Pharma Focus Asia - Issue 30

Issue 30 2018

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Post-Hire

Screening Enhancing workplace safety

Reaching a New Innovation Threshold How can we make it happen?

Safe and Secure Packaging’s role in combating counterfeit drugs

At the service of the pharmaceutical industry.

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Background image is a courtesy of Novasep Holding SAS

Foreword Continuous Employee Screening in Pharma Industry The new normal?

"Continuous screening provides employers with a valuable tool to best evaluate their risks and ensure they place their employees in the most appropriate positions."– Lucia Bone Performing background verification or screening of

Taking the employee screening a step further

new hires has been a practice the world over to

is continuous screening and post-hire monitoring,

ensure the organisation employs individuals that

which can raise a flag about potential risks and

are talented and skilful, and do not have a criminal

thereby reducing occurrence of insider threats. In

background/tarnished reputation. While this happens

today’s business scenario, predicting future employee

in most industries, screening of potential employees is

behaviour is an inherent challenge and the abundance

a well-accepted measure in a highly regulated industry

of key information availability puts organisations at high

like Pharma. Issues such as crime, theft, fraud and

risk of losing their brand value. Continuous screening

violence can directly affect an organisation’s business

is a way to display due diligence, prevent insider

irrespective of the industry it operates in. Prescreening

threats, and protect the workplace. It could be the new

potential employee(s) helps organisations streamline

normal as organisations deal with a dynamic talent

the application process and determine if they meet

pool and find it tough to engage with the millennials

the qualifying requirements.

in the current digital age.

Prescreening helps recruit the right talent, but

While employee screening and monitoring is

that might not prevent an employee from presenting

something organisations need to integrate into their

a future risk to the organisation. Even without any

policies, it is equally important to safeguard employee

criminal background or history of engaging in illegal

interests and morale. Organisations benefit from

behaviour, there is no guarantee that current employees

having an effective continuous monitoring tool(s)/

do not present a potential risk. Periodic verification

system that ensure cross-border due diligence and

or rescreening helps discover the consequences of

covering gaps, if any. The cover story of this issue

an employee’s behaviour and allows them to take

talks about the importance of post-hire screening in

measures to prevent any unforeseen circumstances.

the pharmaceutical industry.

According to the 2017 Asia Pacific Employment Screening Benchmarking Report, only 28 per cent of companies conduct periodic rescreening of their employees. Pharma companies conduct criminal record search, FDA (Federal Debarment) search, OIG search, sex offender search and drug screening etc. Pharma companies perform annual background

Prasanthi Sadhu Editor

checks or bi-annual drug tests to ensure employees keep themselves away from resorting to any fraudulent actions.

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Contents Strategy

COVER STORY

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06 The Evolution of Brand Strategy As the pharmaceutical market transforms, so does the meaning of brand strategy

Brian D Smith, Principal Advisor, PragMedic

16 Biosimilars Interchangeability

Regional views aren’t interchangeable Anna La Noce, Executive Medical Director, Clinical Development General Medicine, Syneos Health

20 Setting up a Pharmacovigilance System

Dharmapal Sharoff, Manager, Regulatory Operations, Freyr

Research & Development 26 Reaching a New Innovation Threshold How can we make it happen?

Christopher-Paul Milne, Tufts Center for the Study of Drug Development, Tufts University Medical School

Clinical Trails

The Importance of Post-Hire Screening in the Pharmaceutical Industry Mary O’Loughlin, Vice President, Managing Director, Healthcare and Life Sciences, HireRight

30 Managing Clinical Trial Agreements

Veronica Holloway, CRO General Counsel, Novotech

Manufacturing

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34 System Engineering for a Novel Continuous Pharmaceutical Manufacturing Process Ravendra Singh, C-SOPS, Department of Chemical and

Biochemical Engineering, Rutgers, The State University of New Jersey

42 Modelling and its Applications in Solids-based Continuous Pharmaceutical Manufacturing Processes

Marianthi Ierapetritou, Chair, Department of Chemical and Biochemical Engineering, Rutgers University

Zilong Wang, PhD Candidate, Department of Chemical and Biochemical Engineering, Rutgers University

48 Safe and Secure

Packaging's role in combating counterfeit drugs Chandan Pat, Business Development Manager, Essentra

56 Books 58 Latest Happenings

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48

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Advisory Board

Editor Prasanthi Sadhu Alan S Louie Research Director, Health Industry Insights an IDC Company, USA

Christopher-Paul Milne Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA

Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany

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

Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA

Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK

Editorial Team Debi Jones Grace Jones Art Director M Abdul Hannan Product Manager Jeff Kenney Senior Product Associates David Nelson Peter Thomas Product Associates Austin Paul James Taylor John Milton Sussane Vincent Veronica Wilson Circulation Team Naveen M Nash Jones Sam Smith Subscriptions In-charge Vijay Kumar Head-Operations S V Nageswara Rao

Pharma Focus Asia is published by

In Association with

A member of

Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India

Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US

Confederation of Indian Industry

Ochre Media Private Limited Media Resource Centre,#9-1-129/1,201, 2nd Floor, Oxford Plaza, S.D Road, Secunderabad - 500003, Telangana, INDIA, Phone: +91 40 4961 4567, Fax: +91 40 4961 4555 Email: info@ochre-media.com www.pharmafocusasia.com | www.ochre-media.com Š Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions.

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

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

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Strategy

The Evolution of Brand Strategy As the pharmaceutical market transforms, so does the meaning of brand strategy The basic structure of brand strategy evolved decades ago and has barely changed since. Its key components-clinical indication, advantages and communication methods-are relics of a time when professionals prescribed on the basis of clinical claims and little else mattered.

But as our market has evolved into one where payers and patients shape decisions, the nature of brand strategy has adapted to that new environment. In this article, I describe the newly emerging characteristics of brand strategy and how it can guide your own strategic planning.

Brian D Smith, Principal Advisor, PragMedic

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magine being a fly on the wall when I conduct one of my research interviews in a pharmaceutical, medtech or diagnostic company. Observe what happens when I ask one of my carefully worded questions: Please describe your brand strategy? Since I research across many countries and disease areas, the answers vary in detail. But witness enough interviews and you would notice that the typical reply conforms to a formula: The indication, followed by the claims and then the tactics for communicating those two things. Step back from the detail and you would see that that this is the implicit industry recipe for brand strategy. It is remarkable that this formula is shared across the industry, whatever the product or market, but it is even more astonishing that this formula has persisted

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for decades. Forty years ago, during my induction process as a very young research chemist, I recall a brand manager reciting the same thing.

That the form of a brand strategy has remained constant for decades is puzzling for a management scientist like me, who uses evolutionary science to understand our industry. Since I was that young man, technology has leapt forward in both biology and information science. Sociologically, globalisation, demographics and other trends have been inexorable. Surely, the nature of brand strategy should evolve to adapt to this very different world? And yet my research interviews mostly suggest that brand strategy is stuck in the 1970s, an era when I wore flared trousers and listened to Abba on my AM radio.

But only mostly and not entirely.

In a small minority of interviews, I uncover evolutionary change in the way that brand strategy is defined and created. Its emergence is uneven and erratic, but it is there. And, in those adaptations, we see the future of brand strategy. As I describe in my book “Brand Therapy�, my research identifies no less than 15 such evolutionary adaptations (see figure) and in this article I’ll describe some of them.

The first and most fundamental adaption is the way that brand leaders define their market. Traditionally, this was done in terms of product (e.g. the statin market) or clinical condition (e.g. the hyperlipidaemia market).

But modern marketers have come to realise that these definitions hinder

Strategy

insightful understanding of the market.

After all, it is people who purchase, prescribe and consume. Neither lipids nor statins place orders. More evolved brand planning processes therefore begin with a customer-centric market definition: What is the fundamental need to be addressed (e.g. avoidance of cardiovascular disease), who is involved (e.g. prescribers, payers and patients) and what are their needs? The answer to this last question has two parts as it includes both hygiene needs (e.g. regulatory approval) and differentiating needs (e.g. for health economic evidence).

This market definition, an adaptation to the changes in how choices are made and by whom, provides a much better framework for any subsequent analysis of the market.

A second adaption to changing markets is the way that market segmentation is done. Industry convention has been to divide the market by product category (e.g. mode of action) or sometimes disease stage (e.g. first vs second line). But this approach doesn’t fully address the heterogeneity of customer needs, which vary both clinically and in other ways. As a result, this simplistic categorisation leads to poor targeting and proposition design.

In response to this issue, we see the emergence of contextual segmentation.

This involves the segmentation of each decision maker group (e.g. prescribers, payers and patients) according to their differentiating needs (e.g. for reassurance, for value or simple posology). These three analyses then combine to allow the www.pharmafocusasia.com

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identification of segments made up of decision contexts characterised by the same needs and therefore behaviours. These segments form the basis for effective targeting and proposition design.

Flowing from the adoption of contextual segmentation is the emergence of a third adaptation of brand strategy: the concentric value proposition. Whereas, historically, the value proposition was almost synonymous to the product claims approved by regulatory, the concentric value proposition goes much further.

It involves identifying the entire set of needs of the target segment: Core (e.g. efficacy) Extended (e.g.

Information that enables product use) and Augmented (e.g. Feelings of confidence). Those needs are then translated into an integrated set of company activities that meet those needs (e.g. product claims, beyond-the-product services and CME programmes). The concentric value proposition is an adaption to the pressure from generics and the costs of developing strongly differentiated products. Unless a product is exceptional, its claims alone no longer represent sufficient value in today’s market.

Contextual segments and concentric value propositions combine to create a fourth important adaptation of brand strategy. Whilst formerly the brand strategy was implied from (and often lost in) the mass of detail in a brand plan, modern marketers have learned that this hinders execution. As a response, we see the emergence of very explicit brand strategies stated in three parts: the allocation of effort between contextual segments, the value proposition made to each targeted segment and, importantly, a specific statement of which segments will not be targeted. This clarity, which in my work I call “Drucker’s Definition” after the great management guru 8

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Peter Drucker, makes it much easier to translate strategy into action and reduces the threat of implementers going ‘off strategy’. It is, therefore, a response to tighter marketing budgets and stiffer compliance controls.

Perhaps the most radical adaption I observe in my work is that which happens between defining the brand strategy and its execution. The accepted process has been for the chosen strategy to be ‘socialised’, meaning it was discussed and tweaked until everyone in the team felt it was acceptable. This social alignment approach is now seen to be ineffective, resulting in the political dilution of the strategy until what remains is a set of choices that is agreed but which are obvious and do not create competitive advantage. What has evolved to replace socialisation is a rigorous process of brand strategy diagnostics, in which the strategy is tested against a number of transparent criteria. Those criteria, such as how well the strategy anticipates the future and how well it mitigates direct competition, are assessed using risk scales structured not unlike those used for diabetes management or to assess risk of cardiovascular disease. They allow the identification of weaknesses in the brand strategy.

This in turn guides the reiteration of the brand strategy process until it an objectively strong strategy emerges.

A further advantage of the diagnostic tests is that, by being transparent, the diagnostic tests enable effective ideasharing within cross-functional teams.

This is much more efficient than the all too common alternative of politicised, subjectively based arguments that occur otherwise.

Many other adaptations of brand strategy in life sciences emerge from my work. These are summarised in figure shown. As the figure shows, these techniques connect together to create brand strategies that are stronger and a better fit for today’s competitive markets.

Effective brand strategy processes culminate in the final adaptation; the

A u t h o r BIO

Brian D Smith works at the University of Hertfordshire in the UK and Bocconi University in Milan, Italy. This article is based on his latest book “Brand Therapy: 15 Techniques for Creating Brand Strategy in Pharma and Medtech."

wedge brand plan structure. Most readers will be familiar with the typical brand plan, consisting of hundreds of pages of detail that, whatever its merits as a data collation tool, fails completely to communicate the strategy to those who must implement it. Such tomes consume time and hinder implementation. In the most advanced companies, however, we see a different structure emerging.

The plan document itself is very short, containing only the essentials of the situation, strategy and activity plans. This short readable document is, however, heavily cross referenced to a large number of appendices covering market analysis, budgets, activity programmes and so on.

This short document with appendices – the so-called wedge structure – is a

much more effective communication document without losing any necessary details. It is a necessary adaptation to today’s time-poor work environment.

It is sobering to think of the changes in the life sciences market since I first entered the industry. It is thought-provoking to reflect that the brand strategy process in many companies has not adapted well to those changes. In those less-evolved companies, brand strategy has the same process and format as it had before the average brand manager was born. But, as is the way with evolution, we can discern the emergence of brand strategy processes and formats that are more adapted to today’s market. It is up to today’s brand leaders to adopt those emerging practices. www.pharmafocusasia.com

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CoverStory

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The Importance of Post-Hire Screening in the Pharmaceutical Industry Pre-employment background checks are generally wellaccepted as part of the hiring process in highly-regulated sectors such as the pharmaceutical industry. But what happens post-hire once a new employee is onboard and welcomed into the company? While many aspects of a pre-employment background check are static, that certainly does not mean that the same employee cannot present a future risk, as the organisation, the staff member and his/her role and, personal circumstances most certainly will evolve and change over time. This is especially imperative, in an industry where patents and other valuable intellectual property-often worth millions-are in jeopardy.

