focus on achieving innovations within their operations to deliver high-quality yet safe and effective drugs for the mass market? These are serious considerations for the pharma makers large and small.

Any other significant trends impacting Asia’s pharmaceutical industry today?

Governmental policies and regulations are another strong industry influence. One example is China’s 4x7 project where major cities band together to purchase certain drugs. This forced drug prices to drop dramatically, impacting pharma supply chain from manufacturers to distributors, but the country will continue this policy and is working on extending this program to include more cities and drugs.

Another major trend is the drive towards traceability and authentication. On February 9, 2019, the (FDA) imposed a requirement in the Drug Supply Chain Security Act (DSCSA) to include a product identifier on prescription drug packaging for drugs coming from the European Union. This is an important step to reduce drug counterfeiting. According to reports, as much as 40% of the drugs in developing markets are counterfeit.

Yes, counterfeit drugs pose a serious health risk for patients. What can Asia’s pharma industry do about it?

For Asia’s pharma makers who are already facing price pressures on their products, the fight against fakes just add to the many challenges that they face. The pharma supply chain is so complex that it will involve cooperation of every stakeholder in the industry to work together in an interoperable and integrated framework to ensure a high level of integrity in the supply chain for the safety of patients.

Apart from counterfeits, Asia has also been impacted by recalls of drugs by the FDA. What are your comments about that?

Drug recalls have a negative impact on Asia’s drug manufacturers who will have to deal with audits, more www.pharmafocusasia.com

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tests as well as production downtime. Recently, on September 13, 2019, the FDA issued a statement “some ranitidine medicines contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA).”

The European Commission (EC) issued its final legally binding decision on medicines containing valsartan, candesartan, irbesartan, losartan and olmesartan on 2 April 2019. It stated “As N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are classified as probable human carcinogens, manufacturers must ensure that their manufacturing process does not generate such impurities and develop appropriate control strategies. To allow manufacturers to make the necessary changes to their process, a transition period has been agreed by Competent Authorities and strict temporary limits on levels of these impurities introduced in the Test section.” The EC revised the Test section with this requirement: “Nitrosamines.

Carry out the test by a suitable method.” This means that manufacturers will have to test every production batch for those nitrosamine impurities.

How is Thermo Fisher Scientific helping your customers in Asia’s pharma industry deal with recalls and more stringent regulations?

At Thermo Fisher Scientific, we are constantly looking ahead and anticipating possible scenarios and situations, which allow us to develop instruments that help pharma makers get off on a clean start with their testing.

For instance, the FDA recently published its method validated to ICH Q2(R1) for detection and quantitation of NDMA in Ranitidine. This high-resolution accurate mass (HRAM) liquid chromatography mass spectrometry (LC-MS) method developed by the FDA uses our Thermo Scientific™ Q Exactive™ LC-MS/MS system. For instrument control and data processing, the Thermo Scientific™ Chromeleon™ Chromatography Data System (CDS) may be used to address the regulatory and GMP requirements asked to be fulfilled by pharma industries. Editor’s note to readers: Please download the method here - https:// www.fda.gov/media/130801/download The FDA also shared a method validated following ICH Q2(R1) for the determination of six nitrosamine impurities (NDMA, NDEA, NEIPA, NDIPA, NDBA, & NMBA) in Angiotensin Receptor Blockers (ARB) drug products including Valsartan.

Thus, a single HRAM LC-MS method developed by the FDA can quantify all six nitrosamine impurities

simultaneously. This method utilizes the exceptional acquisition speed, sensitivity, and resolving power of our Thermo Scientific™ Q Exactive™ HF-X LC-MS/MS system for the determination of these trace level genotoxic impurities. Editor’s note to readers: Please download the method here https://www.fda.gov/media/125478/download We’ve come to the close of our interview. What would you like to say to our readers in Asia’s pharma industry?

In closing, I want to reiterate that rather than risking drug recalls in the future, Asia’s pharma makers can take the bold step to collaborate with stakeholders in the supply chain in order to make the world healthier, cleaner and safer.

Coming back full circle to what I mentioned at the start, connectivity is the key to avoid costly downtime. Pharma makers should consider connectivity using solutions for instrument control and data processing. An example is Chromeleon CDS. With an integrated system, it empowers drug makers with choice and can help make the flow of information from research to routine seamless and effective. What we want to aim for is a seamless, robust flow from the Discovery stage to the Quality Control stage. If done well, we can avoid future problems of drug recalls and economic setbacks.

A comprehensive and integrated solution can also help manufacturers address all the regulatory and GMP requirements asked by pharma industries.

I also want to stress the importance of collaborations involving knowledge sharing. Thermo Fisher Scientific has always been proactive in our outreach and education in Asia. We have industry forums or workshops for stakeholders to gain a better understanding of the causes of contamination, how to improve early detection and ultimately achieve better control of impurities within acceptable limits.

One example of such outreach activities is the third Annual Elemental and Genotoxic Impurities Workshop which took place in Hyderabad, India where leading global experts are gathered to focus on updates and developments in impurityrelated challenges and breakthroughs, aiming to address what went wrong and how to avoid it in the future.

Ultimately, Asia’s pharma industry needs to have the framework of collaboration and information sharing to better respond to their changing landscape impacting the industry today and tomorrow.

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Promoting Regulatory Collaboration and Convergence in Asia I Regulatory reliance is increasingly being used by National Regulatory Authorities (NRAs) with different regulatory systems and is actively promoted by the World Health Organization (WHO) as a mechanism to better manage resource capacity issues and strengthen regulatory systems. NRAs in Asia remain key in spearheading efforts and offer opportunities for all stakeholders.

David Jefferys, Senior Vice President, Global Regulatory, Healthcare Policy and Corporate Affairs, Eisai Europe and Chairman, Eisai Global Regulatory Council

n 2016 the WHO published an article in its Drug Information Bulletin titled Collaboration, not competition: developing new reliance models1 The article´s authors argued that modern medicines manufacture and distribution were becoming more and more globalized and that as a consequence the manufacturing processes and supply chains of pharmaceutical products, including generics, were increasingly complex´. They went on to say that the same medicinal product was often distributed in several countries or world regions and used by patients all over the world, pointing out too that it was also common that different manufacturing phases for the same product takes place in different countries, often separated by long distances.

The authors highlighted the fact that new medicines coming onto the market such as biotechnology, gene therapy or cell therapy products were complex products and that some National Regulatory Authorities (NRAs) may lack the resources or specific competences to carry out assessments of these products before they are put on their markets.

They argued that collaboration among NRAs was vital to avoid duplication of work, release scarce resources for more critical areas and speed up patient access to both new and existing medicines and vaccines.

The article was prescient in its analysis and the ideas behind it are even truer today. The growing awareness of the need for regulators to work together has led to 1 https://3zb9gz1us4bxkdpdb1n79pv3-wpengine.netdnassl.com/wp-content/uploads/2018/01/Mental-Capital.png

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the emergence of new models of cooperation, such as regulatory reliance.

Reliance is a broad concept and can be achieved in real life in different ways.

The WHO defines regulatory reliance as `the act whereby the regulatory authority in one jurisdiction may take into account and give significant weight to – i.e. totally or partially rely upon – evaluations performed by another regulatory authority or trusted institution in reaching its own decision. The relying authority remains responsible and accountable for decisions taken, even when it relies on the decisions and information of others. ’ For example, when an assessment report for a medicine authorised in the EU is shared with an NRA in Africa, the receiving authority might still need to consider differences in conditions of use, patient population and other parameters.

In many cases reliance on the assessment or inspection work carried out by another trusted NRA can be the best way to cooperate effectively. Reliance can be unilateral, bilateral (mutual) or multilateral.

Regulatory reliance is a concept whose time has come.

Strengthening regulatory systems and increasing their efficiency is something all players in the biopharma sector wish for and ultimately benefit from. Momentum for the move towards regulatory reliance is being driven by various bodies such as the WHO , the Pan American Health Organization (PAHO) and the European Medicines Agency as a mechanism for NRAs to better manage resource capacity issues whilst simultaneously strengthening regulatory systems. This allows them to focus on core national activities and is a key exemplar of a risk-based review system.

More recently, the International Conference of Drug Regulator y Authorities announced recommendations to NRAs that included `exploring approaches to utilise concept of reliance and collaborative decision-making to increase timely access to safe and effective medical products.’

Over the last decade we have seen the growing emergence of regulatory reliance 24

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Collaboration and dialogue will help to create and build trust between stakeholders, which is the foundation of regulatory reliance.

in the sphere of infectious diseases: vaccines or medicines used to prevent or treat public health priority diseases are a case in point. Examples of this include the WHO Expanded Programme on Immunisation, medicines for protections against diseases such as HIV/AIDS, tuberculosis and malaria and products of global health interest (innovative small molecule and biologicals, biosimilars, vaccines and generic medicines).

There are numerous other examples.

Switzerland has in place a system that legislates for its regulatory authority Swissmedic to approve medical products that have been approved in other countries provided that the applicant approaches it do so.

Singapore and Mexico have similar agreements with the latter having revised agreements with the European Union as well as the U.S., Canada, Australia and Switzerland.

But regulatory reliance is becoming increasingly important in regions like Asia where efforts are being spearheaded both by influential bodies like APEC and countries like Singapore.

APEC established a Regulatory Harmonization Steering Committee (RHSC) in 2010 to advocate for regulatory convergence in pharmaceuticals for improved public health and economic development among its

21 economies (APEC Member Economies 20172). Convergence will focus on the process of aligning multiple countries’ regulations for greater regulatory cooperation and does not necessarily require the regulations to be ‘harmonised’. The ultimate aim would be for APEC economies to achieve the maximum level of regulatory convergence feasible by 2020 and would focus on four key areas: Certificate of Pharmaceutical Product (CPP); the Pharmaceutical Inspection Co-operation Scheme (PIC/S) membership; managing multiple sites in one license; and risk-based reliance evaluation system.

Huge progress has been made, but in some countries it has been uneven.

Singapore, for example, has led the way on both CPP and risk reliance evaluation.

The CPP was developed by the WHO as a tool to support product registration among national regulatory authorities, especially in developing countries. It serves as evidence that a product has been approved by the national regulatory authority that issued the CPP. Previously, Singapore (a member of both APEC and ICH) used to request for CPPs but as its regulatory system matured, the requirement for the CPP has been removed from both its pre- and post-marketing control requirements3.

On risk reliance Singapore signed an agreement with Australia nearly two decades ago, which has treaty status and includes the sector on Medicinal Product GMP Inspection. Under the MRA, the Therapeutic Goods Administration (TGA) of Australia accepts the conclusions of inspections of manufacturers carried out by GMP Auditors of (Singapore) and vice-versa4. In 2011, two of Singapore’s Reference Agencies, Health Canada and the Swissmedic, invited Singapore to begin sharing work 2 https://link.springer.com/article/10.1186/s41120-0180024-2#CR4 3 https://link.springer.com/article/10.1186/s41120-0180024-2 4 https://link.springer.com/article/10.1186/s41120-0180024-2

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on generics evaluation. This cooperation led to a four-member regulatory consortium (ACSS) established in 2007.

Elsewhere though there is room for improvement. Several NRAs in Asia still dictate on cumbersome and duplicative regulations that continue to stifle efficiency and the development of regulatory partnerships.

What then are the conditions needed for the effective implementation of regulatory reliance?

First of all, regulatory reliance should be considered by NRAs regardless of their resource or capacity level and independent of their maturity. In fact, streamlined processes for handling regulatory reliance can be seen as an exemplar of maturity. All agencies in future will need to engage in reliance whether this is through information sharing, work sharing, collaborative evaluations, targeted assessments or full mutual recognition.

Second, clear public health priorities based on medical needs and regulatory capacity should guide NRAs’ approaches to regulatory reliance.

Third, the timeline from reference country approval to submission of dossiers in a reliance-based regulatory procedure should be flexible. Country filing decisions are based on multiple factors - not only regulatory considerations.

Reliance-based regulatory procedures that require submissions within a defined time of reference country approval may limit the usefulness of the procedure.

Fourth, pilot programs for reliancebased regulatory procedures will provide initial practical experience for NRAs and applicants. Robust evaluation of results from these programs, including feedback and dialogue between NRA and Industry users, could swiftly capture opportunities to improve processes and procedures leading to increased trust and acceptability by all stakeholders.

Fifth, reliance-based regulatory procedures can be implemented at many stages in the product life-cycle.

Sixth, when products are approved through reliance-based regulatory 26

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procedures, then post-approval changes should also be managed through reliancebased procedures.

Lastly, the key to effective implementation will be getting the simple practicalities right- publishing a list of accepted reference NRA countries; providing guidance on what documents are required and how they are used for the assessment; clarity on who is providing which documents (e.g. reference NRA vs applicant) should also be given and confidentiality should be assured; assessments ought to be based from one reference NRA, and not upon two or more reference NRA countries.

There will of course be challenges along the way.

Regulatory reliance cannot happen in a vacuum so there will inevitably be a need to map out implications of increasing reliance globally within existing regulatory networks/schemes. It also means that administrative requirements for existing reliance schemes need to be taken into account going forward.

The misalignment over the source (NRA or manufacturer) and volume of information is a potential problem as would be the lack of advance agreement between NRAs on the information to be relied upon. The lack of safeguards of confidentiality also need to be addressed.

BREAKOUT BOX With the recognition by the US Food and Drug Administration (FDA) of Slovakia, the European Union and the United States have now fully implemented the mutual recognition agreement (MRA) for inspections of manufacturing sites for certain human medicines in their respective territories.

Each year, EU national authorities and the FDA inspect many production sites of medicinal products in the EU, the US and elsewhere in the world, to ensure that these sites operate in compliance with good manufacturing practice (GMP). Under the MRA, EU and US regulators will now rely on each other’s inspections for human medicines in their own territories and hence avoid duplicative work. As a result of the MRA, both the EU and the US will be able to free up resources to inspect facilities in other countries.

The MRA is underpinned by robust evidence on both sides of the Atlantic that the EU and the US have comparable procedures to carry out GMP inspections for human medicines. Since May 2014, teams from the European Commission, the EU national competent authorities, EMA and the FDA have been auditing and assessing the respective supervisory systems. With the positive assessment of Slovakia, this process has now concluded for GMP inspectorates covering human medicines.

From now on, a batch testing waiver will also start to apply. This means that the qualified persons in EU pharmaceutical companies will no longer have to carry out quality controls for products manufactured in and imported from the US when these controls have already been carried out in the US. The MRA implementation work will continue with a view to expanding the operational scope to veterinary medicines, human vaccines and plasma-derived medicinal products .

Source: European Medicines Agency

STRATEGY

Collaboration and dialogue will help to create and build trust between stakeholders, which is the foundation of regulatory reliance.

So, who are the winners in a system of regulatory reliance?

Certainly, patients and healthcare providers are huge beneficiaries - regulatory reliance can improve timely access to safe, effective and quality medical products.

AUTHOR BIO

But the reward and opportunities of buying into regulatory reliance are enormous and still very much untapped - implementing regulatory reliance provides stakeholders with opportunities that go beyond regulatory processes.

Harmonisation will foster regulatory reliance and implementing WHO and ICH guidance can facilitate the implementation of regulatory reliance mechanisms. At the same time changes to regulatory and legal frameworks should aim to leverage the benefits of regulatory reliance.

Regulatory reliance supports capability building - the learning and experience-sharing aspect of regulatory reliance will allow NRAs to address potential capability gaps in the longer term.

The NRAs also gain enormously by efficiently utilising resources that avoid duplication of work and providing opportunities to strengthen the regulatory system, while maintaining sovereignty over decision-making. As does industry with streamlined management of regulatory submissions and global supply systems as well as predictable, timely approvals.

References are available at www.pharmafocusasia.com

David Jefferys is currently the Senior Vice President for Global Regulatory, Healthcare Policy and Corporate Affairs, Eisai Europe and Chairman of the Eisai Global Regulatory Council. He also sits as a member of the European Working Group of the UK Ministerial Industry Strategy Group and UK Innovation Board. He is Chairman of the ABPI Regulatory Affairs Group and a member of several EFPIA committees. He is also Chair of the IFPMA RSC.

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COACHING

BRAND STRATEGY IMPORTANT BUT DIFFICULT

Coaching works well when the performance issues are wellunderstood, clearly defined, and individual. But coaching a strategy team is much more difficult because the issues are usually fuzzy, interconnected and systemic. This article describes the challenges of coaching a strategy team and a three-step process for overcoming those challenges.

Brian D Smith, Principal Advisor, PragMedic

W

hen researching my latest book (1), life sciences CEOs told me that the most important and fulfilling part of their job was developing the people who worked for them.

