ipi - dec 2014 - volume 6 issue 1

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Volume 6 Issue 4

Peer ReviewedInternational Pharmaceutical Industry Supporting the industry through communication

‘Personal Pill’ RegulationsCurrent Landscape and Future Scenario

Revisited Cell Cultures and Valuable MethodsFor Pre-clinical Studies

Transforming Temperature Data Management PracticesTo Reduce Labour Costs and Improve Visibility and Control

Beyond Item Level SerializationExtending Traceability Schemes to Secondary and Tertiary Packaging

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1www.ipimedia.com

Contents

DIRECTORS: Martin Wright Mark A. Barker

EDITOR:Cecilia [email protected]

EDITORIAL ASSISTANTOrsolya [email protected]

BOOK MANAGER: Anthony Stewart [email protected]

BUSINESS DEVELOPMENT:John [email protected]

DESIGN DIRECTOR: Fiona Cleland

CIRCULATION MANAGER:Dorothy [email protected]

FINANCE DEPARTMENT: Martin [email protected]

RESEARCH & CIRCULATION:Heather [email protected]

COVER IMAGE: iStockphoto ©

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All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers.

The next issue of IPI will be published in February 2015. ISSN No. International Pharmaceutical Industry ISSN 1755-4578.

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright.

2014 PHARMA PUBLICATIONSVolume 6 issue 4 - Winter - 2014

International Pharmaceutical Industry Supporting the industry through communication

06 Editor’s Letter

REGULATORY & MARKETPLACE

08 The Hunt for Talent in Asia: Mind the (Generation) GapAs more global life sciences firms see their Asian businesses skyrocket, the search for strong, internationally-savvy talent in Asia-Pacific has never been more competitive. After four years of living and working in China and Singapore, Susan Macdonald, Director of Channels and Global Partners for RSA, the leading global Life Sciences Executive Search and Interim Management specialist, returned to the UK this year. Here Susan chats with Thomas Meininghaus of Siemens Audiology Solutions about the unique challenges of recruiting to fill senior roles in Asia.

12 “Personal Pill” Regulations: Current Landscape and Future ScenarioThe rapidly-evolving science of pharmacogenetics brought in the amazing concept of “personalisation of medicines” also referred to as the “personal pill”. Balamuralidhara V., Blessy A. Daniel, T.M. Pramod Kumar and Pratik Thakkar of JSS College of Pharmacy, Mysore, India aim to showcase the potential of this “personal pill” to revolutionise drug discovery and development as the explosion of interest in pharmacogenomics raises a number of concerns in the regulatory environment.

20 Cost Savings for Healthcare Estates: Delivered through Improved Waste Management

You only have to read a newspaper or turn on the news to see how the NHS is struggling to meet the balance between demand for healthcare services and funding. Tony Mottram of GPT Waste provides this white paper as a reference tool for healthcare estates managers and finance directors to demonstrate the opportunities for cost savings through the implementation of effective, improved waste management strategies. It is based on a simple example, a new approach and the impact it has had on a healthcare organisation’s bottom line.

24 A Hard Pill to Swallow: Meeting the Needs of Modern ConsumersConfronted with the “patent cliff”, dwindling drug discovery success and a host of other challenges, pharmaceutical companies are being forced to reconsider how they can remain profitable. This includes looking to external experts to foster innovation and a move towards actively placing every need of the modern patient at the centre of their strategy. Dr Thomas Hein of Hermes Pharma analyses the results of a recent survey that revealed a number of clear trends, highlighting that approximately 50% of the population have difficulties swallowing tablets and capsules.

28 How Much Data Should You Include in a Patent Application?In the life sciences and chemistry fields it is important to be aware that a perceived lack of data in a patent application can have an impact on the eventual scope of protection available. Chris Bond of Forresters explains that is often necessary to decide how much data to include in a patent application in support of the claimed utility, for example, a biological activity; too much data there shows an effect at the edges of a broad claim; too little is likely to make the claim vulnerable to attack under inventive step.

32 ISO IDMP – Four Challenges in Preparing Organisations for the July 1, 2016 EMA Deadline

Most pharmaceutical companies face challenges in becoming compliant with the ISO IDMP standards. In this article, Rune Bergendorff, responsible for NNIT’s ISO IDMP services shares experience from NNIT’s IDMP work for a handful of pharmaceutical companies over the past two years, letting you in on the conclusions from the IDMP Experience Exchange Group where another handful of pharmaceutical companies shared their insights.

34 Developing Healthcare FacilitiesIf you are the operator of a nursing or care home, and you are considering commissioning the building of a new care or nursing home, or extending or refurbishing an existing building, you should

2 INTERNATIONAL PHARMACEUTICAL INDUSTRY Winter 2014 Volume 6 Issue 4

Contents

consider taking advice on the terms of appointment of architects and other design consultants, as well as on the appropriate form of building contract. Andrew James of Harrison Clark Rickerbys provides information on a specialist construction unit whose members are very experienced in the procurement of healthcare facilities and resolving any issues which can arise out of them.

DRUG DISCOVERY, DEVELOPMENT & DELIVERY

38 The Expanding Role of MRI in the Pharmaceutical Industry With ever-increasing pressure on drug development pipelines and a growing need to demonstrate convincing mechanisms of action as a part of the registration process for new drugs, innovative methods are being sought that can streamline the traditional drug development process. Matt Wall of Imanova proves that imaging methods have a substantial potential to impact the development and clinical trials process at several stages, and have begun to be used as a method of bolstering the uptake and marketing of already-marketed compounds.

44 Special Report: How to Ensure the Proper Behaviour of Excipients and their Best Possible Use

As in recent years excipients have proved to be anything but “inert”, ensuring the proper behaviour of excipients in the various phases of the industrial production process has become one of the missions of the pharmaceutical Application Development Centres in France, the USA and China. Cecilia Stroe, Editor of IPI, takes you to Lestrem, France, to the high-technology pharmaceutical Application Development Centre recently inaugurated by Roquette Group, a key supplier of excipients and active ingredients globally.

CLINICAL RESEARCH

46 Revisited Cell Cultures and Valuable Methods for Pre-clinical Studies

During the last ten years, the development of transgenic techniques has rendered possible the creation of mutant strains of rodents mimicking human diseases and the assessment of the role of biochemical lesions in their development. However, maintaining and expanding colonies of transgenic rodents is time-consuming, expensive and above all, the characterisation (phenotyping) of these new animals needs highly experienced people. Pr. Philippe Poindron of Neuro-Sys looks into the development of alternative methods for studying efficiency and mode of action of new compounds in preliminary preclinical studies.

50 Opportunities for Monoclonal Antibodies in Bacterial Infectious Diseases

The management of infectious disease is challenged by trends that impact patient welfare on a global scale; the emergence of multi-drug-resistant (MDR) forms of new and old bacterial pathogens, the world’s increasing population of immunocompromised patients where antimicrobial therapy is less effective, and fewer new antibiotics being licensed. If these trends continue, the dreaded “post-antibiotic era” could become a reality. Fraser Leslie of Arsanis discusses the vast potential of monoclonals for combating antibiotic resistance with many anti-infectious mAbs currently in development.

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Contents

56 Advocating an Integrated Approach to the Global Diabetes Epidemic

The non-communicable disease of diabetes has reached epidemic proportions, and it knows no geographic boundaries. It`s time to take a sombre look at the consequences of letting the worldwide diabetes epidemic continue to progress, and decide how we, as a globally unified body of health professionals and health agencies, wish to proceed, points out Dr J. Rick Turner of Quintiles. He advocates for the adoption of an integrated approach to addressing the global diabetes epidemic, because it offers the most promise for the prevention of future cases of diabetes, and for the treatment of patients who currently have diabetes.

LOGISTICS & SUPPLY CHAIN

68 Logistics: The Power of Clinical Trial Supply VisibilityAs a result of the globalisation of clinical trials, one of the biggest challenges that pharmaceutical companies face is the management of the clinical trial supply chain. This work is increasingly outsourced to specialised clinical trial services companies, who become key partners in helping the pharmaceutical company efficiently navigate the clinical supply chain. Claudia Williams and Rishi Saini of Biotec-PCI address the specific features that an online reporting system should provide in order to maximise the visibility and efficiency of the clinical supply chain.

70 Securing the Global Pharmaceutical Supply Chain against the Threat of Counterfeit Drugs

According to the WHO, the prevalence of spurious, falsely-labelled, falsified, or counterfeit medicines, or SFFC medicines as they are known - medicines that are deliberately and fraudulently produced, packaged and/or mislabelled - is a growing trend worldwide which threatens both patient safety and public confidence in the health systems and regulatory bodies designed to provide oversight and control. Dr Rudiger Lomb of World Courier tells us what pharmaceutical professionals can do to ensure that their organisations and the patients they serve are not impacted by counterfeit drugs.

80 Transforming Temperature Data Management Practices to Reduce Labour Costs and Improve Visibility and Control

Central to the good distribution practices of a biopharma company is the reliability and traceability of temperature data associated with temperature-sensitive shipments. There are a number of temperature-monitoring database options available to improve workflow which will reduce administrative time. Patrick McGrath of Berlinger provides insight into practices for improving common processes through enhanced database functionality in the areas of managing data loggers by expiry date, storing and retrieving calibration certificates and acknowledging/documenting common temperature excursion events.

84 Temperature Mapping of Vehicles Used for the Transportation of Pharmaceutical Products

Andy Hughes of Pharmafreight UK and Kane Edgeworth of Biomap Ltd talk about the recent history of temperature-mapping expectations, the approach of mapping temperature-controlled vehicles, the use of risk when deciding to map or not, a recent mapping study undertaken, and what to do with the data gathered. Things are changing, and more and more mapping is taking place throughout the transport industry. It is in everyone’s interest to hope that this upward trend continues, ensuring regulatory compliance and getting drugs to the patient in the best possible condition.

MANUFACTURING

88 Advances in Tissue Processing: The Supercritical AlternativeDespite the promising future use of stem cells, extensive research over the last decade has shown how the augmentation of, e.g., damaged tissue not only depends on the inherent potential of stem cells to adjust and differentiate, but also on the presence of the right micro-environment where the cells reside. Marco Thio of EMCM examines the current methods by which tissue grafts are manufactured, presenting also a promising new method based on carbon dioxide that has been shown to be very effective in cleaning and sterilising tissue grafts.

94 Implementing SerialisationThe subject of serialisation and track-and-trace has been on the industry's agenda for quite some time. Several of the major drug manufacturers have, in fact, made considerable inroads into implementing solutions whilst others have waited for the regulatory standards to be in force before addressing the issue. Alexander Ulbrich of Vetter outlines how, regardless of the approach taken, the industry as a whole is keenly aware of the need for serialisation and is working hard toward developing appropriate solutions.

PACKAGING

102 Beyond Item-level Serialisation: Extending Traceability Schemes to Secondary and Tertiary Packaging

The challenges of serialisation are well-documented; however aggregation requires an altogether higher level of data processing and joined-up thinking. Inserting the correct quantity of goods into a box and applying a label is only half the battle. Craig Stobie of Domino proves that where serialisation is required, aggregation is a logical extension – even if not mandated – and one that delivers a range of benefits.

110 On its Way: New ISO Standard on Interoperability of Anti- counterfeit Systems, Based on Unique Identifiers

Identification systems based on unique identifiers are no longer restricted to individuals' ID cards, car plates or telephone numbers. For many years now, object identification has been established in the world of things, using unique identifiers on sales items and their packaging, as well as other sales and transport units. Dr Marietta Ulrich-Horn of Securikett reveals the reasons why this is a major step forward in consumer safety, in particular in uncovering counterfeit and illicit trade activities.

112 Serialisation: The Great Challenge for the Pharmaceutical Industry – Considerations on China

Most of the big pharma players have been working during the past years to implement projects linked to serialisation, despite the uncertainty regarding concrete rules, data and specific regulations. Marga Romo of Nekicessa discusses China: the next deadline for serialisation in China is 2015, with the well-known 128C code, different from the expected data matrix that is likely to be implemented in Europe; and this code is becoming a nightmare for the serialisation-responsible people in the companies, due to technical problems related to length and grading.

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Editor's Letter

In this final issue of 2014, IPI takes an in-depth look at the fight against counterfeit drugs. The problem is hardly new, but it`s been growing incessantly in complexity and

scale and needs to be fixed. Dr Rudiger Lomb of World Courier argues

that none of today’s drugs or therapeutic treatments is exempt from being fraudulently produced, packaged and/or mislabelled; everything is targeted, from low-cost generic painkillers and antihistamines to high-value blockbuster drugs and speciality medicines used to treat life-threatening conditions. And while pending regulatory changes hold the promise to tighten the supply chain and new packaging technologies will make the identification of counterfeit products easier, the logistics of global distribution is still the weakest link.

Alexander Ulbrich of Vetter looks into the challenges of implementing serialisation, telling us how the interested parties can be brought together to implement a form of serialisation that meets future needs. Part of a team of experts who have developed a system that targets brand protection and anti-counterfeiting, Dr Marietta Ulrich-Horn of Securikett reveals that in the pharmaceutical industry, the “early birds” introduced unique data matrix codes to their individual packaging long ago, but the new “hype” is fostered by legislation.

Supply chains can be long and complex, with security only as strong as their weakest point, admits Craig Stobie of Domino. Therefore, in his article, he goes “beyond compliance” and brings to the table the

benefits of “aggregation”: while serialisation is in itself a challenge that is currently “warming up” pharmaceutical manufacturers ahead of impending legislative deadlines, it is one that is best dealt with in conjunction with aggregation.

It looks like, properly implemented, aggregation has the power to save pharmaceutical companies time and money and is essential for the crackdown on counterfeit drugs. Otherwise, warns Stobie, “implementing serialisation without at least planning for a subsequent aggregation deployment could prove to be a very costly and time-consuming strategy”. Find out all about the practical problems of transferring serialised products from the primary packaging line to aggregated products in the secondary and tertiary stages.

Also in this issue, IPI has Marco Thio of EMCM introducing a promising new method of cleaning and sterilising tissue grafts; Fraser Leslie of Arsanis exploring the vast potential of monoclonal antibodies for combating antibiotic resistance; Matt Wall of Imanova looking into MRI technology and scanning and analysis techniques, with applications in constant evolution and likely to play an ever-increasing role in future research and development across nearly all sectors of the pharmaceutical and consumer healthcare industries.

In current clinical practice, drug development and drug regulation, individual variability in drug efficacy and drug safety is considered a major challenge.

By “tailoring” medicines according to the patient genetic profile, pharmacogenomics enables a dramatic improvement in

drug safety and efficacy; no wonder pharmaceutical companies are now integrating pharmacogenomics into their development strategies for medicines. However, although pharmacogenetic / pharmacogenomic information is now taken into account by drug regulatory agencies, the shift from the “one size fits all” approach of prescribing medicines to the “tailor-made” prediction, diagnosis and treatment of the patient is far from being straightforward.

As Balamuralidhara V., Blessy A. Daniel, T.M. Pramod Kumar and Pratik Thakkar of JSS College of Pharmacy, Mysore, India show in their paper, there are major hurdles to overcome in translating pharmacogenomics into individualised medicine, drug development, and regulation, but there is no doubt about it, the full potential of pharmacogenetics cannot be achieved unless regulatory and legal frameworks follow the progress of scientific knowledge.

Last but not least, IPI will be at the 14th edition of Pharmapack Europe, taking place on 11th & 12th February 2015 in Paris Expo, Porte de Versailles; at the 14th Annual COOLCHAIN Temperature Controlled Logistics Europe, Europe`s biggest and best meeting place for life sciences logistics; and at the 13th Annual Cold Chain, GDP & Temperature Management Logistics Summit, in Montreal – Canada`s number one event covering all temperature ranges and life-science products.

I wish our readers a prosperous 2015!

Cecilia StroeEditor

Bakhyt Sarymsakova, Head of Department of International Cooperation, National ResearchCenter of MCH, Astana, Kazakhstan

Catherine Lund, Vice Chairman, OnQ Consulting

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters

Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

Georg Mathis Founder and Managing Director, Appletree AG

Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

Jagdish UnniVice President- Beroe Risk and Industry Delivery Lead- Healthcare, Beroe Inc.

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP

Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmac

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

Stefan Astrom, Founder and CEO of Astrom Research International HB

Steve Heath, Head of EMEA - Medidata Solutions, Inc

T S Jaishankar, Managing Director, QUEST Life Sciences

Editorial Advisory Board


Regulatory & Marketplace

The Hunt for Talent in Asia: Mind the (Generation) Gap As more global life sciences firms see their Asian businesses skyrocket, the search for strong, internationally-savvy talent in Asia-Pacific has never been more competitive. After four years of living and working in China and Singapore, Susan Macdonald returned to the UK this year. Here Susan chats with Thomas Meininghaus of Siemens Audiology Solutions about the unique challenges of recruiting to fill senior roles in Asia.

The need to build manufacturing and commercial infrastructure in Asia-Pacific with the associated regulatory, quality and compliance processes to satisfy Western authorities is reaching new heights for life sciences companies of all shapes and sizes. Healthcare spending in traditional markets has all but flat-lined, and Asia’s emerging middle class will double its spending on healthcare by 2020. As the market’s eastward shift appears more permanent, the incentive for medical device, pharma, biotech, nutrition, generic and consumer healthcare companies to establish and grow their businesses in Asia-Pacific has never been more urgent.

This sense of urgency translates into a highly competitive environment to recruit suitably qualified individuals. The ability of companies to attract, develop and retain highly knowledgeable and skilled business leaders in Asia is critical to many companies' ability to gain, build and maintain a strong foothold in this rapidly growing region.

Although global corporations with Western HQ have long operated in the Asian market, many have done so under the leadership of Western executives temporarily transplanted to key Asian markets as expatriates. The regulatory and commercial environments in Asia-Pacific today demand a shift toward more home-grown leadership. From finding the right partners to managing complex regulatory regimes and routes to market, local employees have knowledge, networks, gravitas and cultural sensitivity that can be the difference between the success and failure of a new product or therapy in Asia’s contemporary health market.

Building the Requisite Skills Inside a Country and a CompanyLike many growing markets, the skills gap is a major hurdle to overcome when identifying, attracting, retaining and developing the senior talent that will grow a life sciences business. Traditional MBA programmes teach local and foreign talent the basics of running a commercial operation, but in specialist life sciences and medical device companies, industry knowledge and experience are critical.

“We provide international training opportunities to all our key international hires,” explained Thomas Meininghaus, VP of Quality Management and Business Processes at Siemens Audiology Solutions. “We always choose the best trainer for the subject matter, of course. But when it comes to nurturing local Asian talent, those development programmes that take the best of the European training model are very attractive. By sitting in a classroom alongside their peers from across the world, our senior leaders and high potentials are exposed to other cultures’ norms, opening them up to consider different ways of addressing and subsequently solving common management challenges.”

For instance, clients often remark that change management programmes are a particularly tough learning curve for a new Asian executive to lead and execute. Many Asian cultures are based on modesty, politeness, and taking a tempered approach. It therefore goes against cultural norms to lay off teams quickly, and to tell people what they are doing wrong in the matter-of-fact way we take for granted in many Western cultures.

This is by no means a barrier to local Asian executives’ ability to effectively lead a change programme. Rather, it is a cultural reality that companies must take into account when putting home-grown talent in charge of a significant restructure or corporate change initiative.

At Siemens, Meininghaus said, local

leaders receive extensive support and training from corporate HQ to learn corporate values and norms, which, over time, will influence the cultural values and norms they act on in the workplace. If culture is a defining factor in how business leaders manage, every effort to immerse leaders in your company’s distinct corporate culture is a fail-safe way to ensure teams and projects are managed consistently across borders.

Siemens, for instance, is considering

investing in a global institute for training its high-potential staff. This approach gives Asian leaders early, first-hand exposure to its distinctly Western company culture, while exposing Western executives to the huge potential and fast-paced nature of the life sciences industry in Asia-Pacific today.

Many life sciences firms have put narrowing and resolving the skills gap at the centre of their Asia-Pacific human resources and external affairs programmes. Today in Asia we see more Western firms working with universities, government education departments and national professional bodies to develop world-class professional qualification programmes, or to offer scholarships or internships to high-potential students. These options are increasingly popular for global life sciences businesses with long-term Asia-Pacific growth plans. By putting their business at the very heart of STEM (Science, Technology, Engineering and Mathematics) subject education in the region, these companies enjoy the benefits of building well-known employer brands while ensuring that future generations of scientists and engineers have the right knowledge, skill sets and competencies to work comfortably with colleagues from around the world.

From Permanent to InterimAlthough the average education level of the Asian labour market is progressing rapidly, there are still not as many senior executives with the same qualifications or experiences as we find in Europe. (Young Asians are a separate story, as Asia-Pacific countries rapidly outpace the US and Europe in the number of career-ready STEM graduates it produces per

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capita each year.) However, the search for a senior leader with experience in a specific function of the global health industry can be challenging.

Siemens recently overcame such an obstacle while working on a challenging search for a new Head of Regulatory Affairs and Quality System in Singapore. When no perfect full-time candidate with the right experience was forthcoming, Siemens decided to examine other recruitment options, and this included the appointment of an interim. The gentleman in question, like a number of other Singaporeans of his generation, was a semi-retired professional looking to keep busy and reassert himself in society through gainful employment. With decades of experience navigating the local regulatory regime, the interim candidate ended up offering Siemens much more than a warm body to keep the plates spinning.

“I was not looking for an interim at the start of this process,” Meininghaus said. “But when it became clear that a permanent hire was not forthcoming, we did what we always do – got creative.”

The senior quality system expert Siemens hired in an interim capacity is proving to be even more valuable than a permanent hire in many ways.

“He is helping us to define a permanent job spec much more sophisticated than anything we’ve developed internally. He is auditing our existing function to ensure we remain best in class, and has kept us up to date with the government’s recent regulatory demands. He is introducing process innovation to ensure efficiency. And most importantly, he is using his professional network and local connections to recruit his eventual replacement. I never set off looking for an interim solution, but in this case, it was undoubtedly the right choice.”

Partners: Two Pairs of Eyes are Better than One Many global healthcare firms are not in the habit of recruiting external senior leaders – not in Asia-Pacific, and not anywhere. “We have leadership that tends to move up the ranks, and is fiercely loyal,” Meininghaus explained. “Because

of this we are great at so many things, but executive search is not one of them.”

Siemens is not alone in its acknowledgement that when looking to fill a senior position, it is often more effective to run that search in partnership with an executive search firm.

“A search firm will always have more contacts in the field than even the best-networked talent manager,” said Meininghaus. “But besides that, top talent expects to be courted.”

This is particularly true in Asia, where the field of senior life sciences talent has been small for quite a long time. Although the tide is turning and younger generations are producing more highly skilled scientists, among today’s senior businesspeople, Asia’s life sciences industry is still a tightly knit community where everybody talks. Executive search firms make it their business to know who’s looking for a role, what roles are available, and what it will take to make the cultural fit between company and business leader. In-house talent managers and recruiters have an important role to play in working effectively with their executive search partners. A clear brief, a country-specific job description, and a strong employer brand all help a search firm secure the best candidate for its client.

Communication is the Key to Successful International RecruitmentWhen recruiting local talent, Siemens values strong communication skills above all. “If we hire a brilliant engineer with decades of experience, he won’t be worth his first pay cheque if he alienates his team or can’t work well with colleagues from other cultures or nationalities,” Meininghaus said.

But to attract candidates with strong communication skills, the company must demonstrate its own communication savvy. Strong candidates want to understand their exact role requirements and benefits packages and a company’s expectations before moving too far along in the interview process. Being clear about what type of leader you are looking for will also go a long way toward finding the right man or woman for the job.

For life sciences companies planning to make senior-level hires in the Asia-Pacific region this year, it is clear that

engaging early and being clear about what you want and what you offer as an employer brand are all critical. Strong local candidates are growing in number year-on-year, but for now, the talent pool remains somewhat shallow. As it grows and your business expands, remember that the strategy of networking, investing in education and being flexible will serve you just as well in an Asian executive search as they do in your home market. Happy hunting!

Susan Macdonald, joined RSA in 2005 as a Consultant in the UK and was promoted in 2006 to Sales & Marketing Practice Leader. Over the next three years I undertook Global and

pan-European searches in the sales and marketing function for a wide range of Life Sciences clients.

In 2009, I moved to Shanghai to set up RSA Foster Partners, a joint venture between RSA and Foster Partners in China. Having established this joint venture, I returned to RSA in Europe where I served as the firm’s UK General Management Practice Leader.

In 2010, I returned to Asia as Managing Director of RSA Singapore and over the following three years successfully completed global and regional Executive searches, filling “C” level and APAC regional roles.

I am now based back at our UK HQ where I am Director of Channels and Global Partners.

A nursing graduate, I began my career as a Staff Nurse in Glasgow before joining the Pharmaceutical industry in 1988. My 17 years' in industry includes roles at Farmitalia Carlo Erba and Pharmacia (now Pfizer) and IVAX (now TEVA) in commercial sales, marketing, project management and business development roles that encompassed branded, generic and VMS products. Email: [email protected]

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‘Personal Pill’ Regulations: Current Landscape and Future ScenarioAbstractPharmacogenetics, a rapidly evolving science wherein drug therapies are designed to be compatible with a patient's specific genetic makeup, brought in the amazing concept of “personalisation of medicines” also referred to as “personal pill”. The objective of this review article is to bring forth the potential of this “personal pill” to revolutionise drug discovery and development. The explosion of interest in pharmacogenomics raises concerns in the regulatory environment. The study focuses on the present regulatory scenario, the approved guidance, and the newly-drafted guidance for this approach. It also illuminates the benefits, the recent clinical therapies employed, and also the barriers which have hindered the progress of this modern venture. Pharmacogenomics has streamlined clinical trials to target approved drugs to patients scored on the basis of their drug metabolism. A host of hurdles in the way of pharmacogenomic progress, if overcome, would represent a major step in the progress of medical science.

K e y w o r d s : P h a r m a c o g e n o m i c s , Personalisation of Medicines, Personal Pill, Regulations, Pharmacogenetics

1. Introduction The past saw most drugs designed to work on the population level, relying on the outward expression of disease - the signs and symptoms that physicians call the phenotype. Traversing the trend, pharmacogenomics refined the focus of treatment and brought in the concept of “personalising medicine”. These medicines examine and treat the genotype1. The response of a drug can be learnt by variations in clinical outcomes that can be assessed by the genetic variations. Table 1 illustrates the five categories looked into to study the drug outcome2. Pharmacogenomics (PGx), studies the individual’s genetic inheritance on how it affects the body’s response to drugs. The study of the effect of genetic or genomic variation on drug response is intended to improve the safety and efficacy of prescription. Genetic testing combined with protein expression analysis and in vitro drug metabolism not only helped to screen patients in advance

for responsiveness toward drugs, but also proved to judge the effectiveness of a drug, i.e. it could predict the drug in question, helping to make a patient well or ill3.

Pharmacogenomics and pharmacogenetics tend to be used interchangeably. An exact, consensus definition for either of the terms remains elusive. Major regulatory bodies and authorities like UDFDA, EMEA, and MHLW define pharmacogenomics as “The study of variations of DNA and RNA characteristics as related to drug response” whereas pharmacogenetics is qualified as a subset of pharmacogenomics which involves “study of variations in DNA sequence as related to drug response”4. In simplified terms, pharmacogenetics can be regarded as the study or clinical testing of genetic variation that gives rise to differing response to drugs, whereas pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterisation of older drugs5.

2. Why Pharmacogenomics? Pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes, proteins, and single nucleotide polymorphisms. This study has already identified its clinically relevant loci, which alter the response to several drugs. Pharmacogenetic / pharmacogenomic information is now taken into account by drug regulatory agencies as evidenced by recent drug label modifications integrating pharmacogenetic-based prescription by the USFDA6. Although pharmacogenetic traits influencing drug disposition are presently relatively well identified, the genetic variability of drug targets is yet to be explored.

Genotype is the internally coded, heritable information carried by any organism. Variation in genotype is the key to pharmacogenetics, which is measured as sequence variation in individual genes. This genetic variation is independent of individual drugs and forms the basis for variation in response to drugs. Figure 1 illustrates the PGx (pharmacogenomic biomarker) information flow. Pharmacogenomics involves the use of genome-wide analyses to identify genes

with altered expression or activation as a result of exposure to a drug. It identifies markers to aid drug development in four key areas: exposure, efficacy, stratification and toxicity.

2.1. Markers of exposure determine whether the subject’s desired target tissues have been exposed to a drug at physiological concentrations. 2.2. Efficacy markers can provide molecular evidence above and beyond traditional clinical endpoints. 2.3. Stratification markers can identify a subset of patients who uniquely benefit from a given therapy. 2.4. Toxicity markers can predict and prevent adverse events7.

Many factors like environment, diet, age, lifestyle, and even state



of health can influence a person's response to medicines. Even though it is practically impossible to determine the contribution of all factors that affect drug response, pharmacogenetic studies on inter-individual polymorphisms (e.g. nucleotide mutations) of genes that code for drug-metabolising enzymes and drug targets (e.g. cytochrome P450 mono-oxygenase and its subtypes) have shown a significant proportion of heterogeneous response of medicines in patients8. This inter-individual variable drug response, correlated with sequence alterations in genes encoding drug-metabolising enzymes and transporters, affects drug absorption, distribution, metabolism and excretion9. Sequence alterations may occur not only within the coding region of a gene, but in its regulatory elements too, affecting gene transcription and gene expression levels. It’s this understanding of an individual's genetic makeup which acts as the key to making personalised drugs with greater efficacy and safety.

3. Potential Benefits: The technology involved with pharmacogenomics is getting bigger and better with time. It has very much advanced, bringing in good for all mankind.

3.1. Potent Medicines: This technology employs drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases. Facilitating drug discovery, it has allowed drug makers to produce a therapy more targeted to specific diseases. This accuracy has not only maximised therapeutic effects but also decreased damage to nearby healthy cells10.

