Pharma Focus Asia - Issue 35

ISSUE 35 2019

www.pharmafocusasia.com

Digital Technology

Heading towards an effective transformation

Drug Substance Scale-up Impacting successful outcome Artificial Intelligence Bridging the Pharma Sector www.pharmafocusasia.com

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Foreword Digital Technologies and Pharma Heading towards an effective transformation “When a human body is the biggest data platform, who will capture value?” – EY Scenario 1: A patient suffering from schizophrenia

a study of C-suite executives from life sciences

forgets to take his medicine and within no time

and technology sectors, and unsurprisingly, more

receives a reminder call from his doctor. His regular

than two-thirds of respondents believe digital

medicine is a digital pill, and the microchip linked

transformation is happening in the life sciences

to the pill transmits data to both patient and the

industry. However, majority of them felt a little over

doctors thus enabling them to monitor patients’

10 per cent of digital health opportunities make

medicine intake and prevent any issues.

it to the execution and companies fail to perform

Scenario 2: For an oncologist, keeping a

due diligence in implementing the rest. So, what

check on patient’s regularity of medicine intake

hinders these companies from leading a digital

is a challenge. With a digital pill, the ingestible

transformation? Data security and regulations.

sensor transmits signals from within the body to a

The industry has been crippled with regulatory

wearable patch connected to a mobile app provid-

challenges and the protecting huge amounts of

ing key information to both patient and doctors.

patient data is equally challenging. While doctors

Who would have imagined internet-connected

and pharma companies have at their disposal

medicine to be a reality until the FDA approved

huge amounts of patient data, making effective

schizophrenia pill came into the market in late

use of this data without compromising patient

2017? In the hope of better patient outcomes, the

safety is a tremendous challenge in itself.

pharma industry has turned to digital technologies

In the cover story, Lydia Torne, Managing

and platforms such as Artificial Intelligence (AI),

Associate, Simmons & Simmons LLP presents

Machine Learning (ML), Internet of Things (IoT)

perspectives on the impact of digital technolo-

and focusing their studies to produce digital pills

gies in the life sciences industry and how the

to treat critical illnesses. Be it clinical trials, drug

future is going to revolve around digitalisation.

development, or therapeutic solutions, efforts

The author opines time is ripe for digital disrup-

have been underway to accelerate digitalisation

tion in the industry and seamless collaboration

of the industry. In pursuit of digital transformation,

between pharma and technology companies can

the industry has witnessed a huge investment of

help navigate legal and cultural issues to achieve

US$9.5 billion for collaborations and acquisition

a holistic digital transformation.

deals.

Digital technologies have been here for a long time helping industries progress and stay ahead in the marketplace, but pharma was a late entrant in the digital space. However, the industry has

Prasanthi Sadhu

made notable progress in embracing technology.

Editor

Law firm Simmons & Simmons LLP conducted

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Contents STRATEGY 06 Designing Sustainable

High Performance in Business-to-Business Collaborations with a cognitive systems engineering approach

Andrew A Parsons, Reciprocal Minds Limited

14 Today’s Line Managers

More of mentors and facilitators and much less of bosses

DIGITAL TECHNOLOGY IN PHARMA

44

Ripe for disruption

Lydia Torne, Managing Associate Simmons & Simmons LLP

Srinivasan V, Consultant/Advisor for Pharma Business/Enterprise

RESEARCH & DEVELOPMENT 18 Precision Medicine

Matching biospecimens becomes a more exact science

Cathie Miller, Director, Product Marketing Personalised Medicine, BioIVT

28 Apoferritin as a Nanocarrier

Its applications in medicine

Anchala I Kuruppu, University of Sri Jayawardenepura and University of Kelaniya

COVER STORY

MANUFACTURING 32 Drug Substance Scale-up

Impacting successful outcome

Anders HĂśgdin, Senior Sales Director, Recipharm

INFORMATION TECHNOLOGY

28

40 Artificial Intelligence

Bridging the pharma sector

Surabhi Johari, Institute of Management Sciences School of Biosciences

48 Big Data and Artificial Intelligence in Pharmaceutical Manufacturing

Emerging technologies can lower costs, speed up production and improve research and development

4

Sean Riley, Sr. Director, Media and Industry Communications PMMI, the Association for Packaging and Processing Technologies

P H A RM A F O C U S A S I A

ISSUE 35 - 2019

EXPERT TALK 54 Pharma Logistics Trends Karen Reddington, President, FedEx Express Asia Pacific

59 Research Insights 62 Books

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ready for thew wresource w . p h a r m a f o c revolution usasia.com 5

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

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

In Association with

A member of Confederation of Indian Industry

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Sanjoy Ray Director, Scientific Data & Strategy and Chief Scientific Officer, Computer Sciences Merck Sharp & Dohme, US

Stella Stergiopoulos Research Fellow Tufts University School of Medicine, USA 6

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STRATEGY

Designing Sustainable High Performance in Business-to-Business Collaborations

With a cognitive systems engineering approach

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STRATEGY

Creating the right partnership is an essential skill in the complex eco-system of biopharmaceutical collaboration. This article outlines some approaches from safety sciences that allow effective collaborations to be designed not only to manage and mitigate risks, but to create the right interactions to develop sustainable high performance.

Andrew A Parsons, Reciprocal Minds Limited

I

n today’s fast paced world of biopharmaceutical innovation, no one individual or single organisation can really work alone. Partnerships and collaborations are the normal way of doing business, whereas only a few years ago they may have been treated with suspicion.

The innovation cycle described in 2004 was a linear process. It was characterised by high cost, high attrition, long cycle times and a closed internal innovation loop. This allowed a close alignment of product and profit cycles. Today there are a number of different products, with classical NCEs, biopharmaceutical and gene/immune therapies brought to the marketplace by a range of investors, contract research and manufacturing organisations helping great ideas turn into useful medicinal products.

Experience shows that sustainable high performance of cross-organisational teams is not just dependent on having resources and a plan. To be effective, they need to be able to work together, share knowledge and integrate activities not only with themselves but also with a variety of governance and operating processes that may exist across organisational and cultural boundaries. With the development of digital technologies and artificial intelligence in support of decision making these complex systems will also increasingly need to integrate with automation.

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STRATEGY

Working in the interface between humans and machines, the science investigating the interplay between human cognitive processes, the environment and effective communication processes that relay the right meaning to operators have been developing for many years. This interface between humans and technical processes in engineering and systems design has led to the development of cognitive systems engineering or more broadly human factors.

A Human Factor PerspectiveTraditionally a Focus on Minimising Risks

Human Factor integration into technical work processes is an essential element of safety critical industries such as Aeronautics, Oil & Gas, Defence, and Nuclear Power. Minimising error in these industries is critical in preventing significant loss of life and/or environmental destruction as can be seen within the human history of accidents such as the Space Shuttle, Chernobyl and Oil Platforms in the Gulf of Mexico. Within the Pharmaceutical Industry, risks in application of powerful biological agents are also evident with the sad loss of life involved with the development of the CD28 antibody TGN1412 and FAAH modulator BIA 10-2474. These errors occurred across business-to-business (B2B)partnerships and have been well described with some key learnings being implemented across the industry.

Such accidents occur when there is alignment of a situation with an individual or team mistakes with an organisational or system failure that results in a loss. This perspective has been coined the ‘Swiss Cheese Model’. For a situation to result in a failure/loss it must align with gaps in a range of organisational, professional, regulatory, team, individual and technical defences as if it was aligning with the holes in the Swiss cheese. This approach was first outlined in the 1990s and has developed across many sectors including healthcare. Safety sciences recognise the crucial need to think about the system rather than the 10

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role of the individual to design the best system available. In the pharmaceutical industry, the plethora of individuals from patients, scientists, physicians, investors, and regulators who may be working in partnerships between private or public Companies, LLP and within the public sector all create potentially different views of the system.

In a first step toward supporting a Human Factor methodology, the UK Chartered Institute of Ergonomics and Human Factors Pharmaceutical Special Interest Group took a system engineering approach called STAMP (Systemictheoretic accident modelling process,) and reviewed top level development plans of a range of case histories to create a potential map to allow human factor integration into the medicines development system. The team developed four key emergent themes of relevance to all members of the system from a startup company to a government agency.

These were: • Value • Effectiveness • Quality • Safety Using these outputs was suggested to create a common and transparent language of all members of the innovation process.

What is the Human Factor in B2B Partnerships?

Human factor or cognitive engineering approaches require us to take a system-

With the development of digital technologies and artificial intelligence in support of decision making the complex systems will also increasingly need to integrate with automation.

wide view of the interaction of individuals with not only automation, but other humans, managerial, organisational, cultural, and technical interfaces. Ideally, the system also brings in the end users and legislative and governmental aspects.

With medicine innovation, there is a dynamic and complex ecosystem that involves many contributors and stakeholders. We are only at the start of being able to describe the system as a whole.

However, there are some approaches that could be implemented to enhance performance within the boundaries of business to business collaborations. The first step is to be able to describe the boundaries of the collaboration. One simple way involves comparing what type of data is produced (known at the start of the collaboration or emergent as the collaboration progresses) and what type of work is involved (Rule-based or Knowledge-based).

The “Data Type – Work Type Matrix”: What type of Collaboration do We have/want?

In the R&D eco-system, sustainable value (profits) can be created along the different phases in development by reaching key value inflection points.

These are often pre-defined with known quality attributes for the project. For example, in the old linear model of innovation these were often defined by committing resources to start target validation, compound screening, optimisation of leads, committing to scale up and Phase I. However, as more data is created, the ‘asset’ trade-offs can be made between these attributes so that decision making becomes less binary (yes/no) and more dependent on the emergent data. This becomes more evident as the project moves through early and late clinical studies and through the more complex registration and post registration processes.

As the project develops, the amount of information increases so that better decisions can be made around the key emergent properties of value, quality, safety and effectiveness.

STRATEGY

Knowledge-Based

Developing Products

Breakthrough Products

Defined Data

Emergent Data Exploring

Screening

Rules-Based

© All Rights Reserved, Reciprocal Minds Limited 2019

Figure 1 Data Type – Work Type Matrix

Early models of cognitive systems engineering identified different types of decision making in working on the product (work agent). There are three types of work: skills-based, rules-based, and knowledge-based working/behaviours and problem-solving approaches.

Skills-based work is often thought of as being automatic such as skilled motor coordination. This requires little conscious effort and is developed by practice. Rules-and knowledge-based working requires increasing cognitive demands. Rules-based working requires knowledge, but it is described in forms of processes and targets and runs the risk of becoming automatic and based on a set of artificial signs or data points where situational violations occur and can be managed. Knowledge-based working requires the highest cognitive demands. In this type of work, decisions are made not on the data (sign) itself, but on how the information is processed and may require the generation of new hypotheses and information.

Exceptions and even dangerous violations in this setting can be managed. For example, an air crew being presented with contradictory data / information can form new perspectives to manage and resolve the situation. Examples such as the emergency landing of planes on

the freeway and rivers are examples of this type of behaviour.

Within the context of biopharmaceutical drug discovery, it is tempting to think that all our collaborations involved knowledge-based workers. The high level of skills and knowledge required to operate laboratory services is not in question. However, with the complexity of the innovation ecosystem, work activities may be limited to rules-based activities (e.g., screening). Knowledge-based work around meeting multiple predetermined endpoints (e.g., review of phase 1 data).

Less well-defined outcomes can even be emergent with decisions being based on the outcome itself (e.g., black box screens to explore biological pathways) or be required to work multiple conflicting data points to process (e.g., breakthrough innovations).

Within the context of today’s ecosystem, it may even be unlikely that organisations complete all these activities without any outsourcing or collaborating on work activities. Larger pharmaceutical companies often outsource rules-based work activities with preferred suppliers to capture the economies of scale that contract research organisations can provide. Smaller companies may work with a range of consultants to provide knowledge-based work activities such as

understanding pre-clinical and/or clinical safety findings. In this case, a number of data sets may need to be processed to come to an overall conclusion and recommendation. These ‘service-based’ collaborations involve delivering a service from a vendor to a buyer, here a cognitive systems engineering approach would most likely provide a better opportunity to manage and mitigate errors and risks.

When the system gets this wrong— as in Tegnero and Bial examples— the impact on patients and volunteers and their families is only too obvious. As we move into more complicated advanced technologies (e.g., gene modifications such as CAR-T immunotherapies), the impact of failure to manage errors effectively will not only be devastating to the patients and their families, it will also have significant impact on all the other members of the innovation system including researchers, institutions, and investors.

Risk-sharing collaborations can also be of a service type, where one partner offers services at discounted rates or in exchange for an equity state in the other.

I am sure many start-up companies are really grateful for this type of a relationship. It brings the opportunity to grow.

More complex risk-sharing arrangements are also common place. Here, smaller companies may be looking to scale their www.pharmafocusasia.com

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STRATEGY

Collaborative Decision-making Processes

The psychology of human decisionmaking and judgement processes is complex. It involves the interplay of individual and group perceptions, cognitions and affective processes with regard to the technical aspects of the project.

Cognitive systems engineering pays attention to these areas to create models that manage errors in safety critical activities so they can be mitigated effectively. This type of a systems thinking can, therefore, also be used to develop sustainable performance with collaborations. Risks of mis-communication and perception of data in the process of collaborative decision-making is often where mistakes and suboptimal performance can occur.

A simple tool to design appropriate decision-making processes can prove be essential. There are four key areas that include: 12

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Rules-and knowledgebased working requires increasing cognitive demands.

tional organisations have a range of business processes that have often developed to manage risks associated with previous projects and operate in addition to any legislative procedures. Challenging the individual and organisational assumptions underlying data enables better decision-making.

The Balance of Governance and Autonomy

• Assumptions of the Individual and organisational or cultural groups • Processes that ensure alignment of perception of data to knowledge and meaning • Context, the understanding of individual and organisational rewards and risks • Consequences of trade-offs that could be made For all types collaborations, it is critical that there is a clear and consistent alignment on the knowledge and meaning that is taken from data. To do this effectively, explicit awareness of individual, organisational and cultural assumptions is needed on an ongoing basis, not just at the start of the collaboration. Project members may change in each partnering organisation and it is likely that business priorities and drivers will also evolve. With the long life-cycles involved in the biopharmaceutical industry, it is almost a guarantee that people involved at the start of collaboration will not be the ones involved at the end. For collaborations where the work creates a better understanding of the product, this is a particular challenge.

Organisational assumptions also need to be managed. For example, multinaAUTHOR BIO

projects through the clinical development phases to reach a potentially global customer base. In this type of collaboration, the definition of what type of technical data is required may be less clear. The knowledge-based collaboration could be focussed on attaining registration / reimbursement whereas accessing a cellular screening assay might provide simpler rules-based (e.g. metabolites produced from cells) outcomes.

Figure 1 provides a summary of the types of collaboration that can be produced within the matrix. Of course, within the context of a fast-moving business relationship, it is possible that all aspects of the matrix may be involved.

Knowledge of the type of collaboration allows alignment of communication processes and better understanding of the partners goals and motivations.

This mutual recognition of what data is to be produced by what type of work activities allows design of appropriate processes to take into account human factors (e.g., rewards and motivations), cultural aspects, and governance processes.

It also allows appropriate diligence on the skills and processors in prospective collaborators.

Effective performance needs alignment of motivations and skills with an understanding of a sense of autonomy for individuals and partnering organisations. Agreeing up-front and reviewing regularly how decisions are made allows all members of the collaboration to develop a sense autonomy and alignment to the project. This process will also allow development of appropriate measures to be tracked. Three key areas appear to be crucial for the governance process. The first regards the technical production: ‘are we creating what we wanted to?’.The second is regarding the emergent properties of the collaboration: “are we providing value, quality, safety, and effectiveness for all parts of the innovation system?”The third and last area is on the engagement of staff: “are there enough resources for people to manage the demands of the collaboration?”Paying attention to these areas at a senior level will enable the creation of the human-centred organisation to maximise performance at all levels.