Nowhere is this more true than when formulating brand strategy. Deciding 28

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how best to allocate limited resources to achieve brand objectives is a missioncritical task that is usually delegated to a cross-functional team that brings together marketing, market access, medical and other skills. Typically, however, brand teams consist of colleagues still in the

first third of their career; their strengths of energy and enthusiasm are balanced by relatively little experience in brand strategy formulation. For that reason, it falls to more senior heads, perhaps carrying some grey hairs and the scars of previous experience, to guide the brand team. For these more senior executives, there can hardly be a more important task than coaching the brand teams. But effective coaching, which involves both guiding and developing, is a rare skill. Most leaders find it much easier to instruct instead of coach but whilst this may direct activity it doesn’t deliver development. Let’s look at what we know about how coaching works and why it is so hard to do in practice. Finally, I’ll describe the three-step

STRATEGY

process that highly competent coaches use to support their brand teams.

Relevant, Specific, Constructive

When coaching works for brand teams, they describe it as having three characteristics, each of which is necessary but not sufficient. Firstly, it has to be relevant to their business situation; closely related in all significant respects to the challenges the brand team face. Nothing disengages a brand team more than leaders’ war stories that have little connection to the challenge facing them. Secondly, coaching must be specific; making detailed and unambiguous points that that the brand team does not have to interpret or infer from. Vague, general platitudes are of little use to a brand team facing competitive challenges. Finally, coaching must be constructive; resulting in positive new ways to tackle issues. Negative, destructive remarks merely serve to destroy the brand team’s morale.

That coaching works only when it is relevant, specific, and constructive is not a huge insight. What is perhaps surprising is how few leaders manage to coach their brand teams in this way.

Since these senior executives are neither stupid nor lazy, it suggests that there are some intractable, problematic barriers that hinder them.

Tacit, Ambiguous, Imperfect

Three challenging barriers to effective strategy coaching are present in every organisation and all three must be overcome if leaders are to help, rather than hinder their brand teams. The first is the tacit nature of leaders’ knowledge; like riding a bicycle, they know very well how to make strategy but their knowledge is unconscious and unstructured. Unless it can somehow be made explicit, it is very difficult to transfer that expertise to younger heads. The second is a language issue; in a business environment, words like strategy, segment, value and positioning are often thrown around without precise and agreed meanings. If the words leaders use are ambiguous, their meaning is often misconstrued, deliberately or 30

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The Three Habits of Strategy Coaching

When one observes senior leaders coaching brand teams in a relevant, specific and, constructive and, therefore, effective manner, it is not that they do not face the issues of tacit, imperfect knowledge and ambiguous language. Instead, it is that they have developed three habits to overcome these barriers. These three, sequential habits are the result of many years of practice, success and failure are described below and are summarised in figure 1.

Effective coaching at the ‘Measure and learn’ stage typically involves structuring and sharing experience about the value and limitations of different kinds of metrics.

Structure and Share

otherwise. The third barrier is imperfect knowledge; even the most knowledgeable leader cannot be current and fully versed on the detail of every market. And small imperfections in leaders’ knowledge can lead to fundamental misunderstandings and also to loss of credibility with the brand team.

Again, it should come as no surprise that leaders’ knowledge is imperfect, that semantic ambiguity hinders communication and that hard-won experience creates tacit knowledge that is hard to convey clearly. Every leader struggles with these issues. The question is how can they be overcome in a systematic, reproducible way.

Tacit knowledge is structured into methods and models that are shared with those being coached

Structure and Share

Effective leaders have the habit of reflecting on their tacit knowledge and turning it into an explicit model or method that can be suggested to the brand team.

For example, one leader I observed had listened to the brand team describe their target audiences in terms of job roles, in this case consultant cardiologists.

Reflecting on her own past successes and failures, she suggested that a good model for segmentation involved not only the prescriber but the situation. She talked about segmenting the context, rather than the person, as a better way of understanding the heterogeneity of the market (2). This process of first structuring and then sharing her tacit knowledge moved what she knew from being intangible

Clarify and Codify A precise set of terms is developed that becomes commonly used and understood

Figure 1: The Three Habits of Strategy Coaching

Specific suggestions about what to do are made and used to stimulate original thinking

Specify and Sell

STRATEGY

and uncommunicable to being tangible and intelligible.

Clarify and Codify

Effective leaders have a habit of eliminating semantic ambiguity by clarifying exactly what they mean, especially if what they say is open to misinterpretation. For example, I worked with one leader whose habit was to listen carefully and then home in the words or terms he thought especially in need of disambiguation. In one case, it was the word “positioning”, which had been used many times in the discussion but never defined. Observing that everyone in the room was using the word loosely, he suggested that everyone agreed on a definition that was much tighter: positioning is the design of the offer and activity around the needs of the target segment (3). Until that moment, most people in the room had used “positioning” in the much narrower sense of “customer perception”. This process of first clarifying and then codifying the meaning of key words made the strategy discussion much more focused and allowed the team to resolve key issues.

These three habits, although often unconscious, allow leaders to share their wisdom with the brand teams. It does much more than simply instruct them; it raises the brand teams’ capabilities. This three-habit approach has its academic foundations in Nonaka’s learning spiral model, which reminds us that the three habits form a continuous loop; they only work if performed together.

Applying the Three Habits in Practice

The three habits of strategy coaching are not conceptually difficult to understand.

Nor is it hard to see that they must be applied together for best effect. However, even leaders that do sometimes fail in guiding and developing their brand teams.

That is because, like any idea one wishes to apply in practice, the devil is in the detail. In this case, the detail of how a brand strategy is built.

The Three Habits and the Strategy Loop

Strong brand strategy processes are iterative loops. As shown in figure 2 (developed from the work of Professor Malcolm McDonald), there are five essential steps in making and executing brand strategy. A weakness at any of these stages weakens the whole brand strategy, so it is important that the leader applies the three habits to every sequential stage.

For example, at“Understand the market” stage the most effective coaching often involves structuring and sharing experience of what knowledge leads to competitive advantage and which is merely necessary for operations. This may lead to a clarified and codified definition of the term market insight and this, in turn, may lead to specifying and selling prototype market research methods.

Discussion of those suggestions leads to better market understanding.

Understand the market

Specify and Sell

Effective leaders have a habit of moving the strategic discussion forward by proposing very specific suggestions not as instructions but as prototype ideas that are meant to be challenged, improved and built upon. For example, in one difficult decision about targeting limited resources, I watched as a leader suggested an alternative approach. Rather than a binary target/don’t target decision, he proposed one of four levels of resource allocation for each segment. He proposed the idea as one to challenge and, as he intended, the discussion revealed reasons why segments varied in their attractiveness and the firm’s ability to win them.

A sophisticated, non-binary approach emerged. The process of specifying and selling had brought out new ideas and replaced a traditional targeting approach with a much subtler and more sustainable one.

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Measure and learn

Execute

Figure 2: The Stages of the Brand Strategy Process

Decide on the marketing strategy

Develop the activity plan

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Often, the most valuable coaching of brand teams comes at the point where marketing strategy is decided. Here, experienced leaders might structure and share their experience of what choices are strategic (e.g., which customers, with what offers) and which are tactical. This would enable the team to clarify and codify exactly what they mean when they talk of strategy, tactics and objectives, so removing ambiguity. Finally, that terminology can be used when specifying and selling prototype marketing strategies, the healthy debate of which is essential to a strong final choice.

In the same way, effective coaching at the ‘Measure and learn’ stage typically involves structuring and sharing experience about the value and limitations of different kinds of metrics. This may lead to a clarified and codified definition of different kinds of metrics (e.g. lead, lag and learning metrics) and to specifying and selling a dashboard that includes all three types of metrics. Constructive challenge of this prototype dashboard is likely to lead to better measurement and learning, which feeds into the next planning cycle.

Coaching, Crystallised

Every brand team benefits from relevant, specific and constructive coaching by their more experienced leaders, but there are

formidable barriers in the shape of tacit and imperfect knowledge and ambiguous language. This explains why, although we know what effective coaching looks like, it is remarkably rare in practice.

We can learn how to overcome these barriers from those leaders who have learned to coach brand teams well. If we look carefully, we can see that they have developed three habits, which may be unconscious to them but which this article makes explicit.

We can also see that applying one or two habits is insufficient: all three are needed. Finally, we can see that three habits work when they are applied at every stage of the brand planning process. As Aristotle said, excellence is not an act, it is a habit.

References 1. Leadership in the Life Sciences: Ten Lessons from the C-Suite of Pharmaceutical and Medical Technology. Available from Amazon and other bookshops.

2. For my article about this approach to segmentation, “Superior Segmentation”, please contact the author.

3. For my article about the definition of terms in strategy, “Mind Your Language”, please contact the author.

AUTHOR BIO

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

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IS THE INDIAN PHARMA INDUSTRY AS BLACK AS IT IS PAINTED? The Indian pharma industry has received substantial negative publicity about the quality of medicines in the past couple of years. This article while acknowledging the gaps and attempts to show the other side of the Indian pharma industry. It briefly touches on its history, contribution made to India and the world. This article, however, goes deeper into the intent and purpose of the industry to ensure that quality medicines are delivered to the patient while operating in an extremely tough business environment. If after reading this article, the reader gets a new perspective on the Indian pharmaceutical industry then the purpose of writing this would be achieved.

Vikram Munshi, Founder, WhiteSpace Consulting & Capability Building

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et me put up the disclaimers up front. I have been an employee in the Indian pharma industry and currently run a consultancy business where several leading pharma companies are our clients. I am writing this piece wearing the dual hat of an industry person as well as a patient.

The Indian pharmaceutical industry has been in the news past year mainly not for commendable reasons but ‘quality’ issues. We have read books and articles where industry insiders have shown the world how Big Bad Indian pharma

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manipulates data to sell poor quality medicines not only in India but also across the world. The high noise level impacts the perception of the consumer of information.

I am not defending the pharma industry. I firmly believe that there are areas where the Indian pharma industry has to reflect and take drastic measures to cope with the changing times. However, every coin has two sides and this writing is my humble attempt to show the other side of the Indian pharma industry that we tend to miss at times.

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History

Acharya PC Ray laid the foundation of the Indian pharmaceutical industry in 1901 with the establishment of Bengal Chemicals. Six years later, T.K Gajjar, A S Kotibhaskar, and BD Amin started Alembic Chemical Works. Khwaja Abdul Hamied founded Chemical Industrial and pharmaceutical Laboratories (Cipla) in 1935.

Thus we can say that the Indian pharmaceutical industry is close to 120 years old. The reason for citing this little bit of history was only to give a sense of perspective that the industry has been there for a long time and founded by visionaries.

Contribution to the World

From those humble beginnings, today the Indian pharma industry produces more than 1/5 of the generics in the world. It supplies more than half of the worldwide demand for vaccines. More than 80 per cent of the antiretroviral drugs (ARV) in the world, which are used for fighting the dreaded disease AIDS are supplied by Indian pharmaceutical companies at an affordable price for the patients. Overall, the industry is the third-largest in the world in terms of volume catering to all therapy areas at a cost that helps increase access to patients.

Contribution to the Country

The industry earns close to US$20 billion through exports. In terms of employment, it is estimated that the industry provides employment directly or indirectly to more than 2.86 million Indian citizens.

These numbers just don't happen by manufacturing and selling medicines.

They are all driven by the purpose and vision of the leadership comprising the Indian pharma industry over the past decades.

The regulatory landscape in which the Indian pharmaceutical industry operates is also not favourable. The National pharmaceutical Pricing Authority (NPPA) is a government regulatory agency, which controls the prices of pharmaceuticals in India. It fixes the price of

the drugs place in the National List of Essential Medicines (NLEM) under the Schedule-I of the Drug Price Control Order (DPCO). As of now close to 1000 have been brought under price control under this initiative.

The Indian pharma industry deserves appreciation to manufacture and market quality drugs under this kind of VUCA (Volatile, Uncertain, Complex, Ambiguous) regulatory environment.

Any therapy in India requires education and knowledge updation of the doctors as well as the patients.

The industry has played a critical role in disseminating knowledge on disease and management to doctors that had helped them to treat patients effectively.

Let's look at a couple of examples.

Every time an Indian asthma patient reaches out for an inhaler, there is close to 50 years of therapy education, which has gone behind it. Cipla, the pioneers in asthma, didn’t just sell inhalers. They had to educate the doctors on asthma diagnosis and management. An innumerable number of asthma patients have been screened and trained on the usage of their medication by some of the other initiatives of the Indian pharma industry.

Tuberculosis was a scourge in India; it was companies like Lupin that pioneered Tuberculosis education and management in India with a range of affordable and quality medication.

Recently, the drug ranitidine has been in the news for it being recalled as

it contained a cancer-causing impurity that is believed to have crept in due to change in the manufacturing process.

While this is indeed a cause of worry and the right action has been taken, the pioneering brand Zinetac, was responsible for educating the doctors about ulcer management apart from surgery.

I am sure either we or someone we know would have been prescribed Cifran (ciprofloxacin) which was one of the many antibiotics marketed by the erstwhile Ranbaxy which was a pioneer in anti-infectives.

In the hinterlands of India, when a rural doctor confidently administers an anti-rabies vaccine to the patient, the confidence in the usage comes from the education initiatives on all aspects of rabies and its management, taken by the manufacturer of ant rabies vaccines.

It is these pioneering initiatives, which create infrastructure. The knowledge dissemination role of the pharma industry sometimes does get eclipsed.

Yes, some companies are known to take doctors for conferences that do get labeled as joy trips. But, at the same time, some doctors go for these conferences to get educated on newer developments and protocols that they use on patients like you and me.

Now look at an analogy to understand this aspect better. Production of cars leads to the construction of roads, availability of fuel and repair facilities.

As cars get more advanced, they create

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So what is quality and acceptable quality?

Quality standards are always evolving.

Let us go back to our car example. The emission standards have changed over the past two decades. Though cars have been on the roads of India even before independence, the first emission standards were rolled out in 2000 after which they have got progressively more stringent. I am not an expert in the changes of regulatory standards of the industry but I can assume that if there are evolving emission standards in the vehicle industry that are becoming more and more stringent, there would be a similar evolution in quality standards of medicines.

The Indian pharma industry needs to keep abreast of the changing quality standards of all the markets it caters to.

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The Indian pharma industry deserves appreciation to manufacture and market quality drugs under this kind of VUCA (Volatile, Uncertain, Complex, Ambiguous) regulatory environment.

ity can be attributed to the intent of compromise.

The Indian pharma industry is stringent about quality. They invest in packaging that maintains the stability of the medicine in the diverse climate conditions and retail situations across the country. Some vaccine manufacturers have invested in temperature indicative packaging, which changes colour in case there is a disruption in the cold chain from the manufacturing plant to the patient.

Manufacturers of leading brands invest in anti-counterfeit packaging to ensure that the retail chemists are educated to distinguish between genuine and counterfeit medicines so that the patient is not compromised.

They ensure that there is no invoicing of medicines to distributors, whose expiry is less than 6 months away. These companies also ensure that the expiries are disposed of in the right manner so that they do not find their way back into the market.

AUTHOR BIO

a demand for better roads, fuels, etc.

The medicines the Indian pharma industry produces are like cars. These medicines, lead to knowledge up-gradation in disease management. This, in turn, creates demand for specialised fields of medicine.

Many of the super specialties of doctors created today like Chest Specialists, Gastroenterologists, Diabetologists, Cardio-Thoracic Surgeons, and Dermo Cosmetologists have been an indirect impact of the efforts of the Indian pharmaceutical industry.

At this point, the reader might think that do these facts justify any compromises in quality. Absolutely not.

Try to evaluate this from a different perspective by asking two questions.

• Do we believe that the Indian pharma companies have the intent to deliberately make medicines that can harm the patient?

• Is it possible for an industry like this to grow to what it has grown by making substandard or poor quality medicines?

I am sure the answer to both those questions is a ‘No’. Everything starts with intent. If the intent is fine, then the rest falls into place.

Apart from its mission of ensuring quality medicines, every leading pharma company is very conscious of its reputation and place in the industry.

Deliberate shortcuts that can impact the patient experience and reputation are not a norm in this industry.

We all know that integrity is about doing the right thing when no one is watching. I have known companies to have voluntarily destroyed stocks of expensive vaccines stored in a depot where there was a human error in recording the periodic temperature of the cold storage room. The company could have easily released the vaccines into the market without anyone knowing.

After all, vaccines are essentially vials of trust and faith that the doctor injects into a patient that he or she will be protected against that particular disease.

The company chose to do the right thing despite the commercial loss of lakhs and lakhs of vaccines.

This is just one of the stories which epitomise the spirit, intent of the standards of the Indian pharmaceutical companies and I am sure for every ‘bad’ story there would be many more examples of pharma companies taking steps to ensure that the trust of all the stakeholders does not get betrayed.

So next time when you are purchasing a medicine, do remember it's a part of a 120-year-old industry which is a global contributor and an employer to millions of talented Indians who have a mission and intent to provide quality medicines at an affordable cost at capped margins in a very demanding domestic and international regulatory environment.

Vikram A Munshi has over 22 years of experience in the life-sciences and healthcare space. Munshi has vast experience in the pharma industry and holds a Ph.D. from the Birla Institute of Technology.

Former Head of Marketing pharma at Ranbaxy, he has also been a part of GlaxoSmithKline for over half a decade. Passionate about making the industry patient-centric, Vikram started WhiteSpace in 2012 to enable transformation and bring an impact.