3.2. Better, Safer Drugs the First Time: Instead of the standard trial-and-error method of matching patients with the right drugs, doctors will be able to analyse a patient's genetic profile and prescribe the best available drug therapy from the beginning. The application of this technology studies the toxic elements with an exact level which allows the possibity of developing better drugs with fewer side-effects and more efficient delivery systems11.

3.3. More Appropriate Drug Dosages: Current drug dosages are based on weight and age of a patient. Advancement of pharmacogenomics can replace the trend of dosages based on a person's genetics. To maximise the

therapy, it’s important to design a dosage by determining how well the body processes the medicine and the time it takes to metabolise it. This would also decrease the likelihood of overdose10.

3.4. Improved Screening for Disease: Knowledge of one's genetic code avoids or lessens the severity of a genetic disease in a person. Pharmacogenomics likewise advances knowledge of particular disease susceptibility for careful monitoring and treatments at the most appropriate stage to maximise disease therapy12.

3.5. Better Vaccines: Vaccines made of genetic material, either DNA or RNA, ensure all the benefits of existing vaccines without risks and side-effects. These activate the immune system without causing infections. Vaccines employed in this manner are inexpensive, stable, easy to store, and capable of being engineered to carry several strains of a pathogen at once10.

3.6. Advancement in the Drug Discovery and Approval Process: The use of genome targets has made the discovery of potential therapies easier. Previously failed drug candidates may be re-formulated so as to match the needs of the niche population. The drug approval trials process has eased by targeting specific genetic population groups,

providing greater degrees of success. The cost and risk of clinical trials will also be reduced, targeting only those persons capable of reacting to a drug10.

3.7. Fall in the Overall Cost of Health Care: Individualisation of drug therapy facilitated by pharmacogenomics has offered the potential to improve drug effectiveness. It has reduced adverse drug reactions, the number of failed drug trials (by simplifying the drug response monitoring), drug approval time, and duration of time a patient is on medication. It also decreases the number of medications a person should take for effective therapy, and the effects of the disease on the body, by early detection providing cost-effective pharmaceutical care10.

3.8. Pharmacogenomic Biomarkers on Drug Labels: Pharmacogenomics describes responders and non-responders to medications avoiding adverse events, and optimising drug dose. Drug labels contain information

on genomic biomarkers and describe the elements below:

• Drug exposure and clinical response variability

• Risk for adverse events • Genotype-specific dosing • Mechanisms of drug action • Polymorphic drug target and

disposition genes13

4. Regulatory Overview: The mapping of the human genome predicts rapid development of new technologies and more regulatory challenges. Pharmacogenomics, an individualisation of drug therapy based on genetics, is one of the most imminent advances from genomics. Though this promises fewer adverse drug reactions, more effective pharmaceuticals, and lower drug development and healthcare costs, the advent of pharmacogenomics presents challenges to regulators.

Table 2 gives the list of scientific guidance documents available on pharmacogenomics.

The guidance for pharmacogenomic data submissions issued by FDA (US) provides recommendations to sponsors holding investigational new drug applications (INDs), new drug applications (NDAs), and biologics licence applications (BLAs) 14. It explains when the sponsors should submit pharmacogenomic data to the FDA during drug development and review, what formats to use for submissions, and how the data might be used in regulatory decision-making. Key information, including examples of when pharmacogenomic data submissions would be required and when voluntary genomic data submissions (VGDSs) would be welcomed, are also provided in a separate companion document (Pharmacogenomic Data Submissions, Attachment: Examples of Voluntary Submissions or Submissions Required Under 21 CFR 312, 314, or 601). FDA encourages INDs as a voluntary genomic data submission (Figure 2). Exploratory pharmacogenomic data, in general, should be submitted to a new NDA or BLA in a synoptic report; however, the FDA encourages their inclusion in NDAs or BLAs as a full voluntary genomic data submission (Figure 3). For an approved NDA or BLA, pharmacogenomic data generated using valid biomarkers should be submitted in an abbreviated or synoptic report (Figure 4). Appendix D of



Guidance for Industry Pharmacogenomic Data Submissions gives a quick reference of the genomic submissions as given in Table 314, 15.

In the USA, genetic testing kits are categorised as medical devices (Medical Device Amendments Act, 21 U.S.C.

§360)3, 16. Genetics-based diagnostics are labelled Class III devices. In the same way that an investigational new drug application (IND) is required to market a new drug, for devices, m a n u f a c t u r e r s must apply for an i n v e s t i g a t i o n a l

device exemption (IDE). Under the Clinical Laboratory Improvements Act (CLIA), genetic testing falls within cytogenetics (42 U.S.C. §263). CLIA regulations require laboratories to comply with all applicable federal laws, including the Federal Food, Drug, and Cosmetic Act (FDCA). It also enforces the requirements on assay performance for accuracy, sensitivity/specificity, reproducibility, reportable ranges of patient results and reference range of assay.

The ICH E15 guideline contains definitions of key terms in the disciplines of pharmacogenomics and pharmacogenetics, namely genomic biomarkers, pharmacogenomics, pharmacogenetics, and genomic data and sample coding categories17. This guidance ensures consistency in the terminology used by the different regions to develop harmonised approaches for

drug regulation. ICH E16 is a harmonised guideline on the important aspects for the qualification of pharmacogenetic (PG) biomarkers. This guidance also provides recommendations regarding context, structure and format of regulatory submissions for qualification of a genomic biomarker. The biomarker qualification submission is aligned with the CTD format, which consists of five parts as follows:

• Section 1 (Regional Administrative Information) corresponds to CTD Module 1 with specific information on the qualification procedures

• Section 2 (Summaries) corresponds to CTD Module 2

• Section 3 (Quality Reports) corresponds to CTD Module 3

• Section 4 (Nonclinical Study Reports) corresponds to Module 4 and;

• Section 5 (Clinical Study Reports) corresponds to Module 5 18.

Some aspects of PGx samples like pre-analytical, analytical and postanalytical steps, testing and data handling, and the key for the scientific reliability of PGx data submitted for regulatory evaluation has been discussed in a reflection paper on pharmacogenomic samples, testing and data handling issued by the European Medicines Agency19. The pre-analytical aspects cover sampling, storage, fixation and nucleic acid extraction and quantification. The analytical aspects include the test performance and quality assurance aspects, and other aspects include sample handling systems and also storage duration.

The FDA and the EMA issued Guidance for Industry: Pharmacogenomic Data Submissions and Guideline on Pharmacogenetics Briefing Meetings, respectively. Both documents encourage

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the voluntary submission of genomic data by the sponsors to the agencies. The guiding principles describe how the agencies process voluntary submissions (i.e., submissions that are not required as part of a regulatory submission) and the associated briefing meetings20.

Genetic variation is likely to translate into important differences in the systemic and/or local exposure for a few substances or their active or toxic metabolites, which potentially affect safety and efficacy of treatment. Pharmacogenomics (PG) on pharmacokinetics (PK) becomes necessary for the PK evaluation of such a new chemical entity. PG variants affect absorption, distribution, metabolism and excretion of the compound. A reflection paper issued by EMA on the use of pharmacogenetics in the pharmacokinetic evaluation of medicinal products targets the place of PG in the clinical PK evaluation of medicinal products during drug development and use21.

Significant progress in the regulation is seen with the issue of a few other draft guidances and reflection papers in 2011. The “Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies” guidance issued by USFDA assists manufacturers engaged in new drug development by addressing how variations in the human genome could affect the clinical pharmacology and clinical responses of drugs. This guidance provides recommendations on when genomic information should be considered to address questions arising during drug development and regulatory review. It also provides advice on general principles of study design, data collection, and data analysis22.

The reflection paper on methodological issues with pharmacogenomic biomarkers in relation to clinical development and patient selection highlights key principles that should be considered by stakeholders, with a focus on the use of genomic biomarkers (GBM) in relation to patient selection and associated issues with trial methodology, according to EMA. These principles are applicable to the development and validation of a GBM throughout the life cycle of a medicinal product, i.e., pre-authorisation and post-marketing stages23.

The reflection paper on co-development of pharmacogenomic

biomarkers and assays in the context of drug development 24 intends to support the qualification of pharmacogenomic biomarkers (PGBM), reflecting on the key scientific principles that need to be met in order to ensure that the performance of the chosen PGBM assay is sufficiently reliable for the further use of optimising drug development and regulatory submission. It also addresses issues related to timing of test and drug co-development.It’s always been a challenge to regulate new technologies. This developing research field of pharmacogenomics is still in its infancy. Several barriers will have to be overcome to realise its benefits.

4.1. Complexity of Finding Gene Variations: Single nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single nucleotide (A, T, C, or G) in the genome sequence is altered. SNPs occur every 100 to 300 bases along the 3-billion-base human genome. Hence, millions of SNPs must be identified and analysed to determine their involvement in drug response. Since many genes influence responses, obtaining the big picture on the impact of gene variations is highly time-consuming and complicated 10.

4.2. Limited Drug Alternatives: Only one or two approved drugs may be available for treatment of a particular condition. Patients have gene variations that prevent those using particular drugs; hence they are left without any alternatives for treatment10.

4.3. Disincentives for Drug Companies to Make Multiple Pharmacogenomic Products: Most pharmaceutical companies have been successful with their "one-size-fits-all" approach to drug development. Hundreds of millions of dollars are invested to bring a drug to market which brings these companies huge profits. The same investment to develop alternative drugs that serve only a small portion of the population is not worth making10, 23.

4.4. Educating Healthcare Providers: Introducing multiple pharmacogenomic products to treat the same condition for different population subsets will complicate the process of prescribing and dispensing drugs. Physicians must execute an extra diagnostic step to determine which drug is best suited to each patient. To interpret the diagnostic

accurately and recommend the best course of treatment for each patient, all prescribing physicians, regardless of speciality, will need a better understanding of genetics10.

5. Pharmacogenomic Therapies: Pharmacogenomics leads to more effective targeted therapies. The incorporation of genomics in the preclinical and clinical research of anticancer drugs has resulted in significant progress in the development of new drugs. A feature article in the USFDA website25 clearly identifies these therapies which can be employed. Personalised medicine identifies patients who are more prone to experience adverse events from a drug, and also identifies patients who are likely to gain benefit from a particular therapy.Pharmacogenomics has been able to very effectively reveal the action of drug on drug response in certain populations.

5.1. Warfarin, an anticoagulant, has a narrow therapeutic window. It has a wide range of inter-individual variability response, hence requires careful clinical dose adjustment for each patient. The genetic variants in the warfarin target the vitamin K epoxide reductase (VKORC1), as well as the warfarin metabolising enzyme, cytochrome P450 2C9 (CYP2C9) which influences the variation in patient response. Patients with certain variants of these genes eliminate warfarin more slowly and typically require lower warfarin doses. In these patients, a traditional warfarin dose would more likely lead to a higher risk of serious bleeding events25.

5.2. Ultrarapid metabolisers of codeine have multiple copies of the gene for cytochrome P450 2D6 that converts codeine into morphine, its active metabolite. Nursing mothers who are taking codeine and are ultra-rapid metabolisers could have high levels of morphine in their breast milk, increasing the risk of morphine overdose in their nursing infant. Though codeine is safe after childbirth, healthcare practitioners should prescribe the lowest dose for the shortest period of time to relieve pain, and nursing infants should be carefully monitored when breastfeeding women receive this drug25.

Likewise, valid genomic biomarkers are currently a part of FDA-approved drug labels that can be found. The



USFDA lists a table of drugs with their pharmacogenomic information in their labels. A few of these biomarkers, with links to pharmacogenomic data supporting their validity and recommendations for clinical use, are listed in Table 413.

Yesterday saw most doctors using a "one-size-fits-all" approach to prescribing medicines. Using a trial and error process, patients were given doses starting from the standard dose. The biochemical reasons of why certain medicines did not work for a small percentage of people or why some patients experienced serious adverse side-effects was unknown. Although scientists and doctors suspected a person's genes to play a role in the response to medicines, genetic technology was not advanced enough to reveal which genes — and which variations of those genes — were relevant. But now the technology is quite advanced.

Any technology when introduced will have diverse consequences that need to be taken into account if the benefits are to be maximised and the negative effects minimised. Though pharmacogenetics promised efficient and safe medicines, ethical and policy issues caused a lot of hindrances earlier. The issues were as follows:

6.1. The first was information. Genetic information obtained from pharmacogenetic tests about individuals raised complicated and delicate questions about consent and confidentiality.

6.2. The second was resource. Certain aspects of pharmacogenetics lower the cost of developing and delivering

medicines, but others drive it up. The net effect of the two was difficult to calculate.

6.3. The third was equity. Because of inadequate financial incentives to bring a drug to market, pharmacogenetic tests may be very effective only for a small population, or for a large but not poor population.

6.4. The fourth was control. Who would decide whether a patient should take a pharmacogenetic test? Should the tests be made available directly over the counter or the web? Should patients be entitled to a drug even if they do not wish to take an associated test?

But in today’s scenario, a significant change can be seen. The above mentioned issues were taken off and to quite an extent improved with the efforts put in by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Several guidelines were adopted and drafted in this context which are mentioned in the regulations section earlier in this article.

• Today, doctors are increasing their awareness of genetic variations and their effect on different patients to respond in different ways to the same medication.

• Scientists have identified more than 3 million genetic variations, many of which may relate to disease risk or drug responses.

• Researchers are starting to use this information to predict whether a medicine might be effective, ineffective, or toxic in certain individuals. For example, researchers recently linked a common gene

variant to poor effectiveness of an anti-clotting medicine, Plavix.

• Several pharmacogenetic tests are now available which can help doctors design the best treatment for patients with childhood leukemia, breast cancer, and heart disease. More tests are expected in the future, including those for drugs to treat asthma and depression.

• Combined actions of two or more drugs are now well understood. E.g. one of the NIH Pharmacogenomics Research Network (PGRN) researchers found tamoxifen (Nolvadex®), which is commonly used to treat breast cancer, is less effective in women who also take fluoxetine (Prozac®) to treat hot flushes caused by the anticancer drug.

• The US Food and Drug Administration has modified the labels of more than a dozen medicines to include pharmacogenetic information. This ensures that the drugs are as safe as possible and helps doctors customise doses for individual patients. Examples of drugs whose labels have changed are irinotecan (Camptosar®), used to treat colorectal cancer, mercaptopurine (Purinethol®), used to treat inflammatory bowel disease and childhood leukemia, and the blood-thinner warfarin (Coumadin®), used to prevent heart attacks and strokes.

• To ensure privacy and speeding research progress toward a complete understanding of individual drug responses, the database does not include identifying information about research subjects.

• Scientists are using computers to analyse publicly available genomic information to predict new uses for existing medicines. The approach could save time and money compared to traditional drug discovery methods. E.g. researchers have already revealed based on their effects on the human genome, that an anti-ulcer medicine might treat lung cancer and an anticonvulsant might alleviate inflammatory bowel disease.

The present, with this hyped-up technology, shows us a promising future beyond. A steady progress of this technology makes for more accurate dosing in individuals, new and more targeted drugs, reducing toxic and


adverse events in individuals. This is a great leap of mankind towards an improvised healthcare system.

Pharmacogenomics indicates a signif icant evolut ion in medical history. Though this novel technology brought in a dramatic improvement in drug safety and efficacy, it is still in its infancy, facing regulatory challenges. The explosion of interest in this sector has raised concerns that the regulatory environment could inhibit progress.

While drug discovery and preclinical studies are not likely to be significantly affected, there is concern about the use of pharmacogenomic biomarkers in clinical trials. Many factors determine the success of genomics-based technologies, products, and services designed to improve human health and disease. Pharmacogenetics and pharmacogenomics claim to increase safety and efficacy in prescription, but clinical uptake has not been widespread. Complex criteria are involved in the clinical success of drugs and drug-related tests based on pharmacogenomics. The introduction of a conceptual framework and its application can only help to evaluate the current pharmacogenomic strategies and also help in guiding their future development, licensing, and prescription. All these are major hurdles

and overcoming them would represent a major step forward in the progress of medical science.

7. Conclusion: It is a well-known fact of medical history that a medicine effective for one patient may not work for another, even though both suffer the same condition. Genes not only determine how an individual looks, but also how a person’s body responds to medicines. It is indeed pharmacogenetic technology that yields a substantial medical benefit that provides simple genetic tests to determine in advance which drugs will work for a given individual and which will not.

References1. http://discoverysedge.mayo.edu/pharmacogenomics/

(visited on Oct 2011).2. http://www.pharmgkb.org/ 3. Bristol, L.A. A regulatory protocol for pharmacogenomics

services. Pharmacogenomics J.; 2, 83-86 (2002).4. Vogel, H.G. Drug Discovery and Evaluation: Methods

in Clinical Pharmacology. Springer-Verlag Berlin Heidelberg, (2011).

5. Klotz, U. The role of pharmacogenetics in the metabolism of anti-epileptic drugs: Pharmacokinetics and therapeutic implications. Clin Pharmacokinet. 46 (4), 271-279 (2007).

6. Becquemont, L., Alfirevic, A. & Amstutz, U. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics. 12 (1), 113-124 (2011).

7. h t tp ://pharma l i cens ing .com/pub l i c/ar t i c l e s/view/1090249172_40fbe1d4c4ef9

8. Mahlknecht, U. & Mahlknecht, S.V. Pharmacogenomics: Questions and Concerns. Medscape. Available from: http://www.medscape.com/viewarticle/508543

9. Georgitsi, M., Zukic, B., Pavlovic, S. & Patrinos, G.P. Transcriptional regulation and pharmacogenomics. Pharmacogenomics 12 (5), 655-673 ( 2011).

10. http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml

11. http://www.healthguideinfo.com 12. Shah, J. Criteria influencing the clinical uptake of

pharmacogenomic strategies. BMJ 328, 2004.13. h t tp ://www. fda .gov/drugs/sc i ence re search/

researchareas/pharmacogenetics/ucm083378.htm 14. h t t p : / / w w w . f d a . g o v / d o w n l o a d s /

RegulatoryInformation/Guidances/ucm126957.pdf 15. h t t p : / / w w w . e m a . e u r o p a . e u / e m a /

i n d e x . j s p ? c u r l = p a g e s / r e g u l a t i o n /g e n e r a l / g e n e r a l _ c o n t e n t _ 0 0 0 4 1 1 .jsp&mid=WC0b01ac058002958e&jsenabled=true

16. h t t p : / / l a t i m e s b l o g s . l a t i m e s . c o m / b o o s t e r _shots/2010/06/direct-to-consumer-dna-testing-kits-fda.html

17. h t t p : / / w w w . f d a . g o v / d o w n l o a d s /RegulatoryInformation/Guidances/ucm129296.pdf

18. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Ef ficacy/E16/Step4/E 16_Step_4.pdf

19. h t t p : / / w w w. e m e a . e u r o p a . e u / d o c s / e n _ G B /document_library/Scientific_guideline/2009/09/WC500 003864.pdf

20. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/12/WC500017982.pdf

21. h t t p : / / w w w. e m e a . e u r o p a . e u / d o c s / e n _ G B /document_library/Scientific_guideline/2009/09/WC500 003890.pdf

22. http://www.fda.gov/downloads23. DrugsomplianceRegulatoryInformation/Guidances/U

CM243702.pdf 24. http://www.ema.europa.eu/docs/en_GB/document_

l ibrar y/Scient i f ic_guidel ine/2011/07/WC500 108672.pdf

25. http://www.ema.europa.eu/docs/en_GB/document_l ibrar y/Scient i f ic_guidel ine/2010/07/WC500 094445.pdf

26. h t t p : / / w w w. f d a . g o v / D r u g s / D r u g S a f e t y /DrugSafetyNewsletter/ucm119991.htm


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Cost Savings for Healthcare Estates: Delivered Through Improved Waste ManagementHow the Process of Effective Waste Management can Lead to Greater Efficiency in the Healthcare SectorYou only have to read a newspaper or turn on the news to see the NHS is struggling to meet the balance between demand for healthcare services and funding. The NHS faces an unprecedented financial dilemma: the supply of funding is struggling to match the growing rate of demand for healthcare. The financial challenge for the NHS is immense; it includes funding variations, in terms of treatment areas, procedures and regions, differing approaches to budget management across the regions and the impact of rising demand for services on healthcare costs. All this is against a background of pressure to make progress and deliver efficiency.

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Spend in the NHS can be simplistically split into four main areas:

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The NHS spends in excess of £700m each year on waste disposal. How waste

is managed within the healthcare sector has a direct impact on the bottom line for each healthcare organisation.

Poor management of medical waste potentially exposes hospital staff, healthcare workers, waste handlers, patients and the community at large to infection, toxic effects and injuries, and risks polluting the environment. The term “medical waste” encompasses all waste materials produced within healthcare facilities such as clinics, hospitals, dental practices, blood banks, veterinary clinics as well as medical research facilities, cleanrooms and laboratories.

The Medical Waste Tracking Act of 1988 defines medical waste as "any solid waste that is generated in the diagnosis, treatment, or immunization of human beings or animals, in research pertaining thereto, or in the production or testing of biologicals."

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A Case in PointIn 2011, the waste solutions company began talks with a global hospital group with a network of over 30 hospital facilities in the UK. As part of the process, they undertook site visits to audit the existing waste across each of the facilities.

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achieved through a more considered approach to the procurement of waste services and the management of the service. Those funds could be reinvested into budgets that are closer to the point of care. How many hip replacements could an NHS hospital provide for a £225,000 reduction in costs?

Savings of 15 to 25% can be achieved through a more considered approach to the procurement of waste services. Clearly, understanding how to get the best procurement deal is important, but so is developing a robust waste management strategy through understanding the options available to process waste. If your healthcare estate is looking to reduce cost, increase

operational efficiency and improve their environmental credentials, then a revised approach to waste management should be considered. The key difference is between ‘waste disposal’ and ‘waste management’. Waste disposal is costly, and waste management is less costly but more effective, because it identifies how to reduce waste arising.

The leading waste management company that undertook the project provides clinical healthcare and pharmaceutical waste management services, specialising in protecting people and reducing risk. They work with local and national companies across the public and private sector to improve employee and customer safety, ensure legislative compliance and minimise the environmental impact of waste disposal.

Their services include:

• Resource management guidance Hazardous waste management programmes

• Pharmaceutical waste disposal• With an extensive UK network

of service providers and their disposal facilities, GPT Waste provide a range of services to NHS trusts, GPs, dentists, pharmaceutical manufacturers, private sector businesses, research companies and many more.

To speak to someone about your pharmaceutical and clinical waste disposal requirements, call 0844 854 5000 or email [email protected]

Tony Mottram is Commercial Director for GPT Waste who provides Waste M a n a g e m e n t solutions for the FM, Construction, Defence, Pharma and Healthcare sectors.

Tony has an extensive expertise in the pharmaceutical sector. He specialises in operational and environmental process development and delivers sustainable waste solutions for both private and public sector organisations.Email: [email protected]

Total Waste Cost per HPDThe waste cost per HPD dropped from £4.18 to £3.02

Domestic Waste ProfileThe level of domestic waste recycled by the group increased from 50% to 69% and over 31% of domestic waste was diverted from landfill.

Total Waste ProfileThe expensive clinical waste disposal reduced from 40% of waste to 30%, which equates to a difference of £0.30/Kg (clinical @ £0.42/Kg vs. recycling @ £0.12/Kg).`



A Hard Pill to Swallow: Meeting the Needs of Modern Consumers

Confronted with the ‘patent cliff’, dwindling drug discovery success and a host of other challenges, pharmaceutical companies are being forced to reconsider how they can remain profitable. This includes looking to external experts to foster innovation and a move towards actively placing every need of the modern patient at the centre of their strategy. A recent survey conducted by Hermes Pharma in collaboration with the impartial and renowned market research agency, SPIEGEL INSTITUT Mannheim, has further highlighted the need for a fresh approach. The survey revealed that over 50% of people, independent of age, gender and nationality, have experienced various problems swallowing traditional solid tablets and capsules. This highlights a significant opportunity for pharmaceutical companies: by formulating medicines as user-friendly dosage forms that are easier and more pleasant to take, they can increase market share, boost revenues, revitalise ageing products and better meet the needs of modern patients and consumers.

Reversing an Uphill StrugglePharmaceutical companies have been facing mounting challenges over the past decade. For example, the so-called ‘patent cliff’ continues to claim billions of dollars in revenue: in 2014 Sanofi will lose Renagel, Fabrazyme, Multaq and Actonel to the patent cliff, amounting to $8.1 billion1. The use of generic medicines is also becoming increasingly common, accounting for 75% of all prescription medicine sales during 2014 in the US2. In addition to this, the R&D costs associated with medicine development continue to rise, while the return on R&D investment continues to fall: the number of medicines approved per billion US dollars spent on R&D has halved roughly every nine years since 1950, falling around 80-fold in inflation-adjusted terms3.

Currently, pharma is responding to this in a number of ways. Firstly, large pharmaceutical companies now look to acquire smaller, more innovative

companies, rather than going through the risky and expensive process of developing new medicines from scratch themselves. Another strategy that has gained momentum over the last fifteen years is how pharma looks to external sources of innovation via outsourced suppliers. This can serve to eliminate the costs of developing innovative solutions in-house and allows pharma to tap into dedicated expertise in specific areas.

Over-the-counter Medicines The pharmaceutical market is also changing. Life expectancy in developed countries continues to rise, increasing the burden placed upon healthcare systems across the globe by ageing populations. This has seen healthcare providers explore multiple avenues to try to reduce healthcare costs. One possible solution involves making more medicines available over-the-counter (OTC), by switching them from prescription (Rx)-only to OTC, thus reducing the need to visit a doctor simply to obtain a well-known medicine for a potentially mild disease. Thanks to the internet, patients are also better informed than ever before, either requesting specific medicines from their doctors or making the choice themselves when purchasing medicines from pharmacies and supermarkets. This trend has the power to influence how pharma sells its products and could

provide forward-thinking companies with an opportunity to capture market share by better meeting the needs of patients and consumers.

To account for these changes, pharmaceutical companies are beginning to put patients at the centre of everything they do. This means paying more attention to factors beyond novel API development and embracing characteristics such as ease-of-use, convenience and others that could improve user experience, while breeding brand loyalty and increasing compliance at the same time.

At this point the opportunity is no longer hypothetical, as a recent survey carried out by Hermes Pharma and the SPIEGEL INSTITUT Mannheim has shown. Out of approximately 2000 people surveyed in the US and Germany, over half found it hard to swallow traditional tablets and capsules. The survey also revealed a host of other insights about how modern consumers view solid dosage forms, as well as their awareness, experience and preferences for using alternative dosage forms such as effervescent and chewable tablets, instant drinks, orally disintegrating granules (ODGs) and lozenges (see Figure 1 for more information on these forms).

Figure 1. There are several types of user-friendly dosage forms available, providing customers with a range of alternatives to traditional dosage forms like tablets and capsules.



A Bitter Pill to SwallowAs mentioned, over half of the people in the survey reported difficulties when swallowing tablets or capsules. Interestingly, none of these people recounted difficulties when swallowing food or drink, suggesting that this trend is specific to tablets and capsules. A broad range of reasons were cited, but most frequently the difficulties were due to the tablet or capsule being too large, becoming stuck in the throat and having an unpleasant taste or odour. In some cases, these responses were extreme: approximately 6% of people reported feeling nauseated and around 3% had trouble breathing or experienced a suffocating feeling (Figure 2).

In order to overcome these difficulties, people primarily reported consuming more water. Worryingly, many have gone much further, with over a third compromising the effectiveness of their treatment: 32% have broken tablets up to swallow them, 17% have crushed them (before trying to dissolve them in water), and 9% have tried chewing them. Interfering with a medication like this can compromise API release profile, bioavailability and medical efficacy. Most worryingly of all, 8% of people have simply stopped taking their medication altogether, rather than face the difficulties associated with swallowing tablets or capsules.

These data have important implications for healthcare providers, governments and reimbursers. It also opens up strategic opportunities for pharma companies to capture market share by better serving the needs of patients and consumers.

A Diverse DifficultyDifficulty swallowing, known as dysphagia, is a condition prevalent in the elderly population4 and this is a trend that was also reflected in the survey results: around 44% of participants 65 years or older reported swallowing difficulties when taking tablets/capsules. Somewhat surprisingly, 70% of younger people aged 16–34 also reported having the same problem (Figure 3). Tablet size was an issue across all age groups, but younger people also reported disliking the taste or odour of tablets/capsules. This is not entirely unexpected, since those in the younger age group have grown up in the ‘era of choice’, where displeasing experiences are frequently

challenged and expectations around choice and ease-of-use tend to be higher.

People Expect More Modern consumers expect more from their medicines (Figure 4). When asked about important product characteristics, survey participants reported a large number of preferred features. In addition to the 64% of participants who indicated that products should be easy and comfortable to swallow, 41% said that a pleasant taste or odour was important and 38% wanted a product that integrated easily into their lives. Around 30% of participants said they wanted packaging that was easy to open. A clear emerging trend among modern consumers is that they want access to convenient products that taste and smell pleasant and are easy to swallow.

Alternate Dosage Forms as a Solution How can we make medicines easier and more pleasant to take? One possible solution is provided by user-friendly

dosage forms, which offer a more positive experience because they are easy to swallow, taste pleasantly and feel good in the mouth. From a more technical standpoint, user-friendly dosage forms also allow a greater concentration of API to be encapsulated within a single dose, or even the combination of multiple APIs, as they are not constrained by size in the same way traditional tablets and capsules are. This works to simplify dosing regimens, further highlighting how user-friendly dosage forms integrate effectively with daily life to make administration easier and more convenient.