Mary O’Loughlin, Vice President, Managing Director, Healthcare and Life Sciences, HireRight

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re-employment background checks are generally well-accepted as part of the hiring process in highly-regulated sectors such as the pharmaceutical industry. With patents and other valuable intellectual propertyoften worth millions-at risk, the potential

of sabotage from activist groups, theft from industry rivals, potential insider threats, and, not to forget, employee access to prescription drugs once onboard, pharmaceutical companies must perform their due diligence before hiring new staff members.

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But what happens post-hire once a new employee is onboard and welcomed into the company? While many aspects of a pre-employment background check are static (for example, establishing that the individual’s credentials are indeed valid), that certainly does not mean that the same employee cannot present a future risk, as the organisation, the staff member and his/her role and personal circumstances most certainly will evolve and change over time.

For example, in November, an arrest in Queensland, Australia, involved a pharmacist stealing more than US$20,000 worth of prescription drugs for personal use1. Earlier this year, a doctor in Singapore was jailed for selling 2,300 litres of cough mixture on the black market to drug abusers2. Within Asia, where lesser developed healthcare systems and low-paid doctors have rendered the sector vulnerable to corporate malpractice and bribery, corruption involving healthcare workers and pharmaceutical executives can become rife-as in the case involving a pharmaceutical giant in China 34.

The APAC Employment Screening Benchmark Report from HireRight in 2017 5 found that less than three in ten (28 per cent) APAC companies re-screen employees periodically. This remains a major 1 https://ajp.com.au/news/legal/pharmacist-steals-20000-worth-drugs/ 2 http://www.straitstimes.com/singapore/courts-crime/doctor-gets-jail-and-fine-for-selling-2300-litres-ofcough-mixture-to-drug 3 https://www.reuters.com/article/us-gsk-china/gsk-case-a-warning-to-all-foreign-firms-in-china-xinhuaidUSBREA4F01P20140516 4 https://www.economist.com/blogs/analects/2014/07/corporate-corruption-china 5 https://www.hireright.com/apac/resources/view/2017-apac-employment-screening-benchmark-report/

The APAC Employment Screening Benchmark Report from HireRight in 2017 found that less than three in ten (28 per cent) APAC companies re-screen employees periodically.

area of exposure to organisations, as an employee’s personal history or external circumstances may have changed in a way that could impact their abilities, certifications, or behaviour in the workplace.

To minimise the risk of criminal activity, substance abuse, or other misconduct-potentially making the company liable for negligent retention or exposing it to other claims-pharmaceutical companies should consider new procedures such as periodic re-screening that take these realities into account. Besides identifying new risks, such post-hire screening programs act as a deterrent and create an audit trail should issues emerge.

Setting the groundwork for continuous screening protocols Background checks encompass a wide variety of areas, and need to be tailored to an organisation’s unique needs as well as the broader regulatory environment. HR departments should carefully consider the areas that require rescreening to make the process simple, yet effective. A biennial criminal background check, for example, helps mitigate risk to an organisation without being too arduous. Randomised drug tests every six months, law permitting, minimise the temptation to divert controlled substances. Ensuring that checks are supported by easy to use, mobile-enabled technology will drive a positive user experience and reduces the impression of imposing onerous requirements on staff.

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Pharmaceutical companies may also want to consider what drugs employees have access to, and tailor screenings accordingly with expanded drug panels, or additional saliva, hair strand and blood tests.

Furthermore, organisations should consider re-screening employees who have been promoted or moved into a new role that is more senior or carries with it new responsibilities, expectations and access – a gap identified by the same Employment Screening report.

In the US, a high-profile case involving the illegal sharing of trade secrets and business information (source) 6 between two romanticallyinvolved top executives from rival companies, resulted in the leak of around 900 confidential company files from one firm to the other. In the case of the executive who leaked the documents, it was found that she had been hired in 2012, and rose up the ranks to become the company’s senior director of regulatory affairs between 2014 and 2016, when she allegedly committed the illegal disclosure. 7 New roles naturally equate to new responsibilities, possibly different access, and with that, a change in risk profile.

The initial screening performed pre-hire might not have been tailored to the new role or to the changed circumstances.

It is therefore essential that companies, as a matter of course, tailor and apply different checks to different roles, and seek to mitigate risk by performing the relevant checks as employees move within and across the organisation.

Maintaining Employee Morale and Company Culture

Indeed, a significant challenge in implementing continuous screening practices lies in maintaining employee morale and company culture, and to avoid giving the wrong impression to 6 http://www.philly.com/philly/business/sex-drugs-andsharing-trade-secrets-20170712.html 7 http://www.philly.com/philly/business/sex-drugs-andsharing-trade-secrets-20170712.html

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A u t h o r BIO Mary O’Loughlin is the Vice President and Managing Director of Healthcare and Life Sciences of HireRight, responsible for the strategic growth of the healthcare industry within the organisation, while managing the cross-functional team responsible for the overall service of HireRight's healthcare customers.

loyal staff. It needs to be made clear from the outset that this is not a monitoring program developed to dismiss people without a word of warning. Instead, the company is looking to protect the safety of its patients and employees, preserve its reputation, and build upon already high standards of professionalism.

With that in mind, it is important to make any changes in company policy-and the consequences of such -transparent and well understood.

In most APAC markets, conducting drug and alcohol tests for example requires prior informed consent from the employee-what happens then if the employee refuses to comply? Equally, if something were to be uncovered during a screening - such as a positive drugs test -what action would be taken? Would that employee be immediately dismissed

or would they be given a second chance?

Would they be offered any support or counselling? There can be little room for ambiguity, particularly when it comes to existing staff who may be reluctant to embrace new protocols.

Finally, companies should keep in mind how continuous screening fits into the bigger picture of promoting a culture of safety and integrity-it is a part of the solution, and needs to be complemented by other initiatives. These could include health assessments, training to enable coworkers to identify warning signs, and enhanced processes to share information and data.

Regardless, all these elements must come together to form one united strategy, aimed at equally protecting the organisation and its employees.

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Biosimilars Interchangeability Regional views aren’t interchangeable

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With many biosimilars reaching the market, interchangeability/ substitution with the reference product has become a hot topic.

The FDA has released draft guidance on this topic requiring specific and quite complex study designs to demonstrate interchangeability that raised several comments from all types of stakeholders. A short overview will be presented.Biosimilars interchangeability/ substitution in Asia will be also discussed highlighting the peculiarities of the biosimilar market of selected Asian countries..

Anna La Noce, Executive Medical Director, Clinical Development General Medicine, Syneos Health

A

round the world, regulators view biosimilars rather differently in terms of designating them as interchangeable with the reference product. To date, the US has taken a conservative approach, not with standing the experience Europe has gained in monitoring thousands of patients who have switched from originator to biosimilar products. Meanwhile, in Asia, access issues stemming from the cost of biologics render concerns over interchangeability moot.

FDA Guidance Reflects a Caution Outlook

In 2017, the US Food & Drug Administration (FDA) released longawaited draft guidance on biosimilar interchangeability – intended as the substitution of the reference biologic drug with its biosimilar product, done without the intervention of the prescribing healthcare provider.

The document, “Considerations in Demonstrating Interchangeability with a Reference Product,” specifies that in order for the agency to deem a biosimilar as interchangeable with its reference product, there must be sufficient evidence to demonstrate that: • The biosimilar product “can be expected to produce the same clinical

result as the reference product in any given patient” and • “ The risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

The FDA recommends that sponsors intending to demonstrate interchangeability perform an adequately powered switching study in a sensitive patient population. The study should be designed to include two parallel treatment arms: one in which patients receive the reference product only and the other in which the treatment is switched at least three times between the reference and biosimilar products. Intensive pharmacokinetics (PK) sampling should be conducted, with clinical PK and pharmacodynamics, when applicable, representing the primary study endpoints with immunogenicity and safety as the secondary key endpoints.

Although in the US biosimilar substitution is governed by individual state laws, state policies implemented so far tend to show a consistent approach, allowing substitution only for biosimilars designed as interchangeable by the FDA. However, policies tend to www.pharmafocusasia.com

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diverge for what concerns the required notifications or the measures a physician can undertake to prevent substitution therefore introducing some variability across states.

To date, no biosimilar has been granted interchangeability status by the FDA. In fact, no study has yet been completed on a biosimilar according to the agency’s full specification, although Sandoz has incorporated a multiple switch design into its adalimumab and etanercept biosimilar efficacy and safety studies in psoriasis. However, the intensive PK sampling recommended to prove interchangeability was not performed. More recently, a psoriasis study following FDA interchangeability guidance has been initiated by Boehringer Ingelheim (Voltaire-X) with their adalimumab biosimilar Cyltezo® that recently received market authorisation.

A number of different organisations commented on the FDA’s draft guidance before the consultation period closed in May 2017. The comments are publicly available on the FDA’s website1.

Interestingly, the Biosimilar Medicine Group, a sector of Medicines for Europe, observed, “The draft guidance emphasizes the theoretical risks associated with biosimilar medicines development and approval, without balancing those with the wealth of evidence gathered over the last decade in the EU where biosimilar medicines have been used in clinical practice.”

In particular, the group made reference to the number of switching studies performed thus far and their positive results; although multi-switching as recommended by the FDA was not applied. The group also explained that, based on current knowledge, EU regulators have stated, “It is unlikely and very difficult to substantiate that two products comparable on a population level would have different safety or efficacy in individual patients upon a switch.”

1 https://www.regulations.gov/docket?D=FDA-2017-D0154 18

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The FDA recommends that sponsors intending to demonstrate interchangeability perform an adequately powered switching study in a sensitive patient population.

The Biosimilar Medicine Group has, therefore, recommended that the FDA develop a “pragmatic guidance document” that incorporates “what the learnings from practice have been to date.”

Lessons from the EU Experience

The terminology adopted in Europe to define interchangeability is different from the US definition, creating some confusion. Interchangeability for the European Medicines Agency (EMA) is a broad term referring to “the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect”, while “substitution (automatic) is the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber” corresponding to the FDA definition of interchangeability.

In the EU, the EMA has delegated decisions regarding interchangeability and automatic substitution to member states. In general, so far, automatic substitution is not allowed or recommended at a national level; exceptions are France, where substitution is allowed with restrictions, or countries like Poland, where it can take place due to lack of regulations. That said, the situation is very dynamic, and

substitution at the pharmacy level may occur in certain countries if the biological product is prescribed by its International Non-Proprietary Name (INN), or if the products are purchased by a bulk tender.

Over the last few years, non-medical switches, those performed for reasons other than a patient’s health or safety have, indeed, taken place within Europe, and these cases provide robust, longterm, follow-up data. Admittedly, the majority of cases have been single switches, i.e., transitions from the reference product to its biosimilar, thus not fulfilling the FDA’s requirements for an interchangeability study. Nonetheless, this practice has generated a considerable amount of realworld experience which has been published and presented at international conferences. A review of switching studies involving infliximab, adalimumab, etanercept, or rituximab biosimilars identified such studies up to October 2016.

Large numbers of these switches have taken place in the Nordic countries. One of the largest postmarketing studies to explore the effects of switching conducted thus far is the NOR-SWITCH study, sponsored by the Norwegian government. It randomised nearly 500 patients with various inflammatory diseases to either continue the originator infliximab (Remicade®) or switch to its approved biosimilar, CT-P13 (Remsima®/Inflectra®) for 52 weeks. The results showed that after one year patients who had switched showed no worsening of the disease and did not present any special safety issue, as compared to those that remained on the originator product.

Overall, other smaller observational studies of Remsima®/Inflectra® have tended to agree that switching from Remicade®to CT-P13 did not lead to loss of efficacy or safety concerns. Several single-centre studies from different European countries involving follow-up with patients who had switched from different types of reference products have also been reported.

Strategy

In May 2015, Denmark implemented a national guideline mandating non-medical switching of all patients treated with Remicade® to Remsima®. As a result, more than 800 patients suffering from rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis were switched to the infliximab biosimilar and were followed for more than one year in an observational study. The study showed that there was no impact on disease activity, although retention rates were slightly lower after one year than those of an historical Remicade® cohort.

Generally positive results were also found following the approval and launch of the first etanercept biosimilar, Benepali®, in 2016. Uptake was rapid and impressive, and prescription data from biologic registries have been revealing.

• In Denmark, more than 1,500 patients with rheumatic diseases were switched from Enbrel® to Benepali®.

A three-month follow-up post switch showed that the disease activity was largely unaffected , although about nine percent of patients stopped treatment by the five-month follow-up, with high disease scores and lack of methotrexate use being associated with the discontinuation.10 • In Sweden, 55 percent of more than 5,000 rheumatology patients who initiated treatment with Benepali® had undergone a non-medical switch from Enbrel®.11 Similar data have been reported in Germany. Follow-up data thus far indicate no overall worsening of the condition, although a small percentage of patients tended to interrupt treatment and, in some instances, return to the originator. This phenomenon deserves further investigation for the potential causes. Researchers have highlighted the importance of following a communication strategy to help patients understand the reasons for, and benefits of, the switch, as well as the importance of adherence to therapy and persistence with the treatment regimen.

Variety of Approaches Taken in Asia

When it comes to biosimilars and views on interchangeability, Asian countries are quite different from their Western counterparts. Copies of biologic drugs, also called follow-on biologics, have been developed and marketed for quite some time in countries such as China and India, although these drugs do not meet the criteria for a biosimilar established by international guidelines.

Regulations about development and approval of biosimilars vary among Asian countries, with Japan and South Korea having adopted stringent guidelines similar to the EMA whereas other countries have been more lenient.

With the help of generous government funding, South Korea has accelerated its development of biosimilars that meet international standards.