COATED LIDDING SIGNIFICANTLY REDUCES PACKAGING-RELATED PARTICULATE IN DRUG DELIVERY SYSTEMS* New independent study proves Jenn Goff, Director of Product Marketing Oliver Healthcare Packaging "Coating technologies reduce particulate generation by up to 96% in pharmaceutical manufacturing" As the demand for prefilled and prefillable syringe applications grows, one consideration for many pharmaceutical manufacturers is particulate; in particular, how particulate can be reduced in the manufacturing process.

The sterility of a drug delivery system is extremely important for pharmaceutical companies and manufacturers. Choosing the right sterile barrier system can be an afterthought, especially considering the long process which includes drug development, product launch, and choosing a partner for syringe filling & packaging. Many of the partner companies have expertise in filling high volume applications, often using robots and syringe tubs with glass vials, in ultra-clean manufacturing environments. In addition to this expertise, these companies are often adept at interpreting and operationalising regulatory standards as a part of their manufacturing process.

ISO 11040-7, Prefilled Syringes – Part 7: Packaging systems for sterilised sub-assembled syringes ready for filling provides the requirements for drug manufacturers regarding sterilised sub-assembled syringes that are filled and secured in tubs and nests.

The standard states that the packaging system shall have acceptable microbiological and particulate levels to support the introduction of the sterilised sub-assembled syringes into an aseptic filling environment.

Material selection can impact particulate generation, and coating can often help reduce particulate. Coating

technologies also play important roles in maintaining the sterility of the drug delivery packaging system.

During the manufacturing process for prefillable syringes, the syringe tub and lid are brought into a production location and opened. Once the lid is peeled and removed from the syringe tub, the syringes are then prepared and filled with the applicable drug.

During the peel process, it is important that particulate generation is minimised so nothing enters the syringes. It is highly recommended that lidding used for this application have a coating applied to it to lower particulate level.

Oliver Healthcare Packaging recently organised a third-party study to look at the relationship between coating technology and particulate generation. The test included drug delivery systems utilising tubs and syringes – injection molded polystyrene sealed to a coated 1073B Tyvek lid. The study included a sample set of 60 sealed drug delivery tubs. The tubs were peeled open and tested for particulate generation.

Three types of peeling methods and four different coatings were selected for this study to represent the variety in the current drug delivery industry. Oliver sought to understand how different peeling methods and coating types affected particulate generation. The study focused primarily on understanding whether hot-melt coating or water-based coating were more advantageous with regards to particulate generation when peeled from the polystyrene tubs.

Research Approach & Methodology The study was conducted by a third-party lab with certified testing methods based in the U.S.A. www.pharmafocusasia.com

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Testing was conducted in an ISO 7 cleanroom. Baseline cleanroom measurements were considered as a part of data collection prior to the study.

As stated, three different peeling methods were used for this study, including mechanical, manual, and heated peel. Figure 1 reviews the approach of each peel method. Each method used five samples per coating to generate different size particulate counts (0.3µ, 0.5µ and 5.0µ). Figure 2 highlights the relationship of the particulate counter to the tub and coated lid during the peeling process.

Figure 1: Approach of peel methods

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Research Results Results in Figure 3 show a significant decrease in particulate from hot-melt coating when compared to water-based coating for the mechanical peel method.

Three particulate sizes were collected during the study, 0.3µ, 0.5µ and 5.0µ. The data points in each box plot show the average value of the sample set.

It is also worth noting the variability in particulate between the two coating types. Hot-melt coatings showed much less variability in particulate generation than the water-based coating per the study

Figure 2: Visual of Test Conducted

results. This is important since the variability parameters set from a quality perspective might require manufacturers to have consistency in the allowable particle generation.

Though additional testing is recommended, the initial study shows significantly lower particulate generation by using a hot-melt coating versus a water-based coating.

More on Coating Technologies As discussed, there are two coating technologies currently available for companies looking for sterile barrier packaging. It is important to understand the application and process for your product in detail before determining the appropriate solution.

Figure 4: Hot-melt coating

A hot-melt coating uses a process to apply 100% solids in a uniform dot pattern. See figure 4, where you can see small pyramids that line the Tyvek. The hot-melt coating process maximises coating anchorage and substrate breathability while decreasing particulate generation during peeling.

The coating dots merge during sealing, providing a caulked effect for consistent peel.

Hot-melt coatings are waterless and therefore have an inherently low endotox in population when compared to water-based coatings. This coating type makes an excellent choice for specific applications including but not limited to drug delivery systems.

Another common coating type, and one that Oliver used in this study, is water-based coatings. Many industry professionals like water-based coatings because they are consistent when peeled open. The seal transfer allows for easy inspection by healthcare professionals. See Figure 5.

In conclusion, filling syringes in high-volume automated processes can be a challenge. Meeting various regulatory requirements in different regions

Figure 5: Water-based coating

of the world, setting and consistently achieving particulate standards as required, and ensuring that throughout sterilisation and transportation your drug delivery system is unaffected can be a challenging undertaking. Though the study focuses on one element of the entire manufacturing process, it is one with large implications on the wellbeing of patients.

Coating technologies as show play a vital role in this process, ensuring you choose the right manufacturing partner, and they choose the right coating technology in their manufacturing process becomes critical in launching your drug delivery system in the market. *Throughout this article, we will refer to syringe filling and the unique manufacturing process involved as drug delivery systems. *The study conducted does not consider Oclean processed lids; the study used standard lids, manufactured under normal conditions. Oclean processed lids are cleaner and carry less inherent particulate as a result of their manufacturing process.

AUTHOR BIO Jenn Goff is the Director of Product Marketing at Oliver Healthcare Packaging, where she is responsible for delivering new products to customers in the medical device and pharmaceutical industries, with a specific focus on product development to solve unmet needs within the market. Goff is based in Grand Rapids, Michigan, and is an established leader in the medical packaging field. Prior to joining Oliver, Goff led a group of shared services teams within new product development at Stryker. While at Stryker, Goff gained valuable leadership experience and expanded her knowledge by taking responsibility for labeling and electrical approvals in addition to packaging engineering. Goff began her career at Edwards Lifesciences, where she held a variety of packaging and quality engineering roles. Goff graduated with a B.S. in Packaging from Michigan State University. Her passion for packaging in the Med Tech market pairs well with her commitment to quality and patient safety.

Advertorial www.pharmafocusasia.com

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Reshaping Pharmacovigilance ISOP ISRAEL experience

Multidisciplinarity is a key element for efficiency as illustrated by ISOP ISRAEL projects in hospital and community. Artificial Intelligence (AI), real-world evidence and big data are leading Pharmacovigilance toward a more integrated public health. The industry must bring its expertise to support broad campaigns and projects promoting safe medication practices.

Irene R Fermont, ISOP ISRAEL- IFC

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harmacovigilance has undergone tremendous changes since the Vioxx story in 2004, which triggered the risk management approach worldwide. However, a much disruptive evolution is already on its way with the apparition of news concepts, new tools and new actors, reshaping the pharmacovigilance of tomorrow.

Pharmacovigilance as a Public Health Multidisciplinary Activity

As widely discussed in scientific events and literature, Pharmacovigilance has remained limited far too much to clinical pharmacologists and pharmacists. It is a common understanding in other highrisk industries, such as aeronautics and nuclear power that management of risks

can only be efficient when applied by a multidisciplinary team and considered across the entire system.

Leading Health Policy makers advocate this vision. This is the case for Peter Pitts, President of Center for Medicine in Public Interest and past FDA Associate-Commissioner, and Prof. Herve Le Louet, President of CIOMS (WHO Council for International Organisations of Medical Sciences is advancing public health through guidance which are the basis of all regulations worldwide.) In their respective roles, they are both leading the evolution of Pharmacovigilance and propose redefinition of roles and responsibilities.

It is interesting to note that the Institute for Safe Medication Practices

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(ISMP) is focused on healthcare professionals, mostly in hospitals. ISMP is working, closely with the FDA for more than 30 years, to prevent medication errors. In addition to its extensive training activity, ISMP has designed several tools such as the ISMP Safe Practices Self-Assessment for high alert medications such as anti-thrombotics. This tool allows a hospital multidisciplinary team to screen all aspects and steps of a treatment and to identify weaknesses in the system. Following gap identification, corrective actions are implemented for safer practices.

Where is the industry’s role in this process? In the case of ISMP, the industry has supported and participated to the expert team which has written and is periodically updating the Self-Assessment tool. Another role could be to participate actively to its systematic implementation.

Pharmacovigilance should not and will not remain only the expert’s job but must integrate all stakeholders along the treatment process. The future of Pharmacovigilance lies in it becoming a truly multidisciplinary and integrated public health.

AI is Redefining Roles in Pharmacovigilance

The switch toward real world evidence led naturally to Big Data and AI. AI associated with machine learning means a sky-rocketing evolution of pharmacovigilance, through the new tools that are already present on the market.

Today, AI is able to screen, identify, retrieve, and analyse adverse events (AE) and safety signals, across multiple sources: the patients’ electronic medical records (eMR), the social media and forums, the structured and unstructured databases from the industry or from regulators, the English scientific literature and the local literature, in several languages.

Sensors, as well, are already producing a huge amount of data that are (or will be) integrated into the eMR and therefore included in the AE screening.

AI is already used by numerous hospitals and Health Management

That the pharma industry will have the opportunity to play a major role in bringing its experience and knowledge in pharmacovigilance; staying on track or even ahead of the tremendous evolution of drug safety.

much of the safety information collected and analysed in hospitals will reach the authorities? Except for the most advanced regulatory authorities, are the regulators ready to receive such an amount of data and process them in a way to improve drug safety at national and international levels?

Another hot topic which demands a thorough thinking is the data hosting and ownership. This is political and ethical issue that must be addressed, now.

Patients’ Rights for Transparency

Organisations (HMOs) to prevent medication errors in prescribing or monitoring patient’s adherence. Such evolution toward a systematisation of AI is unavoidable for the whole healthcare system: hospitals, the industry and regulators. The general implementation of eMRs systematic screening for potential AEs, in the entire health care system, is only a matter of time.

Will we need any more the Healthcare Professionals (HCP) and the patients to report an AE when we know that it could be systematically identified through the patient’s eMR? Are we assured that the direct contact with patients and healthcare professionals will provide a more accurate report? The causality assessment of Adverse Drug Reaction (ADR) will certainly remain the last bastion before being processed automatically by AI and deep learning. Certainly, a disturbing thought which is shaking the very foundations of our vision of pharmacovigilance; a disturbing thought, indeed, but one which must lead us to reshape our role.

The core work of screening, analysing, trends detection, near misses, will then be performed by the health care providers.

How and when will this Information reach Pharma Companies?

Looking at the European model, pharma companies are no longer receiving AEs from the authorities but must daily screen Eudravigilance, the EMA safety database, to retrieve AEs reported by local authorities, patients or HCPs. But how

In the era of the internet, patients can have access to an increasing amount of information on their disease and treatment. How much is this information relevant and understandable when provided by ‘Dr Google’? As an answer to the new patient’s role, the EU regulation requires from the pharma industry, and the EMA and national authorities, to summarise in lay language all regulatory safety documents: risk management plans, aggregate data safety reports, alerts, the list of black triangle products, etc.

Answering to patient’s requests to be actively involved in their treatment, many organisations or companies are focused on patient education and are providing accurate and relevant information to support a patient’s understanding thus securing a better treatment adherence.

For instance, the organisation BeMedWise, funded by the US FDA, is providing many documents, videos, and pocket guides for patient education either directly, aimed at the patient, or toward the HCP to help him educate his patients. In addition, BeMedWise organises large campaigns, focused on specific issues such as the opioid crisis, or polypharmacy in elderly people.

New activities are developing, new actors are now strongly involved in Drug Safety , such as hospital multidisciplinary teams, Information Technology /AI engineers, patients .These changes are not led by authorities or the industry, thus illustrating the outreach of Drug Safety outside of the usual pharmacovigilance pathway ‘regulator-industry’. www.pharmafocusasia.com

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The ISOP ISRAEL Experience

Adhering to these new concepts, ISOP ISRAEL, the Israeli Chapter of the International Society of Pharmacovigilance, is experimenting with a new strategy which combines several tools and methods, and integrates several disciplines in a continuum. Supported by key health policy leaders and strong partnerships with ISMP, BeMedWise and others, ISOP ISRAEL puts in practice this new vision.

Relying on a practical approach, where one learns while doing, the first projects are built around a case study — the anticoagulants — and in pilot centres — hospitals and a chain of communitypharmacies.

A medium-size hospital, Maayanei Hayeshualocated in Bnei Braq, Israel, has translated into Hebrew and implemented the ISMP Self-Assessment for anti-thrombotics, which has led to a wide corrective and preventive actions plan (CAPA). Other tools are also under implementation including a mobile application, MyeReport, which is focused on the patient, to report in a few minutes an adverse event. The mobile app is linked to a campaign of information for patients taking anti-thrombotics, using both BeMedWise documents and Educational material of the Risk Management Plans of DOACS (Direct Oral Anti-Coagulants), provided by the industry.

SuperPharm, a private chain of community pharmacies, launched a national campaign on anticoagulants.

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cists, when dispensing anticoagulants to patients, must check the dose, the indications, the renal function, and the interactions; they have intercepted several medication errors, have corrected the dosage, advised the patient and were able to show for each specific drug what kind of actions they have taken.

One-year experience in the pilot centers has shown the feasibility and sustainability as presented in the first ISOP ISRAEL International, Multidisciplinary and solutions-oriented symposium: 360⁰ of DRUG SAFETY, which was held in June 2019 in Tel Aviv. Chaired by Prof le Louet, president of CIOMS, the symposium illustrated the new trends in Pharmacovigilance and has given a glimpse on what is in front of us.

Israel, as the startup nation, is a leader in digital health and, therefore, has several solutions to offer to screen AEs (Data2Life), to prevent prescription errors (Medaware), to promote smart adherence (Water-io and Vaica), and to educate patients (Medivizor). Their results were presented during a full session dedicated to AI and Information technology solutions.

Some hospitals are leading the way, such as Sheba-Tel HaShomer Hospital, Israel, ranked by Newsweek the 10th top hospital in the world. Sheba Hospital has implemented several IT and AI tools such as the Institute for Health Improvement Trigger Tool. The Trigger tool screens eMRs to detect and identify potential AEs through markers such as a sudden drop in haemoglobin in a patient with anticoagulant which could mean occult haemorrhage. Medaware is now fully displayed in the hospital for all prescribers: its AI and machine-learning solution allows, through the access to the eMR, the prevention of medication errors and to fine tune the prescription according to both best guidelines and personalisation.

All presentations are now accessible through ISOP ISRAEL website.

The role of the Pharma industry

The pharma industry, especially the

Marketing Authorization Holders (MAH), has to redefine its role, while relying on its many assets, that should be more focused on multidisciplinary projects.

During the design of such projects, the industry can constructively bring to the table its knowledge on regulation and international standards which can frame the links with authorities. Industry should also train the hospital teams on the organisation of their pharmacovigilance and quality systems.

Experience in risk management and risk minimisation actions will be precious for both sides: for MAHs, risk management plans will be integrated in the projects and, therefore, will be more efficient. For hospitals, at the CAPA time, corrective actions could be inspired by the risk prevention/minimisation actions as proposed in international regulations.

Industry expertise on the products and its use can support the design of new tools as is the case of the ISMP Self-Assessment tool.

The long experience in risk communication can be used to promote national campaigns and provide educational material. BeMedWise is largely supported by the industry in its campaigns of patients’ education, both with expertise and sponsoring. Certainly, also, in promoting and spreading the use of these tools.

Thanks to its long experience in scientific event organisation, the industry will be efficient in enrolling more stakeholders, or more hospitals, spreading the information about campaigns or projects within the healthcare system, through conferences, congresses and workshops.

Over the past decade, patient advocacy became a key strategy for companies with high risk products where the patients’ and healthcare professionals’ training is paramount for a better benefit/risk. This activity will increase in the future.

With the development of real-world evidence, big data and AI, the industry will have to focus its creativity in establishing strong partnerships with multiple stakeholders, proposing new tools and

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And the Regulator?

For the industry to change its paradigms, it will mean a parallel evolution for the regulators. The pharmacovigilance regulations today are mainly ruling the relationship with the industry. Even if the HCP and the patient have now more weight and at least receive a more transparent information thanks to the regulation, they are still more like observers than really involved.

Multidisciplinarity for regulatory authorities will start with collaboration between several departments in the Ministry of Health, which should be involved in multidisciplinary projects and national campaigns.

Will we have to wait for another Vioxx affair for proposing regulations which will be a profound change of paradigm or will the regulators accompany

and support this evolution on real-time?

By 2004, risk management was already a known concept and even an ICH draft guideline. However, it was only after Vioxx that the authorities issued the new requirements for risk management plans. This new breakthrough milestone will require much deeper changes, but let’s hope that lessons have been learned and that regulators will be proactive.

In Conclusion

ISOPISRAEL’s ambitionis to be at the forefront of this sky-rocketing evolution, as a link between all stakeholders, providing a platform for experience sharing, AUTHOR BIO

designing new projects throughout the whole healthcare system.

identifying new tools and implementing innovative multidisciplinary projects.