In order to choose an alternate dosage form, consumers must know that it exists. The survey data revealed that awareness of many of these user-friendly dosage forms is high, especially in Germany, where chewable tablets, lozenges and instant drinks were known by over 90% of German participants. Furthermore, effervescent tablets and lozenges had been used by 90% and 88% of German

Figure 3. Difficulties swallowing tablets or capsules are not problems limited to the elderly, but affect all age groups.

Figure 2: There is a wide variety of reasons why people have difficulties swallowing tablets


participants, respectively. In the US, awareness of chewable tablets, lozenges and effervescent tablets was also high, at around 85% of participants. However, fewer American participants had actually used these user-friendly dosage forms than in Germany.

Those people that had tried user-friendly dosage forms preferred them to solid tablets/capsules, consistently scoring them more favourably across a range of characteristics, including ease-of-swallowing, sensation in the mouth, package opening and ease-of-intake/ingestion. Delving into the data a little further, certain user-friendly dosage forms were found to be more popular in different locations. For example, instant drinks were the most popular form in the US, followed by ODGs, while lozenges scored the best overall in Germany, again followed by ODGs. This indicates that reformulating medicines to meet the preferences of individual nationalities might be an effective way to ensure success in these markets.

For Parent and ChildAs a parent, it is important to feel confident that your child is capable of taking his or her medication with as little difficulty as possible. For this reason, the survey asked parents (a subset comprising 218 people in Germany and 294 in the US) about the dosage forms they would prefer to give to their children aged 15 years and younger. Parents ranked flavour and odour as the most important characteristics when choosing medication for their child, with ‘easy and comfortable to swallow’ in second. Approximately half of the parents surveyed in the US preferred to give children under the age of 11 chewable tablets.

In Germany, dissolvable forms such as effervescent tablets and instant drinks were a popular choice for parents. Depending on the age of their children, between approximately one in five and one in ten parents preferred instant drinks, and up to half preferred effervescent tablets. Regardless of child age, tablets or capsules were never the overall favoured dosage form of choice in either country.

ConclusionsThe survey revealed a number of clear trends, highlighting that approximately 50% of the population have difficulties swallowing tablets and capsules. A large number of people have experienced serious issues with these dosage forms, mostly related to difficulties with swallowing, while convenience also plays a critical role. In some cases these challenges were leading patients to negatively alter their medication or even completely abstain from taking it. The survey made it very clear that people want medications that are easy to swallow, pleasant to take and fit in with their busy lives.

These findings present pharma with an excellent opportunity to win customers by further exploring user-friendly dosage forms that help keep patients both happy and compliant. This will be particularly true if pharmaceutical companies start balancing portfolios with more OTC products, as they will have to put the holistic needs of the patient at the core of their business activities. The traditional strategy of ‘simply’ marketing and selling products to pharmacists, doctors and other healthcare professionals will be insufficient for attracting and retaining this ‘new’ primary customer – the well-informed end-consumer. This means

putting the patient at the centre of the strategy, understanding their needs and challenges, and responding to them with dosage forms they want to take, not have to take.

User-friendly dosage forms are an excellent choice for providing people with the options they want. They are easy to use and swallow which can improve compliance and thus reduce the healthcare costs associated with failed treatments. Pharmaceutical companies that tap into this opportunity have the potential to differentiate their brands in the mind of the consumer, breed brand loyalty and open up new market segments by catering directly to the needs of end-consumers.

References1. Anderson, K. Money Morning

February (2014) http://moneymorning.com/2014/02/18/patent-cl i f f-2014-char t-shows-much-revenue-big-pharma-will-lose, visited on 15 Oct 2014

2. Evaluate Ltd, World Preview 2013, Outlook to 2018: Returning to Growth (2013) http://www.eva lua tegroup.com/PDFs%20for%20Download/EvaluatePharma-World-Preview-2013-Outlook-to-2018-Executive-Summary.pdf, visited on 15 Oct 2014

3. Scannell, J.W., et al. Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discov. 11, 191–200 (2012)

4. Sura, L., et al. Dysphagia in the elderly: management and nutritional considerations. Clin. Interv. Aging 7, 287–298 (2012)


Dr. Thomas Hein is Senior Vice President Commercial and Regulatory Affairs at HERMES PHARMA, the third party division of Hermes Arzneimittel, a leading German OTC

company. Having joined in 1992, he has been responsible for the division’s commercial operations and worldwide portfolio management since 2001. His email address is [email protected]

Figure 4. In the ‘era of choice’, modern consumers want their medication to not only be effective, but also provide a positive experience.

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How Much Data Should You Include in a Patent Application?

In the life sciences and chemistry fields it is important to be aware that a perceived lack of data in a patent application can have an impact on the eventual scope of protection available.

Obtaining data can be time-consuming and costly. With that said, there is a balance between:

1. Filing as early as possible so that you have the earliest date from which patentability is assessed; and,

2. Obtaining the necessary data so that your patent application is not vulnerable to challenge because it does not contain enough data.

1. Filing as Early as PossiblePatents are granted for new and non-obvious inventions.

When assessing whether or not an invention is new and non-obvious, and hence patentable, all disclosures made available to the public (by any means) prior to the filing date of a patent application can be taken into account. In “patent speak” earlier disclosures are often called prior art.

With that said, the earlier a patent application is filed the better!

2. Obtaining the Necessary DataWhen a patent application is directed towards a new compound or formulation, or the new use of a compound or formulation, it is recommended to include information in the patent application setting out how to make the compound or formulation and to include some data supporting the stated utility of the compound or formulation.

If a patent application is perceived to lack the requisite data then the validity of the patent application (or granted patent) can be challenged under the headings of sufficiency of disclosure or inventive step.

A. Sufficiency of DisclosureAs part of the ‘bargain’ for obtaining an exclusive monopoly by way of a granted patent, patent applications must describe

an invention so that a person operating in the field of the invention can work the invention based on the detail in the patent application and their common general knowledge. In “patent speak” the person operating in the field of the invention is referred to as the skilled person.

In the life sciences and chemistry fields, to meet the requirement of sufficiency of disclosure a patent application usually needs to include: a) detail on how a new compound is made; and b) data supporting the intended utility of the compound.

If the skilled person is unable to make the new compound based on the patent application’s teaching, and this chasm in knowledge is not filled by the common general knowledge attributed to the skilled person, then the patent application can be found to lack sufficiency of disclosure.

Additionally, if there is no data in the application supporting the utility of the claimed compound, particularly

where the compound is claimed to be a therapeutic, the patent application can be refused because it would be considered an undue burden on the part of the skilled person to carry out all of the requisite investigations to establish whether the claimed compound had the recited utility.

A finding of a lack of sufficiency of disclosure can result in a patent application being refused, or a subsequently granted patent being revoked. In some extreme instances, an attack under the heading of sufficiency of disclosure cannot be defended by producing additional data which was not in the patent application as originally filed.

B. Inventive StepAs the saying goes, “necessity is the mother of all invention”. With that said, most inventions are arrived at by an inventor trying to provide a solution to a problem.

As with sufficiency of disclosure, as part of the ‘bargain’ for obtaining an



exclusive monopoly by way of a granted patent, the patented invention needs to amount to more than the mere routine development of what is already known. With that said, the step from what is known, i.e. the prior art, to the patented invention needs to be an inventive step.

With a view to ensuring objectivity in assessing inventive step, the European Patent Office (EPO) applies the so-called ‘problem-and-solution’ approach. The steps of the ‘problem-and-solution’ approach are:

a. Identify the closest prior art and the differences between the closest prior art and the claimed invention.

b. Establish the objective technical problem by determining the technical effect of the differences.

c. Consider whether starting from the closest prior art and the objective technical problem the claimed invention would have been obvious to the skilled person.

On establishing the objective technical

problem reference can be made to the data in the patent application as originally filed.

Plausible?

In the extreme situation where there is no data in the application as filed

which supports the utility of the claimed invention, the EPO has been known to take the position that because of the absence of data it is clear that no objective technical problem has actually been solved by the patent application, and hence, if no problem has been solved, it cannot be said that the inventors have made any invention, never mind taken an inventive step!

This is evidenced by the stance taken by one of the EPO’s Boards of Appeal in the decision identified as T 1329/04.

In T 1329/04, the patent application claimed a new member of the TGF-β superfamily. The Board of Appeal (BoA) took the position that based on the teaching of the application and the skilled person’s common general knowledge it would not be plausible to the skilled person that the patent application had indeed identified a new member of the TFG-β superfamily.

Against that backdrop, because there was no data in the application which supported the plausibility that the patent application had indeed provided a new member of the TGF-β superfamily, the application was refused. To this end, although the BoA stated that supplementary post-published evidence might, where appropriate, be taken into consideration, they also stated that it cannot serve as the sole basis for

establishing that an application does indeed solve the objective technical problem. In this case, because of the disclosure of the patent application and the chasm it presented to the skilled person making it plausible that the application had indeed identified a new member of the TGF-β superfamily, the BoA held that it was not appropriate for additional data to be taken into consideration.

This was an extreme situation, because the patent application included a number of statements setting out the expected structural characteristics of a member of this TGF-β superfamily and then in the same breath stated that the claimed product did not include these characteristics!

In a later decision, T 578/06, an EPO BoA looked at the interaction between data and inventive step and held that the burden of proof to substantiate doubts of whether or not a technical effect is plausibly provided by a patent application as filed lies with the person bringing the complaint, in this case with the EPO.

The BoA pointed out that an inventive step attack based on a perceived lack of data should be based on substantiated doubt as to a stated technical effect. The good news here is that an objection along these lines should not be successful merely because a patent application



does not include any data. Having said that, it is recommended to include some data in a patent application as filed which at least supports the plausibility of the patent claims.

In summary, the absence of any data in a patent application can be fatal and moreover, gives a competitor something to focus an attack on; not least because it is clear when a patent application does not include any data!

Credible?

In the situation where there is some data but not enough to make it credible that the objective technical problem has been solved over the whole scope of a patent claim, the EPO can insist that the scope of a claim is narrowed so as to be coterminous with the extent of data in the application as originally filed.

In T 2375/10, an EPO BoA reviewed a decision of an EPO Examining Division (ED) to refuse a patent application on the ground of inventive step. The patentee appealed the decision because the ED did not provide suitable reasoning in support of their inventive step objection.

The invention was chemical in nature and was directed towards a method of using a type of fluid to service (e.g. clean) a wellbore in, for example, oil and gas drilling operations. There was one

example in the application relating to a particular chemical compound (graphite) which showed a beneficial effect. However, the claim covered the use of a number of other materials in addition to graphite.

This case is analogous to a patent application directed to a generic group of compounds with one example compound (showing a biological effect), when an examiner alleges that the scope of the claim is not justified by the one example.

The ED concluded that the claimed invention lacked inventive step because the beneficial effect was not shown over the whole scope of the claim, i.e. there was no data confirming it was credible that the effect was attainable with anything other than graphite. The ED effectively took the position that it was not possible to carry out an assessment of inventive step because it was not credible that the patent application made the whole of the claimed invention available to the skilled person.

As with T 1329/04 (see above) where a BoA held that no invention had been made against which an inventive step could be assessed, the ED took the position that an inventive step could not be assessed because it was not credible that there was a whole invention against which an assessment could be made.

The BoA found the reasoning of the ED incorrect. Instead of their assertion, the ED should have reformulated the objective technical problem addressed by the application and then assessed inventive step in the light of the prior art and the reformulated problem. By reformulating the objective technical problem, the BoA meant that the extent of the contribution to the art should have been lowered, thereby making it easier to attack the existence of an inventive step based on the prior art. By way of example, if the objective technical problem is defined as the provision of an improved product, it is more difficult to attack than if the objective technical problem is defined as the provision of an equally as good alternative product. This is so because when the technical problem is defined as an improvement, an inventive step attack must rely on prior art identifying the improvement and pointing you in the direction of the claimed improvement.

Although the BoA did not go on to

reformulate the problem in this case, it is likely they or the ED would reformulate the problem as simply the provision of an alternative method, rather than an improved method. This case has been remitted back to the ED and we await the outcome of the application.

In summary, the less relevant data present in a patent application, the more difficult it is to argue in favour of inventive step.

ConclusionIt is often necessary to decide how much data to include in a patent application in support of the claimed utility, for example, a biological activity. The more data there is showing an effect at the edges of a broad claim, the less likely the claim is vulnerable to attack under inventive step.

The time taken to obtain data needs to be weighed up against filing as early as possible to get the earliest possible filing date.

We recommend including as much data as possible in a patent application in support of a claimed utility.

Chris Bond graduated from the University of Oxford (New College) with a first class Masters degree in Chemistry in 2005 and has worked at Forresters since then. The findings of

Chris’ final year research project were published in The Journal of Organic Chemistry.

Chris works mostly in the prosecution and drafting of patents in the chemical, pharmaceutical and biotech fields. The technical fields he has worked in are diverse, ranging from battery technology to pharmaceutical compositions. Chris also has experience in preparing freedom to operate and due diligence opinions and representing clients in hearings before the EPO.

Chris regularly files UK and European patent applications and is involved in obtaining patent protection throughout the world. He is a member of the Royal Society of Chemistry.Email: [email protected]



ISO IDMP – Four Challenges in Preparing Organisations for the July 1, 2016 EMA Deadline

Most pharmaceutical companies face challenges in becoming compliant with the ISO IDMP standards. In this article we share our experience from NNIT’s IDMP work for a handful of pharmaceutical companies over the past two years, and we let you in on the conclusions from our IDMP Experience Exchange Group.

Challenge 1: Information IslandsTo determine the maturity of your company, NNIT’s first recommendation is to take the logical first step: Do an impact assessment – or data inventory. This will result in a “table of contents” for ISO IDMP and an overview of the location of the data and its format, independently of whether that data is located in systems or documents.

During an impact assessment we often see that the sources for this information may very well support the data needed for the IDMP submission, but due to the nature of the systems and the scope under which they have developed, no company

actually has an application landscape so well integrated that it allows tying the systems together immediately.

Data is, for the large part, gathered in logical clusters with their own unique identifiers. A common challenge is, for instance, to bind the registration number from your RIMS application to the unique identifiers in the labelling system, not to mention the SKU number in the ERP system. (Or rather ERP systems, because you will often have more than one system and although they may run on the same template, it does not necessarily make your life easier, unless the SKU number is globally unique.) Will you be able to do a one-to-one link between your SKU number and the registration number?

In most cases the answer will be no and that places a heavy task on your shoulders: Should you create the necessary links? Should you route through other applications? Or simply not link the data at all?

These questions are not simple to answer. Yet it is the perfect example that you must get deep within your IDMP data to fully understand the complexities and make the right decisions.

Challenge 2: Partial Source, Redundant Source, EEA Only?Another challenge that NNIT sees lies in the scope of the systems for IDMP. It is generally more of a rule than an exception that identified information is only part of the truth. Let us have a look at an example.

It may be that fields are only filled in for EEA products. A good example is xEVMPD, whereas on other side of the pond we have SPL submissions, containing some of the information needed for IDMP, but they are not available for EEA countries – and the list continues. Furthermore, you may be in a situation where two (or even more!) systems claim to be the master system. Data are built in parallel by



different people, for different purposes, but the data are basically the same. This is particularly pronounced within the substance area, where a lot of data is redundant. The same situation exists if the company has been part of one, or several, mergers where IT systems have not been consolidated entirely. Suddenly a company can have three RIMS systems with a scope that is near impossible to determine, unless you know the detailed history of the mergers.

Also, the challenge is that you have partial sources, that is, systems where more systems are holding essentially the same type of information, but with different scopes, so there is no overlap in data. It may be your ERP systems where for one product it may be necessary to fetch identical information from different sources, depending on, for instance, the region.

Challenge 3: Where are the Clinical Particulars?In the beginning of an IDMP project, most companies are confident that they will find the majority of the data in a structured format in a system. However, it seems that there is a pool of data that, in most companies, is not found in a structured format in any system.

One such area is the clinical particulars, which in itself is a rather big area of the IDMP information model. Only very few companies would have this

area covered in a system and most likely the best source will be the SmPC or PI. In other cases it may be that the information is tracked in governed spreadsheets.

Challenge 4: Do You Really Want to Tie Your Systems Together?Finding data may not always solve your quest for IDMP data. Linking data that have not been linked historically creates a whole new set of challenges for the company. Processes and roles with no current connections to RA, and certainly not to any regulatory submission, may quickly get in scope for just such an endeavour.

This situation is likely to spark a new round of discussions. For instance, if you have identified the details of your packaged medicinal product in the ERP systems, how will you handle the different pack sizes, approved under your registration number, but not currently produced for the market? Do you force production to set them up so you can obtain your data? And how about the upcoming requirements for submission deadlines? If we get a 30-day window for updating products, will this mean that all systems in scope need to be updated within this period of time? That may put unwanted pressure on processes, currently in place to serve a completely different purpose.

Alignment of Systems and Master Data ManagementThese challenges may seem tough – and they are. But actually IDMP compliance is achievable, also before July 1, 2016. The examples highlight that IDMP is a long journey even before you are ready to pick the software to submit your data. You need to go through a discovery phase to get the necessary insight in your data and your processes in order to make the right decisions. And it should be obvious that there is no ‘easy fix’ for IDMP, no miracle solutions that can easily make your data IDMP compliant.

If you have a solid master data management set-up in place, some help could come from this MDM programme. If not, it seems unrealistic to solve IDMP within the next 18 months purely with MDM. In the long run it may be the right solution, and it may be part of your solution in the coming 18 months, but putting all your source systems under MDM so quickly seems like an impossible task. Rather, a pragmatic and IDMP-focused solution is needed to address the challenges outlined in this article.

Glossary

• EEA = European Economic Area• ERP = Enterprise Resource

Planning• MDM = Master Data Management• PI = Prescribing Information• SKU = Stock Keeping Unit• SmPC = Summary of Product

Characteristics• SPL = Structured Product Labelling

Rune Bergendorff is responsible for NNIT’s ISO IDMP services. He has conducted numerous ISO IDMP assessments, is a member of ISO/TC215 WG6 and participates in this group’s ballots and reviews of ISO IDMP standards

and implementation guidelines. Rune Bergendorff has worked with xEVMPD since 2011, advising on issues from requirements to the submission of data. He has written several articles and heads an ISO IDMP networking group for Danish pharma companies.Email: [email protected]



Developing Healthcare Facilities

If you are the operator of a nursing or care home, and you are considering commissioning the building of a new care or nursing home, or extending or refurbishing an existing building, you should consider taking advice on the terms of appointment of architects and other design consultants, as well as on the appropriate form of building contract.

As part of Harrison Clark Rickerbys’ healthcare team, we have a specialist construction unit whose members are very experienced in the procurement of healthcare facilities and resolving any issues which can arise out of them.

Frequently, when a client is considering a new building, or extending or refurbishing an existing one, their first point of contact will be with an architect in order to consider design and feasibility issues. It is, however, important to get the architect’s form of appointment right, as frequently the terms proffered by architects are not ideal, either from a fees

or a liability perspective, and their scope of services will also need to be reviewed. Furthermore, if external funders are going to be involved in a project, then the terms of appointment offered by architects are normally not acceptable to the funders, and they will need to be changed at a later stage, which can give rise to delay and disputes.

Similar issues apply in relation to project managers, civil and structural engineers, mechanical and electrical engineers, and other design consultants involved in the project.

With regard to the form of building contract, legal advice should be sought because there are many different types of building contract, and whilst architects and project managers can give general advice upon them, in our experience frequently they do not fully advise clients on some of the legal issues involved. For example, it is quite common to use a “design and build contract”, typically

from the family of contracts known as JCT. However, one of the main advantages of the design and build route is not achieved using the JCT contract without appropriate amendments. A key amendment is to ensure that the contractor is responsible for the whole design and the build of the building so that if there are defects it cannot seek to blame others. The JCT design and build contract does not achieve this full design risk transfer, without appropriate amendments.

Furthermore, whilst the JCT contracts are a good base document, they do require amendment to address certain other shortcomings and also to meet requirements of most external funders. For example, most funders will want a “collateral warranty”, i.e. a contract from the contractor under which they can step in and take over the contract in the event of financial difficulties. A collateral warranty also gives them the right to make a claim in respect of defects if this

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devalues their security. However, the JCT forms of collateral warranty are generally not acceptable to funders and their lawyers and need some amendment.

If a building is to be let to a tenant, then normally the tenant will require a form of collateral warranty from the main contractor, consultants involved in the design of the project, and also from key sub-contractors. This is so that if there are defects in the building and it is let on a full repairing and insuring basis, they have a right of redress.

From the main contractor’s perspective, if it takes full design responsibility under a design and build contract, then normally it will want warranties from the design team or, more frequently, for the consultants to be ‘novated’, i.e. transferred across to it after it has won the contract so that in the event of any design issues it has rights of action against the consultants, and the consultants can also then complete the detailed design of the project. Therefore, the consultants’ appointment documents and the building contract are all intricately linked and need consideration at the outset.

Once the form of building contract is agreed, then and only then should you go out to tender. If you seek to amend the contract after it has gone out to tender then contractors will almost inevitably seek to increase their prices and this can result in delays and funding problems.

Once the project is underway, it is

important for the healthcare operator to be alive to the payment rules which apply to construction contracts. Whilst any competent project manager should advise you of this, it is important to realise that with most forms of building contract, if you do not respond to a contractor’s application for payment, it will be entitled to be paid the amount applied for, even if the amount is exaggerated. There are strict requirements to give payment notices and “pay less notice” if you disagree with the amount being applied for by the contractor. Furthermore, in the hopefully unlikely event of any disputes, it is also important to be aware that for commercial construction contracts, there is a statutory right for disputes to be resolved by adjudication. This is like a very fast form of arbitration where you can get a decision from an adjudicator within as little as 28 days from the dispute being referred to the adjudicator. It is therefore important that disputes are not ignored or allowed to fester as matters can be brought to a head rapidly and adjudication can take place at any time: it is not uncommon for adjudications to be launched during the summer holidays or over the Christmas period to gain a tactical advantage.

Andrew James, a Partner and Head of Construction and Engineering at Harrison Clark Rickerbys explains: “We can assist with advising upon the appropriate forms of appointment to use, which will be in your interests and also in line with the interests of any external funders. Due to our experience and contacts in the

field, we can also give you guidance on appropriate professional practices to use. On more than one occasion we have had to advise clients who have been let down by designers who are clearly not familiar with CQC design standards and requirements. With regard to the building contract itself, again we can assist you with choosing the right form of contract. The most commonly used “family” of building contracts is the JCT series, but there are many different forms with different risk profiles. Frequently a design and build contract is chosen, but the JCT design and build contracts need to be amended to ensure there is a proper transfer of risk to the contractor. Also, external funders such as banks will require amendments to the contract, and as we are familiar with funders’ requirements we can guide you through this.”

Andrew James is a Partner at Harrison Clark Rickerbys having previously been with Wragge and Co in Birmingham. He is joint Head of the litigation department and heads up the construction and engineering team.

Andrew specialises in construction and engineering law, and advises on procurement, contracts and resolving disputes.He has been an accredited adjudicator since 1998 and is a member of the Chartered Institute of Arbitrators, and is one of the few specialists in construction law between Birmingham and Bristol. He is also an accredited mediator.He regularly gives lectures to the RICS and other organisations on construction-related topics.Andrew and his team also deal with planning law and environmental matters, including Renewables and other energy projects. Andrew also has experience in dealing with professional negligence claims (he is on the Law Society Negligence Panel Referral Scheme).Andrew is the chairman of Herefordshire and Worcestershire Constructing Excellence Club and a member of the Gloucestershire Constructing Excellence Club.Email: [email protected]

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Drug Discovery, Development & Delivery

The Expanding Role of MRI in the

Pharmaceutical IndustryWith ever-increasing pressure on drug development pipelines and a growing need to demonstrate convincing mechanisms of action as a part of the registration process for new drugs, innovative methods are being sought that can streamline the traditional drug development process. Imaging methods have a substantial potential to impact the development and clinical trials process at several stages, and have begun to be used as a method of bolstering the uptake and marketing of already-marketed compounds.

Positron emission tomography (PET) is still the gold standard for many applications in drug development, as it can provide precise, quantitative information about drug bio-distribution and receptor occupancy. Such information can be very valuable in determining likely optimum dosages in early stage trials, and can obviate the need for larger dose-ranging studies. Unfortunately, PET necessarily involves the use of radiolabelled compounds that require a manufacturing infrastructure and suitable chemistry laboratories. PET studies also often require continuous blood-sampling during the scan, achieved through siting an arterial line; an unpleasant and often painful procedure. These factors make PET a relatively expensive and invasive modality.

In contrast, magnetic resonance imaging (MRI) uses a high-strength magnetic field in order to construct images based on the distribution and local chemical environment of hydrogen atoms in the bodily tissues. There are no known risks from exposure to magnetic fields, so subjects can be scanned repeatedly in longitudinal studies with no harmful effects. Depending on the exact type of scan used, the results may be directly quantitative, or semi-quantitative, and a great variety of applications are possible. Standard anatomical MRI scans provide high-resolution (1mm or even less) images of the body’s soft tissues, and various types of scans can provide contrast between different tissue types (e.g. between fat and muscle, or between white and grey matter in the brain). MR-spectroscopy can provide information

about metabolite levels in the brain or muscles, or fat content of the liver. An extension of standard MRI termed functional MRI (fMRI) can also provide an indirect measure of brain activity by imaging regional changes in blood oxygenation.

fMRI and its ApplicationsIn its roughly 20-year history, fMRI has grown through a period of “showy adolescence” (Smith, 2012) into a standard methodology in hundreds of academic and industry laboratories around the world. The flexibility of fMRI designs and the ability for subjects to engage in cognitive, motor, and sensory tasks while in the scanner have made it a workhorse method for cognitive neuroscientists, and have initiated a genuine revolution in the study of the working human brain. The high magnetic field-strength environment of the MRI scanner is relatively hostile, particularly to standard electronic devices, but researchers have inventively found ways to overcome this difficulty and a variety of MR-compatible equipment (response boxes, physiological monitoring devices, presentation screens, etc.) is now commercially available, or can be relatively easily fabricated. These

devices enable almost any standard task that could be completed outside the scanner to also be performed in the MR environment, with the proviso that the subject must remain supine, relatively immobile, and with their head restrained. For an excellent introductory overview to fMRI methods and its limitations and key issues, see Logothetis (2012).

Pharmacological fMRIRelatively early on, researchers also began to explore the potential for fMRI to index drug effects. Compounds that have some mode of action (either directly or indirectly) on the brain are a natural target of such research, and the general conceptual approach is that fMRI (when combined with an appropriate task or stimulus paradigm) can deliver pharmacodynamic information that is uniquely detailed, objective, and also yields information about possible brain mechanisms involved in the drug effects. Since fMRI is essentially a measure of blood oxygenation, the signal can potentially be strongly modified by general changes in cerebral blood flow and metabolism. For this reason, careful design and implementation of pharmacological fMRI studies is essential, in order to distinguish effects of interest

Figure 1. The brain’s canonical cortical response to pain (the ‘pain matrix’), revealed by fMRI studies using acute application of painful stimuli. This well-characterised system is a useful model for the evaluation of pharmacological effects. Image reproduced from Wall et al. (2012).

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(e.g. regional changes in the fMRI signal related to a genuine effect of the drug on the underlying neural tissue) from more non-specific effects (e.g. global changes in cerebral blood flow or oxygenation brought about by the drug under test). A good example is caffeine, which has well-known effects on alertness and attention, but is also a cerebral vasoconstrictor. This vascular effect might be expected to lead to a reduction in the fMRI signal, however recent work (Diukova et al., 2012) has shown the effect is actually more complex, and relative decreases or increases can be seen in different brain regions. These considerations are a key challenge in pharmacological fMRI, particularly with novel compounds where their effects on vasculature and metabolism may be relatively unknown.

Pain as a Useful ModelA solid base of experimental data has accrued which demonstrates the value of fMRI-derived measures as endpoints

in pharmacological studies. Pain (and analgesic) research has been a particular area of interest. The brain’s general response to painful stimuli is well documented and involves a network of distributed regions, sometimes referred to as the ‘pain matrix’ (Tracey & Mantyh, 2007). Activity within this network arising from painful stimulation can be decreased by the use of analgesics, such as remifentanil (Wise, Williams & Tracey, 2004), and such decreases correlate well with other measures of analgesia (e.g. decreases in subjective ratings of the intensity of a stimulus).

Pain fMRI responses have even been validated as a method for distinguishing between putative analgesic compounds. A series of studies by Upadhyay et al. (2012) tested two compounds; one with proven analgesic properties (buprenorphine), and one that had recently failed clinical trials as an analgesic (aprepitant). Only buprenorphine was

shown to significantly modulate the fMRI response to painful stimuli, and only buprenorphine produced correlations between the fMRI measures, and peak drug concentrations in the blood plasma. This landmark study therefore serves to validate the fMRI-based measures as a useful and informative endpoint, and shows that meaningful distinctions (at the very least between the two compounds under test) can be drawn from them. Further exciting developments in pain fMRI are ongoing, with one recent study (Wager et al., 2013) successfully identifying a ‘neurologic signature’ of pain, which proved to be sensitive and specific enough to distinguish between a number of pain-related experimental conditions with around 90-95% accuracy. This derived model could determine with a high degree of accuracy the presence, intensity, and even the type of painful stimuli being applied to the subject, purely from their brain response. More simply, we can now measure how much pain a subject is experiencing by scanning their brain. This advance represents a step-change in the understanding of the brain’s pain response, and has a potentially major impact on future studies using analgesics.

Broadening the ApplicationsThe non-invasive and low-risk nature of MRI also enables applications in other areas beyond traditional clinical topics such as pain. Evaluation of over-the-counter (OTC) medicines or consumer products might be ethically unjustifiable with more invasive modalities such as PET, however the extremely low risk profile and much lower cost of MRI makes such studies practical. This is currently an emerging area of interest, but the need to provide strong evidence of the effectiveness of consumer products and the increasing need for product differentiation in the crowded OTC market means that it may be a growing trend.