There is, potentially, a huge demand for biosimilars in the region, given that the majority of the population cannot afford originator biologics, even if given at a lower cost due to the competition from copies. While the overall consumption of biologics (including copies or biosimilars) remains very low in many Asian countries for economic reasons, the availability of follow-on biologics is contributing to greater use.

In India, for example, the number of people receiving ritixumab increased by

six fold within three years of the launch of the first Rituxan® copy.

The current debate around interchangeability and substitution does not appear to be of special interest in the majority of Asian countries, similarly to other emerging markets, due to the current low use of reference products.

Rather than addressing questions of interchangeability between originators and biosimilars, Asian countries are focused on extending the use of biologics to a larger portion of the population.

In conclusion, in parallel with an increasing number of biosimilars reaching the market, a strong need for regulating the switch from the reference product to its biosimilar is emerging with the purpose to find a good balance between the expenditure of healthcare systems and the safety of the subjects while taking into account the sometime contrasting views of the several involved stakeholders. For the emerging markets, the main challenge for the coming years will consist of extending the use of advanced therapies by making available properly developed biosimilars (rather than copies) to a larger number of patients.

References are available at www.pharmafocusasia.com

A u t h o r BIO Anna La Noce, MD, PhD, serves as Executive Medical Director, Clinical Development, Immunology & Inflammation at INC Research/ inVentiv Health. She is a physician who has dedicated the last 10 years to providing support on planning and executing clinical trials in various rheumatology indications, with a focus most recently on biosimilars. Her professional experience includes more than 25 years in the pharmacology industry, specialising in the clinical development of a variety of drugs in several therapeutic indications.

www.pharmafocusasia.com

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Strategy

Setting up a Pharmacovigilance System

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Strategy

Pharmacovigilance is a complex process for which robust systems are essential. A strong PV system is an important part of the overall medicinal product Regulatory system. It reflects on the stringency and competence of the Regulatory bodies in regulating the market and ensuring the safety and effectiveness of the medicinal product.

Dharmapal Sharoff, Manager, Regulatory Operations, Freyr

P

harmacovigilance (PV) is principally concerned with the identification of Adverse Drug Reactions (ADRs) and reduction of the associated risks.

Detection and reporting of ADRs can make prescription of medicinal products much safer and more effective. This is possible only if pharmaceutical companies and patients report the ADRs as and when they occur.

Before a medicinal product is marketed, its safety and efficacy exposure is limited to its use in clinical trials. Generally, clinical trials cover limited number of patients with strict inclusion criteria, often excluding special patient groups like those with co-morbid conditions, children, elderly and pregnant women. Hence, they do not reflect the experience in bigger population and in different geographical regions. People from different geographical regions differ from one another with respect to genetics, food habits, life style, clinical practices, etc.

This makes it obligatory to maintain a constant vigil on the use of medicinal products during the post-marketing period.

PV is a major post-marketing tool to ensure the safety of a medicinal product.

Apart from the respective drug regulating authorities in each country, International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, Pharmacovigilance

Planning-ICH E2E and World Health Organization-Uppsala Monitoring Centre (WHO-UMC) also play key roles towards developing, enhancing and monitoring global PV system. A PV system is defined as a system used by an organisation to fulfil its legal tasks and responsibilities in relation to PV that monitors authorised medicinal products’ safety and detect if any change to riskbenefit balance.

After the thalidomide disaster in the year 1961, WHO worked along with its Collaborating Centre to establish a programme for International Drug Monitoring. Through this programme, WHO promoted PV at the country level. At the end of 2010, 134 countries were part of the WHO-PV Programme.

The goals of PV are to

• Augment patient care and patient safety with respect to the use of medicinal products • Run public health programmes by providing reliable information for the effective assessment of the risk-benefit profile of medicinal products.

A well-structured PV system can establish safety data in a precise manner from various levels of social healthcare environment. Building-up an effective system demands for harmonisation of different criteria, which requires an early, well thought of plan that ensures perfect execution and tangible benefits.

Prerequisites for a Pharmacovigilance System

Pharmacovigilance is all about drug regulations and is based on thorough collaborative ties, coordination, communications, and public relations.

The most suitable location for setting up a PV centre is dictated by the political governance and its healthcare priorities, including willingness to do, law enactment, its enforcement, funding, organisation, staffing, training, and development.

To Ensure a Good PV System, Certain Operational Requirements must be met, which include

• A properly structured drug safety management team to intensify the communication among the PV network. This will assure an organised structure and smooth functioning. Meetings among the PV physicians, managers, and technical agencies need to be held from time to time • A countrywide database which provides provision for collating and managing ADR reports • A national PV advisory committee • A clear approach, to be communicated in detail, in regular situations as well as situations of crisis • Funding to run different grounds of a system. www.pharmafocusasia.com

21

Strategy

PV System of safety data collection

Clinical Trials Healthcare Professionals Pre-Approval National Regulatory Authority

Patients

Pharmaceutical Companies

Basic Steps in Setting up a PV System Include

Developing guidelines and communications with the health authorities-a general guideline is a standard strategy to confirm that the PV system at all levels meets the national and international standards and regulations. Getting into regular communications with the health authorities, local, regional and national bodies, and professionals involved in clinical medicine, pharmacology, toxicology, epidemiology, briefing them about the importance of the project and its applicability in modern therapeutics.

• Should have adequate qualified and experienced man power to run the system - PV staff should have complete knowledge regarding data collection and verification, coding of drugs and adverse events, causality assessment, signal detection, risk management, interpreting the data obtained etc.

• Setting up of PV centres - Creating a database which is safely stored, retrievable and guarded by required degrees of confidentiality. Some of the basic technological requirements to be met by the PV centre are uninterrupted electric supply and ensuring that the intercom, 22

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Without PV, modern medicine will be continued to be called as allopathy – the science of other suffering.

multi connection telephone, computer, printer, fax, internet, photocopiers are in working condition. The PV centre should have adequate back up facilities so that work is not hampered during breakdowns; anticipated or sudden • Continuous monitoring and improving the PV system performance - the capacity building processes include the management of the medicinal products, the system and the individual in the network, and effective monitoring of medicinal products from a safety perspective. The aim of capacity building is to create a robust system without creating changes in social structures, resources, technologies and personalities

Post-Approval

International Safety Database

• Data acquisition through ADR reporting form - preparing an ADR reporting template and to make it readily available, in different hospital settings and general practitioners, based on which they can provide relevant information to the PV centre • Creating public awareness for ADR reporting – conducting workshops and meetings in the different healthcare institutions, academic institutions, promotional events to educate patients and healthcare professionals on the importance of reporting ADR through medical journals, professional publications, and seminars, and developing printed handouts. All these are done to notify healthcare professionals and public about the definitions, goals, scope, and methodology of the PV system to create awareness about its present relevance • Detecting signals on the reported adverse drug events - based on the case reports, the PV centre should be able to detect a signal with regards to probable ADR • Be associated with health authorities, pharmaceutical companies, other professional associations /organisations and WHO and its collaborating

www.pharmafocusasia.com

23

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Strategy

Funding

The PV system needs to deal with large population and the rate of reporting governs the estimation of the money needed to run the complete system. Huge investment is required in terms of collection of data from the actual source to transforming it into a Regulatory reportable format.

Funding can be obtained from various parties, such as drug Regulatory authority, university departments, health insurance companies, and professional associations.

Conclusion

PV is a complex process for which robust systems are essential.

A strong PV system is an important part of the overall medicinal product regulatory system. It reflects

on the stringency and competence of the Regulatory bodies in regulating the market and ensuring the safety and effectiveness of the medicinal product. The foundation for building a robust PV system demands skilled manpower, support from healthcare professionals and pharmaceutical companies, safety awareness among the patients, information technology, and funding. The system needs to be refined with the help of PV experts in collaboration with technology. Establishing a robust PV

A u t h o r BIO

bodies so that information on observed adverse reactions is shared / notified time to time which may include cases with particular interest; and take proper preventive measures whenever those are necessary.

system is a tough job; however, with thorough preparation, a practical approach, continuing zeal and motivation of the concerned staff, it can be achieved.

PV ensures that future generations will not condemn the present one for its apathy, indifference, and callousness to the gravity of the situation.

Without PV, modern medicine will be continued to be called as allopathy.

References are available at www.pharmafocusasia.com

Dharmapal S Sharoff is a veteran healthcare professional with 12 plus years of extensive experience in pharmacovigilance (PV) and clinical research field. A diversified experience spanning across the industry in establishing PV system and setup/maintain the PV System Master File. Have expertise in developing aggregate reports/periodic safety reports which include both developmental [Developmental Safety Update Report (DSUR)] and during post-marketing phases [Periodic Benefit Risk Evaluation Report (PBRER), Periodic Safety Update Report (PSUR), Periodic Adverse Drug Experience Report (PADER), Canadian Annual safety Reports (CASR)]. Expertise in analysing and evaluating benefit-risk and developing mitigation plans for identified risk. Been an active audit member for regulatory inspections, handled the PV inspections efficiently and has supported in closing the audit findings smoothly.

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25

Research & Development

Reaching a New Innovation Threshold

How can we make it happen?

This article talks about how the difficulty of getting reimbursement in the US and Europe for novel therapeutics, especially ones based on innovative new technology platforms, renders such products less available in AsiaPacific as well, since two-thirds of NASs are developed in the US and Europe. A number of countries in the AsiaPacific region depend on the regulatory and reimbursement decisions in the US and Europe for making their own decisions, especially on breakthrough products for which the resources and expertise for developing the evidence base to make such decisions (for example, with regulatory science tools and/or real world data) are often limited.

Christopher-Paul Milne, Tufts Center for the Study of Drug Development Tufts University Medical School

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T

he difficulty of getting reimbursement in the US for novel therapeutics, especially ones based on innovative new technology platforms, renders such products less available in AsiaPacific as well. Fully half of new active substances (NASs) approved globally each year, ownership of the extant R&D pipeline worldwide, and the end-market for all medicines are in the USA number of countries in the Asia-Pacific region consider the regulatory and reimbursement evaluations conducted in the US when making their own decisions, especially on breakthrough products for which the resources and expertise

Research & Development

for developing the evidence base to make such decisions (for example, with regulatory science tools and/or real world data) are limited in some Asia-Pacific countries.

After surviving the ‘valley of death’, the precarious period that exists between late discovery and early clinical trials, the next critical juncture for an innovative product is getting buy-in from FDA to award it special status in one of its Facilitated Regulatory Programs (FRPs), which expedite development and regulatory review. At that point, however, the imprimatur of the FDA only goes so far to predict future success after launch. The path to commercial success can certainly be delayed by obstacles during the technical process of getting a product through the hurdles of proving safety, effectiveness, and product quality, but the last hurdle is always proving value – to physicians, patients, and especially third-party payers, both private and public. A study by Tufts CSDD in the early 2000s showed that technical success and commercial success do not always go hand-in-hand. That seminal study reported that of 15 major companies, there was a wide range of correlations between technical and commercial success. That gap has only become more challenging over time. Even though the time of development has remained somewhat static over the last decade, the cost of development has doubled, and overall success rates have declined.

Thus, the ramifications of a market failure are much more daunting than in the previous decade, when only 3 out of 10 marketed products earned enough to pay their own freight (and generally the sunk costs of the other products on the market as well). While the number of big pharma company has been cut in half in the 2000s, emerging sponsors (mostly small, young companies with little or no history of prior approvals) are now responsible for close to half of novel approvals in the US as well as ownership of 80 per cent of the R&D pipeline. For these small, start-up

For the Asia-Pacific region with a panoply of government, private and individual payer systems, the ingredients exist to craft fair pricing and coverage solutions as much or even more rapidly than in the US.

companies, reaching the market only to be thwarted by difficult reimbursement conditions or outright rejection for formulary inclusion can be disastrous for the company as a whole. Yet, these very companies are often where the seedbeds of innovation are most fertile, as mid-sized companies often have limited their portfolios to a few therapeutic areas and larger companies over time have been abandoning certain therapeutic areas such as CNS disease after experiencing a lack of success or portfolio realignment due to merger & acquisition or new leadership.

On the commercial side what has to happen to balance the prospects of success for novel products generated by innovative platforms? Two concepts must become mainstream precepts— Risk-Sharing Agreements (RSAs) and Real World Evidence (RWE). These concepts are intertwined and must be integrated to provide a solution for moving therapeutic options forward at the speed of science.

Risk-sharing entails agreements in which the buyer and seller believe that a product is sufficiently promising that it warrants the taking of certain risks by all parties because of the likelihood of potential benefits, i.e., value to the patient and thus to the healthcare system responsible for care

and coverage, even if that benefit may be as barebones as “it’s better than nothing.” The first fundamental factor involved in risk-sharing is that all parties actually share the risk. This is where payers have often been found wanting, either by requesting too much proof too early (i.e., pre-approval) or by an unwillingness to accept any risk at all for an untried product without regard to regulatory approval or patient need. As counterproductive as this seems, there are many examples of this being the case with urgent medical needs in orphan drugs, personalised medicines, and most recently, Abuse-Deterrent Formulations (ADFs) for opioids. In a 2014 study by Tufts CSDD of orphan drugs approved from 1983 to 2013, 9 out of 10 drugs had at least one condition restricting reimbursement, whereas for the 11 most expensive orphan drugs, patient costsharing ranged from 20-35 per cent for drugs costing on average US$400,000 annually. For an early cohort of 10 personalised medicines in 2013, Tufts CSDD found that payers reimbursed all drugs with variable and relatively high payer co-insurance and formulary restrictions, but reimbursement for the companion diagnostics was limited and highly variable. By 2015, product developers still considered reimbursement to be a 4 out of 5 on an index of the most challenging factors facing personalised medicine.