We believe that the pharma industry will have the opportunity to play a major role in bringing its experience and knowledge in pharmacovigilance; staying on track or even ahead of the tremendous evolution of drug safety.

The regulators will have the difficult task to redefine roles and responsibilities in the pharmacovigilance of tomorrow, to address and confront this staggering technologic and organisational evolution.

References are available at www.pharmafocusasia.com

Irene Fermont is the founder and chairman of the Israeli Chapter of the International Society of Pharmacovigilance. Physician, immunohematologist, she created and managed more than 25 departments of Hemovigilance, Pharmacovigilance and Risk Management, at international level, hen in Israel for6 years. Founder of IFC, a strategic safety consulting firm.

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COVER STORY

SUEZ WATER TECHNOLOGIES & SOLUTIONS Enabling efficiency & compliance with Sievers TOC Analysers

Pharmaceutical and biopharmaceutical manufacturers across the globe are increasingly tasked to improve productivity without sacrificing quality or compliance.

At the same time, budget pressures and resource consolidation continue to intensify, forcing manufacturers to do more with less in a highly regulated environment.

Dave Kremer, Senior Leader, SUEZ’s Water Technologies

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F

aced with these demanding pressures, manufacturers turn to technologies and solutions that can help them improve output and increase efficiency. SUEZ, through its Sievers Life Science product line of TOC Analysers, consumables, and instrumentation, enables efficiency and compliance for compendial water testing, cleaning validation, and other applications across pharmaceutical QA/QC, Production, R&D, and Facilities.

Dave Kremer, Senior Leader at SUEZ’s Water Technologies & Solutions - Analytical Instruments business, talks about industry trends in analytical instrumentation, Data Integrity, and efficiency gains for water testing and cleaning validation.

helping companies become more efficient and understand their processes, we can lean out and optimise the use of resources like water.

What is some of the history of Sievers analysers?

Most of our customers in the pharmaceutical market recognise the Sievers name. The company Sievers Instruments was formed in 1984 by two colleagues from the University of Colorado here in Boulder where our headquarters remain. A fact some people don’t know is that our most widely used product line of TOC Analysers evolved through a contract to develop an instrument to monitor drinking water quality in space!

That instrument family has since been acquired multiple times – most notably

by GE and then SUEZ – and has grown into one of the leading TOC technologies in the pharmaceutical industry.

It’s been about two years since GE Analytical Instruments and Sievers products became part of SUEZ. Tell us more about the transition.

It’s been exciting! As part of SUEZ, we not only provide our core expertise in life sciences water testing and cleaning validation, but we also contribute to important challenges related to water scarcity, productivity, and

process control in various industries across the world. Water is an important resource in all industries, and sustainable management of this resource is playing a more important role than ever in business. In the life science industry, we’ve been known for making extremely accurate and reliable instruments for water monitoring – not just for quality control but also process control. By

Besides instrument performance, what other factors come into play for successful TOC analysis?

Beyond accurate and easy-to-use analytical instrumentation, Sievers certified consumables, services, and specialised support offer customers a complete TOC solution. For example, when using Sievers vials and standards, companies can take advantage of our out-of-specification, or OOS investigation support. In the event of a sample, system suitability, or verification failure, our quality team will troubleshoot and thoroughly investigate in-house variables and onsite instrument performance. We will then discuss the findings in a failure analysis report, providing complete traceability.

We constantly ask for feedback from customers related to how they are using our instruments and the challenges they run into. This input from customers has

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enabled us to develop not only new instruments and instrument enhancements, but also new consumables and services that lead to the success of the TOC program overall. Recently we launched our Pre-Acidified Vials for cleaning validation and verification.

These specialty vials improve protein recoveries and can help avoid a false sense of cleanliness. We developed a version of these vials that is pre-filled with water, specifically to address the needs of customers measuring swab samples. These vials ensure consistency and reduce risks associated with sample preparation, ultimately helping customers reduce cleaning sample failure rates.

The application-specific products and support we offer are unmatched in the industry.

UPW monitoring, real-time testing, cleaning validation (plus cleaning verification and monitoring), and testing for leachables/extractables. We see many companies expanding their use of TOC from UPW testing to using TOC for process understanding, control, and troubleshooting. It’s amazing the efficiency many of our customers have gained from using TOC. Take online monitoring and real-time testing (RTT) of pharmaceutical waters – this is an area where Sievers instruments enable better process understanding

TOC analysis is used in various areas of pharma. What are some of the trends you see in where and how companies are implementing TOC? Whether in the QC lab, production, R&D, or engineering facilities, Sievers TOC Analysers can be deployed to meet compliance and lean out processes.

Common applications for TOC include

Sievers TOC Analysers provide stable and accurate data for compliance and process control in pharmaceutical water monitoring, cleaning validation, and other applications.

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As we continue to see FDA warning letters associated with Data Integrity, we know this is something the industry is taking seriously.

so customers can perform corrective actions in real time and ensure quality. We deliver ultra low-level accuracy and reliability without the false positive and false negative readings associated with other simplified TOC technologies.

Customers want continuous, online quality assurance, consistent with regulatory requirements for process control and RTT. That’s where we help them achieve success and increase efficiency.

Another trend we see is the use of Turbo mode to enable real-time profiling for water testing, troubleshooting, or cleaning validation. This is available for online, grab, or lab samples and allows for quick analysis and identification of transient TOC excursions. Again, this level of control and speed is what customers want to maximise productivity.

Overall, with the trend and desire of our customers to increase efficiency and move to online testing, we aim to make online deployment and the potential for automation as easy as possible. When it comes to transitioning from the lab to online deployment of our instruments, leveraging Sievers membrane conductometric TOC technology enables the Process Analytical Technology, or PAT, transition to be seamless with like-forlike technology.

automation, and troubleshoot effectively.

We observe this in QC, Production, R&D, Engineering, and other areas of pharma.

Yes, we do see a trend in customers wanting to implement applications such as real-time testing and online cleaning validation, but they aren’t always sure how to do so effectively.

As instrument manufacturers, we’ve learned the success of our customers depends on a lot more than just an instrument. We take pride in the expertise our team can provide, from helping with method development and feasibility to implementing new applications. We also developed validation support packages for qualification (both instrument and software), RTT, and cleaning validation to help customers navigate the validation process and enable efficient and compliant implementation.

package specifically to address Data Integrity by validating TOC software.

This validation support is unique in the industry and addresses the need for a complete validated solution from instrument to data storage.

You mentioned your instruments are used in the QC lab but also online and for real-time applications. How does SUEZ keep pace with changing needs and ensure successful implementation of different applications?

With limited time and resources, pharmaceutical manufacturers want to lean out processes, increase productivity and

AUTHOR BIO

We hear about Data Integrity and data security constantly these days. How important are these concepts when designing analytical instruments for the pharmaceutical industry?

It’s extremely important that we meet the needs of our customers by ensuring our instruments and software are fully compliant with 21 CFR Part 11 and the latest Data Integrity guidelines.

Especially as we continue to see FDA warning letters associated with Data Integrity, we know this is something the industry is taking seriously.

When we think about the definition of Data Integrity from various government organisations, we think about the completeness, consistency, and accuracy of data over its lifecycle. However, there are many aspects related to the practical implementation of these concepts that are not clear. That’s where companies tend to run into trouble.

For Sievers products, we are committed to helping manufacturers stay on the leading edge of Data Integrity. For example, based on feedback we were hearing in the market, we created a new validation support

What can we expect in terms of future Sievers Life Science products?

As you have seen from our history, Sievers products are defined by expertise and innovation. You can expect to see some ground-breaking innovations in the near future that will broaden the solutions we provide to the industry and enable customers to lean out additional processes in Quality Control – of course without compromising compliance! We are constantly engaged with customers to identify their most pressing needs and innovate better solutions for their analytical challenges. We look forward to showcasing our latest innovations next year. Stay tuned!

Dave Kremer is a Senior Leader within SUEZ’s Water Technologies & Solutions - Analytical Instruments business, formerly GE Analytical Instruments. As part of GE, he led Global Product Management and Applications for the Sievers product line across the Life Science and Industrial industries.

Now, as part of SUEZ, Dave is the Global Leader of Sales and Business Development. Before joining GE, Dave served in senior management roles for Associates of Cape Cod, a global leader in endotoxin products, and in Quality Control for pharmaceutical manufacturing.

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RESEARCH & DEVELOPMENT

Medicines Management and Drug Delivery Unique challenges in older age

Elderly population are facing unique challenges for medicines management and drug delivery. A personalised approach is needed to develop drug delivery systems that recognise their needs such as independent living, functional capabilities, loss of senses such as hearing and memory, frailty, comorbidities and polypharmacy. Optimal treatment using effective delivery systems is needed to achieve best possible outcomes.

Muhammad Suleman Khan, Diamantina Institute, The University of Queensland, Translational Research Institute Michael Roberts, Professor, Therapeutics and Pharmaceuticals. NHMRC Senior Principal Research Fellow, Therapeutics Research Centre, School of Pharmacy and Medical Sciences, University of South Australia and University of Queensland

T

here is a rising opportunity for the pharma industry to consider developing products and administration devices for older age population.

The proportion of the elderly population is growing globally. Age associated comorbidities has resulted in larger need for medication use and appropriate delivery systems. The older age population are extremely heterogeneous, each individual has their own specific needs. The physiological functions varies among the individuals, this depends on ethnicity, genetics, social interaction and life style etc. Generally, the drug delivery systems 48

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RESEARCH & DEVELOPMENT

are being developed more from a technical perspective with the focus to provide more easy, timely and targeted delivery.

However, for older person, especially those who suffer from vision impairment, hearing loss, cognitive impairments, the delivery systems that are easy to use, allowing self-administration, is of importance. As shown in the figure 1 there is age related decline in important senses and functions in older persons that can impact on the proper drug administration and can also impact on adherence. Adherence is a key marker for the efficacy of the medications and is an important factor to be consider in the development of drug administration devices. It is suggested that the administration device, the product safety, including both active and non-active ingredients, packaging/labelling and product information that are suitable as per older person needs and capabilities are required for optimum therapeutic outcome.

The pharma industries are encouraged to focus on patient-centric product development, distinctive from technological driven products. In particular, older person taking large number of medications require assistance in identifying their products and need reminders to take the products timely. Non adherence can be an issue for older patients on polypharmacy, comorbidities, and in patients having dexterity issues, visual impairments, cognitive problems and functional disabilities. Almost 50 per cent of patients suffering from chronic diseases are unable to take their medications as directed. Single unit dose packaging, clear labelling, easily opened products will allow self – administration, will reduce dosing errors and will minimise the wastage and contamination. Product information with large fonts and high contrast imprints will benefit elderly with poor vision in product identification with similar size and shape. Older person with dexterity issue has been shown to benefit from using large triangle shaped screw cap, instead of rounded cap for opening the bottle.

Including calendars and other aids within the drug delivery systems will improve

adherence and minimise risk that are associated with missing and doubling the dose. Commonly used administration routes, related issues in older age and needs for innovation is shown in table1 and will be discussed as follows.

Oral Drug Delivery and Older Age

Swallowing issues are most common with oral dosage forms such as tablets and capsules in older persons. Large size tables can easily stuck in the oesophagus.

Patients are also hesitant to swallow large tablets, in particular those having condition known as dysphagia (a medical condition describing swallowing difficulty). These patients often require crushing their tablets. As example, in nursing home mixing crushed medications with food is a common practice. Some products such as enteric coated tablets cannot be crushed. The size, shape, taste issues can also make patients hesitant to swallow solid oral dosage forms. Developing technologies that facilitate ease of swallowing are required. As example, some of the recent developments include disposable coating devices, where a thin coat of flavour is applied via a spray. This practice was found useful in elderly patients with swallowing difficulties. For powders or

liquids premeasured sticks termed as stick-packs were found useful. These are single dose package that can be filled with either liquid or powder. In older patients with tremors, studies have shown that dosing errors was reduced with the use of liquid stick packs.

Some conditions such as neurogenic oropharyngeal dysphagia reduces sip size, therefore further developments in these technologies are needed.

The concept of using a polypill, where the products are combined together to produce a single tablet is also promising and reduces the pill burden in older person taking multiple medications. Polypill was found cost effective intervention in elderly population and can improve therapeutic outcomes. The challenges with the use of polypill technology is the compatibility of the dosing schedule of different products as well as tablet size can be difficult to swallow. Having knowledge of older person preferences, their needs, habits, treatment duration is important to identify best route, drug and suitable technology development. In the early phase of drug delivery system development, feedback from elderly patients and care givers can be beneficial to improve outcomes.

Figure 1: Changes in vision (A), hearing ability (B), hand strength (C) and cognition (D) in older age. Adapted and modified from. www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

Dosage form modifications are often required in older persons, however the unavailability of licensed dosage forms results in higher cost. An example of such kind is unlicensed quetiapine suspension which was found 10 times more costly than quetiapine tablets. The opportunity to develop alternate licensed products that meets older person’s needs can be of commercial value. An example is the development of riluzole suspension formulation. The oral dosage form of this product was difficult to swallow by almost 80 per cent of the patients. The product was crushed but it was found to have oral anaesthetic effects on the tongue. Another innovation is to include lubricants in solid dosage forms such as Gloup. These can overcome the disadvantages associated with using thickeners which can sometime impact on drug dissolution. In general, viscosity of 150 mPa.s and above impedes drug release. In the absence of alternative dosage forms, a scored tablet can be used to cut tablet in to two pieces, however caution is required as studies have shown the variation in doses of up to 3 fold. Mini tablets have also shown to improve acceptability in older age patients. Older patients found it easy to swallow tablets with a diameter of 3 mm or less.

Some dosage forms such as Orally Disintegrating Tablets (ODTs) dissolves in the mouth and is then swallowed.

ODTs has shown higher preference in patients with dysphagia, migraine, and other CNS disease with rapid onset of actions. In older person, reduce saliva production can affect its use. As example, sublingual Nitroglycerin tablets has shown slower absorption rate in the older patients then younger patients.

Taste, packaging and specialised equipment’s are important consideration for ODTs manufacturing. Multiparticulate controlled release formulations are also rapidly evolving and can be advantageous for older people as they can be compacted to mini-tablets and packed to sachets, however excipients safety can be of concern.

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PARENTERAL DRUG DELIVERY AND OLDER AGE Parenteral route has the advantage of precise dosing, rapid action, and complete bioavailability. It can be alternative route for older patients having swallowing issues, unconscious patients, in emergencies and delivering novel biologics, proteins and peptides, noting immune reactions and infections risk. These products are also expensive and require specialised set up for manufacturing.

Older persons may reject this route due to pain, can be complicated when the veins are not easily accessible and it also requires nursing support. Subcutaneous (SC), Intravenous (IV) and Intramuscular (IM) are most common routes of parental administration. Safety, efficacy and availability of the product, patient preference, and cost determined the choice of these routes. More adverse events were found in patients with IV Epinephrine and opioids as compared to IM and SC product. Pain score in patients using IM route were higher. SC route is preferred for fluid therapy in dysphagia patients and in those having veins accessibility issues. Major concerns with SC route is limited PK data, unlicensed products and risk of accidental exposure. Insulin pumps, auto injectors and pen injectors can be useful for older people. As examples, SC epinephrine, interferonβ-1a is used in multiple sclerosis, Enbrel pre filled syringe is used in autoimmune diseases.

Nasal Drug Delivery Systems and Older Age

Intranasal route has advantage of easy access, fast onset of action and ease of use. This route is currently being investigated for delivering medicines for both local and systemic use. The potential candidate drugs are opioids, respiratory drugs, vaccines and antidiabetic drugs. As example, Butorphanol intranasal product was found as effective and safe as IV product in older patients.

The bioavailability of certain drugs were also found upto 3 fold higher with nasal sprays compared to nasal drops. However there are limited intranasal products available due to specific requirements of lipophilicity, molecular weight etc.

Pulmonary Drug Delivery and Older Age

Pulmonary delivered drugs are absorbed by alveoli of lungs. Alveoli has rich blood supply and large surface area, which ensures high availability of both small and large molecular drugs. However, a range of challenges remain with this route such as development of higher anti-insulin antibodies. The treatment of conditions such as asthma and Chronic Obstructive

Pulmonary Disease (COPD) through these routes is well established. The key challenges associated with this route are age related reduction in lung functions, dexterity issues, patient suffering from arthritis and cognitive issues. These issues can result in altered pharmacokinetic and pharmacodynamic of drugs, ineffective inhaler technique and poor outcomes.

Studies have shown that almost 40 per cent of the older patients aged 80 years failed to use an inhaler.

Common inhaler devices that are in use are pressurised Metered-Dose Inhalers (pMDIs) with or without spacer, Dry Powder Inhalers (DPIs) and nebulisers.

Patient education through instruction and demonstrations has played an important role in appropriate use of these devices. The issues with pMDIs in older people are inability of activation by breath, hand strength requirement, cost of spacer and portability of device.