Work by Hammett et al. (2010) shows that a widely-available dietary supplement (creatine monohydrate; frequently used by body-builders and athletes) has a large effect on the fMRI response to simple visual stimulation. Cole et al. (2010) tested the effect of a standard nicotine replacement therapy (NRT; a 4mg nicotine lozenge) on cognitive and neurophysiological measures and demonstrated a relationship between alleviation of nicotine withdrawal

Figure 2. Body composition MR image of the torso with fat highlighted in yellow-red (muscles and organs in blue-green). Images of this type can be used for quantitative assessments of the kind used in Thomas et al. (2011). Image provided by the Imanova Centre for Imaging Sciences, London, UK.


Product Focus

With its new BIOSTAT A, Sartorius Stedim Biotech presents a compact bioreactor/fermenter designed specifically as an entry-level model for fermentation and cell culture as well as for educational purposes. The system's control tower features a complete array of measurement and control functions like easy-load peristaltic pumps, an aeration module and conveniently accessible probe ports and supply connections. By virtue of its compact design, this new fermenter/bioreactor saves valuable space in your lab.

The aeration system provides automatic flow control over the full range of each gas used. As a result, BIOSTAT A does not require any manual adjustment of flow meters and therefore eliminates problems with pulsed aeration. The system is very easy to operate: all the user has to do is connect the aeration hoses, configure the aeration profile, and enter the DO setpoint. Using the BIOSTAT A version for cell culture applications, aeration with four gases (air, O2, CO2 and N2) is possible for controlling pH and DO. The microbial version features two gas lines (air and O2) for DO control.

The bioreactor is equipped with digital pH and DO probes. These help users immediately recognise whether you can confidently use a probe for the next cultivation process. Thanks to the moisture-resistant plug connection, secure data transmission is also always assured.

Each BIOSTAT A for microbial fermentations is equipped with a chiller that effectively removes heat from the device. This reduces your cooling water consumption and your laboratory does not need to be equipped with a cooling water system. All the user needs to operate the system is electricity and a gas supply.

Thanks to the intuitive user interface, operating the new bioreactor is ideal for beginners because it prevents operating errors and reduces training time to a minimum. Optional operation with a tablet or smartphone allows you to monitor and control the system, whether you're on the go, in the lab, in the office or even at home.

The bioreactor is available with various single-walled borosilicate glass culture vessels with maximum working volumes of 1, 2 or 5 litres. In addition to the UniVessel made of glass, the UniVessel SU disposable bioreactor can also be operated with the same control tower and offers a maximum working volume of 2 litres.

New bioreactor BIOSTAT A: specifically designed as an entry-level model for fermentation and cell culture purposes

A profile of Sartorius Stedim Biotech Sartorius Stedim Biotech is a leading provider of cutting-edge equipment and services for the development, quality assurance and production processes of the biopharmaceutical industry. Its integrated solutions covering fermentation, cell cultivation, filtration, purification, fluid management and lab technologies are supporting the biopharmaceutical industry around the world to develop and produce drugs in a safe, timely and economic way. Sartorius Stedim Biotech focuses on single-use technologies and value-added services to meet the rapidly changing technology requirements of the industry it serves. Strongly rooted in the scientific community and closely allied with customers and technology partners, the company is dedicated to its philosophy of “turning science into solutions.” Headquartered in Aubagne, France, Sartorius Stedim Biotech is listed on the Eurolist of Euronext Paris. With its own manufacturing and R&D sites in Europe, North America and Asia, and a global network of sales companies, Sartorius Stedim Biotech enjoys a worldwide presence. Its key manufacturing and R&D site is in Germany. The company employs approximately 3300 people, and in 2013 earned sales revenue of 588.4 million euros.

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symptoms by the treatment and altered activity in key brain networks.

The potential applications of MRI in this area are diverse and go beyond the brain. Orlistat is a lipase inhibitor that prevents the absorption of dietary fat, and is marketed as an over-the-counter weight-loss (‘Alli’; GlaxoSmithkline) aid in the UK and USA. An evaluation study by Thomas et al. (2011) used anatomical imaging and MR-spectroscopy of the abdominal region to track the distribution of fat tissue in a group of subjects taking 60mg doses of orlistat over a three-month period. The results showed significant reductions in ectopic abdominal visceral and hepatic fat; an important marker of general health.

Most recently, work performed by Wall et al. (2014) has demonstrated the feasibility of studying the neural substrates of smoking using electronic cigarettes and fMRI. Health and safety concerns have previously prevented the use of traditional tobacco products in MRI scanners, however e-cigarettes obviate most of these issues, and provide a reasonable simulation of normal smoking. These results show for the first time the brain regions activated during the inhalation of nicotine, and therefore facilitate future studies investigating not just the nature of nicotine addiction, but the detailed evaluation of e-cigarette products; a market that is currently undergoing explosive growth.

A Promising FutureMRI studies are a powerful and highly flexible family of techniques with a diverse

range of applications, both in traditional clinical drug development pipelines, and in the investigation of more quotidian consumer or OTC products. An additional benefit of MRI for the latter case is that it is a highly visual modality. Endpoints of studies are usually presented as images, either as statistical maps in the case of fMRI, or as quantifiable anatomical images. Such images can be highly visually impactful as well as informative, and can potentially play a prominent role in product marketing. MRI technology and scanning and analysis techniques are also in a state of constant evolution, and the applications of the techniques are being gradually expanded across a wider range of product categories. As a result, it is likely that MRI of various kinds will play an ever-greater role in future research and development across nearly all sectors of the pharmaceutical and consumer healthcare industries.

References1. Cole, D. M., Beckmann, C. F., Long,

C. J., Matthews, P. M., Durcan, M. J., & Beaver, J. D. (2010). Nicotine replacement in abstinent smokers improves cognitive withdrawal symptoms with modulation of resting brain network dynamics. NeuroImage, 52(2), 590–9.

2. Diukova, A., Ware, J., Smith, J. E., Evans, C. J., Murphy, K., Rogers, P. J., & Wise, R. G. (2012). Separating neural and vascular effects of caffeine using simultaneous EEG-FMRI: differential effects of caffeine on cognitive and sensorimotor brain responses. NeuroImage, 62(1), 239–49.

3. Hammett, S. T., Wall, M. B., Edwards, T. C., & Smith, A. T. (2010). Dietary supplementation of creatine monohydrate reduces the human fMRI BOLD signal. Neuroscience Letters, 479(3), 201–5.

4. Logothetis, N. K. (2008). What we can do and what we cannot do with fMRI. Nature, 453(7197), 869–878.

5. Smith, K. (2012). Brain imaging: fMRI 2.0. Nature, 484(7392), 24.

6. Thomas, E. L., Makwana, A., Newbould, R., Rao, A. W., Gambarota, G., Frost, G., & Beaver, J. D. (2011). Pragmatic study of orlistat 60 mg on abdominal obesity. European journal of clinical nutrition, 65(11), 1256-1262.

7. Tracey, I., & Mantyh, P. W. (2007). The cerebral signature for pain perception and its modulation.

Neuron, 55(3), 377–91.8. Upadhyay, J., Anderson, J., Schwarz,

A. J., Coimbra, A., Baumgartner, R., Pendse, G., & Borsook, D. (2011). Imaging drugs with and without clinical analgesic efficacy. N e u r o p s y c h o p h a r m a c o l o g y, 36(13), 2659-2673.

9. Wall, M. B., Gunn, R. N., Koltzenburg, M., & Matthews, P. M. (2012) Spatially overlapping but functionally distinct regions code stimulus intensity for painful and non-painful stimuli. 266.12 New Orleans, LA: Society for Neuroscience, 2012.

10. Wall, M. B., Mentink, A., Lyons, G. (2014) Studying the neural substrates of smoking with e-cigarettes and fMRI: A feasibility study. Abstract presented at the Global Addiction Conference, Rio De Janeiro, Brazil, Nov. 2014.

11. Wager, T. D., Atlas, L. Y., Lindquist, M. A., Roy, M., Woo, C.-W., & Kross, E. (2013). An fMRI-Based Neurologic Signature of Physical Pain. New England Journal of Medicine, 368(15), 1388–1397.

12. Wise, R. G., Williams, P., & Tracey, I. (2004). Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain. Neuropsychopharmacology 29(3), 626–35.


Matt Wall is a neuroscience and fMRI researcher currently working at the Imanova Centre for Imaging Sciences, London, UK. His particular interests are in vision, pain, (f)MRI methodology and psychopharmacology. He completed his PhD

at the University of Cambridge, and post-doctoral positions at Royal Holloway and the Institute of Neurology UCL, before joining Imanova in 2012. He is currently involved in collaborations with colleagues at Imperial College London, UCL, Queen Mary University, Durham University, and Royal Holloway, as well as a number of industry-funded projects at Imanova. As well as his scientific publications, his writing has appeared in The Guardian and Scientific American.Email: [email protected]


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Based on these new technics, in-house automatized platforms and with the serious experience of its researchers and scientists, Neuro-Sys has standardized models of CNS diseases specifically on:

• Alzheimer disease (AD);• Parkinson disease (PD);• Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig's disease);

and• Demyelinating diseases.

What we doNeuro-Sys is an innovative company that provides the pharmaceutical and biotech industry with efficient and highly skilled cell-based preclinical modeling services:

• Cortical neurons;• Glial cells (astrocytes, oligodendrocytes);• Hippocampal neurons;• Mesencephalic neurons (dopa-, gabaergic neurons);• Models of central and peripheral myelination;• Motor neurons;• Muscle cells;• Nerve-muscle co-culture;• Schwann cells;• Sensitive neurons.

With a strong expertize and a hi-end laboratory equipment, Neuro-Sys develops and uses specific preclinical models of CNS diseases to achieve high-quality efficacy pharmacology and mode of action studies. We are dedicated to provide high-level technical expertise and preclinical services in a collaborative relationship with our clients.

A team of expertsOur operational and scientific team is composed of highly-skilled and experienced specialists such as pharmacologists, neuroscientists, neurologists, cell-biologists and phytochemists.

Innovative models and automatized screening platformsNeuro-Sys invests a lot in R&D to continuously enhance its models of CNS bringing then the most advanced solutions to clients.Our high-content imaging platforms composed of the last cutting-edge equipment allows the highest screening quality. Moreover, assisted with a fully robotized system, our platforms including efficacy and mode of action testing can run on a 24/7 basis to

provide the best results, faster. We have selected some of the best automation providers capable to design and setup such platforms.

The starting pointStandard screening platforms on the market generally accept molecular compounds coming from the chemical industry that we also do perfectly.Uncommonly, our processes and platforms have been designed to be capable to receive other entities such as:

• natural products (plants, seaweed…);• extracts from natural source;• compounds from natural or chemical source.

Hence, before providing a full pharmacological and analytical profile of the initial entity, we apply a specific standardized process depending on the input source. The pharmaceutical and biotech industry as well as Governments are now really interested in this approach and the extended service coming from natural sources (more generally from plants) we propose to seize the potential on neurodegenerative diseases of natural products.

Green-ExtractionNatural products are processed into our “Green-extraction” laboratory where “green” stands for ecology.Extraction of natural products using standard methods is a truly polluting activity. Because reducing carbon footprint is important to us, Neuro-Sys also has a strong green policy regarding its activities and extraction which is a major activity. Our green-extraction laboratory composed of brand new extraction technologies (micro waves, ultrasounds, alternative solvents…) is handled by scientists, experts in eco-extraction technics and methods that provides similar or even better results than conventional extraction methods.

Drug discovery programsNeuro-Sys also develops and uses its platforms to perform proper dedicated drug discovery programs. Sharing the same vision and determination, the IDVP (Institut de Développement Vietnam Pacifique) and Neuro-Sys setup an exclusive partnership to bring a new dynamic to neurodegenerative disease drug discovery researches.

The IDVP was founded in 1989 in Nouméa, New Caledonia, to survey the medicinal flora of this rich archipelago, kept intact for 350 millions of years. From this privileged base, IDVP jumped to Vietnam and focused on medicinal plants with a traditional reputation for enhancing graceful aging. Such prevention derives from stimulating the immune system of natural defenses against oxidative stress created by free radicals.

We are then proposing our clients brand new compounds with a proven efficacy and mode of action coming from medicinal plants selected by our scientific board.

Key contactYann Jaudouin, CEONeuro-Sys410 Chemin Departemental 6013120 GardanneFrance

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Special Report: How to Ensure the Proper Behaviour

of Excipients and their Best Possible Use

The best new therapeutic substance in the world would have no value without the right delivery system. Done in parallel with the clinical trials, the pharmaceutical development serves to define the industrial production of the active ingredients, as well as to determine the final formulation of the future drug, whether it be a tablet, cream or injectable drug. This is where Roquette Group comes in, developing the most suitable form. And in the last 40 years, the French family-owned group has become a key supplier of excipients and active ingredients, the “building blocks” of drugs.

It`s a case of “Location, Location, Location!” The high-technology pharmaceutical Application Development Center inaugurated on 10th October 2014 at the Roquette Lestrem site is situated close to the major cereals basins and big consumer zones of Northern Europe, a major roadway network, numerous maritime and river ports, multimodal platforms and railway lines. It`s quite impressive: on a surface area of 150 hectares, it extends 1.6 km from east to west and 1.1 km from north to south.

“The creation of this new Application Development Center on the Group’s largest site at Lestrem enables synergies with all of the Group’s research laboratories and production units at the site. Its ambition however is global as it is in direct contact with the three other major regions of the Group (North America, Asia and India) and will serve pharmaceuticals customers throughout the world”, explains Guillaume Fichet,

Director of the Roquette Lestrem site.

Excipients play a critical role in formulation development. They are defined as “inert” ingredients that transport the active substance exactly where the drug is intended to exert its action. They may keep the drug from being released too early in places where it could cause damage; they may help the drug to disintegrate into particles small enough to reach the bloodstream quicker or protect the drug stability. There are some used only to make the drug taste better, but this is also essential in terms of patient compliance.

According to the experts, in recent years, excipients have proved to be anything but “inert”, that is they possess the ability to react with the other ingredients in the formulation and can cause adverse effects. That`s why ensuring the proper behaviour of excipients in the various phases of the industrial production process is one of the missions of the pharmaceutical Application Development Centers in France, the USA and China.

The biorefinery at Lestrem is the biggest

in Europe with a capacity of 7000 tons of cereals transformed per day and about 700 products on the market. I`m told that 100 trucks and up to seven full trains deliver the raw materials each day and shipments of finished products (syrups, drinkable solutions, tablets, capsules, powders, etc.) represent on average 600 trucks/day.

The excipients produced here are designed to facilitate industrial production and cover a broad range of pharmaceutical applications. The specific physicochemical properties of mannitol for example (a combination of good solubility and some surface hydrophobicity) makes it the ideal excipient in association with a superdisintegrant for the formulation of tablets that are robust yet disintegrate very rapidly.

One of the latest innovations of the Group applies to a galenic formulation that is currently generating a lot of excitement in the industry: an excipient for orodispersible tablets. This new form melts directly in the mouth without the need to drink any water, providing immediate therapeutic action for the patient.

Whatever your requirements, the people at Roquette are committed to deliver the guidance needed to make the best possible use of excipients, right through the development process, from the creation of prototypes to scale-up.

“At Roquette we help you formulate whatever you want, when you want it, where you want it”, says Isabelle Routier, Vice-President – Application Development Centers for Food Nutrition Health. With an annual global growth rate of nearly 5%, the market for excipients offers excellent opportunities as well as numerous challenges in terms of formulation.

“This new pharmaceutical Application Development Center is proof of Roquette’s commitment in the health sector”, adds Routier, explaining that the technologies available now, such as a state-of-the-art compression simulator, coupled with the expertise of the dedicated team, allows the company to pursue innovations and respond to the expectations of this highly demanding sector. And, if you pardon my French: “It`s all about quality, safety and performance!”

Cecilia Stroe,Editor

www.roquettepharma.com

Roquette offers a large range of high quality excipients together with trouble-shooting services and ways to reduce time-to-market, including formulation design, compression simulation and regulatory support.

Our expertise at your service!

We offer a wide range of excipients, but not only...

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Clinical Research

Revisited Cell Cultures and Valuable Methods

for Pre-clinical Studies

During the ten last years, the development of transgenesis technics has rendered possible the creation of mutant strains of rodents mimicking human diseases, or the assessment of the role of biochemical lesions in their development (e.g. the Clinique de la Souris, Université de Strasbourg, France). However, maintaining and expanding colonies of transgenic rodents is time-consuming, expensive and above all, the characterisation (phenotyping) of these new animals needs highly experienced people. It is therefore interesting to develop alternative methods for studying efficiency and mode of action of new compounds in preliminary preclinical studies, before carrying out long in vivo explorations.

Alternative methods rely on the rational use of primary cell cultures originating either from transgenic animals or from normal ones conveniently treated for reproducing the essential features of a given disease. Such an effort first requires theoretical consideration of what a model comprises. As Segev wrote, “a model is something simple made by scientists to help them in understanding something complicated. A good model is one that succeeds to reduce the complexity of the modelled system while preserving its essential features.”

A good in vitro preclinical model of a human disease should fulfil three criteria: (a) isomorphism, or presence of features found in the human disease

to be modelled (e.g. accumulation of α-synuclein in dopaminergic neurons intoxicated with MPP+; (b) the homology or causes involved in physiopathology of the disease (e.g. degeneration of hippocampal or cortical neurons challenged with toxic forms of amyloid peptide [see Callizot et al., 2013]); and finally (c) criteria of predictivity, that is sensitivity to reference drugs, when they exist, known to improve the clinical status of patients suffering from this disease. This implies having at one’s disposal reference molecules to compare effects of the new compounds to those of a reference molecule. This criterion cannot be always fulfilled, when, as in amyotrophic lateral sclerosis or Charcot disease, no efficient drug really exists, except possibly riluzole, which is weakly active.

Considering the in vivo situation, it appears that cellular interactions are essential for a tissue or an organ to work correctly. This fact is essential, especially in the nervous system. This statement prompted us to design what we call reconstituted and mixed cultures, in order to preserve in vitro the main biological and topological relations existing between the different cells of a given tissue.

We describe here some reconstituted and mixed cultures (mimicking human pathologies) we have been practising for many years.

Typical examples of mixed cultures are illustrated by models of central or peripheral myelination. For instance, growing together sensory neurons and Schwann cells from dissociated rat embryonic dorsal root ganglia, and following sequential addition of growth factors and hormones, allows the reproduction in vitro of temporal and topological events leading to myelination of axons (Callizot et al., 2011). Therefore, this model can be used to study effects of factors or drugs promoting myelination or inducing demyelination, which could be used for treatment in CMT 1A (Charcot Marie Tooth disease) or for Guillain Barré syndrome, or peripheral neuropathies. It

is also possible to develop for the same purpose a model of central myelination, involving a mixture of neurons, oligodendrocytes and astrocytes (Fig. 1). In this last case, this model can be used to screen compounds developed in multiple sclerosis.

A slightly more complicated model of partly reconstituted culture is that of nerve muscle cocultures. Coculturing rat embryonic spinal cord explant equipped with dorsal root ganglia onto human muscle myotubes leads to maturation of muscle cells into striated, contracting myofibres, expressing nicotinic acetylcholine receptors clustered into motor plates contacted by axonal terminals from motor axons and forming functional neuromuscular junctions [NMJs]. These co-cultures show spontaneous contractions mimicking the reflex arc. The number and the apparent area of NMJs can be evaluated, so this model reproduces a reflex circuit and allows the study of factors influencing innervation or functioning of NMJ (see Braun et al., 1996 and Fig. 2).

Using purified cells involved in innervation, and mixing them in different configurations (Guettier-Sigrist et al., 2000), it has been possible to demonstrate, in a fully reconstituted culture, that motor neurons alone are unable to innervate myotubes. However, when three cell types (motor neurons, sensory neurons and Schwann cells) were plated onto reconstituted muscular components consisting of cloned satellite muscle cells and cloned fibroblasts in definite proportions, myotubes matured into myofibres and contracted, indicating that functional neuromuscular junctions were formed. Therefore, the three cell types are required for a successful innervation to occur. In addition, it has been shown that successful innervation depends on physical contacts between sensory neurons, motor neurons and myotubes, whereas Schwann cells can be replaced with a Schwann cells-conditioned medium which suggested that these cells produce a putative “innervation-promoting factor”. Such a reconstituted system exactly reflects the

Fig. 1: Model of central myelination: oligodendrocytes (green) myelinating central neurons (red). Cellular nuclei (blue).


Clinical Research

exact topological in vitro situation, but it allows one to somehow unravel the mechanism of synaptogenesis and meets Segev’s definition of a model.

Fortunately, some other reconstituted systems are largely simpler. For instance, it is possible to evaluate the activation state of macrophages by culturing them together with cancer cells first radio-labelled (Kessler et al., 1998; Karsten

et al., 2002). Sources of macrophages are varied and include peritoneal macrophages, broncho-alveolar macrophages, splenic macrophages, and peripheral mononuclear phagocytes (see Dumont et al., 1988).

How can cell cultures for preclinical studies of new compounds be developed? In which direction? Keeping in mind that culture conditions should mimic as closely as possible the conditions prevailing in vivo, several key factors should be taken into consideration. First, the nature and origin of cells to be grown will determine the topology of the culture. Clearly, polarised cells, such as epithelial ones, cannot be grown as non-polarised cells as fibroblasts (see Vrana et al., 2013), and, of course, circulating cells such as lymphocytes or monocytes. The case of monocytes illustrates the question to be answered. Monocytes plated onto plastic or glass substrate will adhere and differentiate into macrophages. When they are prepared for adoptive immunotherapy, they should be grown into Teflon bags, a substrate onto which they cannot adhere and which allows gaseous exchanges with the external

environment. Some naturally polarised cells, such as neurons, do not require special topological conditions. Neurons possess endogenous mechanisms of polarisation and develop multiple dendrites and usually one axon (which sometimes present branches) when grown in appropriate medium. Tridimensional substrate such as collagen gel often may promote cell differentiation. The topological factor certainly is one of the most important to be considered in tissue engineering.

The second important factor to be considered is what Richard Ham named “cellular nutritional type”. Ham pointed out that the presence of serum in high concentrations (ca 10%) essentially favours the growth of fibroblasts which are poorly differentiated cells, and could totally inhibit that of some very specialised cells such as human broncho-epithelial cells, even at very low concentrations (< 1%) and in the presence of a defined complement which usually allows their growth in defined medium devoid of serum (Ham and McKeehan, 1978). Ham intended to replace serum, the complexity of which is too highly elevated

Fig. 2: Model of nerve-muscle co-culture: nerve fibre innervating cell muscles (NMJ = light green dots on nerve fibre).

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to be mastered, with defined supplement consisting of a mixture of growth factors, hormones and adherence factors, especially shaped for each cellular nutritional type. Forty years ago, he sadly stated: “nutritional requirements of primary culture is a neglected problem” (Ham, 1974; see also Bettger and Ham, 1982). This problem is not always well evaluated and numerous contemporary scientists continue to routinely use non-adapted methods for their experiments. Clearly, there is an urgent need to continue the pioneering work of Ham and his coworkers and to refine the classification of nutritional types, improving therefore the composition of adapted defined medium to their requirements.

Another very important factor is that of the substrate coating for those cells which cannot multiply without adhering to a conditioned support. In our opinion, this point is often neglected by scientists who consider that serum itself is sufficient to create an adequate substrate since it contains numerous “adherence and spreading factors”. This approximation can no longer be admitted. For instance, neurons should be plated onto laminin-coated substrate, hepatocytes onto collagen. Generally, scientists use collagen type I despite the fact that basement membranes are rich in collagen type IV. But numerous other factors, such as fibronectin or glycosaminoglycans, can be used for preparing an adapted substrate.

A fourth factor is certainly more difficult to appraise. It pertains to the question of interaction and cooperation between cells belonging to different lineages. Reid and Rojkin (1979) already stated: “We believe that substantial progress in

culturing differentiated cells, including normal cells, will be made possible by study of cell-cell interactions within the tissue matrix. The relevance of tissue architecture to proliferation and functioning of cells has not yet been fully ascertained, but the studies discussed below suggest that some of the interactions within the tissue matrix are critical for normal cellular physiology. An almost ubiquitous and, therefore, probably primary relationship within tissues is that between the epithelium and mesenchyme. In vivo, normal epithelial cells capable

of proliferation or long-term survival are attached to a basement membrane which, in turn, is associated with mesenchymal-derived cells, most commonly fibroblasts. The basement membrane, a layer of secretion located between and produced by the epithelium and the mesenchymal cells, is assumed to contain the extracellular subset of factors affecting the epithelial-mesenchymal interactions.” With the development of cell culture techniques, it will appear that some cells considered as impossible to cultivate or difficult to cultivate will be amenable to cultures in vitro. Growth, in fact, is not obligatorily linked to multiplication, which constitutes its plastic aspect. Growth also includes increased production of living matter that constitutes the trophic aspect of the phenomenon. In this sense, development of dendrites and axon in cultured neurons, which cannot multiply, nonetheless are true growing cells.

References1. Vrana N.E., Lavalle P., Dokmeci

M.R., Ghaemmaghami A.M. and Khademhosseini A. Engineering functional epithelium for regenerative medicine and in vitro organ models: a review. Tissue Eng. Part B Rev., 19, 529-543, 2013.

2. Bettger W.J. and Ham R.G. The nutrient requirements of cultured mammalian cells. Adv. Nutr. Res., 4, 249-286, 1982.

3. Ham R.G. Nutritional requirements of primary cultures. A neglected problem of modern biology. In vitro, 10, 119-129, 1974.

4. Dumont S., Hartmann D., Poindron P., Oberling F., Faradji A. and Bartholeyns J. Control of the

antitumoral activity of human macrophages produced in large amount in view of adoptive transfer. Eur. J. Cancer Clin. Oncol., 24, 1691-1698, 1988.

5. Kessler R., Dumont S., Weitzemblum E. and Poindron P. Antiproliferative properties of human alveolar macrophages. Respiration, 65, 363-368, 1998.

6. Karsten V., Sigrist S., Moriscot C., Benhamou P.Y., Lemarchand P., Belcourt A., Poindron P., Pinget M. and Kessler L. Reduction of macrophage activation after antioxidant enzymes gene transfer to rat insulinoma INS-1 cells.Immunobiology, 205, 193-203, 2002.

7. Guettier-Sigrist S., Coupin G., Warter J.-M. and Poindron P.Cell types required to efficiently innervate human muscle cells in vitro.Exp. Cell Res., 25, 204-212, 2000.

8. Callizot N., Combes M., Steinschneider R. and Poindron P.A long term in vitro model of myelination. Exp. Cell Res., 317, 2374-2383, 2011.

9. Callizot N., Combes M., Steinschneider R. and Poindron P Operational dissection of β-amyloid cytopathic effect on cultured neurons. J. Neurosci. Res., 91, 706-713, 2013.

10. Ham R.G. and McKeehan W.L.Media and growth requirements. Methods. Enzymol., 58, 44-93, 1979

11. Reid L.M. and Rojkind M. New techniques for culturing differentiated cells: reconstituted basement membrane rafts. Methods Enzymol.;58:263-278, 1979.

12. Segev I. Single neuron models : oversimple, complex and reduced.trends Neurosci., 15, 414-421, 1992.

Pr Philippe POINDRON, PharmD, PhD, President of Neuro-Sys Scientific board, Professor of Virology and Cell Biology at Strasbourg University (formerly Louis Pasteur University), has been

one of the BioValley initiative promoters with Swiss and German colleagues. He especially worked on interferon, adoptive immunotherapy of cancer and neurodegenerative diseases, using modelled mixed cell culture.

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Opportunities for Monoclonal Antibodies

in Bacterial Infectious DiseasesSummaryManagement of infectious disease is challenged by trends that impact patient welfare on a global scale; the emergence of multi-drug resistant (MDR) forms of new and old bacterial pathogens, the world’s increasing population of immunocompromised patients where antimicrobial therapy is less effective, and fewer new antibiotics being licensed. If these trends continue, a ‘post-antibiotic era’, where even common bacterial infections won’t be treatable, could become a reality1. Monoclonals have vast potential for combating antibiotic resistance2, 3 with many anti-infectious mAbs currently in development4. Monoclonals confer passive immunisation to recipients following infusion and their efficacy is both immediate and, where neutralisation is required, largely independent of the recipient’s immune status.

The Accelerating Threat of Antibiotic ResistanceAfter 50 years of antibiotics there is now widespread resistance to all major antibiotic classes5, which typically develops within 5-10 years following introduction of a new antibiotic5. It has been predicted that in less than a decade everyday operations such as hip replacements could end in death for one in six6.

The US CDC and European ECDC highlight antibiotic resistance, the spread of MDR hospital- and community-acquired infection and the grave consequences of inaction7, 8. The CDC conservatively estimates that in the US two million people are affected by antibiotic-resistant infections with at least 23,000 dying per annum. The majority of problematic infections are caused by the so-called ESKAPE pathogens9 which include both gram negative10, 11 and gram positive microorganisms.

In the US, nosocomial infection increases the average length of hospital stay by 17 days and costs up to $50,000 per patient. Global annual healthcare costs associated with these infections are currently estimated at $5B.

Vaccination has contributed to improvements in the prophylaxis of

some community-acquired infectious diseases in the young and healthy, but not in hospitalised individuals where vaccination is only effective prior to hospital admission for elective surgery, because a healthy immune system to mount an immune response and adequate time to develop protective immunity are required.

Monoclonal Antibodies Can Induce Multiple Biological EffectsAntibodies are part of the adaptive immune system and play a major role in prevention of infection and amelioration of disease. Antibodies have multiple biological effects which act either independently or in concert with other components of the immune system.