The problem is not confined just to private insurers. For example, the opioid abuse epidemic in the US sounded the clarion call for ADF products. There has been a laudable response by manufacturers with 25-30 new applications pending review, 10 approved, and 4 launched by mid-2017, despite the fact that two years earlier 96 per cent of prescribed opioids were not ADF products. Nonetheless, coverage by the US Government under the Medicare program ranges from only 8 to 54 per cent for these 4 critically needed products.

Payers would say in their defence that they must see proof of clinical www.pharmafocusasia.com

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Research & Development

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it is gaining credence as a supplement to pivotal RCTs in this regard. In fact, FDA’s premier regulatory science experiment – the Oncology Center of Excellence – now just a year old, works to incorporate RWE among just a handful of key advances in regulatory decision-making along with revamping trial design to eliminate the arbitrary phase 1,2, 3 structure, employing master protocols, re-defining trial eligibility criteria in conjunction with patient advocacy organisations to ensure representativeness, and reaching out to professional colleagues outside the agency as well as external stakeholders to generate better patient-reported outcomes metrics and instruments.

Payers, for their part, have to shake off the shackles that bind them to a decision process that requires upfront proof of clinical superiority or rejection as the only two options for whether or not to reimburse a new drug (or a sliding scale of incremental costeffectiveness that purports to implement a public health rationale of ‘greatest

A u t h o r BIO

utility, i.e., that the drug, drugdiagnostic combo, or formulation, demonstrate statistically robust evidence of positive outcomes for the patients for a sufficiently high proportion of patients. The problem is a Catch-22 (i.e., a difficult circumstance from which there is no escape because of mutually conflicting conditions). You cannot provide the quantum of evidence necessary for comparative effectiveness that payers demand until there are a sufficient number of patients who have experienced a therapeutic trial of the product in real world settings. For this to happen, payers must assume certain risks a priori. It’s a hard lesson. One that FDA has struggled to learn, but has finally become reconciled to it as a necessary regulatory paradox – accepting a certain amount of uncertainty in order to advance promising new technologies.

Now payers have to ‘walk a mile’ in the shoes of patients, care-givers and regulators and take this same ‘leap of faith.’

Arguably, faith is not a strong point of public or private payers, and probably we don’t want it to be.

We do want them to be able to make decisions on the best available evidence at the earliest point in time to meet an unmet need as soon as possible.

This is where RWE comes into play.

RWE is defined as data regarding the usage, or potential benefits or risks, of a drug derived from sources other than randomised controlled clinical trials, such as observational studies, registries, insurance claims databases, electronic medical records, wearable devices as well as patient-centred outcomes studies. The regulators are beginning to accept that RWE can be a telling source of evidence to assess the value over time in the life cycle of a marketed drug, and perhaps even answer questions that hadn’t been asked yet, but should have been. However, there is some reticence to substitute RWE for RCTs as the gold standard for providing the necessary quantum of proof for initial approval, although

good for the greatest number of people’ but is really thinly disguised rationing).

Real world evidence in its simplest terms is evidence from the patient, by the patient, for the patient. If the system is serious about becoming more patent-centric—as it should be since regulators serve the people, and patients are the end-customer for manufacturers and payers—then the experience of the broadest swath of patients in the widest range of practice settings should inform payer decisions. Who will pay and how is a different question, and depends on individual, familial, community, and nation-state support as well as cultural norms, but the first threshold is to establish whether a product has sufficient value to bring this next set of considerations into play.

For the Asia-Pacific region, with a panoply of government, private and individual payer systems, the ingredients exist to craft fair pricing and coverage solutions as much or even more rapidly than in the US. In a recent prior article in Pharma Focus Asia, the author has demonstrated that many nation-states in the region have nascent infrastructure or even burgeoning programs to provide for a system of real world data collection that could provide an adequate source of RWE. At the same time, RSA models are not confined to any one global region but are ongoing initiatives in many countries (including, for example, in China and South Korea according to a recent ISPOR workshop summary).

With the judicious implementation of RSAs and RWE, access to novel medicines and a conducive environment for innovative technology can be a reality on the short term horizon for the Asia-Pacific region.

Christopher-Paul Milne joined the Center for the Study of Drug Development, Tufts University School of Medicine (TUSM) in 1998, and is currently a TUSM Associate Professor and Director of Research at the Center. He has published over 75 book chapters and papers on biopharmaceutical regulatory and policy issues worldwide, while serving as an Innogen Center Associate (University of Edinburgh), and recently as Visiting Professor at Kyushu University in Japan.

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29

Clinical Trails

Managing Clinical Trial Agreements Clinical Trial Agreements set out how a clinical trial will be run at the site and are an essential GCP document.

There are a number of key factors that determine whether a Clinical Trial Agreement is successful in achieving that purpose which we will review from Novotech’s perspective as an Asia Pacific CRO. Veronica Holloway, CRO General Counsel, Novotech

C

linical Trial agreements are an essential GCP document and are integral to achieving clinical trial success. They define the legal relationship between sponsors, Clinical Research Organisations (CRO) and sites, and establish the rules under which the clinical trial will be conducted. There are several key criteria which determine whether a Clinical Trial Agreement (CTA) is successful in achieving this.

In this article, we will review the development of CTAs from the CRO perspective – that of being the main party negotiating between sponsors, site management and principal investigators to draft an effective agreement which facilitates clinical trial start-up and the all-important patient recruitment.

Drawing from Novotech’s clinical trial industry experience, we have found negotiating CTAs in some countries can

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(unnecessarily) take months-these delays can impact investigator engagement and the enrolment of patients eager to be part of an upcoming clinical trial. Key to reducing potential delays is ensuring a good working relationship between sponsor, CRO and site to conduct the clinical trial.

Below are four core elements to be considered when approaching the planning of a clinical trial and drafting CTAs: 1. Choosing the Right Parties: Sponsor, CRO, Site and Principal Investigator

There are a number of combinations of parties to a CTA, many of which often depend on country or sitespecific requirements. If a CRO is conducting the clinical trial for a sponsor, they will usually enter into a

CTA with the site, with the site and Principal Investigator (PI) together, or with the site as a party but where the PI acknowledges their responsibilities set out in the CTA. In any given country, understanding the right combination of parties required for a successful CTA depends on local expertise and knowledge.

It is crucial you ensure you have the right parties agreeing terms so your CTA accurately reflects what will occur during in the conduct of the clinical trial – and that this arrangement is consistent with locally accepted practice and global GCP standards.

In Australia, a specific CRO CTA drafted by the industry body Medicines Australia1 is 1 Medicines Australia; Clinical Trials Research Agreement – CTRA: Contract Research Organisation acting as the Local Sponsor

Clinical Trails

required for public hospital sites in the South Eastern Border States of Queensland, New South Wales, Victoria and South Australia. In practice, a form of this CTA is used by most public and private sites. Sponsors who often use CROs in Australia as a local legal entity are required to sign the CTA and provide the patient indemnity to the site – a service which CROs in Australia are able to provide.

In Asia, it is important to note that some country sites (including Hong Kong) may not agree to CTAs with CROs as they require an agreement directly with a sponsor, even though a CRO has been appointed to manage the trial on behalf of the sponsor.

Some countries (like the Philippines) are new to including sites as a party

to the CTA2. Previously, CTAs were signed between a CRO and the PI. This is because, unlike in other countries, PIs in the Philippines are not engaged by the site.

2. Providing the Appropriate Authority for the CRO

If you are a CRO or a sponsor using a CRO to conduct a clinical trial, it is imperative the CTA adequately and clearly outlines the CRO’s scope of authority to conduct the trial, so the site and PI are able to receive information, instructions and funds from the CRO. If the sponsor is a party to the CTA, including a clause to this effect in the CTA can often avoid the need to have separate letters of authority signed by Sponsors.

2. Medicines Australia; Clinical Trials Research Agreement – CTRA: Contract Research Organisation acting as the Local Sponsor

3.Have an Empowered Sponsor Representative Involved in CTA Discussions

Any CRO negotiating CTAs needs to agree negotiation parameters with the sponsor upfront and have a point of contact at the sponsor who has appropriate authorisation to make decisions about CTA terms. Having this point of contact saves time and effort for both the sponsor and CRO going back and forth on minor issues.

An upfront discussion regarding CTA terms provides the CRO with an opportunity to demonstrate and clarify: • What works for CTAs within their region • What they have been able to negotiate in the past • How long negotiations are likely to take www.pharmafocusasia.com

31

Clinical Trails

• What steps they have taken to reduce the timing and complexity of CTA negotiations with sites (such as agreeing template CTAs with key sites).

4. Key CTA Clauses to Include

Clinical trials are increasingly global, multi-site and multiregional affairs; and in this context, agreeing a standard CTA for your clinical trial can be challenging with local country templates and requirements taking precedence.

However, outlined below are several key clauses which should clearly and plainly feature in any CTA:

Any CRO negotiating CTAs needs to agree negotiation parameters with the sponsor pfront and have a point of contact at the sponsor who has appropriate authorisation to make decisions about CTA terms.

Intellectual property

Good Clinical Practice (GCP)

CTAs need to include references to the latest regulatory requirementswhich should also include references to the International Conference on Harmonisation Note for Guidance on Good Clinical Practice (ICH/135/95) and local law requirements around ethical conduct in human research and other applicable publications or guidelines relating to clinical trials.

All CTAs should expressly require the conduct of the clinical trial comply with GCP and that all parties to the CTA conduct their respective roles and responsibilities in accordance with GCP. Conduct of the clinical trial

The responsibility of the PI to conduct the clinical trial in accordance with the protocol, Ethics Committee (EC) / Institutional Review Board (IRB) conditions and relevant professional standards must be included in the CTA. Detail around EC / IRB approvals, study documents, cooperation with CRO, safety and reporting should be included for clarity as who is to do what and when.

Protections

CTAs include protections around confidentiality, personal information and use of the study drug which protects patients, PIs, sites, CROs and sponsors. Crucial points 32

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for both sponsors and sites in relation to funding for future activities. Sites will always require publication rights and sponsors will always want first right of review, authorship credits and time delays on publication.

A good publication clause should include reasonable detail about: • The nature of information which may be published • Credits given • Timelines and triggers for publication • The role of the sponsor to review and amend.

which allow each party have confidence in the other party(s) conduct of the clinical trial include: • What information is considered confidential • How personal information will be handled • How the drug or product being investigated is to be managed at the site

Indemnities

Indemnities which provide compensation to patients who suffer personal injury, harm or death attributable to the clinical trial are a basic requirement. That said, the breadth and scope of an indemnity can vary from country to country.

It is preferable that the indemnity (and any applicable compensation guidelines) are part of the CTA. Some countries and sites may have a form of side letter which sets out the patient indemnity. Either way, the availability and scope of the indemnity ultimately provided by the sponsor to patients participating in the clinical trial must be clear to all parties to the CTA – and of course to the patients themselves via the Informed Consent Form.

Publication

The ability to use results and research from a clinical trial is a key asset

Intellectual property (IP) (such as data, documents, know-how, inventions, etc) in relation to clinical trials can sometimes be difficult to negotiate. Both the sponsor and the site will want to leverage IP derived from the conduct of the clinical trial. What is often agreed is that the site will have rights to the background IP which it contributes to, while the sponsor will have full licence rights to use that background IP to market the study drug.

The Sponsor will usually require absolute ownership of IP created during or arising out of the clinical trial. To avoid any future issues around IP ownership, it is important to require the site warrants that any IP it creates or owns does not (or will not) infringe on any IP owned by a third party.

Insurance

Insurance is a given for sponsors and CROs. However, that isn’t always the case for sites and PIs as professional indemnity insurance is not always applicable in some countries or regions.

While an insurance clause requiring the site and /or PI3 to hold professional indemnity insurance during the clinical trial and for a reasonable time thereafter ought to be included in all 3. Depending on who is a party to your CTA

Clinical Trails

Termination

Termination rights of all parties to the CTA need to be managed against the reality that clinical trials may discontinue at any given time for a variety of reasons.

A CRO must ensure they have the ability to terminate a CTA if the sponsor decides to end the trial early, reduce the scope of the trial to exclude a site (for example where no patients have been recruited by the site) or for safety reasons. Any early termination of a clinical trial often comes with a reasonable amount of effort and time to wind up the clinical trial, so there needs to be a term outlining

A u t h o r BIO

CTAs; it may be that the site or PI do not hold the applicable insurance or that insurance is not locally available to them.

It is important to have an upfront discussion about applicable insurance with the site and PI. If the CTA is signed and is not correct (for example the site agrees to hold insurance when in fact they do not), the sponsor or CRO will have taken on additional risk without factoring this into their decision making around a site or country. There are options available to sponsors where a site or PI doesn’t hold insurance (such as taking out insurance on their behalf ).

cooperation between the CRO, site and PI if that occurs.

Getting your CTA right as early as possible in the clinical trial process will allow the sponsor, CRO, site and PIs to focus their full attention on patient recruitment and the successful conduct of the trial.

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33

Manufacturing

System Engineering for a Novel Continuous Pharmaceutical Manufacturing Process Currently, pharmaceutical industries are going under paradigm shift from traditional batch to novel continuous manufacturing. Such a novel continuous plant has been built at C-SOPS which is being adapted by several pharmaceutical companies.