Conclusions

Taking time to adopt a cognitive systems engineering approach with B2B collaborations will enable all partners to develop the right processes and team members to maximise sustainable performance.

Andrew A Parsons PhD has worked in Biopharma in a variety of Senior Executive and Non-Executive Roles. Initially trained in Pharmacology and Neuroscience he worked in External Innovation to maximise performance across organisational and cultural boundaries. He is an accredited coach and has interests in systems design.

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MEDICAL FAIR THAILAND 2019

Transforming the healthcare ecosystem through technology & innovation

As Asia’s healthcare market is expected to see robust growth of 7.2 per cent in 2019, according to Frost and Sullivan, demands for healthcare technologies and innovations are expected to increase significantly particularly pharmaceutical drugs and medical devices based on advanced technology.

In Thailand, the government is loosening visa restrictions and recently launched the smart visa programme designed to enhance Thailand’s attractiveness in drawing science and technology experts, senior executives, investors and start-ups - as part of their strategic plan to become a global medical hub.

To promote medical robotics, the Thailand Board of Investment (BOI) is also offering a wide range of investment promotion incentives.

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Against this dynamic backdrop, the 9th edition of MEDICAL FAIR THAILAND comes at an opportune time and with its move to a larger venue at BITEC, visitors can expect to see over 10,000 medical and healthcare innovations from around the world; representing the hospital, diagnostic, pharmaceutical, medical and rehabilitation sectors. Together, 1,000 companies from 60 countries including 20 national pavilions and country groups will bring the very best solutions to one central venue.

Member of MEDICAlliance

Organised by Messe Düsseldorf Asia (MDA), MEDICAL FAIR THAILAND is part of the MEDICAlliance global network which shares the expertise of MEDICA – the world’s No.1 annual medical and healthcare

trade fair, organised by the Messe Düsseldorf Group in Germany. Since it was first established in 2003, MEDICAL FAIR THAILAND continues to be the region’s most anticipated trade exhibition on the medical and healthcare calendar.

Concurrent Events

• 11 & 12 Sep: Advanced Rehab Technology Conference (ARTeC) - The Combination of Ultrasonography and Electrodiagnosis: An Innovative Approach to Neuromuscular Disorders. The 2-day conference will include lectures, panel discussions and demonstrations by industry experts from the US, Canada and Thailand, who will discuss various topics from common musculoskeletal conditions to best approaches for diagnosing ulnar neuropathy at the elbow.

• 11 Sep: WT | Wearables Technologies Conference 2019 Asia Organised by Wearable Technologies AG (HQ in Germany), the conference will share insights on how wearables digitise the healthcare industry as well as uncover a new era of fitness wearables and the latest enabling technologies.

Join us from 11 to 13 September, at BITEC, Bangkok, and see the best at Thailand’s leading medical and healthcare exhibition for all your networking, learning and sourcing needs.

Admission is free, register your visit online today at www.medicalfair-thailand.com

New Highlights The Community Care Pavilion features exhibitors from Japan, Taiwan, Hong Kong, USA and many more - showcasing products and technologies specific to the needs of an ageing population; focusing on solutions such as remote healthcare monitoring, geriatrics, rehabilitation products and assistive devices.

Across Asia, demographic trends indicate a growing ageing population with the 65 and above age category projected to more than double, reaching close to 2.5 times the current figures by 2050. With the exception of the Philippines, the proportion of people aged over 65 in ASEAN is expected to triple between the period of 2015 to 2050, according to ASEAN and United Nation’s data.

Start-Up Park – is a dedicated platform for new and innovative companies to present their innovations to potential buyers and investors. With a start-up ecosystem in Southeast Asia estimated to be valued at US$13 Billion, this represents the region’s openness to new ideas and innovative new companies. Here you will see innovations in IoT, from big data, wearable technologies to the latest software.

Advertorial www.pharmafocusasia.com

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STRATEGY

Today’s Line Managers More of mentors and facilitators and much less of bosses

The role of a Line Manager in Pharma Selling/Marketing has been changing, that too quite fast, under the present highly competitive Pharma marketing environment, and the Line Managers are forced to think out of the box to keep the team members motivated, and engaged fully, to facilitate them to deliver the desired results consistently. Some of the 'out of the box' thinkings, and their impact on the performance of the team members are discussed in this article.

Srinivasan V, Consultant/Advisor for Pharma Business/Enterprise

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G

one are the days when line managers used to visit once in a while for joint working with their team members for a few days, meet some important doctors, and before leaving, issue stern instructions to the team members that they should meet their targets without fail, failing which they may not be in the team for long.

The managers used to be bossing around 80 per cent of the time, and 20 per cent of the time was spent on training

STRATEGY

and mentoring. Let’s see below some of the important job requirements of line managers under the highly competitive pharma sales and marketing environment of today.

Help the medical representatives find a purpose for the job: This could be buying a property, contribution to sister’s marriage, buy a new bike, funding for higher studies of brother, etc.

Once the purpose is ingrained in the field staffs’ mind, it may drive them go all out after the objectives in the job.

Let them be very clear about the implementation of sales and marketing strategies in the field: Such as right doctors for the right products, doctors and chemists call averages, personal order bookings, morning and evening working, etc. Once understood, they will be on the right track at all times.

Remove misconception if any about the job/career: Some might have joined the profession as a stop gap arrangement till they get a desk job in a government/ public sector undertaking. Therefore, they may be less serious in the job and just going through the motions mechanically. They may be availing leave or absenting themselves frequently. To them the line managers may explain that such desk jobs may not be that challenging, and career growth might take a lot of time at every stage, whereas a medical representative job offers a challenging environment at all times, career growth is quite faster for those who consistently perform, besides scope for earning very attractive incentives linked to performance. Once understood, they may apply themselves and involve more in the job, leading to better results.

Some need attractive danglers like ‘incentives’ besides normal salary, to go for the kill: To them the Line managers may explain the attractiveness of the sales incentives under different headings like Incentives for monthly target achievement, cumulative target achievement, product wise target achievement, new products target achievement, incentives for growth over last year, etc. and may even quote many frontline salesmen

Help them overcome weakness in communication: Field staff, more so from small towns and rural areas, may struggle with communication, i.e. detailing, and hence feel they are not the cut out for the job, reinforced by the less than satisfactory results in the initial few months of working in the field.

Their line managers must train them to practice more and more detailing, besides suggesting them to join part-time english speaking classes in their locality, to improve oral communication skill. Once their communicating ability improves, their strike/conversion rate goes up, their confidence to do well in the job also grows.

preferably within the same team who have earned lakhs and lakhs of incentive amounts in the current year. Once they realise the lucrative incentive earning potential available in the job, they may go all out to reach for the business objectives, thus earn incentives regularly.

Some are uncomfor table waiting for long for career growth in the job: In the pharma industry, line managers have plenty of examples to quote about people who have started their career as a simple representative, and have grown faster to reach senior positions such as national sales managers, group product managers, vice presidents sales & marketing, and even the CEOs or MDs who are into their early forties, through consistent performance at every stage. Once they understand this, they will do every thing in their reach to

perform well and grow fast.

Some may still believe in 9 am to 6 pm office job: Such medical representatives are more likely to skip evening works.

The line managers need to explain to them how the job of a representative is different from an office job, and that we work according to the working time of the doctors, hence morning and evening workings are important. Once they understand it clearly, then it may become a part of their working habit.

Inflame passion in the job: Talk high about the industry, about the organisation, and about the job like, such as the industry’s performance in India, growing in double digits year after year, and that many countries, including the advanced ones, source their medicinal requirements from India, the job of a medical representative, besides offering a www.pharmafocusasia.com

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STRATEGY

Some may not be comfortable with Product knowledge / scientific information: Instead of using hi-fi and more scientific template, the audience of medical representatives in general may be more comfortable with what is taught in simple and easy to understand lay man’s language. If they still struggle, same can be explained in their local language too. Once learning of product knowledge and scientific information is made simple and easy to understand, they may probably enjoy learning more and more about Product knowledge.

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may not have this attitude in them. The line managers need to be persistent with them in explaining the immense benefits that being disciplined and organised offers in achieving the desired goals not only in work, but also in personal life as well, and ensure that they follow such good habits as fast as possible.

The Line managers need to ensure that all their team members get their salary, reimbursements, incentives,

AUTHOR BIO

decent salary, attractive incentives linked to performance, and faster career growth for consistent performers, also offers the opportunity to interact with respected and highly qualified members in the society, i.e. doctors. Through them we offer products to treat the diseases of the public in the country. Thus, spread all the positive vibes, and avoid gossiping of any kind in the team.

Some may lack discipline and organisation: We all know that being disciplined and organised is the first step towards success. Some habits include getting up early in the morning so that we can be comfortably ready for the early morning work, stuff the working bag with necessary samples, promotional inputs, etc. in tune with the day’s calls, being well groomed, etc. However, some field staff

promotional inputs, etc. on time, and the consistent performers are recognised, rewarded and their career growth aspirations are taken care of without any delay.

The above topics can be covered well and in detail during the class room training programme, if not, by the line managers during the induction period of representatives in their respective offices. In addition to the above, some of the newly joined representatives may have their own specific issues, which might impact their performance. The line managers need to probe, identify the issue, and offer viable and positive solutions to ensure that the employees offer their wholehearted attention and efforts in their job responsibilities, without worrying much about anything else.

Line managers who excel in the above job responsibilities are likely to succeed more than those who simply boss around and work like senior representatives. Their team members may respect them more as their gurus, guides, and mentors, and may stand by them through thick and thin. Attrition may be a rare thing in the teams of such line managers. That’s why we often say field staff may leave their managers, but not the organisations.

Srinivasan V has headed Sales Administration, HR, Personnel and Training functions in reputed Pharma Companies. He has over 35 years of rich experience in the Industry, with over 500 published articles in India and abroad on Pharma Management to his credit. He has been recognised as The Transformational Leader of the Industry in the year 2013. His training manual for Medical Representatives ‘Reach For the Stars’ is like a bible for newly joined and already working Medical Representatives. He can be reached at shridhar1956@rediffmail.com

RESEARCH & DEVELOPMENT

PRECISION MEDICINE

MATCHING BIOSPECIMENS BECOMES A MORE EXACT SCIENCE Growing adoption of precision medicine has led to more in-depth patient screening for inclusion in clinical trials.

It has also increased the inclusion/exclusion criteria for Human Biological Specimens (HBS) for life sciences research.

That makes it harder for drug and diagnostic development researchers to acquire appropriate HBS for their studies.

Cathie Miller, Director, Product Marketing, Personalised Medicine, BioIVT

F

or many drug discovery programmes, HBS form the foundation of many hypotheses and contribute to research that is the basis for go/no-go decisions during the development process. But what if the HBS used in the research do not properly represent the clinical situation with the appropriate representative donors and diagnoses?

The resulting research may not align with the clinical setting and unnecessary drug attrition may occur.

HBS Collection

To fully understand how this may occur, it is important to know how HBS for

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Consistency. Proven

Increase viable Sf9 cell density and Baculovirus-based VLP production by supplementation with recombinant Insulin Human AF Sf9 insect cells are the most widely used platforms during the manufacturing process of recombinant protein therapeutics when a fast and flexible system is needed. The baculoviral-insect cell system has shown to be a powerful alternative for the production of recombinant proteins in short time frames.

As for the CHO cell-based manufacturing process, increased demand for safety and reliability has moved the standard for Insect cell culture media from Serum to Serum free and further on to chemically defined media.

UAB in collaboration with Novo Nordisk Pharmatech (world’s largest supplier of recombinant insulin) has shown a significant increase in viable cell density and baculovirus-dependent VLP production with the addition of animal origin free Insulin into commercially available chemically defined media.

To learn more visit www.novonordiskpharmatech.com

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Cell density NI

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Viability NI

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VLP concentration in ExpiSF CD media 100

Viability (%)

Viable cell density (106 cell/mL)

ExpiSf9 Cell Growth in ExpiSF CD media 30

6 1.2 fold 4

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NI 1 r-insulin concentration (mg/L)

ExpiSF CD is trademarks of Thermo Fisher Scientific.

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RESEARCH & DEVELOPMENT

research are obtained. To begin with, in most cases an Institutional Review Board (IRB) consented donor undergoes a doctor’s exam or surgical resection as part of the standard of care for their disease. At that point, an HBS is collected, generally either biofluid or tissue. Those HBS may be collected prospectively, with known donor consent and written authorisation to donate said specimen for research.

Alternatively, samples may be collected retrospectively, in which case consent is not required prior to collection. In those cases, the HBS is not specifically collected for research but may be a sample destined to be discarded after appropriate tests are performed and the identity of the donor cannot readily be determined from coded private information or the specimen itself. It is important that these remnant samples are collected with the appropriate regulatory oversight.

Best Case Scenarios

In the best case scenario for blood-derived and non-blood derived biological fluids, HBS are prospectively collected according to a specific protocol with associated clinical data that define whether the patient meets specific inclusion and exclusion criteria. However, based on research needs and standard of care, this may not be feasible. Thus, remnant samples with the appropriate donor criteria, such as lab test results within specific ranges, may be procured instead. Any inconsistency or discrepancies in the clinical data must be flagged immediately for resolution with the specimen provider. If they cannot be resolved, the HBS should be quarantined and not used in further analysis.

For tissue samples, the best case scenario has HBS prospectively collected by a surgeon and surgical team when a patient undergoes surgical resection of the diseased tissue, together with surrounding non-diseased tissue to ensure the compromised tissue is completely removed. However, based on research needs and standard of care, this may not be feasible. Thus, upon IRB approval of waiver of consent, remnant samples with the appropriate donor criteria, such as 22

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clinical diagnosis, may be acquired from pathological archives instead. As with biological fluids, any inconsistency or discrepancies in the clinical data must be flagged immediately for resolution with the specimen provider. If they cannot be resolved, the HBS should be quarantined and not used in further analysis.

Tissue samples, whether collected prospectively or retrospectively, are unique and certain issues may arise that impact downstream use of the tissue blocks processed following a surgical procedure.

For example, imagine a scenario where a patient is undergoing surgical resection of a lung adenocarcinoma. The surgeon and surgical team resect the tumour with surrounding non-neoplastic tissue to ensure the tumour is completely removed from the patient. That tumour mass is then collected and processed by speciallytrained personnel. Generally within

30 minutes of removal from the donor, the tissue is placed in formalin or flash frozen for fixation. Depending on the size of the tissue sample, it may be sectioned into smaller tissue fragments to allow proper fixation and microscopic examination.

Tissue Sample Complexities

Macroscopically, it can often be difficult to distinguish tumour from normal or diseased lung tissue; the tumour can be intermixed with haemorrhage, fibrosis, diseased tissue or necrosis.

In addition, it is known that tumours are heterogeneous, and thus the tumour that is excised may have a variation in diagnosis because of the greater volume of tumour that is available to examine microscopically compared to a small biopsy. For example, a lung adenocarcinoma could have areas of squamous cell

RESEARCH & DEVELOPMENT

carcinoma not present on the original needle core biopsy and should be classified as adenosquamous carcinoma.

If the average lung cancer tumour dimension is roughly three centimetres or 1.5 inches upon resection, this tumour mass would need to be cut into approximately three to five tissue blocks to allow proper fixation via either formalin or flash freezing for microscopic examination.

This could result in three to five tissue blocks that contain a mix of tumour and unwanted non-neoplastic tissue that could merit a different diagnosis. This situation provokes several questions, as follows: • How can researchers ensure that the tumour block that they are using contains what they think it does?

• How do they know that there is tumour present within that block?

• How do they confirm that the signalling they are looking at, or receptor they are exploring, is expressed on the tumour cells and not normal cells?