Antibody specificity is critical to functionality and is determined by variable regions called complementarity determining regions (CDRs)12, 13. The Fc region is a constant domain that performs different functions in bacterial and viral infections and in cancer or immune disease. Fc functions include antibody-dependant cellular cytotoxicity (ADCC), antibody-dependant cellular phagocytosis (ADCP) and opsonisation (relevant for bacteria), complement-dependant cytotoxicity (CDC) and direct bacterial killing12, 13.

Development of Monoclonal AntibodiesTherapeutic antibody preparations have been used since the early 1890s when von Behring and Kitasato14 developed an anti-diphtheria serum. These early preparations caused serum sickness in many recipients and were replaced with human-derived hyperimmune products which are still used today15.

In 1975 Köhler and Milstein developed hybridomas for generating mAbs16. The early therapeutic mAbs were murine and later chimeric, so recognised as foreign by the human immune system and inactivated by anti-drug antibodies upon repeat administration. Now, mAbs are engineered to be fully human (humanisation) and are generally safe and immunologically well tolerated. mAbs can be discovered using phage display17 or yeast display18, 19systems that

enable screening libraries of trillions of human antibody genes against clinically relevant antigen baits/molecules derived from the target.

Sequence liability prediction based on primary structure of candidate mAbs to identify potential manufacturability issues associated with the molecule allows uncommon framework sequences and non-germ line mutations that could affect expression or molecular stability to be identified and exchanged with other amino acids. Binding affinity and effector function are then assessed. Forced degradation studies can also be conducted to evaluate molecular stability (e.g. tendency to aggregate) as a final step in selecting the lead candidate. Typically antibodies for human therapeutics are manufactured in mammalian cell-line cells, most often in Chinese Hamster Ovary (CHO) cells.

Monoclonals are manufactured to cGMP which ensures reproducibility and a high level of safety from contamination with adventitious agents. The majority of processes include; batch/fed batch culture using mammalian cells followed by capture/purification steps that rely primarily on chromatography (e.g. Protein A affinity and ion-exchange polishing steps), intermediate filtration, viral inactivation/clearance treatments, formulation and aseptic filling20, 21.

Monoclonal Antibodies as a Therapeutic Approach in Bacterial Infectious DiseasesThe first mAb approved by the FDA was in 1986 (Muromonab-CD3). Today, most approved mAbs are targeted for the treatment of neoplastic and inflammatory disease. As of July 2014, there were 36 FDA-approved mAbs and seven under review22. Antimicrobial mAbs have typically failed from lack of efficacy23,24. To date only two anti-infectious mAbs have been licensed; the anti-RSV antibody Palivizumab25 and the anti-anthrax antibody Raxibacumab26. There are many more in development 4, 24, 27.

mAbs have a very high specific activity (i.e. potency relative to mass of protein) and can be administered systemically.


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Microbial specificity means that mAbs are also less likely to select for drug-resistant strains. Furthermore, because microbes are antigenically distinct from humans, cross-reactivity or host toxicity due to off-target binding are therefore unlikely. They have a long serum half-life (i.e. 21 days), so passive immune protection lasts for several weeks.

mAbs can act either directly on bacterial replication or viability. Alternatively, they can neutralise virulence factors such as exotoxins (which cause tissue damage or disablement of components of the host’s cellular immune system and inflammatory responses) 24,28 or, neutralise quorum-sensing auto-inducers (which regulate bacterial growth and virulence factors)29, 30. Neutralisation of bacterial virulence factors occurs when CDRs bind and sterically block function. Finding surface molecular targets that are both accessible and shared by clinically relevant strains is challenging. In many enterobacterial pathogens, conserved bacterial surface molecules are masked by highly variable surface polysaccharides. The target epitope may in itself be heterogeneous or have low expression as an accessible surface antigen.

Unlike antibiotics which target both pathogenic and host microflora, mAbs target a specific microbe so systemic administration will not destroy the host microbiome. A number of studies have shown a positive correlation between antibiotic use, disruption of the microbiome and the development of allergic and autoimmune diseases and cancers31, 32, 33. Disruption of the microbiome may also create conditions for more resistant bacteria to colonise. Antibiotics do not support immune defence or prevent damaging inflammatory responses in immuno-compromised individuals.

Compared to antibiotics, mAbs have limited cytotoxicity, are large molecules which are relatively unstable, require refrigerated storage, and may show poor penetration of soft tissue. They must be infused rather than given orally, which can complicate administration. Specific identification of the pathogen is needed before mAbs can be administered. Companion or complementary diagnostics allowing for rapid diagnosis may be key to directing mAb therapy and to bio-stratify patients to identify

potential responders and improve pharmacoeconomics.

A theoretical limitation with mAbs is the inability to adapt to a pathogen that undergoes rapid antigenic mutation and the potential for generation of escape mutants34, 35, 36, 37. Key to the prevention of escape mutants is the selection of highly conserved antigen or virulence factor targets, and the use of mAb cocktails to removal of selective pressure driven by single mAbs. This also gives broad coverage of different strains through complementary specificity and functionality. There are now mAb cocktail products in development; including an anti-rabies product which contains two mAbs38 and a product under development by Arsanis directed against S. aureus virulence factors39. In the case of antibiotics, non-completion of a treatment course, or frequent change of antibiotic, predisposes generation of resistance. However, mAbs administered once persist for up to 21 days, depending on pharmacokinetics, so may actually perform better in terms of resistance to treatment.

Monoclonal Antibodies – Some Potential Targets in Infectious DiseasesmAbs must either prevent or clear infection, reduce the infectious burden and/or pathology arising from the infection, reduce time to heal, or prevent infection or intoxication from reoccurring. Highly virulent and acute infections, particularly in outbreak situations where early preventative intervention would limit spread, make good targets. Alternatively, diseases which are not currently preventable by vaccination or where the target population’s immune system is compromised or naïve should be considered.

Staphylococcus aureus:Various strains of the universal human pathogen, Staphylococcus aureus are now methicillin-resistant. The immune-compromised state of many patients and the use of devices such as mechanical ventilators are major risk factors for development of S. aureus-associated nosocomial infections.

Community-acquired methicillin-resistant S. aureus (MRSA) is an increasing problem affecting the young and healthy, for example, in combat or trauma-related wound infections. A cocktail of mAbs directed against

both MRSA and methicillin-susceptible S. aureus (MSSA) could combat both spread of healthcare and community-acquired S. aureus infections.

S. aureus disease manifestation is largely due to production of virulence factors, which include secreted exotoxins. The genome encodes multiple toxins, such as the α-hemolysin (Hla) and several leukocidins, such as hamma-hemolysin, LukED and LukGH. The Panton-Valentine Leukocidin (LukSF) is acquired by viral infection of S. aureus (bacteriophage)40. All these toxins cause extensive tissue damage, therefore therapies consisting of neutralising anti-toxin mAbs could provide both prophylaxis and immediate aid to patients41. Prevention of collateral damage to the host caused by cytolysis or inflammation which can make the host susceptible to reinfection42 and reduction in pathogen evasion mechanisms that facilitate chronic infection.

Antibiotics may exacerbate toxin-mediated disease, by lysing bacteria or activating stress responses associated with increased transcription of toxin genes; indeed removal of one exotoxin can be compensated by another43 and exotoxin-mediated pathology can even progress when the pathogen has been eliminated. A cocktail of mAbs directed against more than one set of exotoxins has a therapeutic advantage over a single mAb-containing product.

Gram Negative PathogensGram negative pathogens account for half of all nosocomial infections, including septicemia and pneumonia. A major concern related to this group of pathogens is the spread of MDR. There have been several recent fatal MDR Klebsiella outbreaks in US NIH hospitals. Pseudomonas is the most common Gram negative pathogen causing ventilator-associated pneumonia44. Extrapathogenic E. coli is the most frequent isolate in urinary tract infections and Gram negative sepsis.

Streptococcus pneumoniae Introduction of pediatric pneumococcal vaccines has proven very successful in reducing the incidence of childhood invasive pneumococcal diseases (IPD). More recent data indicates that herd immunity and active immunisation might also reduce the incidence of community-acquired pneumonia (CAP) and IPD in the elderly; however, after an initial


Clinical Research

decrease in the first years of widespread vaccine use, the rate of invasive pneumococcal disease in the elderly seems to be significantly reduced, but remains constant. Even with antibiotics, the mortality rate associated with acute pneumococcal disease is high, and in the elderly has not changed for 50 years. Pneumococcus is also the most frequent cause of CAP, which is the 6th most frequent cause of death among the elderly in the US, with 4-6 million cases per year. The high mortality rate is partly attributed to release of pro-inflammatory and toxic substances from bacteria killed by antibiotics, which results in immune pathology and tissue damage in the lung.

Biodefense and Pandemic ThreatsThe 2001 anthrax bioterrorism attacks in the USA highlighted the medical need for improved post-exposure prophylaxis and the potential for using mAbs for biodefence45. They can be administered in quantities that exceed IgG levels elicited by vaccines, which may be advantageous where exposure to bioterrorism agents is elevated. The US Center for Biosecurity favourably assessed the potential of mAbs as medical countermeasures in biodefence4 giving a clear endorsement of the potential of mAbs and, in particular the use of mAb cocktails, to prevent infectious diseases. To be effective for dealing with pandemic threats (and emergent bioterrorism agents) rapid product development is essential. Current regulatory paradigms do not support rapid approval of new mAbs. It takes minimum 18 months from start to manufacture of a pilot-scale product. Alternative approaches are required, such as removal of the requirement for clonality, which takes several months to complete and may not be critical if the alternative is no therapeutic. Increasing the scope of expedited regulatory initiatives such as the animal rule to include pandemic threats should be considered46, 47.

Cost of mAbsFor licensed drugs, development costs mainly relate to process development and validation of mammalian cell-based platforms, non-clinical and clinical studies and the regulatory approval process. Routine manufacturing costs comprise direct production costs (i.e. raw materials and utilities) and indirect costs (i.e. depreciation and insurance) and ancillary activities (e.g. cleaning/sterilisation and support activities such as

QA, documentation and quality control). The factors which impact on CoGs of

a given product include yield, number of mAbs in the cocktail (driven by the balance between manufacturing costs and expected advantage in efficacy), the process platform, method of purification, dose presentation (liquid or lyophilised) and the manufacturing facility used 48,49,50. It has been estimated that overall costs split roughly as one-third attributable to cell culture, one-third to purification and one-third to support51.

In theory, the higher production rate (kg/year) and titre (g/L) and the larger the scale (L), the lower the cost per gram. However, it is not automatic that this ratio would change with scale. For example, the cost structure of a single product plant running significantly under capacity could not take advantage of an increase in yield. A facility dedicated to a single product would typically have higher overheads than a multi-use facility where these costs are shared. The use of disposable systems can significantly reduce validation costs/time and turnaround time as the cost of CIP/SIP is removed.

The cost of therapy for a single-shot preventative mAb therapy will be calculated differently to an indication requiring chronic dosing – published treatment costs relate mainly to chronic treatments. From a review of the average sales prices in 2008 for the top 15 mAbs and Fc fusions, costs of therapy range from $2000–$20,000/g, with a median sales price of $800020, and reflect their development and commercial production costs52. To make a fair comparison with antibiotics, the cost of mAb therapy should be set against complications that follow broad-spectrum therapy such as the downstream clinical effects of altered microbiome, MDR and costs of increased hospital stay treatment in high dependency units (e.g. ICU).

ConclusionsmAbs have great potential in infectious diseases and the number in development is expected to grow. Target selection should focus on unmet need, where antibiotic treatment is either ineffective (the causative agent is drug-resistant) or insufficient (toxin-mediated infections). mAbs can be used as first-line treatments, prophylactically or as adjunct therapy together with antibiotics to reach those patients that cannot be helped by

antibiotics alone. Passive immunisation with mAb cocktails is considered to be the optimal approach for complex pathogens. mAbs directed against novel virulence factor targets like exotoxins and quorum-sensing molecules, are poised to become the next generation of licensed products.

References1. Mckenna M. The Last Resort. Nature

99:394-396 (2013)2. Casadevall A & Scharff MD. Return to

the past: the case for antibody based therapies in infectious diseases. Clin Infect Dis 21(1):150–61 (1995)

3. Casadevall A. The third age of antimicrobial therapy. Clin Infect Dis; 42 (10):1414–6 (2006)

4. Center for Biosecurity of UPMC Next-Generation Monoclonal Antibodies: Challenges and Opportunities. Final Report – February (2013)

5. Ho J, Tambyah PA & Paterson DL. Multiresistant Gram-negative infections: a global perspective. Curr. Opin. Infect. Dis. 23: 546–553 (2010)

6. Smith R & Coast J. Title Br. Med. J. 346, f1493 (2013)

7. US Department of Health and Human Services, Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States (2013).

8. European Centre for Disease Prevention and Control (ECDC) Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). (2012)

9. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis 197:1079-81 (2009)

10. Coates AR, Halls G, Hu Y. Novel classes of antibiotics or more of the same? Br J Pharmacol 163(1):184-94 (2011)

11. Xu Z-Q, Flavin MT & Flavin J. Combating multidrug-resistant Gram-negative bacterial infections. Expert Opin. Investig. Drugs 23(2):163-182 (2014)

12. Chan AC & Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol;10(5):301–16 (2010)

13. Schroeder HW Jr & Cavacini L. Structure and Function of Immunoglobulins. J Allergy Clin Immunol. February; 125(202): S41–S52 (2010)

14. von Behring E & Kitasato S. The mechanism of diphtheria immunity and tetanus immunity in animals, 1890 (reprint). Mol Immunol 28(12):1317–20 (1991)

15. Bertolini J, Goss N & Curling J. Production of Plasma Proteins for Therapeutic. 2013. ISBN-10: 0470924314. ISBN-13: 978-0470924310


16. Köhler G & Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256 (5517): 495–497 (1975)

17. Hoogenboom HR. Overview of antibody phage-display technology and its applications. Methods Mol Biol 178:1–37 (2002)

18. Chao G1, Lau WL, Hackel BJ, Sazinsky SL, Lippow SM & Wittrup KD. Isolating and engineering human antibodies using yeast surface display. Nat Protoc. 1(2):755-68 (2006)

19. Van Deventer JA & Wittrup KD. Yeast surface display for antibody isolation: library construction, library screening, and affinity maturation. Methods Mol Biol. 1131:151-81 (2014)

20. Brian Kelley. Industrialization of mAb production technology. The bioprocessing industry at a crossroads. mAbs 1(5) 443-452; September/October (2009)

21. Liu HF, Ma J, Winter C & Bayer R. Recovery and purification process development for monoclonal antibody production. mAbs 2:5, 480-499; September/October (2010)

22. Reichert J. Therapeutic monoclonal antibodies approved or in review in the European Union or United States. Information current as of 28 July, 2014. http://www.antibodysociety.org/news/approved_mabs.php

23. Meulen J. Monoclonal Antibodies in Infectious Diseases: Clinical Pipeline in 2011. Infect Dis Clin N Am 25:789–802 (2011)

24. Oleksiewicz MB, Nagy G & Nagy E. Anti-bacterial monoclonal antibodies: Back to the future? Archives of Biochemistry and Biophysics 526:124–131 (2012)

25. FDA Approval Letter. Reference ID 97-1359. Jay P Siegel. June 19, 1998.

26. FDA Approval Letter. Reference ID 3231530. Edward M Cox. 12/14/2012

27. Xu ZQ, Flavin MT & Flavin J. Combating multidrug-resistant Gram-negative bacteria infections. Expert Opin Investig Drugs Feb 23(2):163-82 (2014)

28. Rouha H et al. Five birds, one stone: Neutralization of alpha-hemolysin and four bi-component leukocidins of Staphylococcus aureus with a single human monoclonal antibody. mAbs. Accepted for publication - forthcoming on NCBI 2014

29. Park J et al. Infection control by antibody disruption of bacterial quorum sensing signalling. Chem. Biol. 14(10): 1119–1127 (2008)

30. Kaufmann GF, Park J & Janda KD. Bacterial quorum sensing: a new target for anti-infective immunotherapy. Expert Opin Biol Ther 8 (6):719–2 (2008)

31. Droste JH et al. Does the use of

antibiotics in early childhood increase the risk of asthma and allergic disease? Clinical and Experimental Allergy 30: 1547-53 (2000)

32. Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA & Taplin SH. Antibiotic use in relation to the risk of breast cancer. JAMA 291:(7): 827–35 (2004)

33. Kozyrskyj AL, Ernst P & Becker AB. Increased risk of childhood asthma from antibiotic use in early life. Chest 131(6):1753–9 (2007)

34. Both L, Banyard AC, van Dolleweerd C, Wright W, Ma JKC & Fooks AR. Monoclonal antibodies for prophylactic and therapeutic use against viral Infections. Vaccine 31: 1553– 1559 (2013)

35. McKeating JA, Gow J, Goudsmit J, Pearl LH, Mulder C & Weiss RA. Characterization of HIV-1 neutralization escape mutants. AIDS; 3(12): 777–84 (1989)

36. Keck ZY, Li SH, Xia J, von Hahn T, Balfe P, McKeating JA et al. Mutations in hepatitis C virus E2 located outside the CD81 binding sites lead to escape from broadly neutralizing antibodies but compromise virus infectivity. J Virol 83(12):6149–60 (2009)

37. Zharikova D, Mozdzanowska K, Feng J, Zhang M & Gerhard W. Influenza type A virus escape mutants emerge in vivo in the presence of antibodies to the ectodomain of matrix protein 2. J Virol 79(11):6644–54 (2005)

38. Bakker AB, Python C, Kissling CJ, Pandya P, Marissen WE, Brink MF et al. First administration to humans of a monoclonal antibody cocktail against rabies virus: safety, tolerability, and neutralizing activity. Vaccine 47:5922–7 (2008)

39. Badarau A et al. Structure-Function Analysis of Heterodimer Formation, Oligomerization and Receptor Binding of the Staphylococcus aureus Bi-component Toxin LukGH. J Biol Chem. Nov 3 (2014) (http://www.ncbi.nlm.nih.gov/pubmed/25371205)

40. Bubeck Wardenburg J et al. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat. Med. 13:1405–1406 (2007)

41. Cheung GYC & Otto M. The potential use of toxin antibodies as a strategy for controlling acute Staphylococcus aureus infections. Expert Opin. Ther. Targets 16(6): 601-612 (2012)

42. Lowy I et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N. Engl. J. Med. 362:197–205 (2010)

43. Aman MJ & Adhikari RP. Staphylococcal bicomponent pore-forming toxins: targets for prophylaxis and

immunotherapy. Toxins (Basel) 6: 950-972 (2014)

44. Ryan S. Arnold, MD, Kerri A. Thom, MD, MS, Saarika Sharma, MD MA, Michael Phillips, MD, J. Kristie Johnson, PhD, and Daniel J. Morgan, MD. Emergence of Klebsiella pneumoniae Carbapenemase (KPC)-Producing Bacteria. South Med J. January ; 104(1): 40–45 (2011)

45. Froude JW, Stiles B, Pelat T & Thullier P. Antibodies for biodefense. mAbs 3:6, 517-527;(2011)

46. New drug and biological drug products; evidence needed to demonstrate effectiveness of new drugs when human efficacy studies are not ethical or feasible. Final rule. Fed Regist 67:37988-98 (2002).

47. FDA. Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, guidance for industry. Animal Models—Essential Elements to Address Efficacy Under the Animal Rule (2009).

48. Farid SS, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 848 8–18 (2007)

49. Shukla AA & Thommes J. Trends Biotechnol. 28: 253–261 (2010)

50. Birch JR & Racher AJ. Adv. Drug Deliv. Rev. 58: 671–685 (2006)

51. Myers J in: Proceedings of IBC’s Production and Economics of Biopharmaceuticals—Transcending the Limits of Manufacturing. Medicines, La Jolla, CA, November 13–15 (2000)

52. Marshall L, Kelsall W & Gooding N. A cost-effective approach to administering palivizumab in a centralised nurse-led community clinic. Arch Dis Child 93(7):638 (2008)

Clinical Research

Fraser Leslie has served in senior management roles in Quality Operations, Regulatory Affairs and as a Site Head, working with IMP’s and commercial biological products

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Advocating an Integrated Approach

to the Global Diabetes Epidemic

The non-communicable disease of diabetes has reached epidemic proportions, and it knows no geographic boundaries. As one example from a country in the western world, the United States (US) National Diabetes Statistics Report, 2014, observed that in 2012, 29.1 million Americans (9.3%) had diabetes and that 86 million individuals aged 20 years and older had prediabetes: the respective figures for just two years earlier were 25.8 million (8.3%) and 79 million.1 Type 1 diabetes has long been a disease observed in pediatric populations, but the same is now true for type 2 diabetes. The prevalence of pediatric type 1 diabetes in the US increased from 1.48 to 1.93 per 1000 from 2001 to 2009: when adjusted for completeness of ascertainment these figures represent a 21.1% increase.2 Although it is true that the absolute number of pediatric patients with type 2 diabetes is less than for type 1 diabetes, the rate of increase is greater: the estimated US prevalence increased from 0.34 to 0.46 per 1000 across the same time span, representing a 30.5% increase.2

Now consider a regional example outside the western world. Close to 20% of all adults in the world with diabetes live in the South-east Asia region. As the worldwide figure is estimated to approach 600 million by 2035, the number of people with diabetes in South-east Asia is estimated to increase to 123 million.3 It is extremely concerning from a global public health perspective that most people with diabetes live in low- and middle-income countries; these countries will see the greatest increase over the next two decades.4 The life expectancy of a patient with type 2 diabetes is likely to be reduced by up to 10 years as a result of this condition,5 a dramatic statistic driven to a large extent by increased risk of heart disease, renal disease, and stroke. Quality as well as quantity of life can also be seriously affected given the additional ramifications of nervous system damage, blindness, and lower-limb amputation.

It has therefore become a moral imperative to do everything possible

to lessen the human toll resulting from diabetes. Reducing the future financial toll to countries' healthcare expenditures should also factor into the overall equation. Although certainly not claiming that the four areas discussed in this paper represent an exhaustive list, the paper advocates for the adoption of an integrated approach to addressing the global diabetes epidemic: such an integrated approach offers the most promise for the prevention of future cases of diabetes, and for the treatment of patients who currently have diabetes.

First, we must do a better job of diabetes education at the individual and public health levels. Second, there must be greater advocacy at the public health and public policy levels for the widespread adoption of behavioural medicine approaches to diabetes prevention: these include planning a better diet and more physical activity, and encouragement to adhere to these dietary and physical activity regimens. Third, when diet and exercise alone have not prevented diabetes, we need to have a greater armamentarium of pharmaceutical agents to treat diabetes in both pediatric and adult populations. Fourth, much more attention needs to be paid to successfully transitioning emerging adults with diabetes from care in a pediatric medical home to care in an adult medical home.

Educational OutreachWorld Diabetes Day, celebrated annually on November 14th, was created in 1991 by the International Diabetes Federation (IDF)6 in conjunction with the World Health Organization7 "in response to the escalating health threat posed by diabetes."8 World Diabetes Day activities have grown encouragingly across this period of time. It is of particular interest that, while appropriately acknowledging the enormity of the overall challenges, relatively easily-achieved incremental steps are a current focus, e.g., emphasising the importance of starting the day with a healthy breakfast to help prevent the onset of type 2 diabetes. Many other organisations worldwide also engage in educational activities.9-12

Many of these activities are instigated at a public health level, but it is also important that individual physicians and allied healthcare professionals constantly remind patients of the benefits of preventing diabetes if they do not currently have this clinical condition, or doing everything possible to manage diabetes if they do. It is certainly acknowledged here that such communication with patients can be less than easy. Indeed, global challenges include the ever-decreasing time physicians can spend in general patient health counselling in some regions of the developed world because of reimbursement issues, and the fact that physicians in some developing regions of the world are frequently faced with focusing on their patients' immediately life-threatening conditions rather than offering long-term preventive counselling. However, the intention to facilitate such communication whenever possible must remain resolute.

Behavioural MedicineThe original definition of the coalescing interdisciplinary and integrative field of behavioural medicine was developed at the Yale Conference on Behavioral Medicine and subsequently published in 1977 by Schwartz and Weiss.13 The definition focused on the development of behavioural science knowledge and techniques, and their health-related applications in diagnosis, prevention, treatment, and rehabilitation. In the last three decades the field has advanced rapidly, and, although the original definition remains informative, the diversity of contributions has markedly increased. Expertise from many disciplines is now incorporated: a brief sampling includes anthropology, behavioural and molecular genetics, behavioural science, clinical medicine, environmental science, epidemiology, health economics, psychiatry, psychology, public health and public health policy, and sociology.14

Three components of diabetes prevention, and adjunctive diabetes therapy once a pharmaceutical regimen has been commenced, fall squarely into the domain of behavioural medicine: diet, exercise, and adherence to dietary, exercise, and


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Clinical Research

pharmacological regimens. Consider first diet and exercise. Randomised clinical trials have provided encouraging results in this regard. With respect to the Finnish Diabetes Prevention Trial15 and the Diabetes Prevention Trial in the United States,16 both reported that the intensive lifestyle interventions addressing weight loss and an increase in physical activity reduced the incidence of diabetes in pre-diabetic individuals.

Based on these encouraging results, the United States National Institutes of Health sponsored the Look AHEAD (Action for Health in Diabetes) trial. Participants in this study were overweight or obese adults with type 2 diabetes. The trial examined differences in cardiovascular outcomes, the primary cause of early morbidity and mortality in type 2 diabetes. Participants were randomised to receive an intensive lifestyle intervention, comprising decreased caloric intake and increased physical activity, or a control group comprising diabetes support and education. The primary outcome was a composite outcome (as is typically used in such trials) that can be referred to as "MACE plus," i.e., the first post-randomisation occurrence of one of the major adverse cardiovascular events (MACE) of non-fatal myocardial infarction, non-fatal stroke, and

cardiovascular death, plus hospitalisation for angina, over a planned maximum follow-up of 13.5 years.

After a median follow-up of 9.6 years, the trial was terminated for futility: that is, it was considered by the Data and Safety Monitoring Board that allowing the trial to continue would not provide the opportunity to determine which of the treatment arms was the more effective based on the trial's primary outcome. This decision was based on interim results showing that the primary outcome had occurred in 403 participants in the intervention group and 418 in the control group: the difference was not statistically significant (p=0.505). However, secondary endpoints painted a different picture. Weight loss, reductions in hemoglobin A1c, and diabetes remission were greater in the lifestyle interventional group, as were initial improvements in fitness and, with the exception of LDL cholesterol, reductions in all cardiovascular risk factors. In addition, those in the lifestyle interventional group experienced less disability, less depression, and reductions in sleep apnea and urinary incontinence.17,18 The decision to continue follow-up of trial participants was made at that time.

Not surprisingly, there have been

many papers published in the literature following the termination of the trial, including additional analyses (enter "look ahead diabetes" in the PubMed search engine at http://www.ncbi.nlm.nih.gov/pubmed to easily locate papers of interest). Various points have been raised and discussed, including the following three examples. Wing et al.19 considered the implications for the design of trials and clinical management of obese patients with type 2 diabetes. The Look AHEAD Research Group20 reported that the intensive lifestyle interventions used in the trial led to clinically meaningful weight loss (defined as ≥5% of initial weight) at year eight in 50 per cent of participants: they, therefore, noted that such intervention can be used to manage other obesity-related co-morbid conditions. Using the Look AHEAD trial as a case study, Kones et al.21 discussed the typical restriction in practice guidelines to recommendations based on the results of randomised clinical trials. The usefulness of evidence from other types of research, and sometimes the relative weight that should be attached to results from a given study design, is also debated in the domain of pharmaceutical medicine, and was discussed in an instructive paper by Avorn.22

Two other areas of study within

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Chapter Title Clinical Research

behavioural medicine should also be mentioned here: adherence, and the built environment. Adherence refers to "the extent to which an individual's behavior coincides with health-related instructions or recommendations given by a health care provider in the context of a specific disease or disorder," and is "as fundamental a component of effective health care as the treatment regimen itself."23 Although not necessarily perfect, adherence to the regimen of interest is arguably greater in a clinical trial than in clinical practice, which leads to acknowledgment of another universal question in clinical research: how representative are the results of a clinical trial once the novel intervention of interest passes into the realm of clinical practice?24 Adherence to dietary and exercise regimens is notoriously difficult and non-adherence therefore remains an obdurate opponent – a fact of life that feeds (no pun intended) an enormous weight-loss programme industry.

The term 'built environment' relates to multiple issues such as land use patterns, transportation systems, and features that provide opportunity for physical activity.25 Other issues include types and location patterns of buildings. The most frequently studied health outcome in this domain is obesity, as both physical activity (energy expenditure) and diet (energy consumption) are influenced by the built environment.26,27 In western countries, and increasingly in some countries in other global regions, areas and features of towns and cities that encourage physical activity are decreasing, and eating establishments serving less-than-optimally-healthy foods have proliferated.

Attention to increasing adherence to health-promoting behavioural regimens must be redoubled at an individual and public health/public health policy level, and the discipline of behavioural medicine has much to offer in this regard.28

Pharmaceutical MedicineWhen diet and exercise alone have failed to prevent progression to diabetes, initiation of pharmaceutical regimens becomes necessary (although diet and exercise should certainly be encouraged/maintained as adjunctive therapy). In the United States, as of this writing there are 12 classes of antidiabetic drugs approved for adults with type 2

diabetes: insulins, biguanides, second generation sulfonylureas, glinides, thiazolidinediones, α-glucosidase inhibitors, DPP-4 inhibitors, GLP-1 agonists, SGLT2 inhibitors, bile acid sequestrants, dopamine agonists, and amylin analogues. Although this may initially appear to be a robust list, the continuing medical need for additional pharmaceutical agents is well captured by the European Medicines Agency's (EMA's) guideline addressing clinical investigation of medicinal products in the treatment or prevention of diabetes, which comments as follows: "Glucose control in type 2 diabetes deteriorates progressively over time, and, after failure of diet and exercise alone, needs on average a new intervention with glucose-lowering agents every 3-4 years in order to obtain/retain good control."29 It is, therefore, encouraging to report that new drugs within various classes continue to be developed, and that there are multiple new classes of drugs being developed, including PPAR agonists/modulators (PPAR-α agonists, PPAR-δ agonists, PPAR-α/δ agonists, PPAR-δ/γ agonists, PPAR-α/γ co-agonists, and PPAR-α/δ/γ pan-agonists), glucokinase activators, C-C chemokine receptor type 2 antagonists, IL-1 modulators, G-protein coupled receptor agonists, apical sodium-dependent bile acid transporter inhibitors, and 11beta-HSD1 inhibitors.