DPIs need certain inspiratory flow and appropriate storage. Nebulisers can be use in elderly with poor strength and cognition but requires support and can be toxic in case of droplets escape.

Some products such as Soft Mist Inhalers (SMIs) Respimat® Soft Mist™ Inhaler is

RESEARCH & DEVELOPMENT

a good example developed to overcome issue with existing devices. The device overcomes the need of hand-breath coordination and inspiratory flow that is required for some other devices and is without propellants, however cost is an issue. Newer products, Smartinhaler™ has remote usage monitoring and dose reminder technology. However, issues are technical complexity and cost. In general studies have shown preferences for inhaler considering size, number of steps, comfort of mouthpiece and opening and once daily dosing. Pulmonary drug delivery in older age can be a promising alternative as compared to invasive delivery systems.

Afrezza (human insulin) inhalation ROUTE

Oral

Parenteral

Nasal / Inhaled

Topical / Transdermal

(Mannkind, FDA approved in 2014), is an alternative non-invasive insulin delivery systems to self-injected insulin.

Transdermal Drug Delivery Systems and Older Age

The advantage with transdermal system is improved adherence and minimising the drug dosing frequency. Oxytrol transdermal patches, used for urinary incontinence, are used twice weekly and are readily available over the counter. Another potential utilisation of transdermal products are in older patients with neurological problems. Rivastigmine and rotigotine transdermal patches avoid swallowing issues and multiple daily dosing in

Parkinson’s disease. Some products may be associated with adverse events, for instance light headness and dizziness were found with transdermal fentanyl use in cancer pain patients. Age related changes in skin physiology, cognition can affect the use of transdermal products. The patients may forget to remove their patches and can be exposed to overdoses. Older people may get skin irritation and allergies with the use of transdermal patches. The nature of the drug for development as a transdermal product is an important consideration.

The potential drug candidates are highly potent, having small molecular weight (MW<500 Da), lipophilic, Log P of 1 to 3 and are uncharged.

ISSUES

OPPORTUNITIES

• Swallowing difficulties • Limited use in unconscious, or vomiting patients • Frequent administration • Enzymatic degradation • Modifications

• Mini tablets • Orally disintegrating tablets • Poly-pill • Lubricants • Licensed alternate products • Pill reminder such as e pill vibrating timer to overcome hearing issues • Electric pill crusher to overcome hand strength issues • Tablet cutter for all shapes e.g.Equadose splitter and Ezy-Cut Pill Cutter

• Cost and support needed • Require accessible veins • Infections and local reactions • Pain • Appropriate storage • Absorption depends on perfusion • Less products • Lack of PK and safety data

• Product development driven by patient preference • Subcutaneous products offer ease of self-injection • Automated pre filled parental products for patients with dexterity issues e.g. Inject-Ease Syringe Injection Aid, Cimzia prefilled syringe

• Specific physiochemical properties • Limited products • Require sufficient inspiratory flow • Technicality • Inefficient targeted delivery • Cost • Maintenance required e.g. nebuliser cleaning

• Product development driven by patient preference • Portable, easy to use with minimum strength • Cost reduction • Intranasal sprays, inhaled products for chronic disease conditions e.g. insulin

• Specific physiochemical properties • Permeation and absorption • Patient with memory issues may forget to remove patch • Skin reactions • Higher blood concentrations not achieved • Risk of misuse

• Transdermal products for wider range of indications • Transdermal delivery of macromolecules such as insulin using various permeation enhancement techniques

Table 1: Commonly used drug delivery routes, their associated issues in older age and opportunities. Adapted and modified from www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

Pharmacokinetic and Pharmacodynamic Considerations in Elderly

Pharmacokinetic (PK) is defined as what body does to the drug and Pharmacodynamics (PD) are the physiological effects of the drugs. PK include four important processes namely absorption, distribution, metabolism and excretion. Important body function that are most relevant to impact on PK of the drugs are changes in body composition, small intestine surface area, gastric emptying, liver function, kidney function and changes in blood flow to these important organs etc. A thorough understanding of the physiological changes with ageing is important to understand the impact on PK of the drugs, these changes are presented in details in our recent articles.

Medications use need caution in elderly due to age related alterations in PK. In general drug distribution can be affected by the changes in body composition such as increase in body fat can prolong halflife and exposure to the drugs such as diazepam. Reduction in liver function such as reduced size, less blood supply can decrease clearance and can expose elderly to higher drug levels. As example, the clearance of lithium is reduced in elderly.

From PD perspective, older people may have increased sensitivity to some drugs such as benzodiazepines and opioids.

A large body of work has already been performed in previous years to address ageing effects on PK of drugs. However there are still limited data in patients with very older age, frail and patients with comorbidities and polypharmacy.

The current focus in drug development is to undertake studies in healthy subjects, excluding patients with confounding factors such as decreased kidney functions, frail and with multiple medications. The data obtained from these studies may not be applicable in actual clinical practice, especially in older frail patients with polypharmacy. Limited data is also available for newer drugs coming to the market such as novel oral anticoagulants and anti-diabetic drugs that are commonly used for the management of 52

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Older age population is currently 9 per cent of the total global population, but are the largest consumers of prescription and over the counter medicines.

chronic disease conditions. In addition PK data is also needed in increasing very older population group 80 years old and above. Supporting and conducting clinical studies in more realistic environment involving older patients with varying degree of organ functions, frailty status, polypharmacy can help in generating data that can be applied to clinical practice in real world. The data from these studies can be used to develop physiological based pharmacokinetic models which can then be utilise to predict pharmacokinetic parameters of drug products in older people. Collaborations between industry and academia are key to successful advance in this area.

The Issue of Polypharmacy in Older Age

As the age increases the medication use also increases. Upto 88 per cent of the older person use at least one prescription medicine. Polypharmacy, generally defined as the use of five or more regular medications is prevalent in almost 40 per cent of the older adults. Among older hospitalised patients with a mean age of 81 years almost half of the patients used 5 to 9 medications and 30 per cent of the patients used 10 or more medications, often referred to as hyperpolypharmacy.

Older persons living in nursing homes, on an average use 14 (±4.7) medications.

The risk of potential drug interactions increases with polypharmacy and can cause serious adverse events and geriatric syndromes such as falls, delirium,

cognitive issues and depression. The use of herbal medicines is generally not recorded in routine practice which has also increased over the years among older persons. In one survey of population above 75 years, almost one third of the patients were using one dietary supplements together with prescription medicines. Interactions of herbal medicines with prescribed medicines can lead to adverse events. For instance, ginkgo biloba extract can interact with warfarin and increase bleeding risk. Similarly in older adults, St. John's wort can increase the risk of serotonin symptoms when taken with serotonin-reuptake inhibitors.

Pharmaceutical industry can play role in supporting patient education which include relevant and easy to understand information about products, drug-drug interactions and drug disease interaction and expected side effects. There can also be a potential role for pharmaceutical industry in promoting health carer education for older patient care.

Conclusion

Older age population is currently 9 per cent of the total global population, but are the largest consumers of prescription and over the counter medicines. Their population is on rise and will reach to 28 per cent of total population in particular regions of the world by 2050. The following recommendation can be considered • Developing useful alternative products in patients with issues such as swallowing difficulties • Develop safety guidelines and information for medicine modification, crushing or mixing with food • Developing delivery systems or administration aids that can be used in elderly with independent living and with varying functional capabilities and senses • Developingpoly-pill or fixed dose combinations product to reduce pill burden on elderly • Involving patients and their career in the early phase of drug delivery systems e.g. devices used in inhaled products • Promoting research and collaboration between industry and academia.

RESEARCH & DEVELOPMENT

Michael Roberts would like to acknowledge the support by grants from the National Health and Medical Research Council of Australia (1107356 and APP1055176) and the US FDA grants (U01FD005226 and 1U01FD005232-01). Muhammad Suleman Khan would like to acknowledge the support by post-graduate research scholarship from University of Queensland and support from NHMRC Translational Australian Clinical Toxicology (TACT) Program Grant. No conflicts of interest to be declared.

Keywords:

Older age, frailty, drug delivery systems, pharmacokinetics, polypharmacy, comorbidity, adherence, innovation.

E.g. hypertension with diabetes Dysphagia: A medical condition describing swallowing difficulty Frailty: A geriatric syndrome characterised by reduction in physical and cognitive reserves that leads to increased weakness

Polypharmacy: Generally defined as use of five or more regular medications Pharmacokinetics: Movement of the drug in the body References are available at www.pharmafocusasia.com

Professor Michael Roberts (Mike) has a particular interest in therapeutics and used a mechanistic approach to develop microdialysis, in vivo multiphoton imaging, in vitro permeation, pharmacokinetic modelling to understand absorption and disposition of drugs (e.g. antibiotics in sepsis, topical delivery) and poisons. He has used mechanistic convection-diffusion, physiologically and chemical structure-based models to characterise various drug delivery systems

AUTHOR BIO

Acknowledgements and Disclosures

Muhammad Suleman Khan is a PhD student and has a particular interest in optimising treatment in older age patients with polypharmacy and identifying factors that can lead to adverse events. He is currently investigating the impact of age, frailty, comedications and varying physiological functions on commonly used antidiabetic and cardiovascular medications.

Terms used:

Comorbidity: The existence of one or more additional condition/conditions co-occurring with a primary condition.

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CLINICAL TRIALS

Barriers Preventing Clinical Trial Software Development

From transforming the design and execution

In 2011, the famous venture capitalist Marc Andressen predicted that software would transform multiple industries. He was correct. However, Andressen also predicted that healthcare would be transformed by software. Why has that not happened?

Steve Galen, Global Head, Clinical Division, Navitas Life Sciences a TAKE Solutions Enterprise 54

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B

ack in August of 2011 in the Wall Street Journal, Marc Andressen, the famous venture capitalist, wrote a now classic editorial in which he predicted that software would â&#x20AC;&#x2DC;eat the worldâ&#x20AC;&#x2122;, that is, many traditional businesses and industries would morph from manual enterprises to ones being run using software and delivered as online services.

CLINICAL TRIALS

Although Andressen’s statement was bold at the time, we now accept it as axiomatic.

However, Andressen also predicted that the healthcare industry, was, as he put it, ’primed for tipping by great new software-centric entrepreneurs’. As explored more in depth in a recent article “Disrupting the Clinical Research Industry by Merging Clinical Trial Software Development and Clinical Trial Delivery”, BioSpectrum, August 08, 2019, the healthcare industry, in general, and the clinical research industry, specifically, have not been transformed by software, nor software’s successor, software-enabled platforms.

There are 5 important barriers that have prevented the clinical research industry from being transformed by software and software-enabled platforms. Logically, the desired transformation could be significantly accelerated if the following barriers were removed: A belief that national regulatory authorities are risk-averse and will penalise companies for undertaking (or leveraging) software-based innovation.

There was a fascinating research paper published by personnel at Utrecht University, the Netherlands, in 2015 that aimed to provide insight into why it is difficult to develop software in the pharmaceutical industry . As part of the research, domain experts developing software in the pharmaceutical industry were interviewed about 14 common problems they confronted.

One of the problems was called ’multi-layered regulatory requirements’, referring to the complexity caused by multiple, overlapping regulatory requirements. Here is the candid observation of one of the domain experts regarding this problem: “It is not only IT, but essentially everything you do in pharma, whenever something is changed or new devices that are not related to IT are implemented…

Everything has to be done according to rules and procedures. You cannot just

change something in a system. There is a very specific change process that is involved. It sure puts a lot of pressure to accomplish this, which is quite different at other types of companies.”

Another related problem, ‘documentative attitude’, is defined as ‘the comprehensive habit of documentation generation during IT projects’ in the pharmaceutical industry. The authors state in this regard: “The problem is so peculiar that one expert made a picture of a stack of test documentation that the expert’s team created …The documentative culture is primarily caused by the need for compliancy to regulations and the fear for regulatory inspections. The current industry standards mainly fuel the need for overhead due to the fear of ‘missing information’.”

Regarding another problem, ’riskoriented decision making’, the authors note that there is a pervasive ‘… risk avoiding mentality instead of a risk oriented mentality …’. In a poignant related comment, one of the interviewees states bluntly: “The fear reigns. So let’s not touch it and take zero risk.”

And regarding this same problem, the paper’s authors state: “Balancing between incompliant but fast software development and compliant but slow and rigorous software development seems to be highly influenced by fear.”

Given this pervasive attitude of fear among pharmaceutical industry software developers, it is not surprising that these software developers are reticent to change current industry practices, even when

Editorial Sections

Topics • M&A trends

STRATEGY

• Pharmaceutical Ethics • Supply Planning Decisions • Drug Regulatory Affairs • Drug Delivery Devices

R&D

• Computer aided drug design • R&D Innovation 8 Partnership

CLINICAL TRIALS

• Clinical Trial Agreements • Patient recruitment

• Innovation of New Drugs

MANUFACTUNNG

• Biopharma manufacturing facility design and operations • Packaging & Labeling

INFORMATION TECHNOLOGY

• Digital rights block chain

EXPERT TALK

• India pharmaceutical market

• Clinical Data Strategy and Analytics

Figure 1 www.pharmafocusasia.com

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regulatory agencies themselves are openly encouraging and supporting change, as evidenced in the following recent statement by Cisco Vicenty, program manager for CDRH (Center for Devices and Radiological Health) at FDA: “The FDA supports and encourages the use of automation, information technology, and data solutions throughout the product lifecycle in the design, manufacturing, service, and support of medical devices.

Automated systems provide manufacturers advantages for reducing or eliminating errors, increasing business value, optimising resources, and reducing patient risk. These capabilities provide significant benefits in enhancing product quality and safety.”

Perhaps more convincing than even public statements such as the one above would be examples of the regulatory agencies following their own guidances and leveraging software and software-based platforms to change the way they conduct critical activities.

In one powerful example of this, it is hard to imagine a population more in need of protection than infants, and the FDA has the responsibility to ensure that infant formula is safe. FDA collects, reviews and approves the composition of infant formula submitted by manufacturers using its Infant Formula Tracking System (IFTS).

Recently, FDA redesigned the IFTS using low-code Platform as a Service (PaaS). The application was designed and

put into production in less than 90 days.

The application itself provides end-toend tracking of the process, full transparency of the review cycle, and enhanced collaboration between the manufacturer and the FDA review team. Paper submissions have been eliminated and approval cycle times have been reduced.

Lack of receptivity on the part of Clinical Operations leadership (Pharma, Biotech and CROs) to adopt software solutions that significantly alter the status quo.

Clinical operations leaders are typically hyper-focused on making sure clinical trial outputs (selected sites, activated sites, screened patients, enrolled patients, inputted data, cleaned data) are delivered on time, on budget and to quality.

Therefore, it makes sense that when they encounter process problems, they typically look for solutions that cause as little downtime as possible, are cheap, and won’t impact deliverable quality.

In a mature, steady-state industry, this approach makes sense. However, if industry transformation is required or desired, this approach will stymie the required or desired changes.

I witnessed this situation when I was working at a large global CRO that was implementing a software solution built to track process steps for clinical trial data collection, data cleaning and data post-processing. The software was built, successfully piloted and then prepared for full-scale implementation. The impacted

operational leader did not actively support the full-scale implementation, as he was focused on “as is” operations. It wasn’t until a new leader was brought in who understood how the software solution would significantly improve operational visibility and resource utilisation, and who was willing to exert influence to overcome organisational resistance to change, that full scale implementation was accomplished.

Lack of understanding on the part of clinical operations leadership (pharma, biotech and CROs) of what software can do, resulting in applying software and softwareenabled platforms in sub-optimal ways.

Even when clinical operations leaders are receptive to applying software or softwareenabled platforms to improve operations, they frequently view these new tools as simply extensions of current state tools and exert pressure on the software development teams to build solutions that are de facto recreations of current state tools in the new environment.

I saw several examples of this lack of understanding at a large global CRO that was working with a PaaS provider whose platform had very powerful and sophisticated functionality. Instead of viewing the situation as an opportunity to rethink and redesign operations (as the FDA did in the example mentioned above), operational leaders instructed their teams to essentially rebuild their Excel

Barriers to transformation of clinical trials with Software/Software-Enabled Platforms

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A risk-averse approach by QA groups responsible for computer system validation assessments that results in software being assessed as GxP when it is not.

In the Utrecht University paper, one of the interviewees states: “And if you say something like; ‘okay people, we did an impact analysis and we choose to not validate it’. People will respond like; ‘wow, wait a second. We are in a pharmaceutical business here, you cannot just put that thing down and use it?’. They [QA representatives] will directly search for arguments that can have great impact.”

Another interviewee comments: “If you look to the people, you can see that there are people that are carved out of oak. These validation specialists have their job to align our practices with GMP regulations. They will do anything … to make sure we do the things [rigorous validation] we should do” I observed this misclassification numerous times when I was involved with software development activities at several large global CROs, resulting in unnecessary and lengthy delays in releasing software to end users. A senior technical leader at a PaaS company commented to me that because of this misclassification, he has seen on many occasions clinical research companies build useful apps in less than a week that then took four or more months to validate.

A lack of understanding by QA groups responsible for computer system validation assessments regarding how software platforms should be validated that result in QA requiring the entire platform to be re-validated even when the changes are limited to the configuration level of the platform.