The Continuous Pharmaceutical Manufacturing (CPM) pilot-plant has been further modernised via utilising process system engineering methods and tools. Process model, automation system, real time monitoring, advanced Model Predictive Control (MPC) system, data management system and material tracing system are critical components of modernised CPM pilot-plant. A validated process model has been developed for in-silico studies and virtual experimentations.

A process model plays a very important role to design, evaluate and tune the control system. The developed control system has been then implemented in to the continuous tablet manufacturing pilot-plant for practical demonstration.

Ravendra Singh, C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey

P

harmaceutical industries as well as regulators (e.g. FDA) are strongly promoting smarter Continuous Manufacturing (CM). Few pharmaceutical products have been recently approved

by U.S. Food and Drug Administration (FDA) to manufacture in continuous line and several others are on the way. There are several advantages but also different scientific challenges for this paradigm shift.

Efficient and optimum process design, process automation, real time monitoring and control, material traceability, diversion of non-confirming products and real time release are few of those CM advantages which are scientifically challenging to address. Systematic Process System Engineering (PSE) methods and tools are 34

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,therefore, needed to efficiently overcome the obstacles on the path of CM shift and thereby to develop smarter continuous pharmaceutical manufacturing process.

The objective of this work is to demonstrate the importance of system engineering to further modernise the continuous pharmaceutical tablet manufacturing process.

1. Overview of Flexible Continuous Pharmaceutical Manufacturing Process

A flexible continuous pharmaceutical tablet manufacturing process is shown in Figure 1. As shown in the figure, there are three continuous pharmaceutical manufacturing routes: (1) via Direct

Compaction (DC), via dry granulation/ Roller Compaction (RC), (3) via Wet Granulation (WG). Some unit operations are common in all three manufacturing routes. The selection of DC, RC and WG routes depends on the type of formulation to be used to make the tablets. A continuous direct compaction tablet manufacturing process is a simplest route. Details of the process dynamics of the direct compaction line have been previously reported, and the open-loop as well as closed-loop operation has been extensively studied.

The continuous manufacturing process via Roller Compaction (RC) is called dry granulation route. It is a preferred route for liquid sensitive formulation

Manufacturing

Figure 1

where wet granulation option is not feasible to use. The roller compactor converts the powder blend into ribbon.

A mill is integrated with the roller compactor that breaks the ribbon and form granules. In the wet granulation route, the granules are first manufactured and then compacted to form tablets.

2. Process Model

The model of each unit operation involved in continuous manufacturing process has been previously developed.

The feeder model is reported in scientific literatures. A mill model is reported in Barrasso et al. (2013). The mathematical model for powder blending, an important

but complex unit operation, has been previously developed as described in Sen et al. (2012, 2013). The model for the tablet compression process is previously reported in Singh et al. (2010). This model is based on the Kawakita powder compression model (Kawakita & Ludde, 1971)and Kuentz-Leuenberger tablet www.pharmafocusasia.com

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Manufacturing

Process Models

Model Forms

Useful References

Feeders

Semi-empirical

Boukouvala et

al. (2012)

Mill

PBM

Barrasso et al. (2013)

Blender

PBM, DEM

Sen et al. (2012, 2013); Boukouvala et al. (2012)

Tablet press

Empirical

Singh et al. (2010), Kawakita and Ludde (1971), Kuentz & Leuenberger (2000) , Barros et al. (2017).

Dissolution

FEM, First order rate, Fick’s second law

Kimber et al. (2011); Singh et

Roller compactor

Empirical

Hsu et al. (2010a, 2010b)

Granulator

PBM

Barrasso and Ramachandran (2013)

Integrated direct compaction line

Mass balance

Boukouvala et (2012, 2013)

4. Process Automation

al. (2012)

al. (2012), Singh et al.

Table 1 Continuous tablet manufacturing process model and references

hardness model (Kuentz & Leuenberger, 2000). The dissolution model was adapted from Kimber et al. (2011). The model of roller compactor is adapted from Hsu et al. (2010a, 2010b). A population balance-based model for the granulation process has been presented in Barrasso and Ramachandran (2012).

The PID controller model is available in the control section of the Process Model Library (PML) of simulation software gPROMS (PSE). The models for the different unit operations have been developed and included in gPROMS (Process Systems Enterprise, PSE) to facilitate the integrated flowsheet modelling. The control relevant process model involving transfer functions has been developed in Simulink (Math works) through step change response analysis (Singh et al., 2015; Barros et al., 2017).

3. Model-based Control System Design of Continuous Pharmaceutical Manufacturing Process

The process model plays a very important role for design of an efficient control system prior to its implementation into the pilot-plant.

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performed. The control system for continuous wet granulation process has been designed and evaluated as well.

Several studies have been performed on design and evaluation of control system around tablet press.

It significantly minimizes the time and resources needed to implement the control system. The design of an efficient process control system is an interactive procedure that involves the identification of critical controlled variables, coupling of the controlled variables with suitable actuators (manipulated variables), selection of suitable monitoring tools, selection of control strategy followed by tuning of controller parameters, and model-based closed-loop performance assessment.

A model library and a knowledge base are important supporting tools for control system design. An integrated mathematic model for continuous tablet manufacturing process that used for design of control system is a part of model library. The knowledge base consists the information about the process as well as the information about the monitoring and control system.

The control system for continuous pharmaceutical tablet manufacturing process via direct compaction has been previously designed and evaluated.

An engineering study on control of continuous pharmaceutical tablet manufacturing process via roller compaction has been also systematically

The automation of continuous pharmaceutical manufacturing process is needed to operate the plant through a centralised control platform, to collect the process operational data in real time and subsequently apply this data to control the plant in order to achieve desired product quality. Traditionally, the pharmaceutical product is manufactured through batch processing with very less or no automation involve and therefore this area of research need more attention.

The continuous pharmaceutical manufacturing pilot-plant has been automated. Fieldbus, serial ports and OLE Process Control (OPC) have been used to integrate these unit operations with the automation system. All the data generated in these unit operations are collected and stored systematically in a data historian.

5. Real Time Process Monitoring

The continuous pharmaceutical manufacturing process need to be monitored in real time. The main objectives and associated challenges are as follows: (1) Identify and integrate different tools needed for real time sensing.

(2) Identify inbuilt, external available and non-available sensors. (3) Demonstrate the application of existing sensors for real time monitoring.

(4) Develop new methods for real time sensing if it’s not exist before. There are some spectroscopic and non-spectroscopic sensors and chemometric tools commercially available that can be adapted for monitoring of continuous pharmaceutical manufacturing process.

However, these sensors, and tools need to be systematically integrated in order to successfully monitored the continuous pharmaceutical manufacturing process.

The first step for real time monitoring

Manufacturing

is to build required calibration models.

The calibration model is only needed for spectroscopic sensors. After building a good calibration model, the next step is to integrate it with a prediction engine and PAT data management tool for real-time monitoring and control of pharmaceutical manufacturing process. There are different tools commercially available that can facilitate it. The central idea is same in case of each tool.

It involves the integration of spectroscopic sensor (e.g., NIR) with the plant through chute. After that, the sensor outlet needs to be connected with a computer in which the sensor operating software is installed. Through the sensor operating software, the raw data (spectrum) are collected in real time. The raw data are accessed from a real-time prediction tool. The PLS model should be already uploaded in the prediction

tool. The prediction tool employed the PLS model and uses the raw data as the inputs to the model and gives the signal of the variables that need to be monitored. The measured variable can then be sent to the control platform via OPC. 6. Real Time Process Control

The process control system need to be implemented for real time

Figure 2 Performance of control relevant process model www.pharmafocusasia.com

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Manufacturing

7. Results and Discussions 7.1. Process model and control system design

product quality assurance. In order to implement the control loops into continuous tablet manufacturing pilot-plant, the first step is to create control loops (PID /or MPC) in control platform. Then tune the controllers. For MPC, a model need to be developed as well. The NIR signal is the input to this control loop that generates the actuator. Finally, the actuator is sent to the plant via a suitable communication protocol.

The type of communication protocol depends on the unit operation where the control signal needs to be sent.

For example, the control platform communicates with the feeder via field bus (e.g., Profibus/Device Net) and with the tablet press via OPC. Finally, the performance of the control system needs to be evaluated experimentally.

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The control relevant process model has been developed.

The model successfully can predict the actuator, critical process parameters and critical quality attributes. The tablet press unit operation has been considered here as a demonstrative example. The model performance for prediction of actuators, critical process parameters and critical quality attributes are shown in Figure 2. The results show the close agreement between model prediction and experimental results.

The process model has been successfully applied for design and evaluation of control system for continuous pharmaceutical tablet manufacturing process. Control architectures for 3 manufacturing routes (DC, RC, WG) of continuous pharmaceutical manufacturing have been previously developed. Feedback control strategy has been also compared with combined feed forward / feedback control strategy. Compared PID, MPC and hybrid control algorithms.

Evaluated control system performance for set point tracking and disturbance rejection ability. Integrated gPROMS (PSE) simulation tool with MATLAB. Integrated gPROMS (PSE) simulation tool with DeltaV. 7.2. Automation, and real time monitoring of continuous pharmaceutical manufacturing process

Feeder has been integrated with control platform via profibus connection. Co-mill and Blender has been integrated with control platform via serial ports. Tablet press has been integrated via OPC. Spectroscopic sensors have been integrated with control platform via different software tools. Non spectroscopic sensors have been integrated with control platform via serial ports.

There are some inbuilt sensors in each unit operation of continuous pharmaceutical manufacturing process

to monitor different variables in real time. Feeder weight, powder flow rate and feeder screw rotational speed have been monitored at feeding operation using inbuilt sensor. Impeller speed has been monitored at co-milling operation. Blender RPM has been monitored at blending operation.

Tablet thickness, compression forces, ejection force, and operating parameters (e.g. fill depth, feed frame speed, turret speed) are monitored at the tableting operation using inbuilt sensor. Integrated supervisory sensors with plant and software tools for real time monitoring. Powder blend composition, uniformity (RSD) are monitored at the blending operation using NIR. Commercial sensors were not available for some variables which were desired to monitored in real time. Developed novel sensing methods for real time monitoring of powder bulk density. Developed method for real time monitoring of tablet weight. Developed method for real time monitoring of powder level in transfer pipe. The real time monitoring of powder level is shown in Figure 3. As shown in the figure, the production rate has been changed in order to change the powder level in transfer pipe. The sensor was able to monitor the powder level in real time.

7.3. Real time control of continuous pharmaceutical manufacturing process

Implemented supervisory control system into direct compaction continuous tablet manufacturing pilot-plant and compared PID with advanced Model Predictive Controller (MPC). Feeder-blender control to assure drug concentration has been experimentally demonstrated (Singh et al., 2014). Develop and implemented control system into connecting transfer pipes. It is difficult to run the continuous pharmaceutical tablet manufacturing process at steady state for longer time without the use of this controller.

This controller also makes sure a consistent powder level all the

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39

Manufacturing

Figure 3 Real time monitoring of powder level

8. Conclusions

Process System Engineering (PSE) methods and tools have been developed and applied to continuous pharmaceutical manufacturing process. The control relevant process model helps to design, tune and evaluate the control system prior to its implementation into the pilot-plant. CM pilot-plant has been 40

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automated to optimise the resources and to establish consistency in plant operation and data management. Real time monitoring and control system has been implemented into CM pilot-plant.

The real time control of continuous pharmaceutical manufacturing is a significant advancement in pharmaceutical industry and is considered essential for real time release as well as patient safety.

A u t h o r BIO

time in front of PAT sensors.

Implemented advanced control system into tablet press unit operation.

Developed control system for pre-compression force (i.e. control of tablet weight via pre-compression force).

Simultaneous control of pre and main compression forces (2x2 MPC) have been also demonstrated (i.e. control of tablet weight and hardness via pre and main compression forces respectively).

Supervisory control of tablet weight (Cascade MPC) has been added as well.

Acknowledgements: This work is supported by the US Food and Drug Administration (FDA), through grant 5U01FD005535, and National Science Foundation Engineering Research Center on Structured Organic Particulate Systems, through Grant NSF-ECC 0540855.

References are available at www.pharmafocusasia.com

Ravendra Singh is Research Assistant Professor at C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA, working in Pharmaceutical System Engineering research field. He is also serving as a manager and key researcher of “multi million dollars projects funded by NSF, FDA and pharmaceutical companies. He is the recipient of prestigious EFCE Excellence Award given in Recognition of an Outstanding PhD Thesis, from European Federation of Chemical Engineering.

He has published more than 52 research papers, written 11 book chapters, presented at over 93 international conferences and edited one pharmaceutical book from Elsevier. He is actively serving as a conference session chair, Journal reviewer and guest editor.

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41

Manufacturing

Modelling and its Applications in Solids-based Continuous Pharmaceutical Manufacturing Processes I The development of solids-based pharmaceutical manufacturing has been facilitated by the use of process modelling and simulation-based process analysis methods. Such in silico approaches are implemented to efficiently predict process behaviours, identify critical process parameters, and quantify the process design space, that contribute to an enhanced process understanding.