A major challenge to bringing a new antidiabetic agent for type 2 diabetes to market in the US,30 and also the European Union,29 is the regulatory requirement for the prospective exclusion of unacceptable cardiovascular risk associated with these agents.29,30 The fundamental consequence of this regulatory landscape is that, for the majority of drugs, a large cardiovascular outcome study is required to show that, compared with a control treatment, the drug does not lead to unacceptably more occurrences of the components of the MACE composite endpoint introduced in the previous section, i.e., non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.31-33 Examples of studies that have demonstrated this have been reported by Scirica et al.34

and White et al.35 Citations of additional recent discussions of cardiovascular outcome trials are provided.36,37

The regulatory landscape is a consequence of a meta-analysis published in 2007 that purported to show an increased risk of myocardial infarction associated with rosiglitazone, an antidiabetic agent for type 2 diabetes,38 and discussions at multiple meetings of regulators and regulatory advisory committees. The frailties of the meta-analysis have been discussed in detail previously,39,40 and it is not necessary to revisit them in detail here. Suffice it to say that the actual calculation

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Clinical Research

that is made in a meta-analysis is just one component of a rigorous process that can better be described by the term meta-methodology,41 and all components require meticulous attention. Of particular relevance here is that, in November 2013, the US Food and Drug Administration (FDA) announced that it had determined that recently presented data for the drug "do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea. As a result, we are requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010."42 This decision followed an independent reanalysis of outcomes data from the RECORD trial.43

Therefore, it can reasonably be argued

that there is currently a burdensome regulatory requirement for all new antidiabetic drugs for type 2 diabetes that was driven by a purported association that has subsequently been refuted. As Hiatt et al. have commented, "Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for that expenditure."44 In the meantime, efforts are underway to

determine the most efficient ways to meet the current requirements.45

Discussions in this section so far relate to obtaining adult indications for new drugs for type 2 diabetes. However, as indicated in the introduction, type 2 diabetes is no longer exclusively an adult disease.46 The Editor-in-Chief of the journal Diabetes Care has noted that type 2 diabetes presenting in youth "is one of the most significant medical problems facing our society."47 Currently, however, despite the multiple drugs approved for adults, the only approved drugs for pediatric type 2 diabetes are metformin and, when metformin alone is not sufficient, insulin: this situation has not changed in the last decade.48 Once a drug has received marketing approval for adult use, there remain considerable challenges in obtaining pediatric approval, including finding sufficient individuals to participate in the requisite pediatric trials.49 Reasons include the low number of pediatric type 2 diabetes patients inadequately controlled on metformin, inclusion criteria that eliminate many potential participants, and the lack of an adequately developed pediatric clinical research infrastructure.50 In a recent editorial entitled "Joining forces: a call for greater collaboration to study new medicines in children and adolescents with type 2 diabetes", Karres et al. outlined various strategies, and advocated for a collaborative effort to "facilitate the collection of adequate and well-controlled pediatric efficacy and safety clinical trial data to inform pediatric use of new drugs" to treat type 2 diabetes.50 Their paper, itself a collaboration, is noteworthy because it has co-authors from both the FDA and the EMA, and also from three leading universities.

As for the dietary and physical activity regimens discussed in the previous section, non-adherence to prescribed pharmaceutical regimens is a serious concern. Turner and Strumph51 addressed the moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity, with a focus on medications for type 2 diabetes. They offered straightforward strategies whereby the biopharmaceutical industry, the media, and academic training institutions can play influential roles in decreasing non-adherence. The current reference list provides citations to additional discussions.52-56

Healthcare Transition from the Pediatric to the Adult Medical HomeHealthcare transition from the pediatric to the adult medical home is a term that refers to the process via which patients that have been cared for by a pediatrician or pediatric diabetes specialist are transferred (transitioned) to an adult healthcare provider. While the shortcomings of this transition process have been acknowledged for many years,57 crossing the chasm between pediatric and adult healthcare remains a remarkably flawed transition process.58 Reid et al. expressed the imperative to do better and make multiple changes as follows: "Transition to adult care (a planned process of discussing and preparing for transfer to an adult health center) is important and should begin well before patients are transferred. The future health of adults with chronic conditions may depend on our ability to make these changes."59

The Society for Adolescent Medicine's 1993 Position Paper57 defined transition as "the purposeful, planned movement of adolescents and young adults from child-centered to adult-centered health care systems," and observed that the ultimate goal of the transition process is "to provide health care that is uninterrupted, coordinated, developmentally appropriate, psychosocially sound, and comprehensive." The paper noted that while the concept and the goals of successful transition can be defined, far too little is still known about the process itself. Much of the research in the domain of diabetes has been conducted in type 1 diabetes since, until relatively recently, that was the dominant pediatric disease. However, the increasing incidence and prevalence of pediatric patients with type 2 diabetes means that research is also required in this disease state. As Peters and Laffel commented, "Most of the limited evidence base has focused on transitions in care for youth with type 1 diabetes. The recent emergence of type 2 diabetes in children and teenagers highlights an absolute deficiency of studies on transitioning youth with type 2 diabetes from pediatric to adult care."60

Much more research is needed in this area. Healthcare transition should be a planned process of discussing and preparing pediatric patients for the transition and then ensuring continued care as an adult with an adult healthcare provider: the greater the collaboration of

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Clinical Research

pediatric and adult endocrinologists in this process, the greater the chance of a successful transition.58

Concluding CommentsEach of the individual areas of research summarised in this paper is undoubtedly challenging and complex. Moreover, it was readily acknowledged in the introduction of this paper that they do not represent an exhaustive list of pertinent areas of investigation. A reasonable argument could therefore be made that the successful integration of these and other components into a unified approach to address the global diabetes epidemic is truly daunting. However, an equally reasonable and, at least to the author, more compelling argument is that the alternative is even more daunting: extrapolating from the most authoritative estimates we have, in several generations' time approximately one-tenth of the world's population could have diabetes.

There would, of course, be considerable financial ramifications of coordinating the integrated approach advocated here, bringing together experts from all of the relevant sub-disciplines to liaise and collaborate closely with each other. However, those costs may be vanishingly small compared with the financial devastation that uncontrolled diabetes will wreak on national healthcare budgets. It is therefore time to take a sombre look at the consequences of letting the worldwide diabetes epidemic continue to progress, and decide how we, as a globally unified body of health professionals and health agencies, wish to proceed.

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2014. Available at: http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf (Accessed 18 July 2014)

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3. International Diabetes Federation. IDF Diabetes Atlas, 6th Edition. Available at: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf (Ac-cessed 18 July 2014)

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16. Knowler WC, Barrett-Connor E, Fowl-er SE, et al. Diabetes Prevention Pro-gram Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

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27. Saelens BE, Sallis JF, Frank LD, et al. Obesogenic neighborhood environ-ments, child and parent obesity: the Neighborhood Impact on Kids study. Am J Prev Med. 2012;42:e57-64.

28. Schneiderman N. Foreword: A per-sonal view of behavioral medicine's future. In Gellman MD, Turner JR (Eds). Encyclopedia of Behavioral Medicine. New York: Springer, 2013, xiii-xviii.

29. European Medicines Agency. Guide-line on the clinical investigation of me-dicinal products in the treatment or pre-vention of diabetes mellitus. Effective November 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guide-line/2012/06/WC500129256.pdf (Accessed 19 July 2014)

30. FDA. Guidance for Industry. Diabetes Mellitus—Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Effective De-cember 2008. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor-mation/Guidances/ucm071627.pdf (Accessed 19 July 2014)

31. Caveney E, Turner JR. Regulatory landscapes for future antidiabetic drug development (Part I): FDA guidance on assessment of cardiovascular risks. Journal for Clinical Studies. 2010; January issue:34-36.

32. Turner JR, Caveney S. Regulatory landscapes for future antidiabetic drug development (Part II): EMA guidance on assessment of cardiovascular risks. Journal for Clinical Studies. 2010;


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March issue:38-40.33. Turner JR, Strumph P. 2012. FDA

and EMA actions regarding the cardiovascular safety of drugs for type 2 diabetes mellitus, 2007-2012: an overview of respective regulatory landscapes. Journal for Clinical Studies. 2012:(3):22-24.

34. Scirica BM, Bhatt DL, Braunwald E, et al. the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.

35. White WB, Cannon CP, Heller SR, et al. For the EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335.

36. Menon V, Lincoff AM. Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus. Circulation. 2014;129:2705-2713.

37. Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet. 2014;383:2008-17.

38. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007 14;356:2457-71.

39. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578-81.

40. Turner JR, Durham TA. Integrated cardiac safety: assessment methodologies for noncardiac drugs in discovery, development, and postmarketing surveillance. Hoboken, NJ: John Wiley & Sons, 2009.

41. Turner JR, Durham TA. Meta-methodology: Conducting and reporting meta-analyses. J Clin Hypertens (Greenwich). 2014;16:91-93.

42. FDA. Drug Safety Communication.FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. Available at: http://www.fda.gov/downloads/drugs/d r u g s a f e t y / u c m 3 8 1 1 0 8 . p d f (Accessed 17 November 2014)

43. Mahaffey KW, Hafley G, Dickerson S, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J. 2013;166:240-249.e1.

44. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes

drugs--insights from the rosiglitazone experience. N Engl J Med. 2013;369:1285-7.

45. Geiger MJ, Mehta C, Turner JR, et al. Clinical development approaches and statistical methodologies to prospectively assess the cardiovascular risk of new antidiabetic therapies for type 2 diabetes. Therapeutic Innovation & Regulatory Science [published online September 26, 2014] doi:10.1177/2168479014549860.

46. Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Long-term complications and mortality in young-onset diabetes: type 2 diabetes is more hazardous and lethal than type 1 diabetes. Diabetes Care. 2013;36:3863-3869.

47. Cefalu WT. "TODAY" reflects on the changing "faces" of type 2 diabetes. Diabetes Care. 2013;36:1732-1733.

48. Christensen ML, Rashed SM, Sinclair J, et al. Type 2 diabetes mellitus in children and adolescents: the new challenge. J Pediatr Pharmacol Ther. 2004;9:15-26.

49. Tamborlane WV, Klingensmith G. Crisis in care: limited treatment options for type 2 diabetes in adolescents and youth. Diabetes Care. 2013;36:1777-1778.

50. Karres J, Pratt V, Guettier JM, et al. Joining forces: a call for greater collaboration to study new medicines in children and adolescents with type 2 diabetes. Diabetes Care 2014;37:2665-2667

51. Turner JR, Strumph P. The moral imperative of improving patient adherence to pharmacotherapy for cardiodiabesity, Part I: A focus on type 2 diabetes mellitus. Journal for Patient Compliance. 2012;1(2):32-36.

52. de Vries ST, Keers JC, Visser R, et al. Medication beliefs, treatment complexity, and non-adherence to different drug classes in patients with type 2 diabetes. J Psychosom Res. 2014;76:134-8.

53. Rwegerera GM. Adherence to anti-diabetic drugs among patients with Type 2 diabetes mellitus at Muhimbili National Hospital, Dar es Salaam, Tanzania- A cross-sectional study. Pan Afr Med J. 2014;17:252.

54. Sweileh WM, Zyoud SH, Abu Nab'a RJ, et al. Influence of patients' disease knowledge and beliefs about medicines on medication adherence: findings from a cross-sectional survey among patients with type 2 diabetes mellitus in Palestine. BMC Public Health. 2014;14:94.

55. Woodward HN, Anderson SL. Once-weekly albiglutide in the

management of type 2 diabetes: patient considerations. Patient Prefer Adherence. 2014;8:789-803.

56. Aeyemi AO, Rascati KL, Lawson KA, Strassels SA. Adherence to oral antidiabetic medications in the pediatric population with type 2 diabetes: a retrospective database analysis. Clin Ther. 2012;34:712-719.

57. Blum RW, Garell D, Hodgman CH, et al. Transition from child-centered to adult health-care systems for adolescents with chronic conditions: A position paper of the Society for Adolescent Medicine. J Adolesc Health. 1993;14:570-576.

58. Turner JR, Schatz D, Cusi K, Strumph P. Healthcare transition from pediatric to adult medical homes in diabetes mellitus. Endocr Pract. 2014;20:714-20.

59. Reid GJ, Irvine MJ, McCrindle BW, et al. Prevalence and correlates of successful transfer from pediatric to adult health care among a cohort of young adults with complex congenital heart defects. Pediatrics. 2004;113(3 Pt 1):e197-e205.

60. Peters A, Laffel L. American Diabetes Association Transitions Working Group. Diabetes care for emerging adults: recommendations for transition from pediatric to adult diabetes care systems: a position statement of the American Diabetes Association (with representation by additional societies). Diabetes Care. 2011;34:2477-2485.

Clinical Research

Dr J. Rick Turner is an experimental research scientist and clinical triallist, with particular interests in the cardiac and cardiovascular safety of non-cardiovascular drugs and the development

and use of drugs for hypertension and type 2 diabetes. He has published a total of 14 authored and edited books, and 130 peer-reviewed papers and articles in professional journals. He is a Fellow of the Society of Behavioral Medicine, a Senior Fellow at the Center for Medicine in the Public Interest, and a member of the Board of Directors of the American Society of Hypertension's Education and Research Foundation. He also sits on the Executive Committee of the Cardiac Safety Research Consortium. Email: [email protected]

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Logistics & Supply Chain

Logistics: The Power of Clinical Trial

Supply VisibilityOver the last few years the number of innovative drugs brought to market has declined as pharmaceutical companies have focussed their resources on improvements to existing drugs or expanding their off-label use. In part, the evolution of this trend can be traced to the advent of corporate mergers between pharmaceutical companies which has left much of the innovation gap in new medications to be filled by biopharma. Indeed, it is from these relatively small companies that the majority of new products and innovations have emerged in recent years (Fernandez and Martinez-Hurtado, 2012).

The cost of developing a new drug is estimated to be close to $800 M. It takes an average of twelve years to develop a new innovative drug and an additional ten to fifteen years to complete the different phases of human clinical trials, before the drug can be launched into the market. One of the main reasons for the high development costs of new drugs is their large failure rate in clinical studies. It is calculated that less than 1% of the products that enter the discovery phase of the pharmaceutical development process make it all the way to market. Traditionally, clinical trials were conducted in the USA, Europe, Japan and Australia. However the saturation of clinical research sites, particularly in the USA and Europe, combined with difficulty in recruiting suitable patients has caused a major change in the landscape of clinical trials. Clinical trials are increasingly conducted in new territories such as India, the Republic of Korea, and many Latin American countries (Melvin and Selvarajan, 2014).

As a result of the globalisation of

clinical trials, one of the biggest challenges that pharmaceutical companies face is the management of the clinical trial supply chain, which involves the packaging, labelling, storage and distribution of pharmaceutical products to clinical sites (Ugalde, 2013). This work is increasingly outsourced to specialised clinical trial services companies, who become key partners in helping the pharmaceutical company efficiently navigate the clinical supply chain. Such a

relationship can often help accelerate the launch of a new drug to market ahead of potential competitors through a concurrent reduction in development costs gained at the clinical trial supply level.

The main challenges in clinical trial supply management originate from three sources: people, planning and process (Swaminath, 2012). Most clinical supply companies focus heavily on resolving the people and planning components of their operations. However, the real competitive advantage is derived from focussing on the process itself. People and planning challenges can be resolved through the use of a team-based approach to the management of clinical supplies. This can be achieved by building a team around a highly experienced project manager who can identify potential problems before they arise, and by investing in people via continuous learning and development to offer the client the best possible service in all areas of clinical supply management. Planning is one of the first challenges to be addressed by clinical supply companies and is often central to their business model.

Effective supply chain management processes are dependent upon the visibility of clinical supplies between manufacturing and packaging sites, central and regional distribution depots, and investigator sites. To improve visibility, clinical supply companies are investing in online tools, which provide information on the global supply chain by integrating data from multiple sources (e.g. couriers, third party depots). As the supply chain grows in complexity, it can be difficult to find a partner who can do everything in all locations. New integrated reporting tools are giving clinical supply teams the ability to control their inventory as if they were working with a single company.

A clinical supply partner that invests in technology to provide partners with clear visibility of their clinical supplies delivers significant added value, which translates into a clear competitive advantage for a pharmaceutical company (Swaminath, 2012). Accurate forecasting of inventory and tracking of supplies from shipment to receipt in real time helps avoid delays

in treating patients. Benefits of having a centralised live data capture system include: (i) the ability to manage budgets to make sure that costs are kept under control and (ii) the complete visibility of inventory that allows the immediate access of information such as expiry dates and amount of product available. This, in turn, allows the user to make decisions regarding the replenishment of inventory or the availability of product for future clinical studies.

Below, we will look at the specific features that an online reporting system should provide in order to maximise the visibility and efficiency of the clinical supply chain.

Client Accessibility and PersonalisationThe search for a product’s batch/lot number and/or location should be quick and easy. Information should be downloadable in a PDF format, or if subsequent data manipulation or analysis is required, as an Excel spreadsheet. Reports should also include the source of the data, and the date when the information is retrieved. In terms of access to the information, the system should allow clients the flexibility to control the number and identity of users and to control the level of data access. This should include the ability to customise the access to blinded and un-blinded data depending on each individual’s role in managing a study.

Data AvailabilityThe system should allow access to real-time data with storage temperature clearly detailed per product. It should tell the user the release/availability status of the product so a user can determine whether it is ready for packing/shipping or if it is still awaiting QA/QP release. If clients have requested storage of their product (e.g. master cell lines) at more than one location to mitigate risk, the system should allow this to be verified. If inventory is stored at more than one location, such as across an entire depot network, the system should be able to report information globally and to clearly identify where each item of inventory is stored.



Order Placement into the SystemIn order to save time and avoid filling out paperwork every time an order is placed, the customer should be able to place orders for drug and ancillary supply shipments directly into the system. Additionally, the customer should have complete visibility of the product from the moment it arrives at their partners’ facilities.

Label ApprovalThe customer should be able to view and approve online the labels for their product prior to packaging. This will minimise the number of interactions with the clinical supply provider and will save time in getting the product to the patient.

Document ManagementThe system should be secure and the user should be able to upload any documents related to the project and use the system as a document repository.

Budgetary Management and ControlManagement of budgets, especially for studies in which clinical supplies are shipped to multiple locations, at varying volumes and at unpredictable frequency, is critical to effective clinical trial management. In order to achieve this, the system should provide the client with full visibility of all expenses incurred at each stage of the clinical supply programme and how this compares with initial forecasts and budgets. If reports highlight a deviation from budget, a good clinical supply vendor will work with the clients to develop strategies to get spending back on track.

Compliant reporting systems should also include a full audit trail of changes made to data in the system. As the number of temperature-sensitive products in supply chains increases, systems should also enable access to downloadable temperature graphs from USB temperature monitors used during transport. To provide a complete shipment history, systems can also be used to access all shipment-related paperwork such as despatch notes and signed PODs.

Visibility is important in every step of the clinical supply management process from storage through packaging and labelling to distribution and final delivery to the patient, including reconciliation and destruction of leftover and returned clinical materials at the end of the trial. The advantages of having a visible supply chain include inventory control, fewer unforeseen expenses and an overall balance between supply and demand. This, in turn, translates into fewer delays in the drug development process. In short, providing clinical supply visibility can reduce or eliminate the time spent investigating errors during shipments, informing investigators of potential delays in drug delivery and informing investigator sites of possible changes in trial schedules due to delayed deliveries.

In conclusion, a centralised reporting system supports accurate budgetary management, allows the tracking of medication to avoid over-stocking in depots and sites, and provides visibility of expiry dates. This translates into significant reductions in the time and cost associated with managing the clinical supply chain. Clinical supply partners are constantly investing in technological improvements to their online reporting systems to help ensure flawless execution of supply management.

References

1. Fernandez, B. C. and Martinez-Hurtado, J. L. Biosimilars: Company strategies to capture value from the biologics market. Pharmaceuticals. 5, 1393-1408 (2012).

2. Melvin, G. and Selvarajan, S. Globalisation of Clinical trials: where are we heading? Current Clinical Pharmacology. 8 (2), 115-123 (2014).

3. Swaminath, G. Juggling clinical trials supplies. 2012. Online source:

h t t p : / / w w w. d d d m a g . c o m /articles/2012/05/juggling-clinical-trial-supplies. Accessed Sep 18, 2014.

4. Ugalde, A. Globalisation and clinical research in Latin America. In: Clinical trials in Latin America (chapter 3): where ethics and business clash. Research Ethics Forum. 2, 55-78 E book Spinger eds. (2013).

Claudia Williams has worked in the pharmaceutical industry since 2010. She has over 10 years’ experience as a Research Scientist and most recently she acquired an

MBA with a Marketing focus from Cardiff University. Prior to joining Biotec Services International as a Business Development Assistant/Marketing Assistant in July 2014, she spent three years with Novartis Canada, the majority of which were as a Clinical Development Scientist in R&D. Prior to that, Claudia worked at Oregon State University and the University of California Davis in the USA as a Scientist. Her previous publications are in the area of Toxicology in journals such as Toxicology and Apply Pharmacology, Cancer Letters and Toxicology and Chemistry. Claudia studied a Ph.D. in Toxicology in Oregon State University in the USA and a M.Sc in Mexico.

Rishi Saini joined Biotec in May 2008, he covered a number of key projects such as the implementation of Sage 200. Since 2008 Rishi has progressed within the company to Data and

Systems Developer within the Operations team and supports all cross departmental function.Data is a key element of any company and being able to extract this information in a format to present KPI’s and reports is to any business success. Rishi uses multiple functions and tools to do this with the support of internal and external suppliers which create efficient and validated data live from the company’s systems and portals.

The authors can be contacted on [email protected]


In 2012, counterfeit versions of the cancer drug Avastin were found in 19 American treatment centres. The impostor drug lacked the active ingredient, rendering it virtually useless for treatment purposes. The same year, counterfeits of Viagra and Cialis smuggled into the UK were found to contain undeclared active ingredients that posed potentially serious health risks to consumers. One year earlier, almost 3000 patients in Kenya were affected by a falsified batch of the antiretroviral therapy Zidolam-N, used in the treatment of HIV/AIDS. And in 2009, counterfeits of a traditional anti-diabetic medicine killed two and hospitalised nine in China before it was determined that the fraudulent drug contained six times the normal dose of glibenclamide, a chemical used to lower blood sugar1.Isolated incidents? Sadly, no. Instead, according to world health officials, this is just the tip of the iceberg as falsified and counterfeit drugs take on a life of their own in burgeoning grey markets and increasingly slip into the legitimate supply chain.

Diagnosis: History and Scope of the ProblemAccording to the World Health Organization (WHO), the prevalence of spurious, falsely-labelled, falsified, or counterfeit medicines, or SFFC medicines as they are known - medicines that are deliberately and fraudulently produced, packaged and/or mislabelled - is a growing trend worldwide which threatens both patient safety and public confidence in the health systems and regulatory bodies designed to provide oversight and control.

SFFC medicines are found everywhere in the world. They range from random mixtures of harmful toxic substances to inactive, ineffective preparations. Some contain a declared, active ingredient and look so similar to the genuine product that they deceive health professionals as well as patients. But in every case, the source of an SFFC medicine is unknown and its content unreliable. SFFC medicines are always illegal. They can

result in treatment failure or even death. Eliminating them is a considerable public health challenge2.

About Counterfeit DrugsFirst identified as an issue in the mid-1980s when counterfeiters began reproducing soft “lifestyle” drugs used to combat obesity and baldness, etc., the replication of mass-market prescription drugs such as birth control, medications for erectile dysfunction, diabetes, hypertension and high cholesterol, as well as vaccines, antibiotics and antimalarials, soon followed.

More than 25 years later, the scope of falsified drugs has mushroomed to include high-value drugs in high demand as well as life-saving drugs used to treat cancer, HIV/AIDS, serious cardiovascular disease and even those used to support organ transplants. None of today’s drugs or therapeutic treatments is exempt from unauthorised replication. Targeted medicines now include both branded and generic drugs and run the full gamut − everything from low-cost generic painkillers and antihistamines to high-value blockbuster drugs and speciality medicines used to treat life-threatening conditions. Even injectables and medical devices have not been spared.

According to WHO statistics3 collected in 2000:• 32.1% of identified counterfeit drugs

contained no active ingredient• 20.2% had incorrect quantities of

active ingredients• 21.4% contained the wrong

ingredients• 5.6% had correct ingredients, but

fake packaging• 8.5% contained high levels of

impurities• 1% were copies of an original

product

The impact on patients from using fraudulent drugs can range dramatically: from failure to treat minor symptoms to failure to treat critical illnesses to drug resistance caused by long-term exposure

to reduced amounts of active ingredients to death. Each year between 100,0004 and as many as 1 million5 people die from counterfeit drugs according to varying statistics. Produced in sub-standard facilities with little to no quality control, these fraudulent medicines contain an array of questionable ingredients including, among other things, caffeine, rat poison, starch, chalk, gypsum, flour, sugar and even acetaminophen, used to lower fevers and promote the belief that the drug is working.

Prevalence and Geographical Reach of Counterfeit DrugsIn today’s globalised pharmaceutical industry, it is thought that 10% of all drugs distributed globally are counterfeit. An estimated 80% of these counterfeits are produced overseas, with China and India identified as the leading suppliers. Worldwide sales of counterfeit drugs are estimated by WHO to be in excess of $75 billion annually, with some sources estimating annual market value to be as high as $200 billion. As one might expect, accurate data is hard to come by.

Developing nations have historically been prime targets for counterfeits, in part because of a weaker import and regulatory infrastructure, but also due to sheer economics and the inability of large populations to widely access expensive drugs. While Asia, with over 60% of the world’s population, currently represents the largest market for counterfeits, Africa, Latin America and politically and economically destabilised regions are all similarly attractive targets for those distributing rogue products. Based on WHO estimates, approximately 30% of the drugs distributed in these geographies are counterfeit. Some estimates for specific countries are as high as 60%. Added to this, the growth of internet-based commercial drug sales - both for products destined for, as well as those emanating from, developing nations -has merely exacerbated the problem.

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median income is higher, where the pharmaceutical supply chain is better protected by stronger customs, import and regulatory oversight, and where law enforcement is more aggressive - the occurrence of counterfeiting is statistically reduced to 1% or less.

Although the percentage may seem negligible, actual numbers help to put the situation into better perspective. In the United States alone, more than 4 billion prescriptions were issued in 2011, equating to over 40 million prescriptions that were filled using counterfeit medicines. A survey conducted in 14 European countries by Pfizer in 2010 estimated that more than €10.5 billion (US $14 billion) was spent each year on illicitly-sourced prescription drugs including those used for weight loss, influenza and erectile dysfunction; many of these drugs were counterfeit. The study further noted that the number of counterfeit drugs uncovered at EU borders increased from 560,598 articles in 2005 to 4,081,056 in 20076.

By all accounts, the situation promises to intensify and although global recognition of the problem now exists, controlling it has been daunting. In 2013, for instance, through joint international law enforcement and the efforts of almost 100 countries, over 10 million potentially dangerous medicines worth some $36 million were seized, resulting in 213 arrests worldwide.

In addition, almost 14,000 websites hosted by illegal online pharmacies were identified and shut down and more than 530,000 packages were inspected by customs and regulatory authorities. Of these, almost 42,000 packages - containing everything from antibiotics, cancer medication and anti-depressants to erectile dysfunction medication and dietary supplements - were seized7.

Prevention: Technological and Regulatory CountermeasuresWith the escalation of drug counterfeiting in the mid-1990s, a number of technological, regulatory, industry-driven and national initiatives were launched to help combat the problem. Clearly it must continue to be a collective effort if inroads are to be made in controlling the occurrence of counterfeit drugs.

Packaging InnovationOver time, pharmaceutical packaging

has evolved to provide better protection for both product and patient. In the past decade, steps were taken to securitise and authenticate pharmaceuticals initially by adding visible and/or hidden security features such as hologram labels and other brand protection features to the packaging. Although these measures provided some deterrents, those same technologies have also fallen prey to counterfeiting and, as such, have not successfully eliminated the problem in any meaningful way.

The newest technologies now being utilised include 2D barcodes applied directly to the packaging which retain considerably more data than previous barcodes, and radio frequency ID (RFID) tags which create an electronic record of chain of custody from point of manufacture to point of dispensing. While many pharmaceutical companies are already using forms of these technologies, pending regulatory changes are slated to move these solutions into the global supply chain in the coming years, with more onus being put on the verification of individual medicines at the patient dispensing level.

International CollaborationIn 2006, the International Medical Products Anti-Counterfeiting Task Force (IMPACT), a partnership involving 193 WHO member states, a variety of international and non-governmental organisations, law enforcement agencies, pharmaceutical manufacturing associations and drug and regulatory authorities was formed. Its mandate has been to work with countries and the industry to better detect and safeguard against the widespread distribution of fraudulent drugs and to minimise criminal activity through stronger and more collaborative international law enforcement.

Regulatory ReformOn a regional basis and as might be expected, the US and the EU are leading the way with regulatory solutions to help circumvent the problem.

Falsified Medicines Directive (2011/62/EU)The European Commission’s Falsified Medicines Directive (2011/62/EU) was written into law in 2011, amending former legislation aimed at preventing falsified medicinal products from entering the legitimate supply chain.