• How can they verify the presence of immune cells?

Providing Quality Control

These questions can all be answered through an independent board-certified pathologist review of each tissue specimen used in the research process.

Pathologist review of HBS provides quality control and assures that the correct tissue is analysed with the right anatomic site and diagnosis, ensuring the validity of research data and accelerating progress toward actionable data. Board-certified pathologists use their knowledge and understanding of current medical practices and standards to diagnosis the tissue block of interest accurately and verify that information matches the clinical data provided by the donor center.

Confirming Diagnoses

In the previous scenario with the three to five lung cancer tissue blocks, each block will undergo a separate review and receive its own diagnosis based on the tissue that is present in the representative H&E slide of that specific

Marrying the right sample with the right clinical data, associated social-demographic information, mutation or genotype data, and potential outcome data under proper regulatory and quality review is a complex process.

block. Thus, while the first two blocks may have a confirmed adenocarcinoma diagnosis, the third block may have a confirmed pneumonia diagnosis, the fourth block could show only fibrosis and inflammation, and the fifth block anthracosis (Figure 1).

In this specific case, the clinical diagnosis provided by the site was adenocarcinoma of the lung, but as can be seen in this scenario only two of the five blocks could be confirmed to be adenocarcinoma. Most importantly, using the blocks that showed only pneumonia or fibrosis versus any of the blocks with tumour obviously would have a significant negative impact on research results.

Refining Diagnoses

In addition, in the lung adenocarcinoma example, a pathologist could use immuno-stains to ensure that it does not represent a metastasis. Immunostaining could also refine or change the diagnosis.

Presence or absence of a specific marker, such as TTF1, Napsin A, Chromogranin or Synaptophysin, is used to distinguish small cell lung cancer from non-small cell lung cancer as well as for identifying glandular or squamous differentiation and is thus important for an accurate diagnosis. Without this valued workup, the use of a specific tissue block may again negatively impact results.

Beyond confirming an accurate diagnosis, review of tissue blocks by a board-certified pathologist offers additional beneficial insights that ensure the validity of research outcomes and downstream decisions. These benefits include determining the percentage of different types of tissue within a block, tissue markup, quantitative measurements, grading slide quality or interpretation of specific research or prognostic immune-stains.

Determining Tissue Percentages

Reviewing these benefits individually will help researchers to understand where they add value. First, it is critical to understand the percentage of different types of tissue within each block used in a research experiment. As discussed above, a single block of tumour tissue may contain other unwanted tissue. For tumour-specific research, it is important to understand what percent of any specific block of tissue is tumour, with generally acceptable levels being 30-90 per cent. Knowing the percentage of diseased tissue is important in many other therapeutic research areas as well.

Confirming that there is a minimal level of necrosis, generally less than 10 per cent, is useful in many downstream assays as necrotic tissue and signals can interfere with sensitivity assays.

Depending on research needs, it is also important to know if there is an immune cell presence within a tissue block. Having each block reviewed by a board-certified pathologist, who provides these estimations, is essential to achieving actionable data. Further information can provide insight into other differences between specimens that may be important in downstream analysis.

Interpreting Prognostic Stains

Some diseases have validated prognostic stains that are required to determine specific treatment options. One of the most important of these is used for breast cancer. The expression pattern for these three receptors – Estrogen www.pharmafocusasia.com

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Figure 1 Schematic of lung tumour specimen split into five blocks with differential diagnoses.

(ER), Progesterone (PR), and Human Epidermal growth factor Receptor 2 (HER2) – is essential in determining the clinical treatment of all breast cancer patients and thus is essential to many researchers studying this area.

As these are validated clinical assays, and their expression is known to be heterogeneous across a single breast cancer specimen, it is important that these levels are determined on a blockspecific basis. It is equally important

that a board-certified pathologist determines the staining intensity and calls whether a specimen is positive or negative in expression for each of these markers consistent with the validated clinical parameters. In a www.pharmafocusasia.com

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similar fashion, pathologists can also be used to interpret research stains because they have a thorough understanding of the requirements needed to validate any stain.

Providing Quantitative Measurements

At times, it is important to have the specific areas of interest, such as tumour, disease, necrosis or other, marked on the slides themselves. A pathologist can markup slides cut and created from tissue blocks to allow macro dissection or other determinations by automated or manual systems, thus ensuring proper input into molecular assays. Pathologists can also provide quantitative measurement of pathological lesions or other areas of significance for density, frequency, coverage, etc. Correlation of these quantitative measurements with clinical data can further validate that the proper tissue blocks are being used and that the research results are in line with the diagnosis of the donor cohort. An independent assessment of these factors can be important in accelerating research and achieving actionable data.

Conclusion

The application of precision medicine is growing across multiple therapeutic areas, most obviously in oncology. Ensuring that research aligns with clinical goals is essential to successful drug and companion diagnostic development. As reviewed here, there are inherent weaknesses in the HBS that are used in these research settings.

Having a board-certified pathologist review tissue specimens truly impacts research and successful outcomes. Starting with the right HBS from the right donor with the right diagnosis will set research on the correct path. Marrying the right sample with the right clinical data, associated social-demographic information, mutation or genotype data, and potential outcome data under proper regulatory and quality review is a complex process. Therefore, it is critical that researchers work with HBS suppliers that have in-depth knowledge of regulatory requirements and expertise to deliver high-quality HBS. 26

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AUTHOR BIO

RESEARCH & DEVELOPMENT

Miller has more than 20 years’ experience as a bench scientist, director and global product manager, using biospecimens to advance cancer, immunology and virology research. She received her PhD from the University of Louisville; School of Medicine and completed her post-doctoral fellowship at the Wistar Institute and University of Pennsylvania.

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Pharma, Food, Chemical & Cosmetic Zona Ind. da Guia, Pav. 14 - Brejo · 3105-467 Guia PBL · PORTUGAL (+351) 236 959 060 · adca@valsteam.pt www.pharmafocusasia.com

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SIMPLIFIED WATER TESTING AND CLEANING VALIDATION Sievers TOC Analyzers When it comes to efficiency and compliance in pharmaceutical water testing and cleaning validation, Sievers products and solutions offer unmatched productivity and peace of mind.

Whether in the lab, at-line, or online, Sievers products can be used to simplify testing and lean out processes, all while complying with the latest data integrity guidelines.

SUEZ, through its Sievers product line of TOC Analyzers and solutions, is leading the way toward the future state of water testing.

How does SUEZ provide expertise to the pharmaceutical industry with its Sievers instruments?

Through its Sievers TOC Analyzers, SUEZ provides superior technology, design, quality, and service to the pharmaceutical industry. Whether in the QC lab, production, R&D, or engineering facilities, Sievers Analyzers can be deployed to meet compliance and lean out processes.

With a history of excellence in the pharmaceutical industry, Sievers product experts are available to help customers develop methods, determine feasibility, and implement new applications as needed. Sievers also provides Validation Support Packages for qualification (both instrument and software), Real-Time Testing (RTT), and cleaning validation. These packages help

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customers navigate the validation process and enable more efficient implementation.

Sievers instrument health and failure analysis reports help efficiently close out any TOC Out-of-Specification (OOS) investigations. With complete traceability of Sievers reference materials, vials, and analytical instruments, the services and corresponding documentation SUEZ provides to close out non-conformances are unmatched in the industry.

Beyond analytical instrumentation, Sievers certified services, consumables, and specialized support offer customers a complete TOC solution. From validation support and application expertise, to certified reference materials, failure analysis reports, and on-site services, SUEZ has the pharmaceutical industry covered to ensure customer success.

How do your analytical instruments keep pace with changing demands and regulations in the industry related to RTT, faster analysis, or automation?

With customers' limited time and resources, it is not enough to simply manufacture instruments that don't provide added value. The industry demands not only tools that are accurate, but also those that exceed compliance requirements and will help increase productivity, automate processes, and troubleshoot effectively.

Starting with online monitoring and RTT of pharmaceutical waters, Sievers instruments enable better process understanding to perform corrective actions in real time and ensure quality.

In alignment with industry guidance ASTM E2656, analytical instrument validation is required for real-time release testing.

This can be achieved only with an analyzer, such as the Sievers 500 RL On-Line TOC Analyzer. The Sievers 500 delivers high quality online results, consistent with regulatory requirements for both process control and RTT. The robust Sievers 500 performance ensures the regulatory expectations can be met that are outlined in the FDA Process Validation Guidance document; ASTM E2656; and the ICH Q8, Q9, and Q10 international guidance. Also, WHO GMP Annex 2 Technical Report Series 970 encourages online TOC and conductivity monitoring.

When it comes to faster analysis, Turbo mode for Sievers M9 Analyzers enables real-time profiling of TOC for water testing, troubleshooting, or cleaning validation. Available for online, grab, or lab samples with an autosampler, Sievers Turbo mode

Using Sievers Analyzers, manufacturers can measure TOC and conductivity simultaneously and cover virtually all potential contaminants and compounds that may be present- whether organic or inorganic. This also provides even more powerful data analytics.

provides four-second analysis time to quickly analyze samples or identify transient TOC excursions. This level of control and speed is vital to maximize productivity.

Sievers products are built to enable automation and efficiencywhether automating aspects of TOC analysis, enabling online deployment of TOC, or facilitating combined functionality such as simultaneous TOC and conductivity. For example, the Auto reagent feature on the M9 automatically establishes optimal flow rates for each sample, and the innovative Super iOS (Integrated On-Line Sampling System) for the Sievers 500 automates validation and system suitability testing. These features that automate aspects of TOC analysis make Sievers Analyzers easy to use and increase efficiency. Ultimately, this simplifies water testing and cleaning validation, allowing customers more time to focus on business growth opportunities.

When it comes to online deployment of TOC, leveraging the proprietary Sievers membrane conductometric technology enables the Process Analytical Technology (PAT) transition to be seamless from the lab to at-line or online deployment with like-for-like technology. Online monitoring maximizes efficiency and offers great opportunity for automation.

Sievers Lean Lab with the M9 streamlines compendia testing in the lab with simultaneous measurement of TOC and conductivity in a singe vial. By combining functionality, customers can save time, eliminate sample-handling issues, and minimize potential failures. Using the M9 for Stage 1 conductivity testing also enables automated instrument verification and sample data collection.

What advantages come from measuring both TOC and conductivity with the same instrument?

For compendia assurance of water quality, attributes such as TOC and conductivity can be tested simultaneously for USP <643> and <645> with Sievers M9 Analyzers. Known as Sievers Lean Lab, simultaneous testing decreases timeconsuming labor and data handling in the lab.

Conductivity testing with Sievers Analyzers enables automated, Stage 1 conductivity testing in an electronic, secured database that is fully compliant with 21 CFR Part 11 as well as the latest data integrity guidance. These added benefits of sample integrity, data integrity, and automation cannot be achieved with a bench top meter and probe.

In addition to compliance testing, both TOC and conductivity are well-suited analytical methods for cleaning validation.

Are Sievers products compliant with Data Integrity guidelines?

With Sievers products and validation support you can be equally assured about your software and data as you are about your validated Sievers TOC Analyzer. Sievers M9 Analyzers and DataPro2 software are fully compliant with 21 CFR Part 11 and the latest data integrity guidelines from the FDA and EMA. Sievers DataPro2 and DataGuard software offer complete solutions for electronic signatures and Audit Trails. To ensure system security, DataGuard restricts access through administratively controlled user accounts and automatically performs authority checks to verify that an individual can perform specific functions. It ensures that each system user has a unique user ID/ password combination and offers the system administrator the ability to configure and enforce length and aging, login time-out, and different levels of access for user ID categories.

DataGuard automatically generates an audit trail containing a date/time stamp for all actions performed and identifies the unique user name associated with each action. The audit trail is a separate, secure electronic record, safe from modification (intentional or unintentional).

With limited regulations but ample guidance, customers are re-examining their electronic records and data management systems to ensure compliance with regulatory and industry guidance. SUEZ is proud to provide solutions that are fully compliant with 21 CFR Part 11 and FDA data integrity guidance.

Company Details: SUEZ 6060 Spine Road, Boulder, Colorado 80301, USA Telephone: +1 800 255 6964 www.sieversinstruments.com A variety of resources related to Sievers products and pharmaceutical applications are available at www.sieversinstruments.com.

Lukas Swanson is the Global Life Science Applications Engineer for the Sievers line of analytical instruments at SUEZ. Lukas has previously worked for Shimadzu Scientific as an HPLC Product Specialist and has a Master of Engineering Degree in Applied and Engineering Physics from Cornell University.

Advertorial www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

Apoferritin as a Nanocarrier

Its applications in medicine

Nanotechnology is impacting healthcare in a big way. Take ferritin, for example. It is naturally derived, and is a nano size protein which incorporates a protein cage for iron storage. Apoferritin is ferritin that is not combined with iron. Plenty of research has been conducted with apoferritin by encapsulation of therapeutic agents and imaging probes. The author will discuss several application of apoferritin as it is a promising drug delivery carrier in therapy.

Anchala I Kuruppu, University of Sri Jayawardenepura and University of Kelaniya

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I

n the recent years, Research & Development (R&D) in the area of nano-science and nanotechnology has increased rapidly. A nanometer (nm) is one millionth of a millimetre, and the prefix ‘nano’ comes from the ancient Greek word “dwarf.”

Nanomaterials commonly range from 1–100 nm and they could be natural, incidental, or manufactured material comprising particles, either in an unbound state, or in an aggregated state. Nanotechnology has shown a huge impact in healthcare. The convergence of nanotechnology and medicine has led to

RESEARCH & DEVELOPMENT

the field ‘nanomedicine’. This field has brought significant advances in diagnosis, treatment and prevention of diseases.

Nanomedicine combines the expertise of medicine, biology, chemistry, physics, mathematics, engineering, and computer science for the creation of devices for human application. Interestingly, a lot of the research in nanomedicine revolves in oncology, where much attention has been for targeting the disease. ‘Other than targeting there are numerous benefits of nanotherapeutics which includes improved efficacy, bioavailability, reduced toxicity, safety, enhanced solubility, greater dose response and personalisation compared with conventional medicines.’ Drug delivery is a technique which administers drugs to accomplish the therapeutic impact in humans and animals, and this process has been in the forefront of nanomedicine. A drug delivery system could be a device or a formulation that introduces a therapeutic substance into the body and improves its efficacy and safety by controlling the rate, time and place of release of drugs in the body. For the effective therapeutic delivery of pharmaceuticals, drug delivery systems comprise carrier systems. From the beginning of medical application systems, many drugs have been administered through various conventional drug delivery forms such as tablets, capsules, solutions, injectables, powders, lotions, creams, pastes, suspensions.

These conventional dosage forms are yet being employed as major drug delivery dosage products. Though these conventional drug delivery systems are effective at releasing drugs to produce a high local concentration, their scope is limited to targeting tissues rather than individual cells. Nevertheless, these may not facilitate the optimal therapeutic responses. Thus, the requirement for delivering drugs to patients effectively with limited side effects has encouraged many pharmaceutical companies to engage in developing newer drug delivery systems. To date the principle types of particles used in drug delivery systems are composed of lipids, polymers and proteins. These systems have been used to deliver therapeutics

The two methods of encapsulation were the use of different pHs, and the use of an in situ procedure at pH 8.5 which resulted in a homogeneous aqueous solution.

efficiently by targeting the disease site.

It should be noted that biological barriers in humans and animals are a challenge to bring about the success of these drug delivery systems. The identification and understanding of the mechanisms of these barriers are important so that these devices/carriers can circumvent the environmental/biological constraints.