Marianthi Ierapetritou, Chair, Department of Chemical and Biochemical Engineering, Rutgers University Zilong Wang, PhD. Candidate, Department of Chemical and Biochemical Engineering, Rutgers University

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n recent years, the pharmaceutical industry has been actively involved in exploring advanced manufacturing processes that can help reduce the manufacturing costs and improve the product quality. One of the most promising route is the switch from batch to Continuous Pharmaceutical Manufacturing (CPM) processes. The continuous production mode enables a steady-state operation, where product quality exhibits only low variability over time. Therefore, a well-designed CPM process can result in improved product quality and uniformity. In addition, since

Manufacturing

a CPM process usually requires fewer steps than a batch process, it also helps to reduce capital and operation costs, which lead to a better economic efficiency.

A successful implementation of a CPM process requires to fully understand how different material properties and operations conditions can jointly affect the process behaviour and product attributes. Process modelling can facilitate this step and be used to store this knowledge. By applying modelling techniques to pharmaceutical manufacturing processes, we can achieve a better process understanding with only a limited number of experiments. A welldeveloped and validated process model can be utilised to further understand the process dynamics and moreover to efficiently transfer this knowledge. The objective of this paper is to present a variety of modelling approaches that have been developed in our lab in the last decade for solids-based CPM process, as well as how to use the models in a systematic manner to enrich the process understanding.

Process Modelling

The difficulties of modelling the solids-based pharmaceutical processes mainly result from the complexity of the particle-level and bulk behaviours of material flows. To address such difficulties, the Discrete Element Method (DEM) approach has been used for modelling various pharmaceutical processes. The DEM tracks the motion and positions of each particle individually, which then provides a huge amount of detailed information of the dynamics of particles. This information is usually hard to be obtained directly form physical experiments, but can be crucial to the investigation of particlelevel phenomena (e.g., segregation,

agglomeration). However, the DEM simulations are computationally intensive and can only be applied to systems with a limited number of discrete particles.

The Population Balance Models (PBMs) describe the time-dependent properties for a group of entities using a set of partial differential equations which involve the mass, momentum, and energy balance for the systems of interest. The term ‘entities’ are referred to particles whose states are described by a vector containing both internal coordinates (e.g., particle size, mass) and external coordinates (e.g., physical locations). Multidimensional PBMs have been used to model pharmaceutical processes with various internal coordinates (e.g., particle size, porosity, composition). However, they require a high computational cost to evaluate the model. Recently, hybrid models combining DEM simulations and PBMs have been developed to describe pharmaceutical processes such as granulation, milling, and mixing.

Data-driven models (sometimes known as Reduced Order Models) are an efficient approach to investigate the system input-output relationship when first-principle models are not available or too expensive to be obtained. A broad range of modelling techniques can be categorised as a data-drive approach.

Response Surface Methodology (RSM), probably the mostly used regression technique, describes the process with a low-degree polynomial model. A RSM model is usually constructed based on physical experiments using a Design of Experiment (DoE) sampling plan.

Partial Least Squares (PLS) regression

is a multivariate regression approach which projects the dataset to a lowerdimensional latent space where the correlation between process inputs (X) and outputs (Y) are maximised.

The PLS approach is especially useful to analyse high-dimensional and noisy data with strong collinearities between X and Y. Artificial Neural Network (ANN) is a modelling technique inspired by the way that human brain processes information. An ANN network consists of a number of single units (known as “neurons”) which are interconnected with coefficients (i.e. weights). The numerous ways of connecting different units constitute the foundation of the flexibility of the ANN models.

Kriging models a process output as the realisation of a Gaussian process, of which the errors are assumed to be spatially correlated. The Kriging model has the advantage of providing both the best linear predictor and the estimated prediction error, which are useful to evaluate the accuracy of the prediction and decide future sampling directions.

Kriging is a powerful approach to approximate expensive simulations which have complex and nonlinear surfaces.

Models for unit operations are the basic elements for understanding a process. At the Center for Structured Organic Particulate System (C-SOPS), a complete (and constantly being improved) model library has been developed for all the major unit operations of continuous pharmaceutical www.pharmafocusasia.com

43

Manufacturing

Figure 1 Flowsheet model used to predict the process dynamic behaviours

manufacturing processes, including feeding, mixing, milling, tableting, etc. Such models are implemented on a gPROMS simulation platform.

On the basis of these models, flowsheet models can be developed as an approximation of the plantwide manufacturing process. In a flowsheet model, unit operation models are connected with flow information being transferred between consecutive processing steps. As such, the process responses to the change in operations (or material variations) can propagate along the process, which can be predicted by the flowsheet model. This is demonstrated with Figure 1. The flowsheet of a Continuous Direct Compaction (CDC) process is shown on the left in Figure 1, where two raw materials (i.e., Active Pharmaceutical Ingredient (API), excipient) are fed to a co-mill for the purpose of de-lumping, after which the mixtures together with a lubricant, are transferred to a blender for mixing. The blends are sent to the press where tablet products are continuously produced. The dynamics of the process predicted from the flowsheet model are shown on the right in 44

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Figure 1. The top two charts show the flow rate and fill level of the API feeder.

We can notice that as the feeder runs, refilling of the materials is needed, which can cause temporal variations to the flow rate. In the bottom two charts, the propagation of such variations after the blender is predicted. It can be observed that after mixing the variations in the API composition are dampened to a much smaller level. Such predictions are useful in choosing the best refilling strategy that leads to products with desired quality attributes.

Model-based Process Analysis

A developed flowsheet model can be used to interrogate the process behaviour as illustrated in the previous section and provide invaluable information regarding risk analysis and process design space as will be described in this section.

Global Sensitivity Analysis

For a complex model with many input variables (X), it is usually the case that only a small subset of such variables has a huge impact on the process outputs (Y) of interest. Such influential model

inputs can be identified by the Global Sensitivity Analysis (GSA). Formally, GSA investigates how uncertainties in X can contribute to variations in Y over the whole input space.

Compared to local sensitivity methods which are based on calculating elementary effects around a single nominal point, GSA methods are based on space-filling sample points, and can reveal both the main effects and high-order interaction effects of X on Y. Various GSA methods have been developed for different engineering problems. In practice, when the sampling budget is limited, a more effective way is to first use a fast screening method (e.g., Morris method) followed by a more computationally costly variancebased method (e.g., Sobol’ method).

The screening method usually requires a much smaller number of sampling points and can be efficient in prioritising input factors by qualitatively comparing their influence on the outputs. After the results are obtained, the less important variables can be fixed at their nominal values, while the remaining input factors are analysed using the

Manufacturing

Figure 2 Intensity plot of the global sensitivity analysis result (22 input factors and 7 output variables)

Table 1 & 2

variance-based method. Although the variance-based method can require more sampling points, detailed information can be obtained to quantitatively examine the percentage of variance in Y that is apportioned to a certain input factor.

To demonstrate the use of GSA, we show a case study of a CDC process in Figure 2. In this example, we investigate how the 22 input factors (horizontal axis), including operation conditions and material properties, can affect the variations in 5 output variables (vertical axis), including product attributes and process responses.

The sensitivity information is visualised with an intensity plot: the darker the colour block, the more sensitive the input factor. From the results, we can see that only 6 input factors (i.e., API flow rate, Excipient flow rate, Excipient bulk density, Excipient true density, tablet die fill depth, tablet thickness

set point) have a critical influence on the 5 output variables of interest.

The results indicate that, when operating the process, controlling strategies should focus on the 6 most influential input factors in order to reduce the variability in the process outputs.

In pharmaceutical processes, the GSA methods have been successfully applied to reduce the dimensionality of a complex flowsheet model. The results are important to identify critical process parameters and provide guidance to the development of control strategies.

Feasibility analysis

To ensure the consistency of product quality, it is important to evaluate the process design space, which is defined as “the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide quality assurance” according to

the document “Guidance for Industry, Q8 Pharmaceutical Development” by Food and Drug Administration (FDA).

The design space can be mathematically defined via the use of feasibility analysis.

The objective of feasibility analysis is to quantify the feasible region within which all the process constraints are met. Mathematically, feasibility can be defined as the maximum violations of all the constraints: ψ(θ)= max┬(j∈J) {g_j (θ)}. As such, the feasibility analysis problem is to identify the region where ψ(θ)≤0.

In our group, we have developed an efficient approach called “surrogatebased feasibility analysis” to characterise the design space for pharmaceutical processes. The advantage of this approach is to accurately predict the design space with the smallest sampling budget. This is demonstrated with the following case study. On the basis www.pharmafocusasia.com

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Manufacturing

Figure 3 Surrogate-based feasibility analysis for a tablet press model

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Summary and Future Work

In this article, we have discussed different modelling techniques that have been used to study solids-based continuous pharmaceutical manufacturing processes. The capabilities of flowsheet models to predict process dynamic behaviours are demonstrated with an example of a direct compaction process.

Further applications of flowsheet models include global sensitivity analysis and feasibility analysis, which are extremely beneficial in identifying critical process parameters and characterising the process design space. Future work is focused on improving the current

A u t h o r BIO

of a developed tablet press model, our objective is to find the design space within the ranges of uncertain parameters (i.e., API flow rate and Tablet die fill depth) in Table 1, that will result in the qualified tablets with properties (i.e., hardness, weight, API composition) within the specified ranges in Table 2.

The surrogate-based feasibility analysis solves this problem in the following 3 steps (Figure 3). First, an initial low-fidelity surrogate model is built with a small number of space-filling sample points obtained by running the tablet press model.

Then, adaptive sampling is performed to iteratively sample where it is more likely to be the design space boundary. At each iteration, the knowledge of the actual design space is improved, and the accuracy of the surrogate model also gets updated.

Finally, when the sampling budget is depleted, the highly accurate prediction of the design is returned by the surrogate model, which is shaded in the grey area in Figure 3. Therefore, in order to produce qualified tablet products, the operation conditions should be controlled within this shaded design space: 9.05≤ fill depth [mm] ≤9.25 ∩2.1≤API flow rate [kg/h]≤2.4. Any combination of operations out of this region will cause violations of at least one of the quality constraints in Table 2.

models with additional experiments, and extending the current model-based process analysis framework to other continuous manufacturing processes.

Acknowledgment: The authors would like to acknowledge financial support from FDA (DHHS - FDA - 1 U01 FD005295-01) as well as National Science Foundation Engineering Research Center on Structured Organic Particulate Systems (NSF-ECC 0540855).

References are available at www.pharmafocusasia.com

Marianthi Ierapetritou is a Distinguished Professor and the chair at the Department of Chemical and Biochemical Engineering at Rutgers University in Piscataway, New Jersey. She completed her Bachelor’s study at National Technical University (Athens, Greece), and obtained her PhD degree from Imperial College (London, UK) in 1995. She did her post-doctoral research at Princeton University (Princeton, NJ) and then joined Rutgers University in 1998. Her research is focused on scheduling, planning, and supply chain management; uncertainty analysis; modelling and optimization of pharmaceutical and biopharmaceutical processes and biomass conversion technologies.

Zilong Wang is currently a PhD candidate in the Department of Chemical and Biochemical Engineering at Rutgers University. He got his Bachelor’s degree from Dalian University of Technology (Dalian, China) in 2012 and his Master degree from Carnegie Mellon University (Pittsburgh, PA) in 2013. His research interests include modelling for continuous pharmaceutical manufacturing processes, applying the sensitivity and feasibility analysis to the simulationbased process development, and investigating surrogate-based methods for optimization under uncertainty.

www.pharmafocusasia.com

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Manufacturing

Safe and

Secure

Packaging's role in combating counterfeit drugs Counterfeiting is currently one of the biggest challenges that the pharmaceutical industry is facing, and the amount of counterfeit drugs in the market globally is continuing to grow. In this article Essentra explains how packaging can help to tackle the issue, showing how incorporating a combination of measures can provide enhanced protection.

Chandan Pat, Business Development Manager, Essentra

A

ccording to data released by the United States Food and Drug Administration (USFDA), approximately 10 per cent of all pharmaceuticals sold globally are counterfeit. Whilst counterfeiters are active around the world, not all markets suffer equally. Unsurprisingly, the World Health Organization (WHO) reports that developed nations - such Europe and the USA -are least affected by counterfeit pharmaceutical goods with an estimated 1 per cent penetration rate, whilst developing nations show particularly severe levels. It is estimated that up to 48

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30 per cent of all medicines in Africa and the Far East are fake, and in 2011 it was reported that a staggering 64 per cent of all antimalarial drugs in Nigeria were counterfeit.

Due to a lack of enforcement capacity and increasingly complex supply chains, particularly with the expansion of e-commerce, these figures are continuing to grow. According to the WHO, it is believed that up to 50 per cent of drugs available online are fake –with estimates reaching up to 70 per cent in some African and Eastern European countries. Plus, counterfeiters

are becoming ever more sophisticated and relentless in their efforts; in some parts of Asia, they are known to pay patients leaving pharmacies to obtain their genuine drug boxes and then fill them with false products afterwards.

This is a critical issue for the industry, as falsified medicines are not only harmful to the brand owners that manufacture the legitimate product-as consumers may not trust brands that are widely counterfeited-but can be extremely dangerous to patients.

In light of this, governments around the world are implementing

Manufacturing

Despite the issues facing the industry, the effectiveness of such legalisation at country level should not be underestimated. Not only has it publicly raised the issue of illic it medicines, but it has also proposed some specific anti-counterfeit solutions.

Indeed, as a leading global provider of healthcare packaging and security technologies, Essentra advocates the implementation of multi-layered solutions incorporating a combination of measures to provide enhanced protection.

Track & Trace: Serialisation

new legislation. However, without a global standard, regulation in this area often differs by country, allowing counterfeiters to exploit these loopholes.