This legislation strengthens controls and checks on products moving through the supply chain and includes stricter controls on the sourcing of active product ingredients and excipients, especially those originating from non-EU countries.It also calls for new or extended obligations on the part of importers and distributors of active substances, brokers, product manufacturers and wholesalers while mandating legal online pharmacies to display a common EU-wide logo on company websites. An additional requirement now demands that an obligatory authentication and safety feature appears on the outer packaging (unique pack identification).

Member states were required to transpose the directive into national law by January 2, 2013 while provisions related to the importation of active substances from third countries came into effect July 1, 2013. Specific legislation on the implementation of safety features (unique identifier) is due in 2014, with mandatory application of this identifier and medicinal product verification expected in the EU by 2017.

In anticipation of upcoming regulatory changes, two product verification initiatives are already in use in Europe. The European Stakeholder Model (ESM) is a cloud-based point-of-dispensing verification system that uses 2D data matrix barcodes to authenticate medicines and ensure that patients are receiving a genuine product. Data matrix codes are affixed by the manufacturer (if necessary, the product is verified and repackaged by the parallel distributor with a new number) and then uploaded to a central European database. This number may also be verified by both the wholesaler and pharmacy. Data includes the product number, batch number, expiry date and a unique serial number, with unregistered codes sending an immediate alert that the product may have been falsified. This system will be overseen by the European Medicines Verification Organization (EMVO), a non-profit organisation that will manage the European Hub which links national systems throughout Europe. Launched in 2012, the system has been successfully tested in Sweden. Germany’s securPharm verification system was integrated with the ESM model in 2013 and the proposed European Hub is expected to be fully operational by mid-2014.

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Also launched in 2012, the European Directorate for the Quality of Medicines and Healthcare (EDQM) eTACT programme is similarly a track-and-trace system that relies on unique identification numbers adhered to individual packaging to verify the authenticity of a medication. This number is affixed by the manufacturer and can be used by all legitimate supply chain members to verify the product. A final verification must be performed at the dispensing location. Unique to this system, however, patients themselves are able to trace and verify the safety of the medication, potentially strengthening public confidence. EDQM is a public, inter-governmental organisation that promotes quality standards for the safe use of medicines worldwide.

Drug Quality and Security Act (DQSA)In the US, the newly-enacted Drug Quality and Security Act (DQSA) was signed into law in November 2013 by President Obama, effectively preempting all existing state laws and regulations related to pedigree. The DQSA is a progressive law that has many milestones which must be met by the pharmaceutical industry, with the end goal of having a full traceability solution in place by 2023. The federal DQSA aims to incorporate drug transactional information into a new electronic traceability system that will allow health systems, hospitals and pharmacies to trace prescription drugs through the supply chain.

Required transactional information will include the name of the drug, its strength, quantity, dosage, National Drug Code (NDC), lot number, container/ packaging size, date of transaction, date of shipment and name and address of both shipper and consignee, all of which will provide additional business value. Included in the legislation are federal licensure standards for third-party logistics providers (3PLs) and wholesale distributors. In addition, manufacturers will be required to apply a 2D barcode that contains a product identifier, serial number, lot number and expiration date by November 2017. Wholesaler drug distributors must follow suit by November 2019 and dispensers by November 2020. The full traceability solution is set to be implemented by November 2023.

National InitiativesAt the international level, countries are implementing their own strategies to combat the growing threat of counterfeit drugs.

China is the world’s top producer of both legitimate and counterfeit drugs. In 2001, the existing Drug Administration Law of the PRC was amended to increase penalties on the production and sale of falsified drugs. Since then other laws have been enacted to control counterfeit activities by regulating API manufacturers, for instance, a key to controlling counterfeit activities. While the State Food and Drug Administration (SFDA) has also increased routine inspection and sampling as well as enacted new labelling laws, enforcement remains weak and the system cumbersome. Technological solutions including 2D data matrix barcoding and RFID tags remain expensive to implement.

As one of the world’s top manufacturers of generic and patent drugs, India has taken steps to limit counterfeit drug production nationally following a 2005 estimate that some 75% of falsified drugs distributed globally have some origins in that country8. Although this estimate has been hotly disputed and never proven, India’s Directorate General of Foreign Trade (DGFT) amended labelling requirements in 2011, making it mandatory for every drug manufactured in that country designated for export to bear a unique product identification code (GTIN) as well as 1D or 2D barcoding on primary, secondary and tertiary packaging.

Meanwhile in Africa, the newly launched mPedigree Network, an SMS-based technology developed by Ghanaian entrepreneur Bright Simons, began its roll-out in Nigeria in 2013 when the system became accessible to over 50 million mobile subscribers. The technology allows patients to authenticate their medicine by sending a free text message to a special hotline and receiving an immediate OK or NO response. The reply is accompanied by the name of the medication and a picture of the packaging for visual comparison. Patients need only scratch off a panel on the prescription packaging to reveal the unique ID number. This technology is now being tested in Ghana and being considered by other African states. Patients in Africa have been highly vulnerable to the negative effects of counterfeit drugs, with as many as 700,000 deaths per year linked to sub-standard malaria drugs and tuberculosis vaccines.

Moving ForwardThe cost associated with counterfeit drugs is staggering - both in human and commercial terms. In some cases, patients are deprived of treatment for diseases and conditions that range from mild to severe to life-threatening. In other cases, they are harmed by dangerous substances in the product, or become resistant to traditional therapeutic treatments or vaccines. In all cases, the public loses confidence in the companies that develop these drugs and in the very agencies that have been established to protect them.

For the pharmaceutical industry, the prevalence of counterfeit drugs can represent loss of reputation, loss of valuable R&D efforts and intellectual property, loss of revenue and increased costs. Many companies, for instance, now operate their own anti-counterfeit units to police their product lines and reduce the impact of counterfeiting on the organisation. Despite these efforts, the growth of counterfeit drugs is only expected to increase within the parameters of a globalised industry, especially as the cost of healthcare spirals worldwide.

What can pharmaceutical professionals do to ensure that their organisations and the patients they serve are not impacted by counterfeit drugs? The answer is to identify their highest risk products and shipments and to secure their supply chain to the fullest extent possible.

In the falsified Avastin case referenced at the beginning of this article, it was later found that the vials were sourced in Turkey and shipped to Switzerland, then Denmark and finally to the UK before being exported to a US wholesale distributor hired by a Canadian company which was ultimately owned by an online retail pharmacy. In another case, counterfeit product was slipped into an existing shipment of legitimate drugs destined for a hospital simply by adding an extra zero to the unit count on the paperwork. In yet another case, a legitimate shipment of temperature-controlled drugs was hijacked, with the product later re-introduced into the supply chain without the benefit of quality assurance.

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Identifying High-risk ShipmentsVirtually every medicinal product is a target in today’s world. Although all pharmaceutical shipments are important, pharmaceutical professionals should evaluate the severity of risks associated with a specific product prior to shipping, and consider prioritising its journey through the supply chain as required.

Questions to Consider Include:• Who is the targeted patient group?

Is it an at-risk group like infants or the elderly who are more susceptible to a counterfeit product?

• How will the drug be used? Will it be used to treat a chronic condition? Does a single dose have the potential to kill?

• How is it administered? By a healthcare professional? By the patient?

• What is the patient impact if the medication contains no active ingredient? An excess of active ingredients?

• Does the product require cold chain handling to maintain stability/efficacy?

• How much annual revenue does the product generate? What role does it play in the product portfolio?

• Is the product a flagship brand? A blockbuster?

• How attractive is the product to counterfeiters (i.e. high unit price? Product shortage? High volume usage?)

• What region is the shipment destined for? What regional risk factors exist

with respect to counterfeit drugs?• Does the provider offer a full suite of

services (i.e. packaging, temperature control, transport, storage, local delivery), or will services be handled piecemeal by multiple suppliers?

• Does the provider have experience/expertise in managing high-value pharmaceutical shipments?

• What type of track record/reputation does he have with clients, airlines, and regulatory and customs agencies?

• Is the scope of operation global or regional?

• Does the company employ staff worldwide or utilise the services of third-party providers? If the latter, what specific locations are not managed by company employees? Do these destinations appear in the distribution portfolio?

• Do operatives in all locations act in strict accordance with documented company-wide SOPs?

• Is the organisation GxP-compliant in all locations, or in select locations? ISO certified?

• Is there a quality management/quality assurance policy and team in place?

• Does it function independently from the operational side of the organisation?

• How is quality oversight managed in the field? Is there an SOP for incidence reporting?

• Are suitable security procedures in place with respect to employee verification and screening?

• Are all security procedures and verification consistent in all locations?

• Can the service provider clearly demonstrate that policies and practices are enacted rigorously and consistently from origin to destination for each elected location?

Tightening the Supply ChainAs today’s global pharmaceutical supply chain grows increasingly longer and more complex, each link provides added opportunity for counterfeiters. While pending regulatory changes promise to tighten the supply chain with respect to production and distribution entities and new packaging technologies will make the identification of counterfeit products easier, the logistics of global distribution remains a weak link. How can the pharmaceutical shipper ensure the security of the supply chain over thousands of miles and extended periods of time when the product is no longer in his possession?

The best strategy to ensure full supply chain compliance is by partnering with and building a long-term relationship with a single closed-loop logistics provider able to manage all aspects of the transport and storage of bulk high-value pharmaceutical shipments worldwide.

Benefits include:• Enhanced control from a proven,

trusted source• Clear chain of custody at all points

during transit• Elimination of unnecessary third-


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party risk• Local representation and

accountability in complex and often unpredictable geographies

By utilising the services of a GxP-compliant logistics supplier, pharmaceutical shippers can automatically ensure that they conform to all current regulatory requirements as they relate to the transport of their high-value pharmaceutical products. Equally important, they can be assured that the same standard operating procedures (SOPs) are employed worldwide to ensure product security to the greatest extent possible.

Shippers may also consider utilising a local warehousing solution in emerging or strategic locations to reduce the costs and peril associated with multiple bulk shipments and to shorten distribution timelines. A fully-integrated logistics provider able to accommodate packaging, cold chain, transport, storage and local in-country or regional distribution is a practical solution for maintaining security in challenging locations.

As a word of caution, however, all logistics providers are not created equal, so pharmaceutical shippers should be prepared to carefully qualify all contenders.

Identifying a logistics provider with trained staff, a well-maintained infrastructure and network-wide processes in place at the global level will go a long way toward securing the supply chain and protecting the interests of both the pharmaceutical company and its patients, particularly in those areas of the world at greatest risk or where local representation is lacking.

References1. “Medicines: spurious/falsely-

labe l led/fa l s i f ied/counter fe i t (SFFC) medicines”, World Health Organization, Fact sheet No.275, May 2012

2. Ibid. 3. World Health Organization,

“General information on counterfeit medicines”, 2000

4. Bate, Roger, “The deadly world of falsified and substandard medicine”, American Enterprise Institute, October 15, 2012

5. Southwickz, Natalie, “Counterfeit

Drugs Kill 1Mn People Annually: Interpol”, InSightCrime.org,October 24, 2013.

6. Grogan, Kevin, “One in five Europeans buying fake drugs -Pfizer survey”, PharmaTimes online, Februrary 16, 2010

7. “Counterfeit Drugs: Fighting Illegal Supply Chains”, a report by Lev Kubiak, Director National Intellectual Property Rights Coordination Center, Homeland Security Investigations, U.S. Immigration and Customs Enforcement, February 27, 2014

8. Lal, Neeta, “Fake drugs a bitter pill for India”, Asia Times online, June 7, 2008.

Bibliography• Ali (Dr), Shaukat, “Growing

Counterfeit in Medicine Worldwide and its Impact on Health and World Economy,” ABHINAV International Monthly Refereed Journal of Research in Management & Technology, ISSN - 2320-0073, Volume II, June 2013

• Bate, Roger, “The deadly world of falsified and substandard medicine”, American Enterprise Institute, October 15, 2012

• Daigle, Lisa A., M.A., “Following Pharmaceutical Products Through the Supply Chain”, ASHP Policy Analysis, American Society of Health-System Pharmacists®, August 2012

• Grogan, Kevin, “One in five Europeans buying fake drugs − Pfizer survey”, PharmaTimes online, Februrary 16, 2010

• Kubiak, Lev, “Counterfeit Drugs: Fighting Illegal Supply Chains”, report by the Director, National Intellectual Property Rights Coordination Center, Homeland Security Investigations, U.S. Immigration and Customs Enforcement, February 27, 2014

• Lal, Neeta, “Fake drugs a bitter pill for India”, Asia Times online, June 7, 2008

• McKeon, Owen J., “Counterfeit Drugs The Challenges of a Deadly Global Epidemic”, FOCUS on the New Jersey Chapter, Association of Corporate Counsel, New Jersey (NJCCA) Chapter, June 2013

• Rice, Andy, “Fighting Africa’s fake-drug monster”, dailymaverick.co.za, June 23, 2013

• Southwick, Natalie, “Counterfeit Drugs Kill 1 Mn People Annually: Interpol”, InSightCrime.org, October 24, 2013

• Sun, Lei, “Anti-counterfeiting Situation in China”, Bureau of Inspection, SFDA of China, 2010-2012

• Trent, Christopher and Moyer, Douglas C., Ph.D., CPP, “Assessing the Risks of Counterfeiting and Illicit Diversion for Health Care Products”, A-CAPP Paper Series, Michigan State University, Center for Anti-Counterfeiting and Product Protection, November 2013

• Woodcock, Janet, M.D., “Securing our Nation’s Prescription Drug Supply Chain”, statement of the Director, Center for Drug Evaluation and Research, Food and Drug Administration, April 25, 2013

• “Counterfeiting in the Pharmaceutical Industry; a look at the Bitter Pill in China”, © Baker & McKenzie 2013

• “General information on counterfeit medicines”, World Health Organization, © WHO 2014

• “Growing threat from counterfeit medicines”, Bulletin of the World Health Organization, Volume 88, Number 4, April 2010, 241-320

• “Medicines: spurious/falsely-labe l led/fa l s i f ied/counter fe i t (SFFC) medicines”, World Health Organization, Fact sheet No275, May 2012

• “Rx-360 Supply Chain Security White Paper: Cargo Risk Assessment”, Rx-360, An International Pharmaceutical Supply Chain Consortium, May 2, 2012

• Jun 1, 2014 by Dr Rudiger LombTags: Transport Security, Global SOPs, GxP Compliance, Distribution Strategies, Regulatory Compliance, Product Integrity

Dr. Rüdiger Lomb is Global Director, Quality & Technical Compliance for the World Courier group of companies. In his role he oversees the QA program for World Courier´s company-

owned network of 13 investigational drug storage facilities and 140+ offices in 50+ countries to keep it compliant with current and future GxP standards like the most recent EU Good Distribution Practices Guidelines.Dr. Lomb is a licensed pharmacist and holds a Ph.D. in pharmaceutical bio-chemistry.Email: [email protected]

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Transforming Temperature Data

Management Practices to Reduce Labour

Costs & Improve Visibility and ControlThere are a number of temperature monitoring database options available to the biopharma supply chain professional, and choosing the right one can significantly improve workflow which will reduce administrative time. This article will provide insight into practices for improving common processes through enhanced database functionality in the areas of managing data loggers by expiry date, storing and retrieving calibration certificates and acknowledging/documenting common temperature excursion events. Additionally, it describes the unique features and benefits of our new data management system. It is a “Software as a Service” (SaaS) platform designed to efficiently and accurately manage both workflow and data in a regulatory compliant manner (21 CRF Part 11 & Annex 11). This comprehensive temperature data management system ensures reliability, accuracy, security, accessibility, and visibility to supply chain professionals, enhancing good distribution practices (GDP) of temperature-sensitive shipments.

BackgroundCentral to the good distribution practices of a biopharma company is the reliability and traceability of temperature data associated with temperature-sensitive shipments. Compliance requires data loggers to have unique serial numbers, calibration certificates and expiry dates. Current and historic temperature information can be questioned for its legitimacy if it is not clear that the data logger was used before its expiry date or during its certified temperature accuracy period as stated on the calibration report. Every organisation has its own methodology for handling these requirements. Often they are decentralised, off-line procedures that expose the company to lost certificates, lack of inventory rotation control and countless man-hours to store and retrieve calibration certificates even years after a device has been used.

Additionally, some data logger

excursions can be classified as routine occurrences. In a survey administered by IQPC’s Cold

Chain IQ group, the respondents who

acknowledge temperature excursions with products in transit, indicated excursions occurring in more than15% of their shipments (Cold Chain IQ 2012). One common occurrence can be observed when temperature sensitive material are received ingoodorder, moved to a secure/temperature-controlled environment, and the data logger is turned off hours later. Biopharma firms have established procedures for documenting these occurrences without launching a full quality investigation. Yet even these simple procedural steps incur significant labour costs. The initiator must alert responsible people to the issue, get them to take action and develop the right technical information to approve the use of the materials while documenting the decision for regulatory compliance files. Delays occur when people do not respond to emails or while files are searched looking for all the necessary information (e.g. a calibration certificate).

Current MethodologyOf paramount importance for a compliant temperature monitoring programme is the ability to effectively manage data logger inventories on a “First Expiry, First Out” (FEFO) methodology. Most companies are managing this process manually, through spreadsheets and/or a “kanban” system (employing the use of product identification cards for demand-driven inventory management) that require significant front-end organisation and data entry. Seldom is the data logger supplier leveraged for management of data logger expiry and certificates of calibration. When they are, it is typically done on a case-by-case basis through email. Hours can be spent tracking down these certificates (see Fig. 1).

Additional time is spent manually inspecting and inventorying devices to create a FEFO inventory management process. Standard ERP systems (SAP,

Oracle) are helpful, but are not robust enough to support the cGDP practices of the biopharma industry.

Unwanted temperature events that occur during manufacturing, storage, transportation, and distribution are commonly referred to as “excursions.” Within an organisation, excursions outside acceptable temperature ranges captured with data loggers can be dealt with in a manual, extremely labour-intensive manner by a dedicated supply chain quality management group or department. Emails are generated, passing data logger temperature information to be compared with the timing of logistics services of a shipment. In many instances, data loggers without a USB interface are transported back to someone with the necessary hardware and software to read the data. An additional labour-intensive process then begins to insure all the required data is collected, that the responsible parties formally address the data and the decision to move materials to the appropriate next step is documented properly. These documents typically require signature approval and must be filed in a retrievable manner. It can take anywhere from one to 30+ days depending upon circumstances associated with the specific materials involved to complete these steps. Indications are that the costs for administering an excursion event are between $10,000 and $100,000 per occurrence (Goff, 2008).

The frequency and severity at which these excursions occur varies from company to company depending on the complexity and structure of their logistics practices and the robustness of their quality management systems.The documentation and sign-off process is rarely streamlined, and can often be disjointed with fragmented roles and responsibilities. If 5% – 10% of shipments experience “common excursions”, as is often reported, it is easy to see how these labour costs can quickly add up to hundreds of thousands or even millions of dollars every year.

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Proposed SolutionThe new system enables workflow steps like excursion alerts and missing data loggers to be automatically generated and sent to the responsible person(s). Additionally, workflow steps for acknowledging the review of temperature data, especially data with a recorded excursion, can take place within the system. Notes about the root cause and other information can be appended to the shipment data. Non- relevant temperature data (e.g. warm temperatures recorded after delivery from an active data logger on someone’s desk) can be easily adjusted out of the relevant data set to close out excursions. All of these workflow steps create an auditable trail based on the unique user ID and password and meet 21 CFR, Part 11 & Annex 11 requirements.

When a completely cloud-based system that incorporates both data storage and software service is introduced to the biopharma supply chain, many costly administrative steps and processes can move towards automation. When data is generated and collected for the purpose of facilitating decision-making and trending over time, thenthe oppor tuni ty for automated additional workflow steps can be realised.

An employee with the appropriate user rights should be able to access one portal, from any computer, anywhere in the world, to review the inventory of devices by expiry, and download the calibration certificates for individual data loggers (see Fig. 1).This database should remain accessible for a time period that

is relevant to the customer’s requirements instead of off-line in a data archive. The system enables a firm to do this with ease, at their discretion. Once it is integrated into a firm’s daily routine, the use of the system to acknowledge temperature shipment data or to document excursion issues will reduce the administrative hours needed for these activities. It also enhances accountability by automatically sending alerts to responsible individuals and escalating the alert if action steps, like acknowledging the event, exceed pre-determined time limits.

With our new system operating in the cloud, email communications of excursion events are sent automatically to the responsible party immediately after a data logger is uploaded.That person can sign into that via his/her smartphone or other enabled wireless device to document

the receipt of an alert notification,

journalise steps taken, and close out an excursion with an assigned root cause. By providing an audit trail for everyone who interacts with the system, we designed to ensure regulatory compliance for document control (21 CFR, Part 11 & Annex 11 compliant).

Supply chain directors are often more interested inaggregate information for trending analysis and process improvement. By storing all temperature data files in one, globally secure system, it is possible to manage the data in unique ways (see Fig.2). It is impractical and grossly inefficient to rely on email,

manual filing systems or a vendor as the means to sift through historic temperature data. It is also costly and time-consuming to rely on outside vendors to compile the data into trending reports and key performance indicators (KPIs).

Personnel with the appropriate user rights can access the aggregate data through a Reports Module contained in Smartview®. In this module, it is possible to trend data using database filters to reveal shifts in trends over time, between shipping lanes, by product, customer, third party service suppliers, or other metrics.

Easy to comprehend infographics allow the user to visually determine where improvements are occurring and where more effort may be beneficial. An organisation can gain full, documented and regulatorily-compliant control over temperature excursion investigations and remediation steps while substantially reducing their time and administrative costs through implementation of the company`s new system.


Patrick McGrath, General Manager, established the company Berlinger USA, LLC as a subsidiary company of Berlinger & Co. AG Switzerland. He is working in the Pharmaceutical Cold Chain industry for 14 years with extensive knowledge of cold chain packaging,

logistics and temperature monitoring. As the North American General Manager for Berlinger, Patrick has introduced unrivaled Swiss precision, accuracy, reliability and innovation to the world of temperature monitoring in the pharmaceutical, biotech, and vaccine industry, having launched 5 groundbreaking products in the past 3 years. Prior to his time at Berlinger, Patrick was Director of Sales at ThermoSafe, the worlds’ foremost designer and supplier of cold chain packaging materials to leading vaccine and biotech manufacturers worldwide. In 2011 Patrick was invited to serve on the CDC’s Equipment Sub-committee whose focus was to develop new guidance for temperature monitoring of vaccines in storage. In November 2012 the CDC issued and adopted this new guidance. Patrick obtained an MBA from Temple University in Philadelphia. He Co-authored the article “The changing landscape for vaccine administration” published in Contract Pharma July/August 2011. He is a long-standing member of the Parental Drug Association (PDA) and the US Pharmacopeia (USP). Email: [email protected]



Temperature Mapping of Vehicles Used for the

Transportation of Pharmaceutical Products

In this article, Andy Hughes and Kane Edgeworth talk about the recent history of temperature mapping expectations, the approach of mapping temperature-controlled vehicles, the use of risk when deciding to map or not, a recent mapping study undertaken, and what to do with the data gathered.

Why Map?“When Pharmafreight brought its first thermo vehicle into service back in the middle of the last decade, temperature mapping wasn’t the first thing on our – or our clients’ – minds,” explains Andy Hughes. “The most important thing was that the vehicle held temperature, it was well maintained, and the drivers knew what they were doing.” Things have certainly changed now, and more specific demands from customers and regulators on what was required from a vehicle used to transport medicines have radically changed. “As things have developed, it soon became apparent that good mapping procedures were essential in order to guarantee client confidence and maintain an increase in our customer base, as well as comply with the GDP Quality System we were operating to,” says Andy.

From a regulatory perspective, temperature mapping studies have been a requirement for some time now within GDP- and GMP-licensed environments. John Taylor’s original article ‘Recommendations on the control and monitoring of storage and transportation temperatures of medicinal products’ back in 2001 was a major catalyst, generating a lot of discussion. More recently, the release of the EU GDP Guidelines in November 2013 and the revised 2014 Orange Guide both led to an increased focus in this specific area (guidelines from the HPRA, WHO, ECA/PQG and the USP are also useful resources for vehicle temperature mapping).

“However despite the new revised GDP guidelines, you shouldn’t necessarily assume that everyone else is undertaking the mapping requirements to that standard,” comments Andy. “We have seen vastly different standards of

mapping reports from other transport providers, and you also get the feeling mapping is still looked upon as a nice to have, rather than a specific requirement that you must adhere to, if in fact the term mapping is understood at all, especially when we look to an international level.” There is also talk of ATP certification for thermo trailers – and how that is sometimes used as a way of circumventing the mapping process – however, although useful it is not generally accepted by the quality departments of pharmaceutical companies.

On the back of John Taylor’s 2001 article – which is still quoted in the 2014 Orange Guide – mapping projects were carried out to varying levels of quality, but as the regulation and requirements mature, the levels of expectation in quality and traceability have increased significantly. Many early projects consisted of a few logger files with basic graphs and diagrams – insufficient for today’s requirements. Depending on the regulatory environment, the documentation approach can be different. For example, the typical qualification approach of IQ/OQ/PQ seems to be mostly adopted in GMP-driven areas. However, a standard but detailed type of protocol leading to a comprehensive final report is often sufficient within GDP areas, and is recommended in the 2014 Orange Guide.

Do You Have to Map?“From our side as a mapping provider, vehicles used for the transportation of pharmaceutical products have been our largest growth category in temperature mapping over the last couple of years, partly perhaps due to the increased focus on transportation by the regulator,” says Kane Edgeworth. “It is true this has been an area where there has been less commitment compared to the more traditional areas such as warehouses, fridges and freezers over the last few years, however things are changing. Vehicle mapping can also be a difficult subject to approach, especially with larger vehicle fleets, knowing how to achieve a balance in what can be realistically achieved against both

cost and risk,” continues Kane. “For example, if a fleet consists of more than one hundred vehicles it is probably not realistic to map every single one; instead adopting a risk-based approach on the fleet can be a good starting point.”

A mapping risk assessment should be step one and will help you document all of the different types of vehicles so that you can build categories of the same or similar types. The information gathered for this exercise might include:

• Trailer/vehicle type (e.g. curtain-sided, solid-sided, rigid vehicle, van, etc.)

• Temperature controlled/or not• Single or dual compartment/Single

or dual temperature• Partition type, and dimensions for

each compartment• Year of construction• Insulation material used for the

panels.• Overall size of the trailer/vehicle • Air-conditioning unit – age,

manufacturer, model• Maintenance history• Temperature monitoring devices and

their locations• Air-conditioning controls, e.g.

always on when engine running, ability to run with external power, etc.

Once the categories have been built, decisions can then be made in regard to which vehicles will be mapped. One approach is to take a ‘master’ vehicle from each category which will be subject to a full schedule of tests. Then, based upon performance, a percentage of the remaining vehicles in the same category can be tested to an abbreviated protocol. Documentation can follow the typical qualification approach of IQ/OQ/PQ; the OQ may be an empty test to determine correct air temperatures and uniformity across the vehicles’ storage space. The PQ may then extend to load challenges and impact tests such as door open and power down events – typically this would be with a stationary vehicle but also as a live shipment with dummy loads.


An Example StudyPharmafreight purchased a number of dual temperature vehicles in early 2014 as part of its ongoing fleet expansion. The vehicles were Mercedes 3.5T box vans, with movable bulk heads and dual-temperature capabilities. This type of vehicle is becoming more popular as it provides a lot more flexibility for load sizes and temperature requirements. However, dual-temperature vehicles present greater complexity in mapping studies due to the number of usable configurations, e.g. +5.0°C front & +20.0°C rear, +20.0°C front & + 5.0°C rear, +5.0°C only, +20.0°C only. This obviously increases the project scope over a standard single-chamber vehicle.

Project OverviewA documented mapping risk assessment was carried out and a test summary was produced. All possible configurations would be

mapped and the vehicles would be subject to FULL and EMPTY load challenges as well as impact tests, most notable a power failure test to simulate an issue with power supply during ferry crossings. The test would be carried out

during the full-load phase and the time noted from the power being switched off, to when the first out-of-specification reading was recorded within the vehicle. The mapping term would run over 48 hrs and the vehicle would be stationary during the tests and the exercises would be carried out in both summer and winter to capture the performance during seasonal extremes.

The next step is to design the mapping protocol and recording location layout (vehicle plan). This will determine the works to be carried out and should be approved by both the document author and the user. The protocol will dictate the final report content and can include the following:

• Unique project code• Mapping duration• Logger positions (loggers

are placed at top, middle and bottom positions

throughout the usable load space. Loggers are also placed in order to record the air outlet and return air temperatures)

• Temperature ranges• Load state• Season

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• Impact test/s• Vehicle description• Monitor type• Mapping type (temperature/

humidity)• Data logger specification • Data logger configuration • Data logger calibration (3pt

traceable to national or international standards)

• Mapping report content overview

• Deliverables • Floor plans/diagram

Reviewing the DataOnce the mapping exercises have been completed and the reports issued with their findings and any recommendations, the next critical step is to review the data with your quality team. The data actually helps to give you a better understanding of how your vehicles perform in certain conditions and situations, allowing you to make good decisions based on actual data gathered during these tests. As mentioned in the vehicle test summary here, one of the key parts in a good mapping exercise is to conduct an impact test. The data illustrates how long the cargo compartment(s) being used will hold the correct temperature range required. Then put that data into a real-life situation, whether that is a vehicle breakdown, or there are no open-deck positions available on a cross-Channel ferry, so leaving the engine running on the vehicle is not an option. The impact test data gives you specific information about what will happen to the temperatures on the vehicle, allowing the transport operator – along with its client – to make informed decisions about what action to take.