In the recent past, the use of proteinbased nanoparticles has grown rapidly in drug delivery. The architecture of most proteins is suitable for drug delivery as it has a hollow interior with a packed protein shell, which has a homogeneous size distribution. Current investigations have shown the potential of protein cages for delivering numerous therapeutics and imaging agents. They can also be used easily for targeting the disease site. The hollow core of the protein allows materials to be encapsulated within the enclosed shell and drug loading is commonly achieved by the assembly and disassembly of the protein cages in altered pH conditions. Then the release of the drug can be regulated by the pore size of the protein cage and the concentration difference between the interior and exterior of the protein cage. Further, the protein cages are usually stable in most physiological environments, offering protection to the encapsulated therapies. It is also an important fact that the surface area and also the interior cavities can be genetically and chemically modified without affecting the entire architecture of the protein, offering a lot of features such as precise targeting and imaging.

Furthermore, protein-based nanoparticles have properties such as being biocompatible, biodegradable, and being metabolisable. Therefore, protein nanoparticles can be used in various targeted therapies such as cancer therapy, and as vaccines.

One such example of proteins as drug delivery carriers is ferritin/apoferritin.

Ferritin is used to store iron, preventing accumulation of toxic levels in living organisms. When the iron atoms are removed from ferritin, apoferritin is formed. The apoferritin protein cage is composed of 24 subunits, which assemble into hollow cages consisting of an outer diameter of 12 nm and an inner diameter of 8 nm. The interior of apoferritin can accommodate up to a maximum of 4,500 iron atoms. Apoferritin has 14 channels which are formed at subunit intersections with diameters of 3–4 A° for exchanging their cargo. Eight of those channels are hydrophilic, while the remaining channels are hydrophobic, allowing transport of both hydrophilic and hydrophobic drugs, and imaging agents. As mentioned above, the disassembly and assembly of the apoferritin cage could be achieved by different pHs where encapsulation of drugs and imaging probes can be carried out. The mammalian apoferritin protein subunits are of two types, heavy and light chains of 21,000 Da and 19,000 Da respectively. The two classes of subunits share nearly identical homology.

Nevertheless, the subunits are expressed in different ratios depending upon the tissue type examined. Heavy and light subunits are shown to play different roles; for instance, the heavy chain is known to catalyse iron oxidation and also facilitates accumulation of iron while, the light subunit lacks ferroxidase activity but facilitates iron nucleation. Due to this structure of apoferritin it becomes a good platform for drug delivery. Below are some of the examples of experimental data where apoferritin is being used in medicine.

A previous study has shown that the anticancer drug gefitinib (an EGFR inhibitor given mostly for non-small cell lung cancer and certain breast cancers) www.pharmafocusasia.com

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noted that not just pH values, but also variables such as ionic concentration, protein concentration, that can increase the frequency of molecular collisions which can promote aggregation, and mechanical stress caused by processes such as mixing, filtration, dialysis can affect the encapsulation efficiency. They also found that the apoferritin protein was intact where the protein structure and charge remained unchanged even after encapsulation of the drug which is a useful property for a drug delivery system. Curtin et al, showed that apoferritin can be used to deliver therapeutic and imaging agents together. They showed that apoferritin loaded with curcumin, a polyphenolic substance endowed with antioxidant, antihyperlipidemic, antitumour and anti-inflammatory activity together with a magnetic resonance imaging contrast agent GdHPDO3A, significantly reduced thioacetamideinduced hepatic injury in mice where the drug delivery efficiency was evaluated by magnetic resonance imaging. â&#x20AC;&#x2DC;This method may help to evaluate in real-time the drug concentration in the target organ thereby providing a possibility to adapt the therapeutic protocol to patients.â&#x20AC;&#x2122; Another group of researchers have designed oxaliplatin-loaded apoferritin (oxaliplatin is a platinum-based chemotherapy drug given for colorectal cancer) conjugated with panitumumab AUTHOR BIO

when encapsulated within human heavy chain apoferritin allows pH-controlled sustained release of cargo. Interestingly the results demonstrated that drug encapsulation enhanced gefitinib activity in the HER2 over-expressing breast cancer cell line SKBR3 compared to gefitinib alone. Generally, the tumour micro environments exhibit lower extracellular pH than normal tissues while the intracellular pH of cells within normal and tumour cells is similar allowing pH controlled release of cargo. Further, the authors have stated that ferritin could be internalised by some tumour tissues, due to ferritin binding sites (transferrin receptors) and endocytosis of ferritin by neoplastic cells.

Ferritin receptors have shown potential value in the delivery of anticancer drugs into the brain by improving the bloodâ&#x20AC;&#x201C; brain barrier transportation, which makes apoferritin a suitable drug delivery system.

Ma-Ham et al, encapsulated the anticancer agent daunomycin (an anthracycline antibiotic drug that has been used for certain types of leukemia such as acute myeloid leukemia and acute lymphocytic leukemia) within apoferritin, to reduce toxicity of the drug. They found that the pharmaceutical properties of the antibiotic drug was not changed due to encapsulation and that it is a viable platform for the delivery of daunomycin to cancerous cells. A similar study encapsulated platinum based anticancer drugs cisplatin and carboplatin in apoferritin using two methods. Carboplatin is usually given for non-small cell lung cancer and ovarian cancer while cisplatin is given for a variety of cancers such as non-small cell lung cancer, ovarian, testicular, cervical, breast, bladder, head and neck and esophageal cancers.

The two methods of encapsulation were the use of different pHs, and the use of an in situ procedure at pH 8.5 which resulted in a homogeneous aqueous solution. By conducting a cell viability study the authors found that the pH method was less pronounced, which might be due to the amount of drugs encapsulated by this method being much less than the in situ method. However, it should be

(a human monoclonal antibody specific to the epidermal growth factor receptor, targeting metastatic colorectal cancer), to target cell lines expressing epidermal growth factor receptor. This design has released oxaliplatin and suppressed tumour cell growth efficiently together with greater accumulation of the drug in in vivo tumour models with high epidermal growth factor receptor expression. Li et al, encapsulated doxorubicin (a chemotherapy drug that belongs to the group of drugs that is called anthracyclines; and is given for bladder and breast cancers, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia), in apoferritin and the surface of apoferritin was modified with a gold nanoshell. This system illustrated high temperature responses for the photothermal effect, and also for the release of drug molecules from apoferritin.

The multi-stimuli responsive drug release system, which can achieve drug release in different conditions such as various pHs, and temperatures with high biocompatibility, may have a huge potential in biomedical applications. Overall, from the above examples it demonstrates that apoferritin is a promising nanoplatform for drug delivery especially compared with nanoplatforms made of artificial materials.

Also, in current research, different types of metals or small molecules have been encapsulated into apoferritin that results in conjugates that have shown promise in drug delivery and imaging especially in the oncology field. However, more research is warranted to understand the mechanism and dynamics of apoferritin and drug complexes for better release and targeting in order to make this a promising drug delivery carrier.

References are available at www.pharmafocusasia.com

Anchala Kuruppu obtained her PhD from the University of Nottingham, UK in cancer pharmacology. Kuruppu also has a MSc from the same university in oncology and she is a double degree holder in biology and information systems. In addition Kuruppu is a charted biologist from the royal society of biology, UK. Currently she works as a research fellow at the University of Sri Jayawardenepura and University of Kelaniya, Sri Lanka.

RESEARCH & DEVELOPMENT

www.pharmafocusasia.com

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MANUFACTURING

Drug Substance Scale-up Impacting successful outcome The scale-up process for moving products from preclinical to commercial scale manufacture presents several challenges and complexities. As the goals of medicinal and process chemists largely differ, it is essential for the process to be effectively managed in order to prevent minor errors impacting a successful outcome.

Anders Hรถgdin, Senior Sales Director, Recipharm

I

n moving a drug substance to commercial scale manufacture, chemists face many scalability and processing challenges. With the potential for minor errors to lead to huge failures, the process must be meticulously managed to ensure a positive outcome. As marked differences will unavoidably exist between the goals of the medicinal and process chemists involved, these should be understood at the initial stages of any project. Medicinal chemistry places emphasis on the diversity

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and flexibility of the synthetic route, while in process chemistry, a practical, safe and cost-effective process must be identified to synthesise a compound on a larger scale.

Anders Hรถgdin, PhD, Senior Sales Director at Recipharm, discusses how projects can be streamlined as they move from medicinal chemistry into a development chemistry environment and looks at the key considerations during both the medicinal and process chemistry stages.

MANUFACTURING

There is no substitution for experience when it comes to taking substances from pre-clinical to clinical and then to commercial scale. Processes applied by medicinal chemists can often lack effectiveness when they are performed on a bigger scale. Consequently, a synthesis proven in a lab can all too easily fail when it is transferred to a large-scale production environment.

These factors should be considered at the early stages of any scale-up project, with clear development steps laid out and responsibilities defined for all individuals involved. By doing this, the opportunity is afforded to troubleshoot potential problems before they occur which can greatly increase the chances of a project achieving its delivery date.

early clinical phases. This means that process chemists need to produce more material to perform the necessary in-vivo toxicology studies. Additionally, preparations need to be made for clinical stage GMP-material. Toxicology material will have a tested impurity profile and, further down the line, it will be beneficial to have the same profile for the material going into first-in-human studies.

Although there isnâ&#x20AC;&#x2122;t a need for a commercial process during the production of the first kg, having the end target in mind may make things easier later in the scale-up process.

However, as there is always the balance between time and cost the first scale up protocols may very well include compromises that will not find their way into later phases and the final process.

From research to development

Route scouting

Although Research and Development (R&D) are synonymous with each other, within an organisation they are often two very different departments that may not even be located within the same building, city or even country. Emerging pharma companies may only possess the research element, while larger pharma and Contract Development and Manufacturing Organisations (CDMOs) may offer both.

During the research stage, medicinal chemists are focused on whether a certain idea is feasible. They operate outside the regulated environment with emphasis placed on securing intellectual property (IP) rights and overcoming any challenges surrounding patent strategy.

Later stage development chemists are more concerned with the scale-up of procedures, and how drug substances can be effectively moved forward. Good Manufacturing Practice (GMP) is key and the strict regulatory environment dictates greater focus on quality and traceability. This is demonstrated through extensive documentation, Quality by Design (QbD) quality control and assurance (QC/QA) activities.

While the aim for medicinal chemists is quickly producing many different test substances, process chemists are producing larger amounts of one substance in a robust and repeatable way.

Overall yield is, therefore, typically of greater importance to a process chemist. In addition, medicinal chemists have free reign for selecting from any available raw materials. Comparatively, cost and material availability are more important factors to consider for process chemists. In addition, there is a stronger focus on the impurity profile. Medicinal chemists can usually wait to remove impurities until the last purification step.

For quality purposes, process chemists need full control of impurities throughout the entire process.

These differences demonstrate the complexity of the scale-up process and the potential challenges that need to be overcome.

Route scouting plays a fundamental role in identifying a safe, practical and cost-efficient process for the synthesis of a compound at large-scale. The existing chemistry route is first fully evaluated to identify if it offers the necessary scalability. Here, a number of questions should be asked.

For example: is the process safe to scale up? Are the raw materials available on a larger scale? Are they affordable?

Are there any patents on any reagents or procedures that would hinder commercialisation of the process? Are there any solid and stable intermediates? How are they isolated and purified? Are there any environmental aspects to consider?

To understand if there are any recognised alternative routes that can be targeted, a literature review will usually take place to generate a number of theoretically viable routes.

The route finally chosen after careful testing in the lab is determined by a combination of factors such as number of process steps, raw material availability, safety, impurity control, stability of intermediates etc. Although there is often a focus on shortening the length of the synthesis, in many cases the decision is determined by other factors with the overriding goal of saving time and costs.

That said, regulatory expectations may also dictate that a synthetic step should be added to have an appropriate number of GMP-steps in the process. Chemists may also be required to develop a stable intermediate during the synthesis and may add a salt forming step allowing for purification of the intermediate by crystallisation.

Challenges in transferring to large-scale production

Taking production from mg. to kg.

Candidate drug substances have often been produced in just a few grams, or sometimes less, prior to late preclinical and

A successful scale-up process

Throughout the development process, several parameters and activities are to be considered. Many of these are already taken into account during the route scouting. In continued work, QbD and Design of Experiments (DoE) will play an integral part. Also, since control of impurities is of such a central importance another critical prerequisite for successful up scaling is to make sure that the analytical methods are properly developed at a very early stage. www.pharmafocusasia.com

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Control of potentially mutagenic impurities plays an increasingly important role when moving from early development into commercial stages and the awareness of these already at an early stage of development may turn out to be beneficial in the end.

Regardless of final dosage form chosen, API production for the clinical development (and commercial) stage also necessitates solid state development for isolation of both solid/stable intermediates and API, but also for control of polymorphic forms, solvates, etc., which can have a critical role for the downstream formulation development of solid dosage forms.

Ensuring quality

Understanding quality requirements, drug safety and GMP is crucial. Globally, regulators such as the FDA and EMA provide guidelines on how these should be addressed during the production of clinical scale drug substances. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss and agree on the scientific and technical aspects of drug

AUTHOR BIO Anders Hรถgdin joined Recipharm in 2015 to head the business development and sales team within development services in Europe. With a wealth of experience working within the industry, he also holds an MSc in chemistry and a PhD in organic chemistry.

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registration. Their regularly updated guidance documents provide the framework for all activities during the course of a substance development programme, describing everything from control of manufacturing, to how to set specifications, acceptable levels of impurities, Quality by design etc. Although these guidance documents provide a very comprehensive framework and support, the need for extensive experience and expertise on interpreting and executing these guidelines is vital.

Final thought

It is incredibly rare that the medicinal chemistry route for a drug substance goes on to become the final production route.

There is simply much more to the process of scaling a drug substance from mg to kg. than greater quantities of materials and larger reaction vessels. Development of an efficient process early on in a project, the avoidance of shortcuts, the outlining of clear responsibilities for all involved, as well as a collaborative mindset between all disciplines is essential. Long term, route scouting will save projects both time and money, while focusing attention on the right analytical methods will control impurities and serve to improve the safety of a substance.

FIRST LINE: DATWYLER’S MOST ADVANCED MANUFACTURING STANDARD Datwyler’s First Line manufacturing standard is the most advanced manufacturing concept in the industry. Designed to provide our customers with the highest level of quality and

www.sealing.datwyler.com

safety, First Line is Datwyler’s solution to the ever-changing needs of the biotech and pharmaceutical markets. With First Line, we can help improve patients’ lives.

OMNI FLEX COATING Datwyler’s revolutionary technology for sensitive drug packaging The prevalence of biologic and biosimilar drugs is increasing in the pharmaceutical market. Due to the sensitivity of these drugs during storage, their complexity during administration, and specific packaging requirements, they demand high standards of packaging performance.

These increasing demands mean that the requirements for drug packaging and elastomer components are evolving. As a leading industrialisation partner in the healthcare market, Datwyler is consistently striving to exceed these requirements by making improvements in the field of parenteral packaging solutions, specifically with regards to their Omni Flex fluoropolymer coating.

application of fluoropolymer coatings on top of rubber components. Datwyler’s Omni Flex was introduced in 1995 and has been the fastest growing product line for Datwyler ever since.

The uniqueness of Omni Flex begins with the way it is applied: it is the only spray-coated fluoropolymer coating that covers the total surface of the rubber component. Once the thin polymer layer is applied through a proprietary spray-coating technology, the products

A unique fluoropolymer application: 360° coverage through spray coating

The primary goal in rubber formulation is drug product compatibility, especially in the case of highly sensitive drugs. This is achieved by reducing the amount of extractables and leachables for every new generation of rubber formulation for primary parenteral packaging components. In the 90’s, the disruptive breakthrough in this objective was the

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Figure 1 The above graph shows that Omni Flex coated products produce significantly less extractables than their uncoated counterparts.