For example, in China all healthcare packaging currently includes a 20-digit Electronic Drug Monitoring Code (EDMC) so packs can be tracked and tested for authenticity throughout the supply chain. However, the China Food & Drug Administration (CFDA) issued a notice in 2016 stating that amendments to the drug system needed to be made following criticism of the system; the key issue being the fact that the EDMC

coding format did not correspond with other traceability systems around the world, with many countriesincluding South Korea, India and Turkey-using the Global Trade Item Number (GTIN) format. Another notable law that was introduced includes the EU Falsified Medicines Directive (FMD) in 2016. The new legislation will apply to a number of medicinal products for human use and will consist of two key elements of safety features – track and trace serialisation and tamper verification solutions.

Serialisation is the system of tracking, tracing and verifying products via unique identification codes. The codes are commonly presented as a linear barcode, 2D barcode or a combination of numbers, and technologies for more advanced solutions are currently being developed. No matter the format, the code will convey key data elements about the drug contained in the box, such as the drug’s product code, national reimbursement and identification number, batch number and expiry date of the unique identifier.

This will reveal a complete history of the drug; from the supplier to consumer, for the entire duration of the drug’s life on the market and additional time necessary for returning and disposing of the pack after it has expired. In addition to confirming the integrity of the medicine and helping to ensure that patients are taking the correct reliable medicine, these data elements also facilitate withdrawal and return procedures should a recall be necessary.

However, there still remain a number of challenges that the pharmaceutical industry must overcome when implementing an efficient serialisation system. Firstly, a uniform system must be put in place that meets the requirements at each level of the supply chain. This may require existing suppliers and companies within the supply chain to integrate new IT systems, databases www.pharmafocusasia.com

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Manufacturing

and business structures, which could prove difficult both financially and administratively. Plus the creation of the required serial codes themselves will call for significant expenditure, particularly if additional elements are included. The more complex the structure of the serial codes, the more challenging standardisation will be across all companies in the supply chain. According to some estimates, the majority of the coding solutions currently used in the pharmaceutical and healthcare industries could be rendered obsolete due to the FMD. The key to the implementation of a successful serialisation system is the ability to run an effective data storage mechanism that allows for precise information management. The process of track and trace will mean that every point within the manufacturing chain will have to carry out a stop-check, resulting in the collection of a large amount of data. Each individual unit will have a unique identifying code which, once printed and supplied to the public, must be noted in the system so any other pack that has the same code cannot be verified. If, under certain circumstances, a box is accidentally damaged and made unusable, the code must be recorded as inactive. The organisation of this vast network of data will prove challenging, so companies and governments must work together to create a successful way of managing it effectively.

One country that is currently running a comprehensive track and trace infrastructure is Turkey. The system was initially implemented as a means of combatting insurance fraud, but is now capable of tracking and tracing all products entering and circulating the country. Goods are constantly documented as they advance through the supply chain and, when the goods finally reach the consumer, these unique identifiers are cross-referenced with the master database to confirm the product’s authenticity and original manufacturer.

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It is estimated that up to 30 per cent of all medicines in Africa and the Far East are fake, and in 2011 it was reported that a staggering 64 per cent of all antimalarial drugs in Nigeria were counterfeit.

Tamper Verification

Indeed, while serialisation verifies the authenticity of the pack of medicine, counterfeiters can easily collect and recycle genuine containers and refill them with fake product, reclosing the original packaging and passing the product off as genuine. This

demonstrates the need for a multilayered security approach, to provide protection for both the packaging and the contents inside.

Tamper verification shows whether the packaging has been opened or altered since it left the manufacturer, ensuring that the contents are authentic.

It gives confidence to the end user, allowing them to personally judge that the product is genuine and originates from the legitimate manufacturer.

Tamper evidence can be built into the design of cartons via the use of glued locks, such as the reverse-tuck end with glued flaps, or dagger locks.

Side-walled glued skillets with scored top openings and standard side-wall glue skillets with zip-tear openings provide additional solutions. All of these ‘built-in’ features involve the destruction of the original carton. These features also allow for easy opening of the pack, helping to improve the user’s experience and eliminate any issues that could make the consumer wary of a particular brand or product.

Manufacturing

Authentication Systems

Lastly, authentication systems help consumers to verify if packaging is genuine. Authentication solutions can come in different forms, mainly categorised as overt, covert or forensic.

light. For an extra advanced layer of authentication there are also forensic solutions—which include molecular markers and biological tracers—which can only be identified using laboratory equipment.

Summary

Overt solutions are visible, and therefore allow authentication by consumers.

Solutions in this category, for example colour shift inks, can offer both security and the ability to provide shelf appeal by enhancing a brand. However, overt technologies highlight exactly what a counterfeiter should target, and as they often rely on consumer verification to distinguish genuine from fake, the counterfeiter only has to be good enough to deceive an untrained user.

Covert solutions are viewed to offer a greater level of protection to a product, as they are not visible and therefore more difficult to replicate. Covert features generally will have a visible response when exposed to the correct activation condition, for example, UV

A u t h o r BIO

In the case of sealing labels, tamper verification can be provided with differing levels of sophistication. At entry level, straight forward fibre-tear labels use a permanent adhesive that, when removed, irreversibly damages both the print and the board of the carton to which it is affixed. However, from a consumer’s perspective, the removal of the label may leave behind unsightly remnants on the packaging, to the point where some may not want to use the same box to store any remaining medication. As a result, consumers may be left with a negative impression of the brand rather than appreciate the tamper verification that has been provided.

Void release labels present a more aesthetically pleasing experience than fibre-tear labels, leaving behind a visual cue on the original packaging upon removal. This cue can be in the form of a void message or a specifically designed pattern. These labels indicate if the product has been tampered with but keep the pack intact, maintaining the consumer’s impression of the brand.

Additionally the upscale look of a specially designed pattern can help consumers identify that the seal and associated remaining image on the original packaging were intended to protect them – giving them confidence in the authenticity of the product.

Even more advanced than this are frangible film labels, which include a substrate that disintegrates the label when consumers attempt to remove it from the carton.

Additional features can also be applied to the label to help consumers engage with the label and the brand. For example, adding a finger-lift feature to a fibre-tear or void release label can help consumers remove the label and gain access to the package more easily.

It is clear that pharmaceutical companies and governments must act now to protect consumers from the threat of counterfeiters and ensure that pharmaceutical products have not been altered. By implementing multilayered solutions, including tamper verification features, track and trace serialisation and authentication measures, pharmaceuticals can ensure that their products are protected. Such layers should, wherever possible, be intrinsic to the item or packaging, to ensure that the item is authenticated rather than the security feature alone.

With various legislation to be implemented around the world in the coming years, many companies have either created new security and serialisation systems in-house or have organised outsourcing to packaging companies, such as Essentra. It is important however that companies arrange security and serialisation solutions for their bespoke, specialist and short-run products, as well as their standardised product lines. Though introducing these solutions may be costly, it is an investment that will benefit individual companies and the industry as a whole for years to come.

Not only will they be compliant with regulation, but patients will also be confident that the medicines they receive are safe for use.

Chandan is an active member in the packaging and the associated industries. In his current position, he handles the business of Health & Personal Care Packaging at Essentra. Prior to Essentra Chandan worked in business development, sales and marketing functions in industries such as personal care, home care and packaged food & beverages.

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WHERE HEALTHCARE CONNECTS WITH TECHNOLOGY 12th edition of MEDICAL FAIR ASIA - International Exhibition on Hospital, Diagnostic, Pharmaceutical, Medical & Rehabilitation Equipment & Supplies 29-31 August 2018 | Marina Bay Sands Singapore

Technology encapsulates our everyday lives, nowhere is this more obvious than in healthcare, where technology goes beyond convenience, it is helping to save lives. At MEDICAL FAIR ASIA 2018, preparation is in full swing for the 12th edition, which will deliver a future-ready platform of drivers and enablers highlighting new approaches that have the potential to revolutionise the medical world.

The 3-day exhibition is the region’s leading event for all those involved in medical and health-

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care, and this year will see technology come alive with products and solutions with far-reaching implications for delivery of care for the future.

MEDICAL FAIR ASIA 2018 is a highly-anticipated event on the medical and healthcare calendar and this year promises to be the largest edition in the twentyyear history with 1,000 exhibitors from 50 countries and 20 national pavilions.

Highlights in 2018 • Start-Up Park • FTR4H Lab & Lounge At the forefront of MEDICAL FAIR ASIA 2018 is the inaugural Start-Up Park, a dedicated showcase for innovative start-ups with cutting-edge healthcare technologies to meet the future needs of the industry.

Visitors can expect to see product presentations as well as source for the latest innovative solutions.

Housed within the Start-Up Park is the Future 4 Health (FTR4H) Lab & Lounge - a networking platform that facilitates the exchange of ideas and discussions among digital health start-ups, tech incubators, new companies and potential investors.

• Community Care Pavilion Further augmenting this focus on technology and futureready solutions at MEDICAL FAIR ASIA 2018 is the debut of the Community Care Pavilion – a comprehensive showcase focused on medical solutions for the ageing population and remote population which will include geriatric medicine, and products and solutions such as rehabilitative equipment, mobility products using robotic technology, assistive technology, smart fabrics and wearable technology.

• MEDICINE + SPORTS CONFERENCE Beyond the stellar line-up of exhibitors and technologies, MEDICAL FAIR ASIA also serves as a centre of knowledge for industry professionals to exchange ideas and share insights. The MEDICINE + SPORTS CONFERENCE is set to return for its second edition, and is a one-day conference and a multidisciplinary exchange forum where participants learn, network, and engage with those passionate about science and sports medicine. The event brings together sports medicine experts, healthcare professionals, athletes and sport techies, and

those from sporting goods, sports, and fitness and healthcare industries.

• Medtech SME Workshop 2018 Organised by Asia Pacific Medical Technology Association (APACMed), the workshop aims to provide start-ups and SMEs with practical guidance on topics such as bench to prototyping, clinical trials and production, commercialisation and post-market surveillance.

Co-location with MEDICAL MANUFACTURING ASIA 2018 The synergistic co-location of the 4th edition of MEDICAL MANUFACTURING ASIA with MEDICAL FAIR ASIA 2018 will see the two exhibitions showcasing the full spectrum of end-to-end solutions for the medical and healthcare sectors. Jointly organised by Messe Düsseldorf Asia and Singapore Precision Engineering & Technology Association (SPETA), MEDICAL MANUFACTURING ASIA will feature an extensive product range from upstream to downstream processes in the medtech sectors - from new materials, components, micro and nanotechnology, testing systems and services, to substance and components for medical technology.

The Southeast Asian market offers a diverse range of business opportunities for potential exhibitors and visitors, making MEDICAL FAIR ASIA 2018 the ideal platform for companies to do business, network and share best practices.

For more information, log on to: www.medicalfair-asia.com Advertorial www.pharmafocusasia.com

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MEDICAL MANUFACTURING ASIA 2018 Delivering solutions for the future of medtech Mark your calendar for the 4th Manufacturing Processes for Medical Technology Exhibition and Conference from 29-31 August 2018

Innovative medical technology is an increasingly important driver for delivering efficiencies in the global healthcare system. Through advances in medical technology, precision engineering, micro-manufacturing processes, and IT, medical devices and solutions have become more sophisticated, accurate and effective.

As a specialist exhibition on manufacturing processes for medical technology, the 4th edition of MEDICAL MANUFACTURING ASIA will focus on new manufacturing technology and automation which play vital roles in driving innovation and operations. The upcoming edition will highlight companies that cover the spectrum of additive manufacturing or 3D printing technologies, imaging and diagnostic

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imaging solutions, as well as nano manufacturing and automated solutions.

Singapore continues to grow its medtech presence on the world stage, with a sizeable number of complex scientific instruments already designed and manufactured in the country, the 3-day exhibition strongly reflects Singapore’s focus on moving upstream to not just production but also value engineering. For companies keen on engaging global medtech companies and see Singapore as an ideal base to develop products for the Asian region, MEDICAL MANUFACTURING ASIA 2018 provides a highly relevant springboard.

MEDICAL MANUFACTURING ASIA 2018 comes against a dynamic backdrop which sees the Asia

Pacific medtech market expected to surpass the European Union by 2020 as the world’s second largest medtech market after the United States1, while on the global front, the medtech sector is expected to grow 5 per cent or more annually through to 2022, to reach nearly US$530 billion2.

With Singapore’s positioning as Asia’s top location for medtech and home to over 30 globally-recognised medtech companies, MEDICAL MANUFACTURING ASIA 2018 continues to attract a highly international exhibitor base coming mainly from Asia and Europe and a trade visitor base that is predominantly represented by the medical devices and instruments, medical and healthcare, and electrical and electronic sectors from around the region.

Complementing the exhibition is the half-day forum on High-technology for Medical Devices where exhibitors will present and share latest developments and trends on the global and domestic fronts and market opportunities for medtech products from Europe. Organised by IVAM Microtechnology Network, the German-based international association has an extensive membership with companies in the fields of microtechnology, nanotechnology, advanced materials, and photonics.

MEDICAL MANUFACTURING ASIA 2018 is also synergistically co-located with the region’s

1. APACMed Annual Report 2016

leading medical and healthcare exhibition, MEDICAL FAIR ASIA – thus providing an end-to-end solutions and business sourcing platform across the entire value chain for the medical, healthcare, medical manufacturing and medtech sectors. Jointly organised by SPETA (Singapore Precision Engineering and Technology Association) and Messe Düsseldorf Asia, the exhibition is modelled after the No.1 global trade fair in the medtech sector, COMPAMED, held in Düsseldorf, Germany.