As previously mentioned, FDA is leveraging PaaS to build GxP applications. PaaS

Concluding thoughts

A lack of understanding by QA groups responsible for computer system validation assessments regarding how software platforms should be validated that result in QA requiring the entire platform to be re-validated even when the changes are limited to the configuration level of the platform.

has also made modest inroads into the pharmaceutical industry as well.

One roadblock to expanding the use of PaaS in the pharmaceutical industry is that traditional QA approaches view any change to the platform as requiring full re-validation of the entire platform.

This onerous requirement can completely stymie the adoption of PaaS for GxP applications.

This re-validation is, in fact, not necessary. Rather, once the initial core platform is validated, only new pieces of functionality need to be validated. For QA groups that are unfamiliar with PaaS validation, there are IT consulting groups that specialize in helping pharmaceutical companies validate PaaS.

AUTHOR BIO

“trackers” on the platform. After witnessing this approach being taken a number of times, a colleague wryly named this the “spreadsheet in the sky” phenomenon.

In order for the clinical research industry to be transformed by software and software-enabled platforms, the unique, structural barriers discussed in this article need to be overcome.

But how?

The authors of the Utrecht University paper offer a straightforward insight that can help us understand what needs to be done: “IT often lacks detailed knowledge about the pharmaceutical industry, while the pharmaceutical industry often lacks detailed knowledge about IT.” With the above in mind, I would suggest that the clinical research industry do two things: (1) Develop a talent pool, first at the functional level and then at the leadership level, that is as comfortable designing and commercializing software as it is designing and running clinical trials.

(2) Build clinical research companies that contain within themselves both software development and clinical operations capabilities, run by the leaders from (1).

Accomplishing (1) and (2) above will be very challenging. However, the rewards will be great for those companies that meet the challenge, as demonstrated by other major industries that have been transformed by software and softwareenabled platforms.

References are available at www.pharmafocusasia.com

Steve Galen is the Global Head of Clinical at Navitas Life Sciences, a TAKE Solutions Enterprise. He is based out of Princeton, NJ. Steve has over 20 years of pharmaceutical and CRO industry experience.

He has held key strategic and leadership roles in Covance, PRA, InVentiv Health and Syneos Health. Steve has been instrumental in scaling global businesses, leading successful tech-enabled clinical operations and has a strong track record of operations leadership, project management, technology and innovation in global roles.

Steve holds a Ph.D. in Materials Engineering from Drexel University, Pennsylvania.

www.pharmafocusasia.com

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MEDICAL MANUFACTURING ASIA 2020

Your strategic platform for medical technology solutions Mark your calendar for the 5th Manufacturing Processes for Medical Technology Exhibition and Conference from 9 to 11 September 2020

The Asian medical market is booming. According to management consulting firm, McKinsey & Company, the company predicts that Asia will become the second highest medical technology market in the world by 2020, accounting for a third of global sales by 2025. In the ASEAN countries, with its population of over 600 million people and a GDP of 2.76 trillion US dollars, there is a rapid growth of the middle class and expansion in healthcare coverage. Both of which are factors driving the use of medical devices across

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Southeast Asia. Such products are likely to see growth of between 8 to 10 per cent in most markets, led by the consumables, diagnostic imaging and lab devices segments.

As a specialist exhibition on manufacturing processes for medical technology, the 5th edition of MEDICAL MANUFACTURING ASIA makes a return to Singapore as the region's leading specialist trade fair for Asia's MedTech and medical manufacturing processes sectors. Jointly organised by SPETA and

Messe Düsseldorf Asia, MEDICAL MANUFACTURING ASIA 2020 will feature an extensive product range covering the upstream and downstream processes in MedTech sectors, including new materials, components, intermediate products, packaging and services, to micro and nanotechnology, testing systems and services, as well as materials, substance and components for medical technology. Industryfocused business forums will also headline the upcoming edition of the specialist trade fair.

Singapore: The heart of MedTech in Asia As Singapore continues to grow as a competitive economic hub for the region in terms of, ease of doing business, best labour force, strong IP protection and robust logistics infrastructure, it has also presented itself as a competitive MedTech manufacturing hub.

The 3-day exhibition therefore strongly reflects Singapore’s focus on moving upstream to not just production but also value engineering. For companies keen on engaging global MedTech companies and see Singapore as an ideal base to develop products for the Asian region, MEDICAL MANUFACTURING ASIA 2020 provides a highly relevant springboard.

This sentiment is also seen in Singapore’s continued growth in manufacturing, where MedTech output has grown annually by 11 per cent versus 6.3 per cent in general manufacturing for the past 5 years.

Backing this is Singapore’s strong supplier base – with 6 of the world’s Top 10 EMS companies undertaking activities from the entire value chain, in medical imaging equipment, analytical lab instruments, medical consumables, patient care devices and diagnostics equipment in the Lion City and the government’s commitment to R&D capabilities, having set aside S$19 billion for Research, Innovation and Enterprise (RIE) activities until 2020. Singapore is also home to a growing community of start-ups thanks to the availability of public funding and a favourable infrastructure for early stage innovation.

Against this industry landscape, MEDICAL MANUFACTURING ASIA 2020 continues to attract a highly international exhibitor base coming mainly from Asia and Europe and a trade visitor base that is predominantly represented by the medical devices and instruments, medical and healthcare, and electrical and electronic sectors from around the region.

MEDICAL MANUFACTURING ASIA 2020 is also synergistically co-located with the region’s leading medical and healthcare exhibition, MEDICAL FAIR ASIA – thus providing an end-to-end solutions and business sourcing platform across the entire value chain for the medical, healthcare, medical manufacturing and medtech sectors. Both MEDICAL FAIR ASIA and MEDICAL MANUFACTURING ASIA 2020 are part of the MEDICAlliance’s network of trade fairs—sharing the global expertise of MEDICA, REHACARE and COMPAMED—by the Messe Düsseldorf Group in Germany.

For booth space booking and more information on MEDICAL MANUFACTURING ASIA 2020, please visit www.medmanufacturing-asia.com.

Advertorial www.pharmafocusasia.com

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CONTINUOUS MANUFACTURING THE ROAD AHEAD

The pharmaceutical industry is experiencing a time of significant change with growth of biopharmaceutical drugs, increasing market fragmentation due to the growth of personalised medicines, orphan drugs and variable demand.

Continuous manufacturing is ready to play a pivotal role in supporting this transformation as a result of technological advances and regulatory support and encouragement.

Kieran Oâ&#x20AC;&#x2122;Connor, Senior Research and Development Chemist, SK biotek

T

he pharmaceutical industry is undergoing a transformation. It is transitioning from a closed, internal, integrated discovery and development business model generating blockbuster drugs by large pharmaceutical companies to a more open, external, collaborative model where drug products are more diversified, treatments are personalised, demand variability is higher and cost pressures are greater (Sadat et al., 2014).

The biopharmaceutical industry is thriving. Sales are projected to reach US$450 billion by 2019 (Hong et al., 2017) with mAbs comprising the largest selling cohort. Biopharmaceuticals accounted for 5 per cent of total biopharmaceutical and pharmaceutical revenue in 2011 (BPOG RTM-Overview Document, 2017) but

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are expected to account for more than 50 per cent by 2020 and will comprise ~80 per cent of the drug development pipeline. The small molecule pharmaceutical industry is experiencing challenges and stresses due to the expiry of blockbuster patents and the dearth of new drug discoveries. Large pharmaceutical companies are addressing this development by primarily focussing on biopharmaceutical discovery and development activities and outsourcing small molecule development and manufacture to CDMOs. Challenges facing the industry include drug patent expiration, increasing competition from generics, biosimilars and biobetters, increasing pressure from governments and health agencies to lower the cost of drug products, the

requirement for in-regio manufacture of drug products and variable demand for products. Drug discovery and development is becoming evermore demanding and costly with payers (governments, health insurers etc.) requiring companies to demonstrate that their drug is more effective than currently available drug products. The US 21st Century Cures Act (2016) mandated the FDA to assess real world data (RWD) when evaluating drug products. This has resulted in need for larger, more comprehensive and expensive clinical trials for the launch of new drugs. A summary of the challenges currently facing the industry is shown in Fig. 1.

The industry is cognisant of the pressures and is responding. Merger

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and acquisition activities have increased, for example, this year saw Bristol Myers Squibb’s US$74 billion acquisition of Celgene and Abbvie’s US$63 billion acquisition of Allergan. Other strategies include investing significantly in research and development, continuous improvement programmes for drug discovery, development and manufacture and greater engagement with payers and patients. Key attributes for manufacturers are the requirements to be lean, efficient and flexible and the primary business drivers identified are flexibility, speed, quality and cost (BPOG,TRMOverview Document, 2017). Technology advances are playing a significant role in transforming the industry. Process Analytical Technology (PAT) applications are well established in the small molecule manufacturing industry primarily in the drug product area where spectroscopic technologies (IR, NIR) enable increased product throughput and improved quality. In the biopharmaceutical industry single use technologies are facilitating increased manufacturing flexibility and improved efficiencies. Levels of automation within the industry are increasing, predominantly in upstream manufacturing where in-line and on-line sensors monitor and in some applications, regulate manufacturing progress. Typical

critical process parameters monitored include temperature, dissolved oxygen, pH, agitator speed etc. Readings from the sensors are used in feedback-feed forward algorithms which control the manufacturing process. Sensor accuracy and robustness has significantly improved over the past ten years resulting in more widespread adoption. Downstream manufacturing has fewer in-line and on-line monitoring applications as a result of the more dynamic environment and fewer numbers of process critical quality attributes. More recent developments involve the application of multi-parameter sensors such as Raman which can monitor multiple parameters simultaneously.

Readings from these sensors are information rich and feed into multi-variate models which are employed to provide enhanced predictive process control.

Sensor technology capabilities and performance continue to improve, which aligned with advances in automation software, is supporting the introduction of continuous manufacturing within the industry. FDA considers Continuous Manufacturing (CM) to be ‘a process in which the input material(s) are continuously fed into and transformed within

the process, and the processed output materials are continuously removed from the system’, where the system is defined as two or more integrated manufacturing units (FDA 2019). There are a number of modes of CM: • Fully continuous mode: each processing unit operation is connected and run continuously. Also known as Fully Integrated Continuous Mode • End to end continuous mode: inputs and outputs of the process are run continuously but the intermediate processing unit operations can be run in batch mode • Hybrid mode: some parts of the process are operated in a continuous mode whereas others are run in a batch mode • Semi-continuous mode: the manufacturing process is run continuously for a defined short period of time • Truly continuous mode: The manufacturing process is operated continuously full time with no product hold up times.

CM is agnostic of scale and can be effectively employed in processes manufacturing drug product from kilograms to tonnes. CM generates many advantages over batch manufacturing.

These include more consistent and higher quality product as in-process monitoring can detect potential process deviations

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INDUSTRY CHALLANGES

REGULATORY UNCERTAINTY

COST PRESSURES

NOVEL TREATMENT MODALITIES

PEER COMPETITION

Health Authority Government Facility / Equipment

Drug Development

FLUCTUATING DEMAND

Generics / Biosimilars

Personalised Medicines

Peer Competition

Speed to Market / Designated Breakthrough Therpay

Orphan Drugs

Personalised Medicines

Stem Cells / Gene Therapy / Cytokines

Political /Health Authority Pressure

LOCAL MANUFACTURE

In Regio Manufacture

Figure 1: Overview of Pharmaceutical Industry Challenges

in real time and apply corrective measures to correct the deviation. CM also facilitates lower manufacturing costs for example capital expenditure (CAPEX) is significantly lowered when employing multiple 2,000 litre Single Use Bioreactors (SUB) in lieu of 20,000 litre stainless steel reactors and operational expenditure (OPEX) is reduced with highly automated manufacturing trains. Other advantages include greater manufacturing flexibility, as the lower manufacturing footprint associated with SUBs and CM enables quicker construction than traditional batch manufacturing trains and also facilitates set up in a greater number of locations and markets due to the lower CAPEX and utilities requirements. The potential elimination of scale-up challenges when transitioning from clinical to commercial manufacture whereby increasing capacity is effected via scaling-out i.e. adding additional, parallel, small scale reactor

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trains rather than increasing reactor volume, is another significant benefit of this mode of manufacture.

CM has the potential to be a transformative technology for the industry.

However, there are a number of challenges to be addressed and overcome for this potential to be realised.

Regulatory Uncertainty

Regulatory authorities have long recognised the advantages of and consistently advocate for CM. As far back as 2002 when FDA announced an initiative titled ‘Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century’, which encouraged the pharmaceutical industry to adopt new technologies and modes of operation with the objective of enhancing and improving the quality and availability of human and veterinary drugs, through the publication of ICH Q8, Q9 Q10 (2005-2008) guidance documents which introduced

Quality by Design (QBD) mode of drug development and manufacture, quality risk management concepts and quality system management, to the ongoing development of ICH Q13 and Q14 guidelines (2021) which address regulatory expectations for CM and enhanced analytical procedure development which could be used to support Real Time Release Testing (RTRT) activities. In addition the ICH Q2 guideline, which addresses validation of analytical procedures, is being updated to include advanced analytical technologies which incorporate multivariate statistical analyses e.g. spectroscopic modelling. Whilst recognising the advantages of CM, the regulatory authorities acknowledge that more regulatory support and guidance is necessary to increase uptake within the industry as detailed in the ICH Q13 final business plan (2018) ; ‘The current ICH Guidelines do not sufficiently address

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technical and regulatory requirements that are unique to Continuous Manufacturing (CM). A harmonised regulatory guideline can facilitate implementation, regulatory approval, and lifecycle management, particularly for products intended for commercialisation internationally’. FDA in their 2019 draft guidance ‘Quality Considerations for Continuous Manufacturing’, which will form the backbone for ICH Q13, acknowledge the nascent status of CM and in the guidance state ;‘FDA recognises that continuous manufacturing is an emerging technology that can enable pharmaceutical modernization and deliver potential benefits to both industry and patients’.

In their press release announcing the draft guidance, Scott Gottlieb, the former FDA Commissioner and Janet Woodcock, Director of CDER, state CM is ‘still new and developing. Harnessing the full potential of these innovations will require us to invest time and resources in developing scientific standards and policy and supporting implementation’.

This commitment to providing resources in supporting the greater uptake of CM within the industry will provide a significant boost to the implementation of CM applications within the industry.

It will also require greater collaboration between the manufacturers and the regulatory agencies including sharing more information/experiences at earlier stages of implementation.

Automated Sampling Technology (MAST) application which is capable of sterile sampling from a maximum of 10 bioreactors and transferring the acquired samples to a maximum of 4 analysers up to distances of 80 feet (Capsugel, 2016). Developments in sensor technologies involve improvements in the ruggedness and accuracy of electrochemical and optical sensors for the measurement of pH, temperature, DO and advances in capacitance and radio frequency impedance probes used for biomass characterisation. Process automation has seen development of ‘soft’ or software sensors. The sensors are comprised of a hardware sensor (e.g.

Raman, NIR) coupled to a virtual sensor (microprocessor) which processes and models output from the hardware sensor to enable monitoring and/or controlling of manufacturing activity. Process control can be effected via either open loop or closed loop infrastructures. Real Time Release Testing (RTRT) will be enabled by this technology.

The technological advances listed above plus others demonstrate that CM is achievable using technologies

that are currently available. However a major drawback with the technologies is the limited standardisation and interoperability between them. This results in the inability to operate in a ‘plug and play’ manufacturing environment and restricts manufacturers to employing a limited number of exclusive technology vendor(s) and necessitates a significant commitment of resources when switching between different vendors applications. This is a significant hurdle for CM which typically operates for extended periods of time and requires manufacturing equipment and machinery to operate precisely, accurately and reliably to assure production of product with appropriate quality, safety, potency and efficacy. Another challenge is the management and storage of the vast amounts of process data that will be generated. Industry is addressing the challenges, inter alia, through increased collaboration between manufacturers, technology vendors and regulators for example the Biophorum Operation Group (BPOG) technology roadmap initiative (2017) and ISPE GAMP and Good Engineering Practice Guides.