Image 2 All Omni Flex coated products are manufactured in facilities that operate under Datwylerâ&#x20AC;&#x2122;s First Line standard.

are further heat-treated to ensure a perfect adhesion to the rubber substrate and the coating itself turns into a pinhole-free, smooth, continuous fluoropolymer film. The Omni Flex coating provides a superior chemical inertness by acting as a barrier between the drug product and the rubber itself. Thus, the coating ensures the highest compatibility, which is especially important for sensitive drug formulations. This feature by itself explains the high success rate for Datwylerâ&#x20AC;&#x2122;s coated portfolio.

Eliminating the need for siliconisation through Omni Flex coating technology

The scrutiny of any kind of particles in injectable drugs continues to grow and remains today the number one concern for many pharma companies and regulatory bodies. By using Omni Flex coated components, additional siliconisation during the final treatment, which is a known cause of subvisible particles, can be avoided. Traditionally, rubber closures are prone to stickiness and, therefore,

silicone oil is added as a surface treatment during one of the washing steps. The silicone oil prevents clumping of bulkpackaged closures, helps with processing the components on filling lines, and, in the case of plungers, silicone oil lubrication helps to control break loose forces.

Unfortunately, small silicone oil droplets may migrate from the stopper surface into the drug product after contact. This is even more likely when surfactants like polysorbate are used. Those hydrophobic oil droplets are of subvisible size and, by

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radius, the gliding behavior in prefilled syringes was further balanced without posing a risk to container closure integrity. The spray coating process offers design flexibility and any customised product design can potentially be coated, as long as it follows certain design rules

determined by the Datwyler R&D Center of Excellence. Today, practically all standard available ISO-based component designs are available with the Omni Flex coating, ranging from 32mm infusion stoppers to 20mm and 13mm injection and lyophilisation stoppers,

Image 1 Analytical tests, such as Finite Element Analysis (FEA), have allowed Datwyler to continually improve its product line to meet the ever-changing needs of the pharmaceutical industry. Pictured above: Datwylerâ&#x20AC;&#x2122;s re-designed 1ml long plunger.

analytical techniques, typically counted as contribution to the total amount of subvisible particle load. The same is true for visible particles. Rubber particles, for example, are mainly generated by abrasion of the trim edge during handling. These particles are no longer an issue since the trim edge is completely covered by the Omni Flex coating.

Figure 2 The above graphs show the break loose and glide force consistency for a variety of sterilisation methods.

Datwyler Omni Flex coated components show excellent machinability and performance

A prerequisite to drug packaging success is the smooth functionality of a rubber closure, be it a vial stopper or a syringe plunger. In 2008, Datwyler became the first in the industry to launch an optimised design for the 1ml long and 1-3ml ISO-based plunger designs. Including a recessed trim edge and reducing the second and third rill in diameter and

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Figure 3 The above graphs show the He Leak test results of an Omni Flex coated stopper after steam and gamma sterilisation, respectively, in comparison to the Kirsch criterion for He Leak testing. As you can see, for both methods, the Omni Flex coated stopper is well below the requirement.

In conclusion, over its 25 years of existence, Omni Flex has become more than just a coated component. It has grown into a complete product platform, as an answer to the challenges posed by packaging highly sensitive drugs. With its Omni Flex technology, Datwyler plays a vital role in creating a safer environment and continues its mission to improve patients’ lives.

AUTHOR BIO

respectively. To complete the platform, 0.5ml, 1ml long, and 1-3ml plunger designs are also available.

Finite Element Analysis (FEA) is applied to Omni Flex coated plungers to optimise the design and verify the response on gliding effect and container closure integrity. This model is a numerical method; the area to be investigated, e.g. a sealing component, is divided into a finite number of elements whose physical behavior has already been established.

The behavior of the individual elements can then be efficiently calculated using appropriate algorithms.

From the results, the behavior of the entire product is derived, and modification and optimisation solutions are proposed.

Omni Flex coated plungers are known for their consistency in glide force without any risk of shattering. In absolute value, the break loose and glide force is in a range similar to classic siliconised, uncoated plunger stoppers, for both steam and gamma irradiation sterilisation. Additionally, Omni Flex coated plungers can be processed by both insertion tube and vacuum placement, although the latter is the preferred method as it produces the least amount of deformation of the plunger itself.

After his Masters in Polymer Chemistry at the University of Louvain, Belgium, Bram Jongen acquired a Ph.D. in Water Soluble Polymers used for advanced drug administration.

Bram started as Technical Support Manager for Datwyler about 14 years ago, supporting customers in a vast area, from Western European countries to countries like India, Korea, and South Africa. Thereafter, he headed the Global Product Introduction & Support team, a global team of highly experienced and educated people, having each their own expertise in the world of pharmaceutical closures.

Bram himself acquired profound Extractables & Leachables expertise. His team managed customer projects of technical nature and supported Datwyler’s product and portfolio management. Since end of 2012, he has been acting as Head of R&D, leading a group that focuses on developing new rubber and new coating materials.

Proven technology offers opportunities for the future

In a world where self-administration and smart devices call for novel product designs and, hence, customised rubber closure designs, Omni Flex creates an opportunity to have such components in a fluoropolymer coated version. One important differentiator for Omni Flex is its resistance to gamma irradiation: both the rubber formulation itself, as well as, the fluoropolymer coating are composed in such a way that they can absorb and dissipate the irradiation energy without significant adverse effects on the properties. Therefore, Omni Flex is offered in both Ready-for-Sterilisation (RFS) and Ready-to-Use (RTU) configurations. In both instances, double laminated bags are used to properly pack the Omni Flex products and vacuum is applied between both bags. The latter serves as a visual indicator to check the bag integrity at the point of use.

Omni Flex, a proven technology for almost 25 years, has production lines available in all of Datwyler’s First Line plants in the US, Europe, and Asia, with all plants producing the same quality products worldwide. With all Omni Flex products produced under Datwyler’s highest-quality manufacturing standard, First Line, they can offer some of the lowest particle levels in the industry. Finally, local proximity is an advantage, as long storage and transport times can be avoided.

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Artificial Intelligence

Bridging the pharma sector Artificial Intelligence (AI) has provoked a digital revolution. This next generation technology with advanced capabilities is bridging the Pharmaceutical industry by designing new algorithms and tools for drug discovery. AI has empowered researchers in healthcare with drug repurposing, translational medicines, and biomarkers development. There is a need to showcase the innovation of AI in healthcare as it will help to solve real-world problems more competently.

Surabhi Johari, Institute of Management Sciences, School of Biosciences

T

here's a need consolidate natural information with computational strategies for extricating important and fitting qualities from the thousands of qualities measured. Artificial Intelligence (AI) has been connected within the sedate disclosure field for decades. Today, conventional machinelearning modelling has advanced into an assortment of unused strategies, such as combi-QSAR and crossover QSAR, and remains a prevalent approach to consider different drug-related themes. There are different drugs on the showcase and/or in clinical trials that have been outlined by computational strategies. As a recently created machine insights method, AI is been investigated as potential for utilise within the unused huge information time of sedate disclosure. With more information getting to be accessible and unused approaches being created, AI will enable a major Computer-Aided 42

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Drug Design (CADD) approach within the close future.

Pharmacologists have demonstrated the classification of various drugs to therapeutic categories solely based on their transcriptional profiles by Deep Neural Networks (DNN) trained on large data sets of transcription response. The LINCS Project's perturbation samples of 678 drugs across A549, MCF-7, and PC-3 cell lines are used here that are linked to 12 MeSH-derived therapeutic usage categories. To train the DNN, transcriptomic data and transcriptomic data are organized using a scoring algorithm for pathway activation.

The DNN achieved high classification accuracy and convincingly outperformed the Support Vector Machine (SVM) model in both pathway and gene level classification on every multi-class classification issue. Models based on path level data, however, performed much better.

A profound learning neural net prepared on transcriptomic information to recognise pharmacological properties of numerous drugs over diverse natural frameworks and conditions is being illustrated for the first time. Here utilising profound neural net perplexity frameworks for medicate repositioning are also proposed. This work could be a verification of guideline for applying profound learning to medicate revelation and advancement.

The ChEMBL database, the most widely used database by chemists, has compared the performance of deep learning to seven target prediction methods, including two commercial predictors, three predictors deployed by pharma, and machine learning methods that could scale to the Kaggle dataset. ChEMBL has 13 million compound descriptors, 1.3 million compounds, and 5,000 drug targets, compared to the Kaggle data-

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set with 11,000 descriptors, 164,000 compounds, and 15 drug targets. Deep learning outperforms all other methods with respect to the area under ROC curve and was significantly better than all commercial products. Deep learning surpasses the threshold to make virtual compound screening possible and has the potential to become a standard tool in industrial drug design.

Studies have shown how the problem of predicting molecular properties can be solved by recursive neural network approaches. However, molecules are

typically described by undirected cyclic graphs whereas the recursive approaches typically use directed acyclic graphs. Thus, by considering an ensemble of recursive neural networks associated with all possible vertex-centred acyclic orientations of the molecular graph, methods are being developed to address this discrepancy.

One advantage of this outlook is that it relies only nominally on the identification of suitable molecular descriptors because suitable characterisations are learned automatically from the data. Several variants of this approach are applied to the problem of predicting aqueous solubility and tested on four benchmark data sets. Experimental results show that according to several evaluation metrics the performance of the deep learning methods matches or exceed the performance of other state-of-the-art methods and expose the fundamental limitations arising from training sets that are too noisy or too small. Through the ChemDB portal a Web-based predictor, AquaSol, is available online together with additional material.

The work of Ramsundar B. et al.; 2015 shows the collection of large amounts of publicly available data to create a dataset of almost 40 million measurements across over 200 biological targets to train the multi-task neural

architectures at scale. Their investigation shows several aspects of the multitask framework by performing a series of empirical studies and obtain some interesting results: Massive multitask networks achieve significantly better predictive accuracies than single-task methods The predictive power of multitask networks improves as additional tasks and data are added Total data volume and total number of tasks both contribute significantly to multitask enhancement.

Multitask networks provide limited transferability to non-training tasks. These results underline the need for more data sharing and algorithmic innovation to speed up the process of drug discovery.

One of the bottlenecks in biopharmaceutical innovation is biological screening.

Virtual screening has been an attractive solution. Molecular Dynamics Based Virtual Screening MDVS can significantly improve the performance of a virtual screening campaign. Reducing the high performance computing HPC cost and increasing the computational speed will significantly accelerate biomedical innovation. There are no disease-modifying drugs against, for example, Alzheimerâ&#x20AC;&#x2122;s, osteoarthritis, metabolic syndromes, and important cancers; the MDVS campaigns described in this article may shorten the time for preclinical studies for diseasemodifying drugs and anti-pandemic drugs. MDVS involves validating the interactions of thousands or millions of individual compounds against a drug target. The task is parallelisable by dividing a great number of compound-protein complexes into smaller computational packages, which are distributed to GPU-CPU units for calculations. MDVS

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With more information getting to be accessible and unused approaches being created, AI will enable a major Computer-Aided Drug Design (CADD) approach within the close future.

which specific drugs can be prescribed to furnish a positive patient outcome.

In 2017, researchers from North Carolina State University established that ML techniques and molecular dynamics simulations could be merged to create precise computer prediction models.

Known as ‘hyperpredictive’ models, researchers claimed that these could be used to predict whether a new chemical compound had the properties of being a suitable drug candidate. As the drug development process tends to be costly and time consuming, this unique combination of molecular dynamics and ML acted as a way to degenerate the number of chemical compounds that could be probable drug candidates. Hence, researchers used computer models that could predict communication of chemical compound with biological target of interest. When an attempt to narrow a field of 200 analogues down to 10 is being made, which is more commonly the case in drug development, the modelling technique must be extremely accurate.

The current techniques are not reliable enough.

AUTHOR BIO

does not a require massive memory but demands only greater HPC power. Many supercomputers adopt GPUs as coprocessors to reduce manufacturing costs and increase calculation speed. However, the architecture of combining CPUs and GPUs is one of the key factors in computing performance. Another key factor is the application programme.

Today, more and more MD simulation programmes offer their parallel or GPU versions, but they have different ways of exploiting HPC power. Consequently, their performances vary. HPC technology may continue to obey Moore’s law, but the updating of application programmes can be a bottleneck. Therefore, it is time to invest more in developing HPC-based application programs while we are building a supercomputer with a higher Linpack Benchmark score.

Today, HPC is a vital part of the research on cancer, but it is at a difficult stage with requirements shifting from simply increasing compute capability in flops to aggregating multiple databases, improving memory bandwidth, using diverse hardware, and enhancing software efficiency. The emergence of rapid and relatively economical genome sequencing has provided scientists and caregivers the ability to study the links between genes and cancer at the level of individual patients, and to use massive genomics and other biological databases to better apprehend patient genotypes and their inferences for disease and treatment.

The National Cancer Institute (NCI) is also delivering more than 20 types of data sources that feed into a neural network model, which then constructs a relationship between drug dosages and patient response. The data sources incorporate information on genetic sequence, gene expression profiles, proteomics, and metabolomics. The NCI also has a large historical database of medical images, for which the neural network can build a relationship with molecular profiles data of cancer, which go back 10 to 15 years.

The objective is to predict a molecular profile using medical image data, upon

They have also demonstrated how a specific compound moves in the binding pocket of a protein into prediction models based on ML. The current method involves the use of two-dimensional structure of molecules for drug discovery but in reality, 3D structures have proved to be more effective. Computing and technological advances have allowed researchers to simulate complex data quite easily, which otherwise would have taken months.

Regardless of how you look at it, AI will unquestionably change each part of our lives. Importantly, administrators over the pharma business are seeing approaches to use AI in their line of business, including human services (or the biotech business to be exact). What's more, major pharmaceutical players are as of now getting their feet wet in the realm of AI and man-made reasoning.

Truth be told, the majority of the 10 alleged Big Pharma organisations (in particular Novartis, Roche, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Sanofi, Abbvie, Bristol-Myers Squibb and Johnson & Johnson) have either explicitly teamed up with or gained Artificial Intelligence advancements to exploit the open doors AI conveys to the table.

References ChemDB portal [http://cdb.ics.uci.edu/] Artificial Intelligence swarms drug discovery.Is India catching up too? https://analyticsindiamag.com/artificialintelligence-swarms-drug-discoveryindia-catching/ Top 5 AI Companies In India Creating Solutions For Pharma Sector https:// analyticsindiamag.com/top-5-ai-companies-inindia-creating-solutions-forpharma-sector/

Surabhi Johari is a Professor in the Institute of Management Sciences at Delhi NCR. She is a member of ABPIO Bioinformatics Platforms. The focus of her research is on applying bioinformatics applications to pharmacology, gene of interest, proteins. She found a home in academia in the intersection of Microbiologists and Medicine.

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COVER STORY

DIGITAL TECHNOLOGY IN PHARMA Ripe for disruption

Digital technology is transforming the life sciences sector: from Artificial Intelligence (AI) mining compound libraries for drug discovery, and software and electroceuticals as therapeutic solutions, to sensors in chips monitoring adherence and absorption, this disruption will only accelerate.

Lydia Torne, Managing Associate, Simmons & Simmons LLP

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W

hile the life sciences sector has incrementally adopted digital technologies over the years, the rate of digital transformation over the next five years looks to be unprecedented.

Collaborations and acquisitions in the pursuit of digital transformation have accelerated significantly. In 2018, US$9.5 billion was invested in the digital health sector over 698 deals. From the FDA approval of Otsuka’s sensor embedded drug Abilify Mycite and the approval of Pear Therapeutics’ app for the treatment of opioid abuse, through to Takeda’s partnership with Emulate

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Inc for the use of organs on chips for drug discovery and development, every aspect of the pharmaceutical sector is ripe for digital disruption.

Areas of particular interest for transformation include: (i) the drug discovery and development phase; (ii) interactions with healthcare professionals and patients; and (iii) complementary or standalone therapeutic software treatments.