The 4th edition of MEDICAL MANUFACTURING ASIA is fast gaining traction as the region’s leading specialist trade exhibition for the medtech and medical manufacturing sectors. Following the success of the 2016 edition, the exhibition welcomed 200 companies from 18 countries, and 5,420 trade visitors from 52 countries. For booth space booking and more information on MEDICAL MANUFACTURING ASIA 2018, please visit www.medmanufacturing-asia.com.

For more information on the exhibition, please contact: Exhibitor Contact: Daphne Yeo Senior Project Manager Tel: (65) 6332 9682 daphne@mda.com.sg Press Contact: Melvin Chye Marketing & Communications Executive Tel: (65) 6332 9652 melvin@mda.com.sg

2 EvaluateMedTech™ World Preview 2018

Advertorial www.pharmafocusasia.com

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Books

Multi-Scale Approaches in Drug Discovery

Biopharmaceutical Processing

Principles and Practice of Clinical Research

Author: Alejandro SpeckPlanche

Author: Gunter Jagschies, Eva Lindskog, Karol Lacki, Parrish Galliher

Author: John I. Gallin, Frederick Ognibene, Laura Lee Johnson

Year of Publishing: 2017

Year of Publishing: 2017

No. of Pages: 1308

No. of Pages: 824

Description: Biopharmaceutical Processing: Development, Design, and Implementation of Manufacturing Processes covers bioprocessing from cell line development to bulk drug substances. The methods and strategies described are essential learning for every scientist, engineer or manager in the biopharmaceutical and vaccines industry.

Description: Principles and Practice of Clinical Research, Fourth Edition has been thoroughly revised to provide a comprehensive look at both the fundamental principles and expanding practice of clinical research. New to this edition of this highly regarded reference, authors have focused on examples that broadly reflect clinical research on a global scale while including a discussion of international regulations, studies, and implications.

Year of Publishing: 2017 No. of Pages: 238 Description: Collecting together reviews and original research contributions written by leading experts in the field, Multi-Scale Approaches to Drug Discovery highlights cutting-edge approaches and practical examples of their implementation for those involved in the drug discovery process at many different levels. Using the combined knowledge of medicinal, computational, pharmaceutical and bio- chemists, it aims to support growth in the multi-scale approach to promote greater success in the development of new drugs.

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The integrity of the bioprocess ultimately determines the quality of the product in the biotherapeutics arena, and this book covers every stage including all technologies related to downstream purification and upstream processing fields. Economic considerations are included throughout, with recommendations for lowering costs and improving efficiencies. Designed for quick reference and easy accessibility of facts, calculations and guidelines, this book is an essential tool for industrial scientists and managers in the biopharmaceutical industry.

In addition to key topics such as bioethics, clinical outcome data, cultural diversity, protocol guidelines, and “omic� platforms, this edition contains new chapters devoted to electronic health records and information resources for clinical researchers, as well as the many opportunities associated with big data. Covering a vast number of topics and practical advice for both novice and advanced clinical investigators, this book is a highly relevant and essential resource for all those involved in conducting research.

Pharmaceutical Medicine and Translational Clinical Research

Process Systems Engineering for Pharmaceutical Manufacturing, Volume 41

Author: Divya Vohora, Gursharan Singh

Author: Ravendra Singh, Zhihong Yuan

Author: Peter Kleinebudde, Johannes Khinast, Jukka Rantanen

Year of Publishing: 2017

Year of Publishing: 2018

Year of Publishing: 2017

No. of Pages: 526

No. of Pages: 692

No. of Pages: 620

Description: Pharmaceutical Medicine and Translational Clinical Research covers clinical testing of medicines and the translation of pharmaceutical drug research into new medicines, also focusing on the need to understand the safety profile of medicine and the benefit-risk balance.

Pharmacoeconomics and the social impact of healthcare on patients and public health are also featured. It is written in a clear and straightforward manner to enable rapid review and assimilation of complex information and contains reader-friendly features.

Description: Process Systems Engineering for Pharmaceutical Manufacturing: From Product Design to Enterprise-Wide Decisions, Volume 41, covers the following process systems engineering methods and tools for the modernization of the pharmaceutical industry: computer-aided pharmaceutical product design and pharmaceutical production processes design/ synthesis; modelling and simulation of the pharmaceutical processing unit operation, integrated flowsheets and applications for design, analysis, risk assessment, sensitivity analysis, optimization, design space identification and control system design; optimal operation, control and monitoring of pharmaceutical production processes; enterprise-wide optimization and supply chain management for pharmaceutical manufacturing processes.

Description: This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both smallmolecule-based products and protein/ peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize stateof-art approaches for innovative new manufacturing principles.

As a greater understanding of these aspects is critical for students in the areas of pharmaceutical medicine, clinical research, pharmacology and pharmacy, as well as professionals working in the pharmaceutical industry, this book is an ideal resource.

Continuous Manufacturing of Pharmaceuticals

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Latest Happenings PreveCeutical Medical Inc. Engineers the World’s First Nose-to-Brain Drug Delivery Platform Canada-based PreveCeutical Medical Inc. has announced its new paradigm in cannabinoid drug delivery. It has introduced new technique to engineer a Sol-gel nose-to-brain delivery platform that provides direct, controlled pharmacological drug release.

Sol-gel technology is designed for enhanced efficacy, targeted delivery and superior time release of cannabinoid (CBD) based medications.

PreveCeutical’s platform circumvents the blood stream and allows specific doses to reach specific targets without the filtering and metabolism that occur in the liver.

Study has proved that Cannabidiol (‘CBD’) may drastically decrease swelling and is now extensively utilised to treat chronic pain, multiple sclerosis and fibromyalgia, epilepsy, and numerous other conditions. CBD also has potential to avoid symptoms of Alzheimer's and appears to restrain the growth of cancer cells and promote the death of these cells.

CBD is a non-psychoactive compound found in the cannabis sativa plant.

Novartis Joins Hands with Bill & Melinda Gates Foundation to Develop Cryptosporidiosis Drug Novartis and the Bill & Melinda Gates Foundation have joined hands to develop the Novartis' drug candidate KDU731 for the treatment of a deadly diarrheal disease called cryptosporidiosis.

KDU731 is a Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) inhibitor, which was observed to treat Cryptosporidium infection in preclinical models effectively and is currently undergoing safety studies prior to the initiation of clinical trials.

Under the terms of the agreement, the Bill & Melinda Gates Foundation will be funding a sum of US$6.5 million to support the development of this drug candidate for the treatment of children by the Novartis Institute for Tropical Diseases (NITD).

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Diarrheal diseases are one of the leading causes of childhood deaths throughout the world, resulting in approximately 525,000 deaths each year and cryptosporidiosis being the second leading cause of infectious diarrhea in children less than 2 years of age.

Gilead to use Sangamo's Technology to Develop Next-generation Engineered Cell Therapies for Cancer Treatments Gilead Sciences' Kite unit enters into global collaboration to use Sangamo Therapeutics' Zinc Finger Nuclease (ZFN) technology platform for the development of next-generation ex vivo cell therapies in oncology.

Sangamo’s zinc finger nucleases provide the optimal gene editing platform.

Kite will utilise the Sangamo’s ZFN technology to alter the genes to develop next-generation cell therapies for autologous and allogeneic use in treating different cancers.

Under the terms of the agreement, Sangamo will receive an upfront payment of US$150 million and is eligible to receive up to US$3.01 billion in potential payments, aggregated across 10 or more products utilising Sangamo’s technology.

AstraZeneca and Merck Announced CHMP’s Positive Opinion for Marketing LYNPARZA AstraZeneca and Merck have announced a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for the use of Lynparza (olaparib) in platinum-sensitive, relapsed, high-grade, epithelial ovarian, fallopian tube or primary peritoneal cancer.

The CHMP opinion recommends marketing authorisation of 300mg twice-daily Lynparza tablets as a maintenance therapy for patients who are in complete or partial response to platinum-based chemotherapy.

LYNPARZA is recommended for treatment in this setting regardless of patients' BRCA mutation status.

The CHMP recommendation is based on two randomised trials, SOLO-2 and Study 19, which showed LYNPARZA (olaparib) reduced the risk of disease progression or death for platinum-sensitive relapsed patients compared to placebo.

Eli Lilly Announces Additional FDA Approval for Verzenio Eli Lilly and Company announced that the US Food and Drug Administration (FDA) has approved VerzenioTM (abemaciclib) in combination with an Aromatase Inhibitor (‘AI’) as initial endocrine-based therapy. VerzenioTM is used for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. ` This approval of Verzenio as initial therapy in combination with an AI is based on the efficacy and safety demonstrated in the pivotal MONARCH 3 clinical trial.

MONARCH 3 is a Phase 3, randomised, double-blind, placebo-controlled trial evaluating Verzenio in combination with an AI as initial endocrine-based therapy that enrolled 493 postmenopausal women with HR+, HER2- advanced breast cancer who had no prior systemic treatment for advanced disease.

This Verzenio new drug application was given Priority Review as part of the FDA's Expedited Programs for Serious Conditions, a program used for therapies that address an unmet medical need in the treatment of serious or life-threatening conditions, such as metastatic breast cancer.

BeiGene Announces Supply Agreement for Tislelizumab BeiGene and Boehringer Ingelheim Biopharmaceuticals (China) Ltd. announced that the two companies have entered into a commercial supply agreement for tislelizumab, BeiGene's investigational anti-PD-1 antibody.

Tislelizumab will be manufactured in Boehringer Ingelheim's world-class biopharmaceutical manufacturing facility in Shanghai as part of a Marketing Authorization Holder trial project pioneered by BeiGene and Boehringer Ingelheim.

Under the terms of the supply agreement, Boehringer Ingelheim will manufacture tislelizumab in China under an exclusive multi-year arrangement, with contract extension possible. In addition, BeiGene also obtained certain preferred rights for future capacity expansion by Boehringer Ingelheim in China.

Biocon and Sandoz to Develop Next-gen Biosimilars in Immunology, Oncology Biocon has partnered with Sandoz, a Novartis division, to develop, manufacture and commercialise multiple biosimilars in immunology and oncology for patients worldwide.

Under the terms of the agreement, both companies will share responsibility for end-to-end development, manufacturing and global regulatory approvals for a number of products and will have a cost and profit share arrangement globally.

Worldwide commercialisation responsibilities will be divided and each company's strengths will be leveraged within specific geographies. Sandoz will lead commercialisation in North America and the EU while Biocon will lead commercialisation in Rest of the World.

Takeda Collaborates with Wave Life Sciences Ltd. to Develop Innovative Treatments for Neurological Diseases Osaka, Japan – Takeda Pharmaceutical Company Limited announced that it has entered into a research, development and commercial collaboration and multi-program option agreement with Wave Life Sciences Ltd. (Wave) to develop antisense oligonucleotides for genetically-defined neurological diseases.

The first component of the collaboration with Wave will focus on programs targeting Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) (commonly referred to as Lou Gehrig’s disease), frontotemporal dementia (FTD) and spinocerebellar ataxia type 3 (SCA3).

The second component of the collaboration provides Takeda with the rights to exclusively license multiple preclinical programs targeting other neurological disorders including Alzheimer’s disease and Parkinson’s disease. At any one time during a four-year term, the companies may collaborate on up to six preclinical programs.

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Products & Services Company.........................................................Page No.

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

STRATEGY CISCO........................................................................... 29

CLINICAL TRIALS IMMEXLS....................................................................... 23

Ethiopian Cargo............................................................ 05

Swiss World Cargo....................................................... 33

F.P.S. Food and Pharma Systems Srl........................... 24 Medical Manufacturing Asia (MMA 2018)......... 15, 54-55

MANUFACTURING Akzo Nobel Chemicals (India) Ltd.............................. IFC

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

BMG LABTECH GmbH............................................... IBC

Medical Fair Asia (MFA 2018)........................... 13, 52-53

FlyPharma Asia............................................................. 39 RESEARCH & DEVELOPMENT CISCO........................................................................... 29

Pharma Connect Congress.......................................... 41

F.P.S. Food and Pharma Systems Srl........................... 24

Vetter Pharma............................................................... 03

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

IMMEXLS....................................................................... 23

Suppliers Guide Company.........................................................Page No.

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

Akzo Nobel Chemicals (India) Ltd.............................. IFC www.kromasil.com

Medical Fair Asia (MFA 2018)............................ 13, 52-53 www.medicalfair-asia.com

BMG LABTECH GmbH............................................... IBC www.bmglabtech.com

Medical Manufacturing Asia (MMA 2018).......... 15, 54-55 www.medmanufacturing-asia.com

CISCO........................................................................... 29 https://ciso.eccouncil.org/portfolio/pharma-cio-2018/

Pharma Connect Congress.......................................... 41 www.pharmconnect.eu

Ethiopian Cargo............................................................ 05 www.ethiopianairlines.com/cargo

Swiss World Cargo....................................................... 33 www.swissworldcargo.com

F.P.S. Food and Pharma Systems Srl........................... 24 www.foodpharmasystems.com

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

FlyPharma Asia............................................................. 39 www.FlyPharmaAsia.com

Vetter Pharma............................................................... 03 www.vetter-pharma.com

IMMEXLS....................................................................... 23 www.immexls.com

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it.

1.IFC: Inside Front Cover, 2.IBC: Inside Back Cover, 3.OBC: Outside Back Cover

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