Technology Harmonisation

CM technologies such as operating platforms (MES, DCS, SCADA), sensors (temperature, DO, nutrient and metabolite monitoring etc.), sampling devices, perfusion, culture media and multivariate modelling applications have advanced considerably over the past ten years. Examples include the development of bespoke cell culture media for perfusion applications that can generate five-fold increases in volumetric productivity when compared to traditional fed batch/enriched fed batch media (Lyons, 2017) and the Modular www.pharmafocusasia.com

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Cultural Attitude

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Biopharmaceuticals accounted for 5 per cent of total biopharmaceutical and pharmaceutical revenue in 2011 (BPOG RTM-Overview Document, 2017) but are expected to account for more than 50 per cent by 2020 and will comprise ~80 per cent of the drug development pipeline.

ration with specialist SMEs (technology vendors, educational establishments) will be necessary. This will require extensive support, guidance and motivation from industry senior management, regulatory authorities and SMEs. Conclusion

The current business environment for the pharmaceutical industry is exciting and challenging with change being the one constant factor. The immunotherapy field is growing exponentially with the discovery of new modalities and indications fuelling growth and innovation in the biopharmaceutical sector. Small molecule development and manufacture is also experiencing significant change with an industry wide move to outsource this activity to CDMOs. The primary business drivers have been identified as flexibility,

AUTHOR BIO

Pharmaceutical manufacturing has operated in batch mode since the beginning of the industry. Product is manufactured in discrete, largely isolated, sequential steps with initial step outputs being used as input material for subsequent steps. This has created a culture where operations are performed in a largely independent manner with minimal interaction with other parts of the manufacturing train. Work practices and guidelines developed which reflected and reinforced this fragmented manufacturing environment. Examples include the discrete and separate functions of manufacturing, quality and information technology usually found in pharmaceutical manufacturing sites and the upstream and downstream processing functions in biopharmaceutical manufacturing sites. Regulatory guidelines also reflected the batch mode mentality for example process validation typically involved successful manufacture of three discrete batches of the drug with no subsequent assessment of the process necessary. Current regulatory thinking, as outlined in the ICH quality guidance documents, emphasises full process and drug product understanding (QBD, risk management etc.) and life-cycle verification approach to validation. This involves cross functional collaboration and information sharing with the focus on ongoing monitoring and verification of process performance.

CM is the manufacturing manifestation of this mode of drug discovery, development and manufacture. It will require a fundamental change to current attitudes to manufacturing whereby individual functions (USP, DSP, manufacturing, quality, IT etc.) will need to collaborate more and work as a coherent and holistic team in manufacturing drug product.

Work practices will require updating, manufacturing trains will be reconfigured (ballroom mode, modular units etc.) training and upskilling of staff will need to be provided (data analytics, model management and maintenance, data integrity) and more extensive collabo-

speed, quality and cost and CM will play a key role in transforming the industry to better support the market demands. Technology advances for, inter alia, sensor probes, automation software, perfusion, remote sampling and purification allied with regulatory encouragement and support have positioned CM to be the next big innovation within the industry. It will most likely be implemented with new drug product launches and will require a disruptive change to current work practices but the benefits and advantages vastly outnumber the challenges.

Glossary BPOG : Biophorum Operations Group CDER : Center for Drug Evaluation and Research CDMO : Contract Development and Manufacturing Organisation CM : Continuous Manufacturing DO : Dissolved Oxygen DCS : Distributed Control Systems DSP : Down Stream Processing FDA : Food and Drug Administration GAMP : Good Automation Manufacturing Practice ISPE : International Society of Pharmaceutical Engineering MAST : Modular Automated Sampling Technology NIR : Near Infra-Red PAT : Process Analytical Technologies QBD : Quality by Design RTRT : Real Time Release Testing RWD : Real World Data SCADA : Supervisory Control and Data Acquisition SME : Subject Matter Expert SUB : Single Use Bioreactor USP : Up-Stream Processing References are available at www.pharmafocusasia.com

Kieran Oâ&#x20AC;&#x2122;Connor, Senior Research and Development Chemist, SK biotek Ireland. Kieran has over 25 yearsâ&#x20AC;&#x2122; experience in the pharmaceutical industry. He worked in the Quality and Research & Development functions at Bristol Myers Squibb for 25 years. During this time he introduced in-line and at-line Raman monitoring capabilities to a drug substance site generating significant business efficiencies whilst also introducing other spectroscopic PAT tools.

He currently works in the Research & Development department, for SK biotek Ireland, a global CDMO, working with customers in development and launch of drug products.

BRIDGING GAPS IN HEALTHCARE INDUSTRY WITH TECHNOLOGY As an internet-based technology and cultural enterprise in China, Tencent has been exploring the healthcare industry over the past five years with the mission of ‘Tech for Good’. This article will share with you how Tencent leverage powerful technology to build bridges between hospitals and the public to help hospitals meet the challenges in China due to a huge patient demand for doctors and limited medical resources.

As global population ageing and limited medical resources become alarming issues, the healthcare industry is facing many challenges and obstacles.

One of them is how efficiency can be improved given the geographical, space, time and resource constraints.

Smart technology is the answer.

Today, we have seen an uptick in cross-sector convergence within global healthcare industry, with a view to enhancing the quality of medical services with the help of technology. Various states in the US have been researching the potential of emerging technologies such as Artificial Intelligence (AI); the UK is promoting telemedicine; South Korea is expediting the building of hospitals with 5G network, while Finland has launched a pilot medical project in a 5G network environment. Not surprisingly, smart tech-

nology has been identified as a key driver in healthcare development in China.

As one of the world's most populous countries, China's healthcare industry has an even more daunting task: China's population accounts for 22 per cent of the world's total, but available medical resources are merely 2 per cent of the world's total.

As a result of insufficient medical resources and its uneven distribution, difficulty in seeking treatment and expensive medical costs were evident while gaps are identified in areas of operational efficiency, provision of information and services.

In the past five years, Tencent has been exploring ways to improve the quality and efficiency of healthcare industry through digital technology. In line with its Industrial Internet strategy, Tencent’s exploration in the healthcare industry focuses on three areas, namely, Tencent Medipedia, Smart Hospital and Medical AI. www.pharmafocusasia.com

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Tencent Medipedia: Addressing Knowledge Gaps in Healthcare

In the era of mobile Internet, more people look for healthcare information online. However, the quality and accuracy of such information is not easy to identify, as erroneous or deficient information is not uncommon on internet. Tencent Medipedia is the specially-designed solution to this issue.

Launched in 2017, Tencent Medipedia is designed as an authoritative, professional and practical platform sharing common healthcare information. Users are provided with knowledge from the prevention, diagnosis, treatment of disease to rehabilitation.

Through text, photo, video, interactive and AI assistant, and 3D visualisation, Tencent Medipedia brings high-quality original healthcare content from around the globe and localises it to best suit the Chinese audience. It is a medical information platform with systematic and in-depth content that translates obscure medical knowledge into more reader-friendly information for the general public.

To ensure the creditability of the platform, Tencent Medipedia collaborated with WebMD, a reputable international healthcare information platform, to obtain access to over 60,000 Chinese research papers on medical and healthcare. Tencent Medipedia also partnered with the Chinese Medical Doctor Association (CMDA) and over 1,000 specialists from hundreds of renowned hospitals nationwide to present healthcare content covering over 8,000 common diseases (including detailed information on 50 diseases).

“As a company well-known for its strengths in Internet and digital technology, Tencent aims to present Tencent Medipedia as a recognised authority on healthcare services, which gives patients proper guidance and eliminates information gaps between doctors and patients. By building Tencent Medipedia, Tencent is fulfilling its mission and vision of ‘Tech For Good’.” said Zhang Meng, Vice President of Tencent Medical.

Smart Hospital: Boosting Efficiency in Hospital Operation to Better Accommodate Public Demand for Medical Care Despite the substantial increase in China’s total medical resources in recent years, accessibility to quality medical treatment and services remains a common complaint amongst patients. This accessibility gap is fundamentally attributed to the imbalance in medical resources distribution. Therefore, it is crucial to set up 66

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an efficient medical service system. Tencent Smart Hospital provides the solution to optimise and accelerate the process. By integrating WeChat Healthcare Security Pay and Digital Healthcare Card as well as Tencent Health, a service platform on WeChat, this solution helps hospitals enhance operational efficiency and provides patients with an improved medical service experience.

Through WeChat, Tencent can reach out to the insured totaling to over 500 million. Nearly 10,000 medical institutions support medical insurance payments by WeChat. Hence, users can pay for medical consultation and medication via WeChat The Digital Healthcare Card is equivalent to a ‘health ID card’ in China, which records a person’s medical records from different hospitals in different regions. It is a key link between the public and medical institutions, amongst such institutions, as well as the institutions and social public services departments.

Tencent actively promotes the issuance and use of Digital Healthcare Cards to enable the public to experience the best online and offline patient care.

Tencent Health, a service platform on WeChat, is Tencent's latest contribution to healthcare.

Starting from March 2019, residents in Shenzhen an emerging city in China, can experience Tencent Health service via WeChat to obtain timely online medical consultation, arrange appointments, access healthcare information, and other useful services.

Tencent Health will be rolled out to other cities gradually.

With these, Tencent’s Smart Hospital solution connects all stakeholders with technology. It does not only help medical institutions to enhance their

operational efficiency but also spares patients from long waiting time for medical consultation. It has effectively connected medical services, healthcare services, and personal health management and created a new healthcare ecosystem.

Medical AI: Assisting Doctors in Diagnosis by Making AI Technology More Accessible

Today, cancer remains the No.1 killer to mankind.

At the moment, China has less than 20,000 licensed pathologists, with an estimated shortfall of over 90,000 licensed pathologists. Such a resourceconstraint seriously affects the quality and standard of clinical medicine in China.

Though there is no shortcut in training medical professionals, technology, however, can speed up the process from screening, diagnosis, treatment to recovery. In the field of ‘AI + Medicine, AI can carry out simple but cumber some tasks to save doctors’ time. It also learns from big data to perform medical image analysis, increasing the efficiency and accuracy in diagnosis while providing personalized medical services recommendation by combining imaging and pathological genetic testing.

Currently, Tencent has three major AI labs which champion breakthrough medical AI research in different application scenarios, they are Tencent Medical AI Lab, Tencent YouTu Lab and Tencent AI Lab. Tencent Medical AI Lab has embarked on research on a new digital biomarker that could be applied to the interpretation or prediction of disease or health outcomes. For patients with Parkinson's disease, for instance, their motion information and audio signals are captured by video and mobile sensors and mobile phones respectively. AI will then analyse such information. The information coupled with professional opinions will produce a comprehensive evaluation of the patients, thus enables accurate and objective treatment.

Tencent Youtu has all along been committed to medical AI. Not long ago, the team just set two records in the global medical imaging competition LiTS, wining two world's first places in liver segmentation and liver tumor segmentation. By deepening its technological R&D, Tencent Youtu has launched its first medical imaging product ‘Tencent Miying’. Currently, this system has supported cancer screening for ophthalmic diseases, esophageal cancer, colorectal cancer, lung cancer, breast cancer, cervical cancer, cooperating with more than 100 top 3A hospitals in China. It not only reduces the workload of doctors, but

also plays an important role in improving diagnostic accuracy and efficiency.

Tencent AI Lab concentrates on the entire process of medical services. It offers products from disease diagnosis to treatment, including guided consultation, AI pre-diagnosis, AI-assisted diagnosis, and guided medication. According to Yao Jianhua, the Chief Scientist of Tencent AI Lab Medical Center, Tencent AI Lab will further probe into pathology from three angles: AI-based pathological diagnosis models, AI-based pathological prognosis prediction models, and quantitative analytics in pathological omics.

In the field of Medical AI, Tencent hopes to assist doctors in diagnosis but never replace the human touch. As the healthcare industry advances, there are many areas where efficiency could be improved with technology. Tencent firmly believes that by helping doctors, it is helping the patients. It will continue to cooperate with medical institutions to further explore and contribute AI technology solutions to address the problems caused by insufficient medical resources.

Tech for Good, Providing More Customized Medical Services

“Those in the medical profession have a heavy responsibility. To ensure sustainable development in the healthcare industry, first we need to resolve the problem of uneven distribution,”said Ding Ke, Tencent’s Vice President, “If this problem is not resolved, it will be hard to make any progress. It is easy to launch individual pilot projects, but the world will only truly benefit from the Internet to function as a whole.”

Published data shows that till May 2019, over 38,000 medical institutions in China have set up official accounts or Mini Programs at Tencent’s WeChat platform. 60 per cent of the hospitals provide various smart healthcare services to patients through WeChat, and about 110 million WeChat users subscribe to these healthcare services.

Tencent firmly believes in ‘serving patients, helping doctors and assisting hospitals,’ and sees itself as a ‘digital assistant’ in providing digital ‘toolkit’ for healthcare partners. Nowadays, the Internet has penetrated all aspects of life. By applying mobile Internet, AI, big data and other technologies in the healthcare industry, it can better cope with the challenges arising out of the uneven allocation of resources and improve the efficiency and quality of medical services.

“Indeed, ‘Tech For Good’ has been fully practiced in the healthcare industry in its true sense,” Ding Ke added.

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INFORMATION TECHNOLOGY

PHARMA SUPPLY CHAIN INTELLIGENCE IT FOCUS

How are IT solutions helping to mitigate pharma supply chain risks? Advanced monitoring systems and asset management software systems are increasingly utilised to collect and analyse data. How new technologies, advancements in GPS tracking and demand for data collection, enabled by the Internet of Things (IoT), are driving developments in the pharma supply chain.

Adam Tetz, Director, Worldwide Marketing, Pelican BioThermal

N

ew technologies, advanced software systems, and the integration of IT within the pharma supply chain are increasingly playing a pivotal part in protecting pharmaceutical payloads worldwide.

Maintaining end-to-end pharma supply chain integrity is critical to mitigate risks within the pharma-logistics cool chain and better ensure the safe and 68

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secure transportation of health-giving and life-saving pharmaceutical products.

The global life sciences industry faces a number of complex challenges: protecting the integrity of their temperature-sensitive high-value payloads while mitigating costs, managing and tracking the assets within a complex cold chain closed loop logistics system, meeting stringent global regulatory standards and

navigating complicated global shipping lanes and unforeseen challenges.

The market for transporting temperature-sensitive materials for the healthcare market, such as pharmaceuticals, blood, tissue, and organs is a subsegment, currently valued at approximately US$2 billion and expected to grow to approximately US$5 billion by 2026.

INFORMATION TECHNOLOGY

With the pharmaceutical companies developing ever more complex and temperature sensitive drugs, there is a growing demand to integrate IT solutions within the supply chain alongside providing improved packaging performance and efficiency within cool chain logistics. It is also vital to ensure there is a secure, compliant cool chain from deployment of shipments to last mile delivery.

In a bid to ensure good distribution practice (GDP) regulations are adhered to within cool chain logistics, innovation, IT integration and new technologies are proving paramount to the emergence and evolution of smart temperature controlled packaging protecting pharmaceutical payloads globally.

The industry is also seeing a growing trend to deploy reusable systems coupled with asset management SaaS (software as a service) and reaping the associated benefits. These systems can automatically collect and analyse data from company smart data logger outputs. These monitoring devices are increasingly being used in cold chain as they are becoming more affordable and thus more accessible to pharmaceutical companies.

A key development includes live data monitoring of payloads, smart loggers and internet of things (IoT) devices which are interconnected to the IoT, making it possible to see the condition of the payload at anywhere across its journey.

Being alerted about a problem within the shipped package before it reaches destination allows preventative or corrective supply chain actions earlier than might have otherwise been possible.

Integrating the cloud-based system supports and enhances engineering expertise that is incorporated into the development and design of the sophisticated systems utilised by the life science industries.

The data retrieved and shared can help the pharmaceutical companies make more informed choices on the most appropriate packaging systems to deploy depending on specific shipping lanes and routes their payload will need to navigate.

Maintaining end-to-end pharma supply chain integrity is critical to mitigate risks within the pharma-logistics cool chain and better ensure the safe and secure transportation of health-giving and lifesaving pharmaceutical products.

Increasingly, passive and active bulk systems are incorporating IoT devices to track the temperature, location and other data throughout the course of the trip.

Issues can arise for the temperature in the payload area, if the parcel is opened during a customs inspection, and the IoT device can track or warn when the parcel has been opened, for how long, and if there is a risk to the payloadâ&#x20AC;&#x2122;s temperature requirements.

Alternatively, IoT devices can be attached to a specialised container to ship a pallet of products providing an isolated monitoring option to pick up data, which can be saved to the cloud via bluetooth or radio-frequency identification (RFID).

Currently operating in the market is a range of SaaS products providing collection and analysis of brand-agnostic sensor data, as its linked to a variety of smart packaging options allowing packaging vendors to track a diversity of data including vibration, light, humidity, and more.

These software platforms can capture and monitor information throughout the course of the shipments trip.

The latest development within the pharma supply chain and packaging industry transporting pharma shipments globally is the move toward GPS devices, which provide real-time location and

tracking. This is a supplemental technology, compared via Bluetooth, RFID or manually-scanned barcodes whereby pharma companies can assess data in the payload at the point it can be retrieved via a nearby mobile device, stationary gateway or manually by package.

It is predicted that advancements in GPS tracking options via an online SaaS system will soon be part of the industry.

There are benefits to pharmaceutical companies knowing where their shipment is throughout its transportation trip.

If payloads are lost or get delayed en-route, the pharmaceutical company can take steps to intervene and recharge or replace coolants so the package or the bulk system gets delivered before expected temperature duration is exhausted. This presents a strong case for using IoT devices and their supporting software and technology to mitigate a temperature excursion caused by a delay.

In an ever-evolving pharmaceutical industry various drug product compounds, utilised in the sector, are developed in certain temperature control conditions or designed to be stored at specific temperatures to maintain their stability.

Itâ&#x20AC;&#x2122;s critical when shipping pharmaceutical products between locations they remain at their storage condition temperatures to maintain their effectiveness at the point of use by patients.