Drug Discovery and Development Phase

Traditional methods of drug discovery and development are expected to last ten years and cost more than US$2 billion.

However, the use of AI, organs on chips, apps and wearables could significantly reduce these timescales and costs.

AI is already being deployed by a number of pharmaceutical companies for a whole range of purposes, including drug discovery. The ability to mine huge volumes of public data, as well as significant private data sets (e.g., compound libraries and clinical trial data), represents an unprecedented opportunity to identify potential targets, drug candidates or even new indications for existing drugs, faster and more costeffectively. These newly identified targets or candidates can then be developed and tested, with the data this generates being processed by the AI algorithm to further refine its learning. Pharmaceutical companies including Astellas, Mitsubishi Tanabe Pharma, Santen, Takeda, and Sumitomo Dainippon Pharma have all announced various collaborations with AI businesses for drug discovery and development. The success stories for using AI are compelling: the Barrow Neurological Institute successfully used IBM Watson to analyse all RNA-binding proteins in the human genome, genomic data and published materials, and identified an additional five amyotrophic lateral sclerosis RNA-binding proteins which were previously unlinked to amyotrophic lateral sclerosis.

While the development of organs-onchips is nascent, if successful, they offer an entirely new approach to clinical trials.

California-based company, Emulate Inc, has developed a liver chip, lung chip and intestine chip and is currently performing studies with the FDA to assess the use of organs-on-chips for toxicology studies.

The possibility of replacing animal trials, and even human trials in due course, with organs on chips could transform the drug development process. Likewise, the use of AI to mine patient data to identify optimal trial subjects as well as trial subject ‘matching’ apps (where interested trial subjects can be matched to potential trials and apply via an app), look set to materially alter the trial recruitment process. The use of apps, wearables and remote devices in trials offers the potential for continuous monitoring of, and increased interaction with, trial subjects with limited interference in the trial subjects day-to-day life, which may improve trial recruitment and retention, as well as the quality of data generated.

Interactions with Healthcare Professionals and Patients

Digitalisation also allows for pharmaceutical companies to interact with Healthcare Professionals (HCPs) and patients in new ways. This might include electronic ‘pop up’ reminders for HCPs, new ways of imparting information to patients, or complementary apps to support patients

A recent study by Simmons & Simmons LLP states that respondents in AsiaPacific were most likely to say digital health was a strategic priority and that they would be investing more in digital health over the next three years.

receiving certain therapeutic treatments.

Digital transformation could disrupt drug detailing which has not seen significant change in approach for many years.

Indeed this digital approach reflects a new generation of HCPs with limited time for detailing meetings and, in some cases, decreasing interest in faceto-face interactions with the sales force.

At the same time, this type of continual remote patient-support offers a new way to develop patient-centric care, while also potentially reducing the need for acute care intervention (e.g., by offering remote monitoring or support, or improving medication adherence) which will improve the patient’s quality of life as well as reducing costs for healthcare systems.

Therapeutic Software Solutions

In addition to transforming how drug products are developed and administered, digital health has the potential to see traditional drug products replaced with therapeutic software solutions.

While historically these types of digital solutions have been focussed on wellness with diet apps, fitness wearables and relaxation apps, or helping patients to manage chronic conditions with symptom journals and trackers, this is now shifting towards true therapeutic solutions. Examples include Pear Therapeutics’ app for the treatment of opioid abuse and virtual reality with bio-data-driven applications to treat acute and chronic pain. Of particular interest is the treatment of mental health diseases, with software platforms offering AI-driven triage facilities, coupled with treatment techniques and access to human physicians interacting via messaging or telephone, at any time.

Challenges

A recent study performed by the international law firm, Simmons & Simmons LLP, asked more than 400 international c-suite executives across the life sciences and technology sector about the opportunities and challenges presented by digital health. Notably 71 per cent of all www.pharmafocusasia.com

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respondents stated that digital health will transform patient care, with 63 per cent putting digital transformation at the top of its agenda. While the US has long been the digital health front runner, the study shows that Asia-Pacific could soon catch up. Respondents in Asia-Pacific were most likely to say digital health was a strategic priority and that they would be investing more in digital health over the next three years. However, only 11 per cent of all digital health opportunities that come to an organisations’ attention enter detailed due diligence and just a third of those are executed. Life sciences respondents indicated that half of their digital health collaborations in the past three years did not meet their stated objectives. Perhaps unsurprisingly, respondents indicated that two of the main challenges for digital

transformation projects result from data protection and life sciences regulation.

Life Sciences Regulation

In addition to ensuring data privacy, businesses will need to ensure that their new ways of interacting with HCPs and patients, as well as new products, comply with applicable life sciences regulations.

For example, in the EU (and the UK) promotion of prescription-only medicines to the public is prohibited and, therefore, businesses will need to ensure that any complementary apps supporting patients do not promote the related (or any other) prescription-only medicine.

Equally, consideration should be given to whether any automated interaction with HCPs constitutes promotion such that it will need to comply with

applicable advertising laws or interferes with any post-market pharmacovigilance obligations.

Under the EU Medical Device Regulation 2017/745, software which has a medical purpose may qualify, and be regulated as, medical devices in their own right (sometimes referred to as ‘software as a medical device’ or ‘SaMD’). Businesses will, therefore, need to carefully consider the purpose and functionality of software it develops as well as the claims made about it, in order to determine whether or not it would qualify as a medical device. If so, then consideration should be given to the classification of the device. Previously, in the EU, most SaMD was classified as a Class I device which is subject to a relatively straight-forward market access pathway involving self-certification of

Data Protection Most digital transformation relies on the mining of vast amounts of sensitive personal data (or ‘special category data’), i.e., “personal data revealing racial or ethnic origin… the processing of genetic data…data concerning health…”.

Consequently, the control and processing of identifiable sensitive personal data will be subject to strict data protection laws such as the EU’s General Data Protection Regulation (GDPR), which will need to be complied with.

The GDPR (which came into force on 25 May 2018 and applies both to arrangements entered into before and after that date) strengthens existing EU data protection obligations and introduces new requirements. Importantly, it has given significant strength to the sanctions which may be imposed by the data protection authorities, namely, fines of up to €20 million or 4 per cent of global annual turnover (whichever is higher) for the most serious breaches.

The GDPR implements a number of changes, including requiring data controllers to factor in and plan for data protection from the outset (‘privacy by design and default’) as well as perform privacy impact assessments prior to processing to ensure the necessity and proportionality of the processing of the data, and that potential risks for data subjects are mitigated. Other points to consider are: Consent: Often consent is the only statutory basis on which identifiable sensitive personal data can be processed.

In such cases, the consent must be explicit, unambiguous and distinct. However, there are often difficulties with consent:

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• consent must be given for each data processing procedure performed (rather than a general consent). However, it may be difficult to predict from the outset what these different procedures and purposes might be e.g., in the future the business may wish to mine the data for a specific (or unknown) purpose • consent may be withdrawn by the data subject at any time after which no further processing of this data is permitted. It will therefore be important to ensure that such personal data can be segregated from any other data for prospective processing.

Pseudonymisation: Importantly the pseudonymisation of data (i.e., “the processing of personal data in such a manner that the personal data can no longer be attributed to a specific data subject without the use of additional information”) does not constitute anonymised data and, therefore, the requirements of the EU GDPR continue to apply to pseudonymised data. It is very difficult to truly anonymise data to the level required by the GDPR and, therefore, businesses should be cautious before determining that GDPR would not apply Right to be forgotten: A data subject may request to be ‘forgotten’ (i.e. to have all data held about that data subject deleted) if certain circumstances apply. In such cases, the business must ‘without undue delay’ erase all data related to that individual. The business should factor its compliance with such an obligation into any data collection model.

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the deviceâ&#x20AC;&#x2122;s compliance. However, increasingly SaMD is being accorded a higher classification which requires a more involved market access pathway including assessment by a regulated third party (â&#x20AC;&#x2DC;notified bodyâ&#x20AC;&#x2122;). For example, apps focussed on the treatment of acute mental health conditions to prevent suicide, could have very serious effects if defective and therefore may be subject to a higher classification. Businesses should also be mindful about how classification might change with revised iterations of the software. If a software solution does qualify as a medical device, then, not only would the business need to comply with market access requirements, but also extensive post-market obligations regarding traceability, supply chain management/visibility, adverse event monitoring and reporting and advertising.

With a 32 per cent increase in investment in digital health in 2018 compared to 2017, digital health looks likely to go from strength to strength. However, in many cases these developments can only be achieved through collaboration between pharma businesses and new and incumbent tech businesses. In doing so, pharma will need to navigate a myriad of

legal and cultural issues in order to realise its digital transformation including IP ownership, regulatory compliance, product liability, data protection and cyber security issues.

References are available at www.pharmafocusaia.com

AUTHOR BIO Lydia Torne is a Managing Associate at international law firm Simmons & Simmons LLP. Lydia specialises in intellectual property transactions in the life sciences sector, in particular licensing and collaborations in digital health. Lydia also advises on regulatory compliance issues including product classification, market access, promotion and supply chain management.

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BIG DATA AND ARTIFICIAL INTELLIGENCE IN PHARMACEUTICAL MANUFACTURING Emerging technologies can lower costs, speed up production and improve research and development Pharmaceutical companies have heightened concerns about traceability, product quality, and process validation. Companies are embracing big data and remote storage more readily, in order to stay ahead of innovation and more easily comply with regulations.

Sean Riley, Sr. Director, Media and Industry Communications, PMMI the Association for Packaging and Processing Technologies

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illions of dollars are invested every year into the discovery and development of new medicines, but it usually takes 10-15 years for a drug or vaccine to evolve from inception to release. Manufacturers invest a tremendous amount of capital long before seeing any return, which means pharmaceutical companies must allocate a high per centage of the budget to R&D. The fail rate for clinical trials is 92 per cent, and drug companies spend an average of US$2.6 billion developing a single drug.

When a pharmaceutical company invests in Research & Development (R&D), it screens 5,000-10,000 chemical or biological compounds to find www.pharmafocusasia.com

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one that exhibits potential for treating new or existing conditions, according to the 2018 Pharmaceutical Packaging and Processing White Paper, produced

by PMMI, the Association for Packaging and Processing Technologies. There is also risk associated with investing in R&D for a drug if it fails or does not meet regulatory approval.

Using big data to design clinical trials better and predict outcomes can make it commercially feasible to develop drugs for smaller patient populations.

Pharmaceutical companies are looking to big data to reduce costs in research and development and manufacturing.

With the explosion of health-related data in recent years, the market for artificial intelligence in drug development, valued at US$200 million in 2015, ballooned to US$700 million in 2018 and is predicted to appreciate more than US$5 billion in 2024, according to a report by big data analytics. Artificial Intelligence (AI) and big data have the potential to lower the cost and time of drug trials, to better determine patient outcomes with established drugs and to better design new drugs. Computer software and algorithms can provide better analytics before and during the manufacturing processes and stimulate insights to fuel better decisions in the pharmaceutical industry.

Pharmaceutical manufacturers collect data on patient responses to drugs during the clinical trial process and using that data with AI, will be able to reverse engineer which aspects of a patient sub population are associated with responses to drugs.

AI can also be used to predict protein interactions and better drug design, a practice called insilico medicine. For example, researchers at Carnegie Mellon University were able to better predict clinical outcomes by using algorithms to virtually stimulate how changes in drug structure would interact with different proteins and receptors. Such a process is much more cost-effective than the traditional trial and error on a lab bench.

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In another example, researchers at the University of Toronto applied insilico methods to find drugs that interacted with proteins associated with the Ebola virus. Using an algorithm that mapped the virus to predict molecules that could potentially bind to these proteins, they were able to identify solutions that might have been overlooked otherwise.

Data for Regulation

Complexities abound in the pharmaceutical industry. Entry not only requires a high initial capital investment, but there are rigorous regulatory controls that demand adherence. The result is a challenging sector to thrive in, which promotes large multinationals that have the resources to meet financial and regulatory requirements.

In particular, traceability legislation established to stem the threats of counterfeiting and grey market drugs is a present market effector, driving rapid growth in the labelling, coding and decorating machinery market.

In North America, the deadlines imposed for meeting the Drug Quality

With the explosion of health-related data in recent years, the market for artificial intelligence in drug development, valued at US$200 million in 2015, ballooned to US$700 million in 2018 and is predicted to appreciate more than US$5 billion in 2024, according to a report by big data analytics.

and Security Act (DQSA) of 2013 will now come into force in 2018 with later deadlines for re-packagers and wholesalers. The regulation requires a transaction document and serialisation of all prescription products, enabling the electronic transfer of specified transaction information and complete supply chain history.

Many counterfeit drugs have originated in China, the largest of the ‘pharmerging’ countries. To combat piracy, it initiated a gradual implementation of its Electronic Drug Monitoring Network as part of the China Food and Drug Administration’s (CFDA) plans to enable traceability of all drug products throughout the supply chain. Serial numbers were to be assigned centrally by the government, requiring reporting of all transactions, from manufacturing to dispensing. The legislation required all drug manufacturers, both domestic and foreign, to be using the network by the end of 2015. Within a few months, however, the law was unceremoniously shelved, confusing pharmaceutical manufacturers.

In July 2016, the CFDA released an update alluding to future serialisation requirements. Possible revisions include alignment with serialisation standards in other regions such as 2D barcodes used in the US and Europe and the ability for companies to generate their own codes instead of having them generated centrally by the government.

The most substantial legislative uncertainties for the global drug industry lie with President Trump’s pledges to bring down US drug prices. This potential for changing healthcare legislation would have a definite but uncertain impact on the pharmaceuticals market, as it calls for draft legislation allowing the US Department of Health and Human Services to negotiate drug prices for Medicare. The proposed legislation is highly controversial, but its details and the impact it may have are unknown.

Regardless, in the last few years, the U.S. Food and Drug Administration (FDA) has encouraged companies

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toward continuous manufacturing and away from the step-by-step approach of batch processing. By continuously monitoring manufacturing processes and collecting feedback, pharmaceutical companies can monitor factors like temperature and moisture change, therefore reducing variability in the final product and patient outcomes, a method called Process Analytical Technology (PAT).

Continuously testing drugs through the production process using PAT is more efficient and cost-effective than batch testing, mainly when synthesising biological proteins at millions of dollars per batch. By better monitoring pharmaceutical manufacturing process operations, we can continually foresee performance and reduce variability in clinical performance. Applying AI to performance and feedback response data generated with PAT can be used not just to control manufacturing processes, but to improve them through automated machine learning.

Pharmaceutical companies are automating in two major areas as the FDA mandates electronic submissions: • The evolution from batch-based production to true continuous production.

• The collection, management, and utilisation of data.

Batch-based processing will be phased out, eventually replaced with continuous production, with quality checks at each stage. This will be achieved as more physical processes are automated, and production schedules and maintenance schedules are planned out and regulated based on past data.

Pharmaceutical companies have heightened concerns about traceability, product quality, and process validation. Companies are embracing big data and remote storage more readily, to stay ahead of innovation and more easily comply with regulations. CMOs (Contract Manufacturing Organisations) are attracting biopharmaceuticals customers, who typically don’t have in-house manufacturing capabilities.

Achieve Sustainability through Serialisation Looking Ahead

A new need that can be related to big data is sustainability. As noted, the serialisation of pharmaceutical products has been mandated for many years now and asks that pharmaceutical products are tracked from their point of manufacture, to when they reach the patient. Where serialisation is concerned, manufacturers need to make sure the information used to monitor products can be read throughout the supply chain - including human readable codes.

The package, therefore, needs to be big enough to carry that information.

Where sustainability enters the equation is that serialisation provides a much better window to the manufacturer as to where a product is and where it’s being distributed. This allows them to create the correct number of products, which saves on production and therefore elements such as material and energy usage and even distribution. While it is not designed to be more sustainable, serialisation increases supply chain visibility and thus adds to the overall control and sustainability of a product.

Automation is playing a role in making lines suitable for several products, supporting the trend of smaller, more responsive facilities that concentrate on flexibility, cost efficiency, and speed.

Improvements in the communications infrastructure internally, with business partners, and throughout the supply chain will be the next steps.

Looking Ahead

With all the benefits of big data, incorporating it into manufacturing processes poses some challenges. Companies need to be prepared to handle the volume of data, the speed at which it accumulates and how to organise it best to create a more detailed future.

Researchers recognise that it would be valuable for companies to share data and learning with others who can apply it to improve the safety and reliability of all manufacturing. But the competitive nature of the pharmaceutical industry means that all information is propriety, and an open source system can be complicated as companies use different technology platforms. A standardisation process would have to be developed. Such a solution may be possible, however, as organisations like the Allotrope Foundation, a worldwide coalition of scientists with a mission

to improve data access and integrity, are seeking to revolutionise the way we acquire, share and gain insights from scientific data. The industry is at the early stages of using electronic data to understand drug structure & function and ultimately that impact on patient outcomes. Big data, AI and machine learning have the potential to change the way we develop, monitor, manufacture and apply drugs.

A Bigger Healthcare Packaging EXPO in 2019

Healthcare Packaging EXPO (Sept.

23-25; Las Vegas Convention Center), co-located with PACK EXPO Las Vegas 2019, will provide a compelling opportunity for pharmaceutical and medical device manufacturers to converge and address evolving consumer and regulatory demands.

PACK EXPO Las Vegas and Healthcare Packaging EXPO 2017 welcomed nearly 1,000 more attendees than 2015 as post-show numbers revealed 29,500 attendees and 2,000 exhibiting companies convened over almost 900,000 net square feet of the Las Vegas Convention Center.

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events, and the 2017 show was no exception,” says Jim Pittas, president and CEO, PMMI. “We expect the overwhelming success of PACK EXPO Las Vegas and Healthcare Packaging EXPO, to continue in 2019 with many new and exciting additions to the event.”

While PACK EXPO Las Vegas provides a platform to explore packaging technologies, equipment and materials from 2,000+ exhibitors serving virtually every vertical industry, Healthcare Packaging EXPO brings healthcare suppliers from the pharmaceutical, biopharma, nutraceutical and medical device industries together with attendees that traditionally represent the top 25 pharma companies by global sales.

To keep up with the growing size, PMMI continues to offer the most up-to-date online technologies like My Show Planner both online and via a mobile app which include enhanced Virtual Exhibitor Booths to ensure attendees and exhibitors come to the show prepared to make the most of every minute.

Pavilions are always a unique opportunity to visit targeted exhibitors in one area. New to Healthcare Packaging EXPO 2019 and PACK EXPO Las Vegas and is the Package Printing Pavilion.

This 35,000 net square feet pavilion is the perfect place to discover the latest printing and converting technologies, including digital color printing for folding cartons, flexible packaging and corrugated packaging; labeling, coding and marking solutions and smart package printing technologies.

Returning pavilions include Containers and Materials, Confectionery and Reusable Packaging Pavilions.

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Drug companies spend an average of US$2.6 billion developing a single drug.

solutions to help their products stand out. The pavilion also houses The Showcase of Packaging Innovations, sponsored by Dow. In addition to confectionery solutions providers, the Confectionery Pavilion is home to the Candy Bar networking lounge sponsored by the National Confectionery Association (NCA). Reusable solutions in the Reusable Packaging Pavilion will help buyers achieve supply chain sustainability and cost efficiency.

Other new additions to PACK EXPO Las Vegas and Healthcare Packaging EXPO 2019 include The Technology Excellence Awards, which debuted at PACK EXPO International 2018. After months paring down the many qualified entries, three days of onsite voting allowed PACK EXPO International and Healthcare Packaging EXPO attendees to be the ultimate judge of the most innovative new technologies at the show. The winners included Triangle Package Machinery Co. (Baking and Snack), Volpak (Beverage and Dairy), Evolabel (General Packaging), Bemis Company

Inc. (Meat/Poultry/Seafood), Neopac The Tube (Personal Care/ Cosmetics), Bausch + Ströbel Machine Company, Inc. (Pharmaceuticals and Medical Devices) and Pearson Packaging Systems (Prepared Foods).

Education is always a big part of the PACK EXPO Las Vegas experience with the return of the Innovation Stage.

Integrated on the show floor to allow attendees easy access, the Innovation Stage presents free 30-minute seminars on breakthrough technologies and techniques focused on a wide range of industry-specific solutions. A new addition to the education program within the PACK EXPO portfolio of Trade Shows is The Forum. After successful debuts at PACK EXPO East, Pack EXPO International and Healthcare EXPO and ProFood Tech, The Forum offers free, unique, interactive learning periods featuring 45-minute open sessions on the latest industry trends by the OpX Leadership Network, World Packaging Organisation, Institute of Packaging Professionals, Contract Packagers Association and PMMI Business Intelligence. Sessions will be interactive, including hands-on activities, small group discussions and Q&A sessions.

For more information on the latest additions to PACK EXPO Las Vegas and Healthcare Packaging EXPO 2019 visit packexpolasvegas.com

AUTHOR BIO

Sean Riley is currently PMMI’s Senior Director, Media and Industry Communications. He was Editor-in-Chief for PMMI’s Packaging Machinery Technology Magazine for nearly a decade and has over 20 years of experience working with and as a member of the packaging and processing media.

AirBridgeCargo Global cargo airlines

ABC is one of the major global cargo airlines, and its expanding route network connects customers in the largest trans-regional markets of Asia, Europe and North America, covering more than 30 major cargo gateways and accommodating trade flows worldwide. All the flights are operated via ABC’s cargo hub in Moscow Sheremetyevo airport, featuring up-todate equipment and guaranteeing seamless connection throughout the airline’s expanded international network within a 48-hour delivery time, including handling, all managed by highly-skilled and qualified ground handling personnel. ABC’s fleet of 18 Boeing 747 freighters is one of the youngest and modern in the airline industry.

• Special packaging solutions and thermal blankets for palletised shipments • abc pharma Active and abc pharma Passive solutions – the first one is for time and temperature sensitive pharmaceutical products that need to be shipped in active containers (including dry ice technologies) and the second is for prepackaged pharmaceutical products; • Dedicated, skilled staff trained in handling healthcare products • Full compliance with IATA TCR and CEIV certification • Envirotainer QEP accredited or CEIV certified stations within ABC network • Customer service support, online track & trace option for all shipments • Boeing 747-8 and 747-400 with three compartments enabling different temperature settings from 4°C to 29°C • Fast temperature pull down times after take-off • Temperature-controlled facilities on majority of stations throughout the ABC network • High-tech pharma hub at Moscow Sheremetyevo International Airport with effective connections to deliver cargo worldwide • Tailor-made logistics solutions based on your individual requirements • Sophisticated, cohesive and forward-thinking approach based on peer learning and networking through industry-related initiatives - Pharma. Aero, Pharma Gateway Amsterdam (PGA) and others • 24/7/365 Control Tower (CT) operation to monitor and manage transportation of special cargo consignments

ABC Pharma ABC is the best partner with an in-depth knowledge of the healthcare and pharmaceutical industry. We have developed special abc pharma product that meets the highest requirements for transportation of pharmaceuticals.

Benefits and special solutions of abc pharma: • Exact temperature monitoring from acceptance to delivery

• Adoption of the latest digital technologies (Sky Fresh for automated notifications, temperature data loggers to monitor consignment conditions, etc).

From vaccines, laboratory equipment, MRI / MRT machines to blood samples and beyond – we, at ABC, will always find the best logistics solutions to cater your needs and expectations.

Contact information: pharma@airbridgecargo.com www.airbridgecargo.com Advertorial www.pharmafocusasia.com

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PHARMA LOGISTICS TRENDS Karen Reddington, President of FedEx Express Asia Pacific, talks to Pharma Focus Asia about the profound transformation occurring in the pharma logistics industry in the region. She describes Asia's changing demographics, the regulatory environment, digitalization and new technologies as key disrupters. Reddington also shares how FedEx is responding to these changes to create more connections and greater possibilities for healthcare customers in this region.

Karen Reddington, President, FedEx Express Asia Pacific

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How is pharma logistics evolving?

Pharma logistics is undergoing profound change throughout Asia as the ageing population drives a growing need for new pharma solutions, together with scientific and technology advances that bring disruptive changes to cold chain logistics. FedEx Express is seeing three clear trends in pharma logistics:

Greater supply chain control through Internet of Medical Things (IoMT)

First, connecting this brand new world is the Internet of Medical Things, an innovation-driven market of medical devices and apps estimated to be worth US$158.1 billion by 2022.

The Internet of Things (IoT) has seen a corresponding growth in

quality and technology innovation in cold chain transportation.

The expectations are for cold chain logistics players to have the same commitment to speed and quality as companies researching and developing this highly specialised pharma.

To service this strong growth in complex cold chains, it is paramount for companies like ours to ensure adequate capacity and yet at the same time ensure safety and regulatory compliance.

Clinical trials are a strong and growing business for FedEx, one where customers are looking for high-end bespoke transportation services and solutions to ship sensitive Investigational Medicinal Products (IMP) and clinical trial drugs worldwide.

Increasingly, we are transporting sensitive biological samples for clinical studies from Japan, Korea, and China to Singapore or US laboratories.

By providing proper infrastructure and cold chain logistics support, we are able to move clinical samples and laboratory supplies including IMP and clinical trial drugs in an efficient and cost-effective manner.

FedEx has also invested in building regulatory compliance as a part of our business process. Through services such as Priority Alert, we have a contingency process for our transportation network, further enhancing our quality compliance to our healthcare customers.

Importance of trust in supply chain partnerships

connected medical devices and sensors, which includes instruments that allow shipments to be monitored.

At FedEx, we offer customers our own pioneering technology, SenseAware, which provides safe and compliant transportation of temperature-sensitive shipments in clinical trials and innovative pharma. Our network of connected

sensors has the ability to gather, send and monitor data, enabling a comprehensive array of real-time tracking and tracing data.

Increasing requirement for quality and regulatory compliance on supply chain

As global pharma is shifting portfolios and priorities towards biologics, we are seeing an increasing connection between

The sensitivity and value of healthcare products demand top-quality transportation service as the lives of patients, doctors and hospitals depend on it.

Pharmaceutical companies are increasingly looking to build partnerships with logistics companies, and not just the engagement of a transportation vendor. They want to have the complete trust and confidence that the time and temperature-sensitive shipments are well taken care of. And even when shipments donâ&#x20AC;&#x2122;t go as planned, customers want to be assured that their transportation partners are flexible and provide for the security www.pharmafocusasia.com

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of the shipment with countermeasures in place that can be swiftly implemented.

One of our customers, Japan’s Chugai Pharmaceutical, a member of the Roche Group, exemplifies the importance of elaborate, temperature-controlled environments for transportation. Chugai is undertaking extensive R&D into promising new drugs, and many of the samples they import and export contain sensitive and valuable components. These samples require 24/7 monitoring, and FedEx gives Chugai a sense of confidence and peace of mind that their shipments are not only being closely monitored and protected with specialised solutions, but speedily moving through transportation networks.

How is digitalisation reshaping pharma logistics?

Digitisation has significantly transformed pharma supply chain operations from improving processes, boosting productivity to enhancing safety via technologies such as big data, machine learning or automation tools. Digitising the supply chain enables pharma companies to realise: New levels of visibility and control in supply chain

Great logistics has always been as much about information as it is about shipments and packages themselves. This

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is even more crucial when it comes to healthcare shipment; it is not just about knowing where the package is, it is also about knowing how it is.

Due to the sensitive nature of many healthcare products that require strict regulated temperatures and conditions, logistics firms like ourselves are upping our game by bringing unprecedented level of visibility and control to the supply chain through innovative means.

• One of the best examples is SenseAware, powered by FedEx. The entire journey of vital healthcare products can now be tracked and shippers are kept updated on whether the cargo is staying within prescribed temperature and humidity limits or has been exposed to excessive light or other factors that might compromise shipment quality The increased visibility in pharma supply chain is essential. Not only is it a critical part of quality assurance, visibility of the shipment is a requirement by many of our customers - 67 per cent of FedEx pharma customers require Good Distribution Practices (GDP), a quality assurance program.

We are also pushing visibility boundaries for cross-border logistics with blockchain. Blockchain uses computer code to record every step of a transaction and delivery in a permanent ledger. This offers

a new level of transparency that can mitigate some of the most common disputes between customers sending and receiving goods involving time stamps, payments and damages.

In fact, FedEx is working closely with the Blockchain in Transport Alliance or BiTA to ensure that every player in the logistics ecosystem can gain from this technology.

Improving efficiency and lowering costs

With billions of dollars of drugs and medical devices moving through the global supply chain each year, manufacturers and their logistics vendors are eager to integrate new technologies from diverse fields into their operations with the goal of improving performance and lowering costs.

Digitisation has allowed vast amounts of data to be captured by a growing number of sensor-enabled devices moving through supply chains. As a result, they have put big data and analytics in the healthcare logistics mainstream.

Logistics services — which used to be considered a more tactical aspect of supply chain operations — are now rapidly evolving due to data analytics integration.

Using big data and analytics, we can now identify where and when deviations in temperature control are most likely

to occur. Historical data can allow us to deploy optimal packaging designs and use cold cold facilities and transportation, while real-time data analysis can spot specific shipments where intervention is required immediately to save a product.

Please share your views on the concept of ‘circular supply chain’ and its impact on the pharma industry.

Natural resources are finite, but innovation and reuse are theoretically infinite.

That’s the thinking behind the idea of the circular economy. By some estimates, a global effort could yield more than US$1 trillion in material savings each year.

At FedEx, we operate responsibly, efficiently, and sustainably. To these ends, we developed our ‘Reduce, Replace, Revolutionise’ approach to FedEx aircraft, vehicles, facilities, and materials.

The programme focuses on improving productivity while creating new, more efficient solutions.

• For example, FedEx MEDPAK VIoC is the first temperature-controlled reusable packaging network that is offered to customers in the healthcare industry on a one-way rental basis • This industry-first reusable packaging uses Phase Change Material (PCM) technology on a ‘peruse and return’ basis.

• With FedEx providing fixed pricing per destination and managing the oneway rental and returns, customers can reduce costs on packaging inventory, product deletion or return logistics.

• We also have an integrated network for the collection and delivery of shipment to support, monitor and control the end-to-end process.

Circular supply chain impacts not only our customers in the pharma industry, we have goals to multiply efficiency and reduce waste.

Based on our recent Global Citizenship Report.

• As of 2018, 100 percent of FedEx branded packaging is recyclable, and 54 percent is made from recycled content.

Big data solutions of the future will integrate data from multiple channels, such as manufacturers, carriers, suppliers, 3PL partners and provider facilities, in order to describe the journey of the product through its complete lifecycle, enabling the stakeholders to identify and address pain points along the way.

• To reduce the potentially wasted packaging, we have approved packaging specifications and ordering allocations.

• Quarterly audits of our packaging suppliers further ensure branded packaging meets all specifications and guidelines.

• We also have a FedEx Packaging Services team who works with customers to optimise package size and design, which reduces costs and environmental impact.

If the driving motivation for the pharma industry is to improve health and wellbeing, it makes sense for them to embrace a circular industry, including circular supply chain.

Emergence of blockchain technology is benefiting healthcare industry in many aspects. What according to you is the role of blockchain in pharma logistics?

Blockchain uses computer code to record every step of a transaction and delivery in a permanent ledger. The emergence of such technology promises a new level of transparency in the supply chain where

information provided are validated and verifiable.