Any spikes, valleys, or deviations in temperature, beyond the range-specific pharmaceutical products that are required to be stored and shipped at, could have a devastatingly detrimental effect on the payload, damaging the containerâ&#x20AC;&#x2122;s contents and impacting on the efficacy of the products being transported for use by patients.

It is essential, therefore, that pharmaceuticals are protected throughout the supply chain as temperature excursions during transportation can even cause them to become toxic. As a result, temperature monitoring is becoming more commonplace, due to the cost of www.pharmafocusasia.com

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the packaging deployed in real time or capture data once the shipment reaches its destination.

Real-time monitoring could be used to know quickly if a shipment has, or may have, a temperature excursion, or will be delayed from reaching the patient.

Therefore, allowing a new shipment to be sent out quickly to the patient, with the original being reclaimed or disposed of, depending on its status.

IoT solutions, GPS tracking, and temperature monitoring are gradually providing vital assistance in the global pharma supply chain enhancing the protection offered by advanced temperature controlled packaging solutions.

The use of that data and the sharing of that data with both packaging providers, logistics providers and the pharma companies themselves is an area of significant interest. It should support the development of better and more effective solutions to meet the challenges that are now better understood through that data.

With the rapid rise of biologics and biosimilars within the pharma development sector, the need for transportation temperature control is ever increasing, where any minor temperature excursion within the supply chain can have costly consequences for patients and pharmaceutical companies alike.

More complex distribution lanes, with emerging markets, geographies and increasing regulatory compliance conditions are some of the challenges when transporting these temperaturesensitive biologics/biosimilars.

Blockchain is another technology finding its place in supporting

AUTHOR BIO

IoT devices and the capture of the data becoming both affordable and accessible.

Increasingly, pharmaceutical companies have a sophisticated understanding of the temperature stresses their products experience during shipment in certain lanes. They can better determine what is a high-risk or low risk lane and then make the appropriate packaging choice to fit that requirement. More data and predictive analytics from IoT devices and supporting SaaS solutions allow pharmaceutical manufacturers to make effective and cost-saving decisions on their cold chain logistics that are driven by data.

We are also seeing an increase in the introduction of information-centric capabilities to assist with the safe shipping of pharmaceuticals around the globe.

Packaging companies are frequently utilising advanced asset management software systems, which are in place specifically to ensure drug products are shipped to the right place, at the right time and, critically, in the right condition.

Companies deploying pharmaceutical shipments worldwide benefit from the introduction of new technological advancements and web-based asset management software solutions designed to track individual shipments around the globe.

These systems offer a range of capabilities benefiting the industry including the option to set up automatic maintenance, next shipments alerts and produce customisable reports.

Whether shipping finished products, transporting clinical trials materials, or delivering sample drugs, temperature excursions can mean the difference between success and failure, profit and loss.

Some of the latest innovations in smart packaging, serving the life sciences and pharmaceutical industries, are critical developments as ultimately the quality of pharmaceutical products being transported has a direct effect on patient safety and the efficacy of patient therapies.

Increasingly, advanced information technology is available to pharma companies, which can be utilised to track

pharmaceutical manufacturingâ&#x20AC;&#x2122;s cold chain logistics processes. Blockchain is having a real impact on pharmaceutical shipments, from prevention of theft and counterfeiting of pharmaceuticals, to tracking root cause of a dangerous event that causes illness in a patient, to government tracking of source of origin to properly assess duties and taxes for imports.

Artificial intelligence (AI) and the predictive guidance it offers is another technology impacting how pharmaceutical manufacturers ship their drug products around the world. AI can quickly sift and sort through massive amounts of data from IoT devices and determine patterns on best packaging or process or mode to use on divergent shipping lanes.

The increased need for last-mile pharmaceutical transportation is another growing trend, as it also requires stringent compliance throughout the cold chain process to ensure the protection of high-value, temperature sensitive, pharma payload through a complex and diverse logistics path to the patientâ&#x20AC;&#x2122;s hands.

These additional trends are worthy of their own articles, due to the intricacies and variability of their applications to the pharmaceutical manufacturing industry and the protection of their temperature controlled shipments.

It comes down to helping pharmaceutical manufacturers better understand the true cost of impact of moving to newer technologies and what impact that can have for their operations. Ultimately, ensuring stability in the supply chain is critical within the pharmaceuticals industry where patient safety and efficacy are an absolute priority.

Adam Tetz is Director of Worldwide Marketing at Pelican BioThermal and has more than 20 years of marketing experience.

He is responsible for worldwide branding, product launch and communications strategy. Prior to Pelican BioThermal, Tetz held positions in product management, marketing communications and account management across a variety of industries, including medical software, financial software and professional services.

He holds an MBA in Marketing from the University of Saint Thomas and a BA in Advertising from the University of Minnesota.

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SAFE AND RELIABLE TRANSPORTATION OF DRUGS AirBridgeCargo Airlines AirBridgeCargo Airlines is one of the leading industry players to guarantee specialist logistics solution for transportation of pharma products with its dedicated 'abc pharma' product.

AirBridgeCargo Airlines (ABC) is the international scheduled carrier with an in-depth knowledge, expertise and experience in transportation of pharmaceutical products. Being an IATA CEIV certified carrier, ABC is ready to offer its customers cool chain air freight solutions in strict compliance with industry standards, as well as with customers’ requirements.

What is the main advantage of air compared to other modes of transport for cold supply chain?

Air transportation guarantees speed, safety and integrity – these are three components vital for pharmaceutical products. During the last five to ten years air cargo industry has made a step forward in cool chain logistics – modern active containers which maintain desired temperature environment, for both standard and extended payload, up-to-date equipment to monitor temperature range (temperature loggers) and shipment movement (GPS devices for unit load devices which transmit the data), special packaging solutions for pharmaceutical products– these are just a few to begin with. Besides speed air cargo sector is ‘wrapping’ up its high-quality services in digital experience the tech-savvy customers are used to as consumers. Online track&trace, real-time monitoring and notifications – we are striving to stay current.

How is the air carrier managing pharma transportations with other supply chain stakeholders?

Transportation of pharmaceutical products is a multi-tiered and complex process with many supply chain stakeholders involved – ground and cargo handlers, carriers, trucking companies. The level of

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their service quality and their reliability are keys to successful delivery of temperature-sensitive cargo.

AirBridgeCargo has been partnering with reliable and trustworthy companies to guarantee safety and security of each shipment. With safety being of paramount importance, we make sure that all supply chain

stakeholders understand it and act accordingly. With this in mind, we organize workshops and training sessions with our customers for networking, peerlearning and ‘educational’ purposes. Furthermore, we make internal assessment of all service providers involved in transportation process to make sure that

they are fully compliant with air freight requirements and understand them.

Does the carrier need special service or product for transportation of pharmaceutical products?

Pharmaceutical products are becoming more complex and profound and require the whole spectrum of requirements to be met during their transportation with the main idea in mind – to help people live healthier and longer lives. This is why it is very important to have a dedicated team in the airline, with each member understanding the significance and importance of their every day ‘routine’ work. We, at AirBridgeCargo, have developed and introduced abc pharma specialty product and team to guarantee high level of quality during transportation of pharma products. Delivery is not only about getting the pills, medicine, vaccines, etc. from point A to point B. It is about creating the perfect ambient environment, shouldered by equipment, digital experience, partners and skilled personnel. With abc pharma active and abc pharma passive solutions we can manage various types of pharma shipments, offering required packaging equipment or special temperature containers, even for long-haul flights.

How can the carrier improve cool chain logistics?

Through refining its dedicated services. The receipt of CEIV Pharma certification in 2016, QEP accreditation for ABC online stations, an adaption of digital technologies with automated notifications to be sent to all supply chain stakeholders via web platform Sky Fresh, networking in industry-related initiatives, likes of Pharma. Aero, generating a home-grown pool of logistics experts and orchestration of all internal handling procedures – these are the initiatives and factors which bolster volumes of temperature-sensitive cargo and improve overall performance of our specialty abc pharma product.

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73

SUPPLY CHAIN INTELLIGENCE Challenges and the road ahead

Karen Reddington, President, Asia Pacific Division, FedEx Express

Supply chain intelligence (SCI) is crucial in Asia â&#x20AC;&#x201C; a region that is seeing dynamic growth and increasing complexities particularly in the pharma and healthcare sectors. For customers in these industries, full visibility of supply chains through big data and AI is increasingly critical. This article explores how SCI technologies can provide strategic information to decision-makers for betterquality supply chains and how logistics providers will aid compliance and cost optimization for their healthcare customers.

Supply chains in Asia are fast evolving into smarter, technology-driven systems for a dynamic healthcare industry. In todayâ&#x20AC;&#x2122;s digital marketplace, supply chains are becoming highly interconnected and competitive.

Now more than ever, investment in supply chains is taking on a strategic priority in Asia. Supply Chain Intelligence is a key area of focus empowering pharma business operators to better track the entire supply chain, get real-time performance insights and get full visibility along the entire process so they are in a better position to tackle todayâ&#x20AC;&#x2122;s global complexities surrounding supply chains. Supply chain investment is a priority in order to enhance intelligence in the system itself so that supply chains continue to modernize.

Role of Supply Chain Intelligence in healthcare logistics

Generally, the supply chain refers to the resources needed to deliver goods or services to a customer.

Managing the supply chain in healthcare is typically a very complex and fragmented process. Due to increasing competition, rising costs, government regulations, and demand for a higher quality of service, healthcare providers are under enormous pressure.

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Logistics is the gateway for pharmaceutical companies to bring their products to a global marketplace at minimal risks. Given the diversified locations, mergers, multiple information systems, changing organizational structures across the globe, supply chain leaders in healthcare and pharma need to optimize supply usage throughout the enterprise. The real value-add lies in innovation. A strong technology-backed supply chain can provide deeper, better insights into transportation including temperature control and cost optimization.

Complete Visibility and Real-time Tracking will be game changers

Products, such as vaccines, biopharmaceuticals and cell therapies, need to be transported under stringent environmental conditions where temperature, humidity, light exposure and other variables are tightly controlled. Tracking and monitoring the ingredients from supplier to factory, measuring temperature, time and the location to deliver reliable data and a clear

line of sight at every stage is critical. This level of visibility and tracking are the top areas which can really help supply chain leaders – and therefore, healthcare and pharma providers – to identify efficiencies and gaps and then tie that to their business profitability.

Historical data can allow supply chain providers to deploy optimal packaging designs and utilize cold storage facilities during transportation, while real-time data analysis can flag specific shipments where intervention is required immediately to save a product. For instance, FedEx regulatory compliance is supported by end-to-end tracking technologies which generate extensive data and continuous visibility on biopharmaceutical shipments. One example is the SenseAware service—a FedEx innovation—that monitors temperature, humidity, light exposure, shock events, and other environmental factors that can impact supply chain integrity. The combined multi-sensor device can gather, send and monitor data, enabling a comprehensive array of real-time tracking. Customers have a clear line of sight at every stage and identify and solve potential risks along a complex supply chain.

FedEx supports clinical trial projects by providing greater transparency throughout the supply chain.

It will not only make the customers’ life easier but also elevate their business and help them connect to a larger network in APAC and worldwide. To add, automation will continue to improve, and automated tracking systems will help to reduce the need for manual inventory management as well as considerably reduce drug wastage due to expiration and spoilage, since facility personnel can be proactively alerted to the status of products in storage. With inventory data digitized, healthcare facilities can work faster, and with added accuracy, to better meet accreditation and government regulation requirements.

Big Data will be central to predicting and mitigating risk

Data and AI will play a key role in supply chain management and will empower business operators to conduct real-time data analysis. Modern-day Supply Chain Intelligence (SCI) is digitally driven and can better help companies slash costs and increase customer satisfaction by combining data and analytics to draw out patterns and look into the future. Broadly speaking, supply chain management (SCM) technologies will enhance operational and transactional efficiencies in manufacturing, sourcing, and distribution. SCI technologies can integrate business intelligence with data from SCM systems, providing strategic information to decision-makers.

By harnessing data and innovating with technology, manufacturers and their logistics providers can further customize solutions and effectively close the shortage gaps.

Predictive analytics can enable scientists to identify patterns and gaps, and suggest efficiencies, revenue opportunities, potential problems or competitive advantages. Real-time data can be processed by manufacturers and their supply chain vendors through descriptive analytics to reveal operations patterns.

Companies can forecast how their supply chain may evolve, and develop risk-mitigation strategies to fix identified weaknesses.

Logistics is the gateway for pharmaceutical companies to bring their products to a global marketplace at minimal risks.

Logistics can drive the development of healthcare industry supply chain The future of the healthcare industry will be global and borderless. The biopharmaceutical boom in Asia is calling for the adoption of new technologies and higher quality cold chain services. With innovative solutions such as "Smart" medical inventory cabinets and sensor-based technologies, FedEx, a logistics industry leader for healthcare and other specialty shipments, continues to identify innovative ways to provide the visibility required by customers up and down the supply chain.

Accurate forecasting, faster response times, ability to recognize shipping patterns to plan for risk, saving on costs, in addition to running a low-to-zero waste operation will be key parameters for the industry to measure business efficiencies, supplemented by effective supply chain intelligence.

Logistics companies must continue to enhance their solutions and remain focused on innovation to aid compliance and cost optimization for their customers in the healthcare industry.

AUTHOR BIO Karen Reddington is president of the Asia Pacific Division of FedEx Express, the world’s largest express transportation company. Reddington is responsible for leading the FedEx Express business across the region, including overall planning and implementation of corporate strategies and operations across more than 30 countries and territories with about 29,000 team members.

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

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

STRATEGY BioGenes GmbH...........................................................................27

CLINICAL TRIALS Hoong-A Corporation...................................................................13

Cantel Medical............................................................................ IFC

Quantys Clinical Pvt. Ltd...............................................................43

Dishman Carbogen Amcis Limited...............................................25

Syneos Health...............................................................................05

Elitech Technology, Inc.................................................................33

Thermo Fisher Scientific................................................... 03, 20-22

Emirates SkyCargo.....................................................................IBC Medical Manufacturing Asia............................................. 31, 58-59 Qatar Airways................................................................................17 Swiss World Cargo.......................................................................19 Syneos Health...............................................................................05 Turkish Cargo............................................................................OBC

MANUFACTURING BioGenes GmbH...........................................................................27 Cantel Medical............................................................................ IFC Dishman Carbogen Amcis Limited...............................................25 Elitech Technology, Inc.................................................................33 F. P. S. Food and Pharma Systems Srl.........................................53

RESEARCH & DEVELOPMENT Dishman Carbogen Amcis Limited...............................................25

Hoong-A Corporation...................................................................13

F. P. S. Food and Pharma Systems Srl.........................................53

Lonza.............................................................................................07

Kompress (India) Pvt. Ltd.............................................................29

Novo Nordisk Pharmatech A/S.....................................................09

Lonza.............................................................................................07

Thermo Fisher Scientific................................................... 03, 20-22

Novo Nordisk Pharmatech A/S.....................................................09

Valsteam ADCA Engineering........................................................11

Quantys Clinical Pvt. Ltd...............................................................43 Syneos Health...............................................................................05 Thermo Fisher Scientific................................................... 03, 20-22

Kompress (India) Pvt. Ltd.............................................................29

INFORMATION TECHNOLOGY Kompress (India) Pvt. Ltd.............................................................29

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

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

AirBridgeCargo.....................................................................72-73 www.airbridgecargo.com

Medical Manufacturing Asia...........................................31, 58-59 www.medmanufacturing-asia.com

BioGenes GmbH........................................................................ 27 www.biogenes.de

Novo Nordisk Pharmatech A/S.................................................. 09 www.novonordiskpharmatech.com

Cantel Medical......................................................................... IFC www.cantelmedical.com

Oliver Healthcare..................................................................37-39 www.oliverhcp.com

Dishman Carbogen Amcis Limited............................................ 25 www.dishmangroup.com

Qatar Airways............................................................................. 17 www.qrcargo.com/qrpharma

Elitech Technology, Inc.............................................................. 33 www.elitech.com

Quantys Clinical Pvt. Ltd............................................................ 43 www.quantysclinical.com

Emirates SkyCargo.................................................................. IBC www.skycargo.com/emiratespharma

Swiss World Cargo.................................................................... 19 www.swissworldcargo.com

F. P. S. Food and Pharma Systems Srl...................................... 53 www.foodpharmasystems.com

Syneos Health............................................................................ 05 www.syneoshealth.com

FedEx Express........................................................................... 74 www.fedex.com/sg/healthcare/index.html

Tencent..................................................................................65-67 www.tencent.com

Hoong-A Corporation................................................................ 13 www.ha1511.com

Thermo Fisher Scientific.................................................03, 20-22 thermofisher.com/OneCDS

Kompress (India) Pvt. Ltd.......................................................... 29 www.kompressindia.com

Turkish Cargo......................................................................... OBC www.turkishcargo.com

Lonza.......................................................................................... 07 http://pharma.lonza.com/

Valsteam ADCA Engineering..................................................... 11 www.valsteam.com

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