This is especially beneficial to the pharma industry given the complexity of its supply chains which requires the input from multiple stakeholders with a number of important requirements placed on them. Speed, quality, and accuracy of the data are big challenges for the industry.

It is our belief that blockchain will transform the package delivery business, including the pharma logistics business: • Blockchain can allow a package to be tracked through every stage of the supply chain, from the moment it is shipped to the moment it reaches the intended recipient. Together with sensor-based technology SenseAware, stakeholders would gain the ability to monitor the condition of shipments before it arrives, thus assuring the shipment quality and peace of mind for customers. This is especially crucial for sensitive pharma shipments.

• Blockchain will allow for a comprehensive overview of the entire endto-end process. It also gives enhanced transparency between the authorised stakeholders. Each party can see the stages of the shipment’s journey to ensure authenticity and quality.

• The information that can be added to a blockchain is not limited to package conditions. Other information could include photo IDs for delivery personnel and procedures for pick-up and delivery, which would strengthen security and reduce the likelihood of theft.

• Better visibility of performance would lead to greater supply-chain efficiency, both by departments in charge of various logistical processes and partner companies. Blockchain also makes it easier to identify efficiencies and other issues in intermediate distribution.

One key focus for FedEx has always been the identification of innovative ways to provide the visibility required by customers up and down the supply chain. FedEx is a founding member of the Blockchain in Transport Alliance (BiTA), www.pharmafocusasia.com

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an industry association, and we chair the BiTA Standards Council, which is establishing industry standards for using blockchain technology throughout the supply chain.

What role do e-commerce companies play in pharma logistics?

The rise of e-commerce has brought about the inevitability of e-everything, and that includes e-pharma.

The core of e-commerce companies, as the name suggests, lies in providing an online platform for consumers to sell and buy products, and not in delivery.

Especially not in pharmaceutical deliveries that require special knowledge and expertise.

That has led us to believe that many online pharmacies will still rely on their delivery partners to safely and securely complete the delivery.

For example, Walgreens has partnered FedEx in the US to launch next-day prescription delivery nationwide.

What is the scope of Big Data and Data Analytics in logistics?

Everyday, FedEx connects people and possibilities spanning six continents and more than 200 countries, we draw on our vast network of more than 5,000 hubs and facilities, 180,000 motorised vehicles to deliver more than 15 million shipments each day. With this scale of operation, we are looking at vast amounts of data that is captured everyday.

At FedEx, we recognise the potential of leveraging big data and data analytics tools to increase efficiency and lower costs. Big data tools are capable of processing large amounts of data in different formats and from varying sources to enable scientists to identify patterns and gaps, which could suggest efficiencies, revenue opportunities, potential problems or competitive advantages that otherwise may not be evident.

Insights into Temperature Management

Every year the global pharmaceuticals industry suffers a loss of over

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US$15 billion worth of product due to temperature variations during transit.

More than 60 per cent of this loss comes during transportation of the products.

This is especially true for the healthcare supply chain, where even minor variations in temperature can affect the integrity of the product.

To alleviate this issue, supply chain providers and their manufacturer customers are using big data and analytics to identify where and when deviations in temperature control are most likely to occur. Historical data can allow them to deploy optimal packaging designs and to use cold chain facilities and transportation, while real-time data analysis can spot specific shipments where intervention is required immediately to save the product.

While data about the shipments themselves is an expected first place to look for supply chain optimization, service providers are also closely evaluating data about the warehousing and transportation assets. Many cargo and storage spaces must maintain constant levels of temperature, pressure, humidity and light exposure.

End-to-End Supply Chain Visibility

Complete, real-time visibility of the healthcare supply chain has potential to alleviate the losses that manufacturers suffer due to counterfeit drugs, theft, damage, and spoilage.

Big data solutions of the future will integrate data from multiple channels, such as manufacturers, carriers, suppliers, 3PL partners and provider facilities, in order to describe the journey of the product through its complete lifecycle, enabling the stakeholders to identify and address pain points along the way.

In many developed countries' healthcare systems, about 15 per cent of drug products delivered to healthcare facilities are wasted due to expiration.

To a large extent, this is attributed to a shortage of skilled labor to conduct drug inventory management in these facilities. Thankfully, predictive analytics are proving extremely useful at improving inventory stock-keeping, storage planning and overall inventory management.

For example, automated tracking systems can reduce the need for manual inventory management and 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 now digitised, healthcare facilities can produce a variety of reports faster and more accurately, helping them meet accreditation and government regulation requirements.

AUTHOR BIO

Karen Reddington is President of Asia Pacific Division of FedEx Express, the worldâ&#x20AC;&#x2122;s largest express transportation company. In this role, which Reddington took up in January 2015, she heads up Asia Pacific from its headquarters in Hong Kong. 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 employees.

Reddington is currently serving as the Board Chair of JA Asia Pacific as well as being on the Board of Governors of JA Worldwide. In addition, she serves as the Secretary of the International Womenâ&#x20AC;&#x2122;s Forum and also sits on the Board of Governors of the America Chamber of Commerce in Hong Kong.

Research Insights A Comprehensive Review on Current Advances in Peptide Drug Development and Design Andy Chi-Lung Lee 1,2,3 Janelle Louise Harris1 Kum Kum Khanna1 Ji-Hong Hong2,3,*

1 QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia 2 Radiation Biology Research Center, Institute for Radiological Research, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan 3 Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou 333, Taiwan * Author to whom correspondence should be addressed.

Received: 19 April 2019 / Accepted: 10 May 2019 / Published: 14 May 2019 Abstract: Protein–protein interactions (PPIs) execute many fundamental cellular functions and have served as prime drug targets over the last two decades. Interfering intracellular PPIs with small molecules has been extremely difficult for larger or flat binding sites, as antibodies cannot cross the cell membrane to reach such target sites. In recent years, peptides smaller size and balance of conformational rigidity and flexibility have made them promising candidates for targeting challenging binding interfaces with satisfactory binding affinity and specificity. Deciphering and characterizing peptide–protein recognition mechanisms is thus central for the invention of peptide-based strategies to interfere with endogenous protein interactions, or improvement of the binding affinity and specificity of existing approaches.

Importantly, a variety of computation-aided rational designs for peptide therapeutics have been developed, which aim to deliver comprehensive docking for peptide–protein interaction interfaces. Over 60 peptides have been approved and administrated globally in clinics. Despite this, advances in various docking models are only on the merge of making their contribution to peptide drug development. In this review, we provide (i) a holistic overview of peptide drug development

and the fundamental technologies utilized to date, and (ii) an updated review on key developments of computational modeling of peptide–protein interactions (PepPIs) with an aim to assist experimental biologists exploit suitable docking methods to advance peptide interfering strategies against PPIs. Keywords: binding site; docking; Interface; modeling; peptide; peptide–protein interaction; protein–protein interaction; scoring Funding: This work is supported by National Health & Medical Research (NH&MRC) Program Grant [ID 1017028] and medical research grants from Chang Gung Memorial Hospital [CMRPG3F2232, CMRP3G1491 and CMRPG3H1241].

Conflicts of Interest: The authors declare no conflict of interest. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Research Insights Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies Anthony J. Garcia-Prats, H. Simon Schaaf, Heather R. Draper, Maria Garcia-Cremades, Jana Winckler, Lubbe Wiesner, Anneke C. Hesseling, Rada M. Savic Published: April 30, 2019 https://doi.org/10.1371/journal.pmed.1002789

Abstract Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Methods and findings Children routinely treated for MDR-TB in 2 observational studies (2011â&#x20AC;&#x201C;2015, 2016â&#x20AC;&#x201C;2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid.

The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose.

Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted

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in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.

Conclusions Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.

Citation: Garcia-Prats AJ, Schaaf HS, Draper HR, GarciaCremades M, Winckler J, Wiesner L, et al. (2019) Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies. PLoS Med 16(4): e1002789. https://doi.org/10.1371/journal.pmed.1002789 Academic Editor: Claudia M. Denkinger, FIND, SWITZERLAND Received: November 9, 2018; Accepted: March 26, 2019; Published: April 30, 2019 Copyright: Š 2019 Garcia-Prats et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: Research reported in this publication was supported

by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health under award number R01HD069169 (ACH) and R01HD083047 (AGP, RMS). ACH (the SaRCHI Chair in Paediatric Tuberculosis) and HSS receive support from the National Research Foundation of South Africa.

The University of Cape Town (UCT) Clinical PK Laboratory is supported in part via the AIDS Clinical Trial Group (ACTG), by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701 (LW). Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) at UCT was provided by the National Institute of Allergy and Infectious Diseases (U01 AI068632), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Mental Health grant AI068632 (LW).

Overall support for the Stellenbosch University Clinical Trial Unit (SUN-CTU) Unit, Clinical Research Site 31790, Desmond Tutu TB Centre is provided by National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award number UM1 AI069521 (ACH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: AUC0–24ss, area under the concentration time curve from 0 to 24 hours at steady state; BSV, between-subject variability; CL, clearance; Cmin, minimum linezolid concentration; CSF, cerebrospinal fluid; DAIDS, Division of AIDS; FOCE, first order conditional estimation; HAZ, height-for-age z-score; IQR, interquartile range; Ka, rate of absorption; LC MS/MS, liquid chromatography tandem mass spectrometry; MDR-TB, multidrug-resistant tuberculosis; MIC, minimum inhibitory concentration; QC, quality control; RMST, restricted mean survival time; RSE, relative standard error; SCM, stepwise covariate modelling; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; V, volume; VPC, visual predictive check; WAZ, weight-forage z-score; WHO, World Health Organisation; XDR-TB, extensively drug-resistant tuberculosis

Strategies for the Development of Glycomimetic Drug Candidates Rachel Hevey Molecular Pharmacy, Dept. Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland

Received: 15 March 2019 / Revised: 3 April 2019 / Accepted: 9 April 2019 / Published: 11 April 2019 (This article belongs to the Special Issue Carbohydrates 2018) Abstract: Carbohydrates are a structurally-diverse group of natural products which play an important role in numerous biological processes, including immune regulation, infection, and cancer metastasis. Many diseases have been correlated with changes in the composition of cell-surface glycans, highlighting their potential as a therapeutic target. Unfortunately, native carbohydrates suffer from inherently weak binding affinities and poor pharmacokinetic properties. To enhance their usefulness as drug candidates, ‘glycomimetics’ have been developed: more drug-like compounds which mimic the structure and function of native carbohydrates.

Approaches to improve binding affinities (e.g., deoxygenation, pre-organization) and pharmacokinetic properties (e.g., limiting metabolic degradation, improving permeability) have been highlighted in this review, accompanied by relevant examples.

By utilizing these strategies, high-affinity ligands with optimized properties can be rationally designed and used to address therapies for novel carbohydrate-binding targets. View Full-Text Keywords: carbohydrate; glycomimetic; drug development; lectin; lead optimization; binding affinity Funding: This research received no external funding.

Acknowledgments A very grateful acknowledgement goes to Dr. Jacqueline Bezençon for her time and helpful feedback in preparing this manuscript.

Conflicts of Interest: The authors declare no conflict of interest. © 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Books

Clinical Trial Optimization Using R (Chapman & Hall/ CRC Biostatistics Series) Author(s): RAlex Dmitrienko, Erik Pulkstenis

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Economic Evaluation of Cancer Drugs: Using Clinical Trial and Real-World Data (Chapman & Hall/CRC Biostatistics Series)

Cancer Clinical Trials: Current and Controversial Issues in Design and Analysis Author(s): Stephen L George, Xiaofei Wang, Herbert Pang

Year of Publishing: 2019

Author(s): Iftekhar Khan, Ralph Crott , Zahid Bashir

Year of Publishing: 2019

No. of Pages: 337

Year of Publishing: 2019

No. of Pages: 474

Description: This book presents in depth the Clinical Scenario Evaluation (CSE) framework, and discusses optimization strategies, including the quantitative assessment of tradeoffs. A variety of common development challenges are evaluated as case studies, and used to show how this framework both simplifies and optimizes strategy selection. Specific settings include optimizing adaptive designs, multiplicity and subgroup analysis strategies, and overall development decision-making criteria around Go/ No-Go. After this book, the reader will be equipped to extend the CSE framework to their particular development challenges as well.

No. of Pages: 436

Description: Cancer Clinical Trials: Current and Controversial Issues in Design and Analysis provides statisticians with an understanding of the critical challenges currently encountered in oncology trials. Well-known statisticians from academic institutions, regulatory and government agencies (such as the U.S. FDA and National Cancer Institute), and the pharmaceutical industry share their extensive experiences in cancer clinical trials and present examples taken from actual trials.

P H A RM A F O C U S A S I A

ISSUE 35 - 2019

Description: Economic Evaluation of Cancer Drugs using Clinical Trial and Real World Data is the first unified text that specifically addresses the economic evaluation of cancer drugs.

The authors discuss how to perform cost-effectiveness analyses while emphasising the strategic importance of designing cost-effectiveness into cancer trials and building robust economic evaluation models that have a higher chance of reimbursement if truly costeffective. They cover the use of real-world data using cancer registries and discuss how such data can support or complement clinical trials with limited follow up. The book includes many detailed practical examples, case studies and thoughtprovoking exercises for use in classroom and seminar discussions.

The book covers topics that are often perplexing and sometimes controversial in cancer clinical trials. Most of the issues addressed are also important for clinical trials in other settings. After discussing general topics, the book focuses on aspects of early and late phase clinical trials. It also explores personalized medicine, including biomarker-based clinical trials, adaptive clinical trial designs, and dynamic treatment regimes.

Biocontamination Control for Pharmaceuticals and Healthcare

Digital Science (Advances in Intelligent Systems and Computing)

Author: Tim Sandle

Author(s): Tatiana Antipova, Alvaro Rocha

Year of Publishing: 2018 No. of Pages: 374

Year of Publishing: 2018 No. of Pages: 475

Redefining Innovation: Embracing the 80-80 Rule to Ignite Growth in the Biopharmaceutical Industry Author(s): Ruchin Kansal, Jeff Huth Year of Publishing: 2018 No. of Pages: 228

Description:Biocontamination Control for Pharmaceuticals and Healthcare outlines a biocontamination strategy that tracks bio-burden control and reduction at each transition in classified areas of a facility. This key part of controlling risk escalation can lead to the contamination of medicinal products, hence necessary tracking precautions are essential. This book offers guidance on building a complete biocontamination strategy.

• Provides the information necessary for a facility to build a complete biocontamination strategy • Helps facilities understand the main biocontamination risks to medicinal products • Assists the reader in navigating regulatory requirements • Provides insight into developing an environmental monitoring program • Covers the types of rapid microbiological monitoring methods now available, as well as current legislation

Description: This book gathers the proceedings of the 2018 International Conference on Digital Science (DSIC’18), held in Budva, Montenegro, on October 19 – 21, 2018.

DSIC’18 was an international forum for researchers and practitioners to present and discuss the latest innovations, trends, results, experiences and concerns in Digital Science. The main goal of the Conference was to efficiently disseminate original findings in the natural and social sciences, art & the humanities.

Description: In the book, we examine the evolution of the biopharmaceutical industry to understand how it became what we term a "unicorn industry" with a unique, US-centered business model that has led to multiple blockbuster products (aka, unicorns) year after year. We explore how past success has created perceived barriers to innovation diversification beyond the chemical or biological-based biopharmaceutical product, and highlight the warning signs of the industry’s decline. We define a potential pathway for transforming the industry’s business model by broadening the definition, sources, and enablers of innovation beyond the traditional biopharmaceutical product.

We introduce and advocate for the 80-80 Rule - "Being 80% confident that you will only be 80% right the first time should feel normal." The 80-80 Rule is a theme that emphasizes speed and willingness to embrace uncertainty and overcome internal barriers to change.

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