RecommendationsThe data will also highlight any unusual hot or cold spots within a vehicle, giving you the appropriate information to be able to make decisions about where not to load product in a vehicle, or to make some changes to a vehicle’s configuration or layout. Any structural changes to a

vehicle will of course result in another mapping test being undertaken, but better a new test than have temperature issues when shipments of actual product are loaded inside the vehicle. It’s also important to implement ‘load limit’ lines to avoid the vehicle being overloaded, which can result in poor airflow and out-of-specification readings in some areas.

Ultimately things are changing, and more and more mapping is taking place throughout the transport industry. It is in everyone’s interest to hope that this upward trend continues, ensuring regulatory compliance and that vehicles are suitable for use, but ultimately ensuring we are doing our part in getting drugs to the patient in the best possible condition.

References European CommissionGuidelines of 5 November 2013 on Good Distribution Practice of Medicinal Products for Human Usehttp://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2013:343:0001:0014:EN:PDF

The ECA (European Compliance Academy) & the PQG (Pharmaceutical Quality Group)Draft Chapters on GDP Interpretation of the EU GDP Guidelines – Section 9 Transportationhttp://www.pqg.org/shop/guidelines/43-eca-pqg-gdp-guideline-chapter-9-good-distribution-practice.htmlhttp://www.good-distribution-practice-group.org/gdp_news_3973_7940,S-GDP.html h t t p : / / w w w. g m p - c o m p l i a n c e . o r g /enews_03973_.html

WHO (World Health Organization)Annex 9 - Model guidance for the storage and transport of time and temperature sensitive pharmaceutical productsSection 6.6 Qualification of temperature-controlled road vehicleshttp://apps.who.int/prequal/info_general/documents/TRS961/TRS961_Annex9.pdf

MHRA 2014 Orange GuideRules and Guidance for Pharmaceutical Manufacturers and Distributors 2014 – the ‘Orange Guide’h t tp://www.mhra.gov.uk/Publ ica t ions/R e g u l a t o r y g u i d a n c e / M e d i c i n e s /O t h e r m e d i c i n e s r e g u l a t o r y g u i d a n c e /CON2030291

HPRA (Health Products Regulatory Authority)

Guide to Good Distribution Practice of Medicinal Products for Human Usehttps://www.hpra.ie/docs/default-source/publ icat ions - forms/guidance-documents/ia-g0046-guide-to-good-distribution-practice-o f -med ic ina l -p roduc t s - fo r - human -use - v2.pdf?Status=Master&sfvrsn=6

Kane Edgeworth, Managing Director, Biomap Ltd. Kane has worked in cold chain compliance since 1999 and launched Biomap Ltd in 2008, specialising in temperature

qualification services. Kane works across the pharmaceutical industry with clients throughout the UK and the Middle East, regularly presents at GDP workshops and is also a member of the GDP working group driven by the ECA and PQG for interpretation of the 2013 EU GDP guidelines. Email: [email protected]

Andy Hughes started his logistics career in 1992, with a multi-national freight forwarder. He moved on to work for the UK’s freight association, BIFA, as its head of c o m m u n i c a t i o n s , lobbying Government

on transport issues. In 2003 he helped establish Pharmafreight, a freight company handling only pharmaceuticals and related products, under good distribution practice (GDP). Andy travels extensively, setting up GDP operations at partners around the world, and offers advice to key industry organisations.Email: [email protected]


Based in Hammersmith, West London, Biomap works exclusively in the life sciences industry providing temperature monitoring solutions designed to fit with the ever-growing list of guidelines in regard

to the storage and transportation of temperature-sensitive pharmaceutical products, especially around the requirements of GMP (good manufacturing practice) and GDP (good distribution practice).

With experience of working across industry, from pharmaceutical manufacturing & distribution (API & finished), full and short line wholesalers, clinical trials supplies, freight forwarders and specialist logistics companies as well as blood storage, labs & hospitals, Biomap provides a portfolio of service-based solutions as well as temperature-monitoring hardware and software packages.

The last few years have seen a number of updates in regulation from various organisations, especially the MHRA with the new 2014 Orange Guide and the European Commission with the new GDP Guidelines in November 2013. Our clients have a lot to do in regard to overall compliance, so Biomap aim to take the guesswork out of the requirements for temperature monitoring and qualification. The guidelines include a lot of ‘what you have to do’ but not ‘how you to have to do it’.

Biomap regularly present at GDP events and are part of the GDP working group driven by the ECA and PQG for interpretation of the 2013 EU GDP guidelines.

Temperature MappingBiomaps temperature-mapping service is a tailored solution to map a wide range of storage and transport environments. Regulatory guidelines demand that environments such as warehouses, cabinets, cold stores and vehicles are all mapped and driven by a regularly reviewed risk assessment. The mapping service includes full protocol documentation with floor plans and execution of the installation process, and concludes with a full data analysis service produced in a final report with calibration documentation, data summaries, multi-graphs and recommendations.

Packaging QualificationPackaging qualification projects can be for any packaging method and can include temperature and humidity exposure tests as well as vibration and impact tests to simulate worst-case shipping scenarios. Winter and summer profiles are designed to meet the specific environments a particular shipping lane will be subject to during transit.

Route Qualification/Shipping StudiesA route qualification project documents the temperatures a product is exposed to during transit and can help illustrate trends through certain lanes. There may have been a number of excursions that have already been experienced and need further investigation, or there may be plans for a new shipping lane with no data. Projects are tailored to meet individual client objectives and goals.

Temperature Data LoggersBiomap is the UK distributor for the Cryopak range of electronic temperature data loggers, an extensive range of options for monitoring both temperature and humidity. Single- and multiple-use PDF devices are available and amongst some of the most reliable and accurate loggers available.

Continuous Monitoring SystemsBiomap supplies the Radiolog wireless monitoring system, consisting of a range of different wireless loggers (transmitters) to accommodate almost all requirements for the monitoring of temperature, humidity and pressure. In addition, flood detection and energy use solutions are also available.

Typical installations include but are not limited to warehouses, cold stores and labs consisting of fridges, freezers, incubators and stability chambers, as well as cryogenic monitoring down to -196°C.

Each system is offered with a suite of validation options including full IQ/OQ script completion to support 21 CFR Part 11 requirements.

Temperature-controlled CabinetsBiomap distributes the range of Labcold fridges and freezers. Labcold Pharmacy and Vaccine refrigerators have been designed from the ground up, for the safe and secure storage of temperature-sensitive pharmaceuticals.

All Labcold Pharmacy and Vaccine fridges are lockable refrigerators and automatically alarm if the temperature goes out of range.

Available in a wide range of sizes, Biomap has the ability

to offer a full package including the required cabinet supplied along with a full mapping service and monitoring system, allowing for a simple transaction with one provider.

Contact details:Biomap LtdBritannia HouseGlenthorne RoadHammersmithLondonW6 0LH

Tel +44 (0) 203 137 1820 Fax +44 (0) 207 904 2015Email [email protected] Web www.biomap.co.uk



Manufacturing

Advances in Tissue Processing:

The Supercritical AlternativeThe term regenerative medicine was introduced in the mid-nineties. Regenerative medicine may be defined as “a branch of translational research in tissue engineering and molecular biology which deals with the process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function". Ever since the discovery of stem cells and their potential to augment a wide variety of tissue/cell-related defects, this field of medicine has been identified as one of the most promising advances in modern medicine with a wide-spanning impact in multiple disciplines. In its most basic form, cells from the patient can be isolated and may undergo several steps of differentiation until re-implanted into the body. Despite the promising future use of stem cells, extensive research over the last decade has shown how the augmentation of, e.g., damaged tissue not only depends on the inherent potential of stem cells to adjust and differentiate, but also on the presence of the right micro environment where the cells reside. This environment has been identified as the extracellular matrix (ECM) and consists of a wide variety of structural and functional proteins such as collagen, glycosaminoglycans and proteoglycans1. Current clinical applications are nowadays aimed at providing the right ECM environment in concert with the right cells.

The ECM has been extensively investigated over the last decade, with a view to unravelling its incredibly complex structure and multitude of functions. Describing the molecular and structural organisation of the ECM is beyond the scope of this editorial, yet several key protein-based components such as collagens, fibronectin, laminin and a wide range of glycosaminoglycans are worth mentioning as their importance in providing structure and functionality is becoming more clear. Current opinion suggests that the complex composition and three dimensional structures are key factors for effective tissue restoration. Clinical application of purified (i.e. cell-free and sterile) ECM constructs has been shown to be a promising way to treat hard-to-heal wounds such as chronic

wounds (e.g. diabetic foot ulcers), extensive trauma (e.g. second-/third-degree burns) and sport-related injuries (e.g. rotary cuff rupture). In addition, hard tissue grafts (i.e. bone) are extensively used for hip, knee and spinal surgery. This has led to the establishment of a whole new industry focussed on manufacturing ECMs (so-called interactive or advanced dressings) from human, animal and synthetic materials supplying to a market that is expected to grow towards a $225M market in Europe and $900M in the US by 2018. Not surprisingly, several methods to clean and sterilise these dressings have been developed.

In this review, we wish to give a scope of the current methods by which tissue grafts are manufactured followed by an introduction to a promising new method based on carbon dioxide. This promising technology has shown to be very effective in cleaning and sterilising tissue grafts with minimal impact on the quality of the grafts.

CleaningThe first critical step in the establishment of a safe tissue graft is efficient decellularisation and defatting. The presence (or even residues) of cells are potentially capable of invoking an immune response, rendering the graft virtually useless. This negatively impacts the recipient’s clinical prognosis. Furthermore, the presence of any viral and bacterial microorganisms can induce severe inflammations, which again can worsen the patient’s outcome and drive costs up significantly. The ideal tissue graft should, therefore, be free of any residual cells and pathogens, yet retain the inherent structural and mechanical properties of the ECM. Several studies have shown that the removal of fat is of particular importance, since fat or any lipid compound can serve as a storage place for, e.g., viruses. Furthermore, lipids have been identified as potential immune-activating compounds, mitigated via, e.g., toll-like receptors (TLRs). In contrary, synthetic grafts are ideally suited to minimise the risk of disease transmission and rejection, yet these products are, to date, not capable

of fully mimicking the ECM compared to animal-/human-based tissue grafts.

In a review by Crapo et al.2, the various methods of cleaning tissue are described. The use of chemical and enzymatic agents to decellularise and defat (delipidise) are currently used by various major tissue processing companies and tissue banks. Cells and lipids are efficiently removed by breakdown of the cell membrane and dissolving the cytoplasmic content, including denaturation of proteins and nucleic acids. On the down side, these compounds can have several side-effects such as costly removal of any chemical traces, disruption of the ultrastructure of the ECM and less efficient cell and lipid removal.

In general, the methods mentioned above are efficient in removing cells and lipids, yet extensive and time-consuming washing is required to remove the chemicals and enzymes. Furthermore, the agents themselves are known to have detrimental effects on the ECM.

Omitting the harsh treatment in the above-mentioned paragraph, many European tissue banks utilise a six-month freezing period, since this period is necessary to exclude the presence of HIV in serological testing. After the six-month freezing period, tissue will be thawed prior to surgery. Surprisingly, very little donor-to-host disease transmission has been reported over the last decade despite the lack of efficient tissue decellularisation and delipidisation. This may be largely explained by extensive donor testing defined in the regulations of both the American Association of Tissue Banks (AATB) and European Association of Tissue Banks (EATB). This method may cause less harm to the ultrastructure of the ECM although supportive data is still very minimal. However, this method requires expensive storage in large freezers, increasing costs significantly.

The ideal tissue graft would follow the process of decellularisation and delipidisation which would result in a cell and lipid-free ECM scaffold consisting of an unaltered ultrastructure and molecular consistency. Besides this, the scaffold

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should be easy to handle and store, and be cost-efficient. Current products offered by several commercial and non-profit organisations (tissue banks) often present a compromise between these important factors. Clearly, innovation in novel methods for better grafts is much desired.

SterilisationDisease transfer of allografts is a major concern according to numerous publications, despite the low reported incidences over the last 10 years. Nevertheless, a sterile ECM graft is highly desired as it minimises the risk for pathogen-based transfer of diseases. Sterilisation is defined as the process or act of inactivating or killing all forms of life, in particular microorganisms. A standard has been set in which a log 6 reduction of viable microorganisms has to be achieved in order for the medical device to be called sterile. This level is called Sterility Assurance Level 6 (SAL 6). By default, efficient cleaning of tissues prior to sterilisation greatly assists in reaching SAL 6.

A sizable number of studies have shown that the current available methods of sterilisation can affect the quality of ECMs to a variable extent. Irradiation, heat and gas-mediated sterilisation are all commonly used methods to sterilise anything from surgical scissors to biologicals. Irradiation by gamma or beta rays has been shown to reduce the biomechanical strength of tissue grafts3. Likewise, the use of heat as a method of sterilisation is less preferred as the ECM is not able to withstand the high temperature. The use of ethylene oxide, EtO, has been heralded as a very promising method to provide sterilisation for sensitive medical grade products such as ECMs. However, residues of EtO have been shown to induce unwanted immunological reactions. Elaborate and time-consuming degassing of EtO is required to meet the safety standards set by organisations such as the Association for the Advancement of Medical Instrumentation (AAMI).

The increasingly aging population and climbing rate of chronic diseases such as diabetes are examples that drive the need for tissue grafts. Currently, this demand cannot be met as was shown during a tragic fire in a bar in Volendam, the Netherlands, when tissue grafts had to be imported from all over the world to treat the severe burns. Similar actions

were observed during 9/11 and in wartime conditions.

Clearly, there is a need for ready-to-use tissue grafts which comply with the SAL 6 standards, contain minimal cell and fat residues, are easy to store at room temperature and possess a prolonged shelf-life. Second, the grafts, whether bone, skin or membranes, should have retained the inherent ECM ultrastructure. Third, the graft should be cost-effective. The currently available technologies as described above are, to date, unable to comply with all these critical factors.

Going SupercriticalAs mentioned in the previous chapter, efficient decellularisation and defatting are key factors in the first stage of tissue processing. Ideally, dissolving and extraction of these undesired biological components should be combined in one step. With this in mind, the use of supercritical carbon dioxide (scCO2) has been proposed as a promising method. Supercritical fluids are obtained by increasing the pressure and temperature of a gas or liquid at a specific point. This point is called the supercritical point, where both the liquid and gaseous phase become indistinguishable. Figure 1 illustrates the gas/liquid transfer to a

supercritical state. Following the gas-liquid curve for CO2, increasing both pressure and temperature results in a decreased density of the liquid CO2, but an increase in density of gaseous CO2. At 31 degrees Celsius and 74 bar pressure, both densities are equal; hence the supercritical point has been reached. Interestingly, at this point and beyond, CO2 combines characteristics of both a fluid and a gas. scCO2 can still penetrate dense structures like a gas and dissolve/extract compounds like a fluid. It is this inherent characteristic that has attracted much scientific and industrial interest into scCO2. Why CO2 and not other gasses or liquids? The reason for this is that scCO2 can be achieved under fairly mild conditions (31 degrees Celsius, 74 bar) whereas supercritical water would require 370 degrees Celsius and 217 bar. scCO2 is nowadays widely used as an alternative to the use of chemical treatment to extract unwanted components from a manufacturing process. For instance, decaffeinated coffee is now almost solely produced by exposing the coffee beans to scCO2 which extracts the caffeine, omitting the use of hazardous chemicals. Further examples are the extraction of hop during beer brewing, and the isolation of essential oils.

Figure 1

IPI December 2013.indd 91 23/12/2013 14:14:15


Manufacturing

Given the characteristics and widespread use of scCO2, scCO2 as a method to decellularise and defat tissues has been investigated. Sawada et al. showed that exposing porcine aorta tissue to scCO2 resulted in a nearly 80% reduction in phospholipids, while retaining the inherent mechanical stability4. Adapting scCO2 as a method to decellularise and defat tissue grafts can only be fully effective if the following step, sterilisation, retains the preserved mechanical and structural characteristics. Actually, almost 10 years prior to the study by Sawada et al., a study conducted in the lab of Prof. Langer5 had already revealed that scCO2 is capable of inactivating microorganisms. They hypothesised that the scCO2 is capable of penetrating the cell wall of bacteria and causing an internal change in pH via deformation of carbonic acid, inactivating the bacterium. Several other theories suggest that disruption of the cellular membrane, due to the mass transport of CO2, causes microbial inactivation. Also, denaturation of essential enzymes within the bacterium has been postulated as a possible method of operation. Despite the lack of a clearly defined mechanism, the application of scCO2 as a method for tissue graft sterilisation has been extensively investigated both on synthetic material and on tissue. Focussing on the latter, consecutive studies showed that scCO2-based sterilisation of rabbit humeri resulted in a retention of the bone’s mechanical properties. In addition, the study also compared the results with up to 25kGy gamma-irradiated humeri, which showed up to a 50% reduction in maximum torque of the bone. These results were further supported by others where bone and tendon allografts were inoculated with Bacillus atrophaeus endospores and showed that scCO2 treatment resulted in no significant reduction in mechanical properties and collagen crosslinking. In contrast, gamma irradiation showed detrimental effects. Our own data has revealed that scCO2 treatment in validated models for sterilisation can result in tissue grafts in compliance with the SAL6 standard.

These and other studies clearly show that scCO2 is a promising method for addressing the need for efficiently cleaned and sterilised tissue graft. However, since the discovery of biodegradable polymers, it is expected that eventually, the use of synthetic grafts will surpass the use of biological tissue grafts. Poly(lactic-

co-glycolic acid) (PLGA) or polyether ether ketone (PEEK) have been identified as very promising synthetic scaffolds to replace biological tissue grafts. However, sterilisation based on, e.g., irradiation has been shown to have negative effects on its biocompatibility. Although no extensive data exists, scCO2-based sterilisation may provide a solution to this problem. Indeed, our own initial results have indicated that treatment of polymers with scCO2 did not affect its inherent properties.

Retention of (ultra)structural and mechanical properties has been a key issue in this review. The use of bioactive peptides such as growth factors and infection-controlling agents (antibiotics) are increasingly used in concert with tissue grafts to address specific needs. For instance, a high dose of vancomycin/tobramycin is used in patients who have undergone hip-revision surgery with an increased risk for infection. Growth factors, such as BMP-2/7 or VEGF/PDGF have clearly shown their effectiveness in promoting bone and vascularisation, respectively. It is generally accepted that future grafts, whether biologic or synthetic, will likely include the release of such bioactive compounds to improve their efficacy. Using scCO2, the group of Prof. Subramaniam have shown that it is possible to coat/impregnate bioactive compounds to implant surfaces6, further expanding the use of scCO2 in tissue restoration. ConclusionWithout doubt, scCO2 is a promising method to address the need for efficiently cleaned and sterilised tissue grafts. It potentially addresses all the requirements for optimal tissue grafts, combining biological safety with retention of (ultra)structural properties. With this growing attention, cost-effective manufacturing of tissue grafts by scCO2 has become a reality. Ongoing scCO2 research holds numerous applications that may be translated into the clinic. References1. Cornwell, K.G., Landsman, A. &

James, K.S., Extracellular Matrix Biomaterials for Soft Tissue Repair. Clin. Podiatr. Med. Surg. 26, 507-523 (2009)

2. Crapo, P.M., Gilbert, T.W. & Badylak, S.F., An overview of tissue and whole organ decellularization processes. Biomaterials, 32, 3233 –

3242 (2011)3. Fideler, B.M., Vangness, C.T. &

Moore, T., Gamma irradiation: Effects on biomechanical properties of human bone-patellar tendon-bone allografts. Am J. Sports Med., 23, 643 – 646 (1995)

4. Sawada, K., Terada, D., Yamaoka, T., Kitamura, S. & Fujisato, T., Cell removal with supercritical carbon dioxide for acellular artificial tissue. J. Chem. Tech. Biotech., 83, 943 – 949 (2008)

5. Dillow, A.K., Dehghani, F., Hrkach, J.S., Foster, N.R. & Langer, R., Bacterial inactivation by using near- and supercritical carbon dioxide. Proc. Natl. Acad. Sci. USA, 96, 10344 – 10348 (1999)

6. Niu, F., Haslam, J., Rajewski, R. & Subramaniam, B., A fluidized-bed coating technology using near-critical carbon dioxide as fluidizing and drying medium. J. of Supercrit. Fluids, 66, 315 – 320 (2012)

Marco Thio is EMCMs Product Manager for its tissue division. He has over 13 years of experience in cell biology and biomaterials gained in both academia and industry. His work is

focussed on delivering the supercritical carbon dioxide platform technology as a novel method to manufacture high quality tissue grafts for a wide range of clinical applications.Email: [email protected]

Müller GmbH - 79618 Rheinfelden (Germany)Industrieweg 5 - Phone: +49(0)7623/969-0 - Fax: +49(0)7623/969-69A company of the Müller [email protected] - www.mueller-gmbh.com

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Lawmakers and regulators around the world are demanding serialisation for drug products. It is their belief that this process, where the result is a clear identification of drug products, is a major step in the struggle against counterfeiting. While some countries have already embraced certain guidelines, others will be doing so in the coming years. Whatever their timeframe, all drug companies, along with their suppliers, are facing the challenge of implementing appropriate solutions.

Counterfeit drugs have become an enormous problem both for developing nations and the industrialised world as a whole. Counterfeit drugs jeopardise the health of patients and, in some cases, have resulted in deaths. They have also had a major negative economic impact on a global basis. According to the WHO, counterfeit drugs have cost nations an estimated $75 billion1 a year combined.

Typically, due to their high costs of development and manufacture, counterfeiters have focused on complex medications such as cytostatic and virostatic drugs, as well as antibiotics and hormones. Therefore, as a means of managing this problem, lawmakers and industry representatives have turned their attention to the tracking of these products beginning with the production line, on through to the pharmacy. The process is called ‘serialisation’, and it entails clear identification of the smallest packaging unit with a unique identification number.

While there has been some debate about this approach, it is clear that serialisation is quickly being embraced on a global basis. For every stakeholder in the supply chain, the rapid rise of serialisation means there has to be an appropriate response. And, it is essential that this solution meets the requirements as defined by official agencies while offering greater security for the patient. An economic solution is important, allowing for the optimisation of production and distribution processes. The question for companies then is ‘how can the interested parties be brought together to implement

a form of serialisation that meets future needs?’

A Variety of ChallengesThe subject of serialisation and track-and-trace has been on the industry's agenda for quite some time. Several of the major drug manufacturers have, in fact, made considerable inroads into implementing solutions. Others have waited for the regulatory standards to be in force before addressing the issue. Regardless of the approach taken, the industry as a whole is keenly aware of the need for serialisation and is working hard toward developing appropriate solutions.

However, serialisation is not a simple process. Therefore, in order for it to be effective, it is backed by some important technological transformations in both the IT and engineering areas. For those companies seeking a suitable partner and supplier, there exists a bottleneck since only a limited number of specialists are available to design and implement the required IT system, applications and plant engineering. Alternatives are difficult to find since there is some risk involved to consider suppliers unfamiliar with the industry. Packaging processes that meet stringent regulatory standards or supply chain structuring requires considerable pharmaceutical expertise.

Also complicating the issue is the fact that there exist important differences in the plants and the IT landscapes of large companies that have several locations. Each individual subsidiary usually has its own history. Thus, the plants have usually been built by a variety of suppliers and are often run by several different IT systems. The rule of thumb is the larger the company, the more extensive the challenge. Thus, the effort needed to retrofit ten lines is significantly different from the effort required for retrofitting 100 lines. Finally, the same product is often manufactured on various lines and has to go to a variety of markets that are all regulated differently.

Another set of challenges is faced by smaller or virtual companies, which usually lack in-house production facilities,

and also have to exchange serialisation data directly with officials. This entails a great deal of learning about in-line and distribution processes and packaging. And, there is also the cost factor ultimately forcing the question, “Do we make it or buy it?” It is clear: companies are facing a large number of multifaceted challenges and need to have a comprehensive knowledge of the subject.

Questions AnsweredHow then, can companies best address the tasks at hand? The first step is to get a good understanding of the extent and demands of a serialisation solution that best fits their specific needs. Those in key positions to implement serialisation, along with experts in this area, should first identify and develop the most important parameters, determine what they can put into practice themselves, and what can be outsourced to a service provider. The following questionnaire can provide some help:

• Which regulatory authorities’ serialisation rules have to be met?

• What firm guidelines do the individual agencies offer for structure and presentation?

• How should the serialisation data be shared with the regulating agencies?

• How, and in what form, should companies administer and manage the serial numbers?

• What solutions are in place to deal with the serial numbers on the manufacturing level?

• What kind of systems and transmission systems will be used in advance of the packaging line?

• How will the serialisation solution be integrated into the existing enterprise resource planning (ERP)?

• What interfaces and transfer protocols are required?

• What are the key processes demanded by warehouse management?

• How can in-process controls and quality management be integrated into the serialisation solution?

These questions are critical since they determine the tasks that a company

Implementing Serialisation

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implementing serialisation has to be aware of. Each task is analysed in detail in order to produce a list of precise specifications a candidate supplier will need to meet. Clearly, companies without actual packaging lines will have to direct greater attention to a management solution. However, drug companies with their own production facilities will also have to make sure their equipment is up to the task of serialisation. Ultimately, there are two clear areas that need to be attended to. First, companies will need to implement an IT solution covering both hardware and software, and second, they will need an engineering project to retrofit the lines.

Solving the IT IssueKnowing the requirements that are expected to be met is central to implementing both hardware and software solutions. Companies that deliver products to various markets face the challenge of having to meet a variety of standards for serialisation. In such cases, the guidelines will be determined by the following:

• Code type • Serial number characteristics• Serialisation level• Reporting requirements

What is most needed is a flexible serialisation solution that can meet all regulatory requirements. Companies will have to make every effort to be sure of various aggregation depths,

as some official agencies demand aggregation from the sales packaging unit to the shipping carton, on through to the transportation pallet. Therefore, the following elements will have to be taken into account when implementing the solution:

• Integration into ERP• An IT solution for the management of

serialisation data from aggregation through sample withdrawal

• Interfaces and data transmission

The IT solution should then link order data with the corresponding serialisation data. This will allow the serial numbers to be monitored prior to delivery and generation of the subsequent data reporting, including the aggregation data. Basically there are two options to solve the IT issue: either you implement and develop an IT solution in-house, or you go with a cloud or hosted solution. Each solution has its advantages depending on your company’s IT strategy. Going with an in-house solution will take more time, but it gives your organisation more control of your data and is easier to integrate with your internal IT systems. If you have a short timeframe and don‘t have the budget for high investments upfront, a cloud solution could be the answer.

Engineering SolutionThe guidelines for serialisation demand clear identification of the smallest packaging units, i.e. the folding boxes

that the drugs are to be packaged in. Even a cursory glance at the secondary packaging such as an injectable, will reveal what system will be needed for implementation on the lines. After filling and visual inspection, the syringes are blistered and then packed into the folding boxes on the packaging line. Afterwards, the boxes are packed into shipping cartons and loaded onto pallets. Variable data are already printed onto the folding boxes, including batch numbers and expiration dates. The shipping carton and the transportation pallet also carry product information. Printing the serial numbers at the same time as the production data is recommended for serialisation.

A plant can be both retrofitted and connected to printers that can print in either number or some machine-readable form such as bar codes or 2D data matrix codes. Networked camera systems are also needed for monitoring in addition to scanners that are necessary for the in-process controls and rejects which allow for rebooking. A mobile machine might be a good start since it allows companies the flexibility to do serialisation on various lines. The fact that the machine can be qualified separately and offline also means that you are able to gain experiences without influencing your existing packaging lines. It also avoids down time and allows those in charge to collect important information on the process itself without risk of breakdowns.

Once the ‘know-how’ has been gathered and integrated, a stationary serialisation unit can be commissioned. The on-line systems will still need to be rounded off with a label printer and a camera unit for manual aggregation of the individual boxes with the shipping carton. The same principle applies to the manual aggregation of the shipping carton with the transportation pallet. The systems for each packaging line are connected via a line controller, which is controlled by means of a site server directly connected to the central IT platform.

Software and HardwareIt should be clear to the reader at this point that serialisation can only work effectively if implemented with an IT system, combined with a well-conceived engineering project. The two sides of serialisation implementation are carefully meshed with all existing integration

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systems and communicate with them as well, which requires an on-site server to control production. Integration can be performed using SAP process integration (PI) for example, with standard interfaces like EPCIS and reports using XML in EPCIS design.

The IT solution has several other tasks to perform, including recording and documenting events along the entire supply chain, and then generating full documentation as well as reports. A link-up with ERP is also vital to initiate orders and to generate, administer, and share print information and key materials, such as serial numbers. And, because the serialisation solution involves many different layers, the IT solution is important to support the work across different systems to generate and disseminate commissioning reports for the serial numbers, aggregation reports, etc. In-process controls can be used for sampling during production, while a

handheld solution could allow exception handling at the warehouse. Relabelling will then need to be completed at the warehouse as well.

Key DetailsThe official guidelines for serialisation solutions require certain fundamental elements. All sales packaging units will bear a clear set of serial numbers and other identifying features. These numbers can be in 1D linear code or 2D data matrix code, as well as the information being in text form so they can be read by humans and robots alike. The 2D data matrix code has the advantage of providing more data, i.e., expiration date and batch number, in addition to the number of folding boxes in the shipping carton. This information needs to meet the GS1 standard.

There are, of course, national differences. China, for example, demands very special guidelines, including 1D linear codes as well as aggregation with shipping boxes. For the exchange of data such as serial numbers, and reports which contain integrated photos of serialised

shipments, Chinese authorities also require a manual interface with the drug company, to enable the transition of the serial numbers and reports. South Korea follows at least for 2015 another concept, serialisation on item level. They will meet the GS1 recommendations depending on data matrix code information like GTIN, expiry date, batch/lot and serial numbers using a 2D data matrix.

Toward a Safe FutureIn summation, serialisation involves the clear tagging of the smallest packaging unit with a unique identification number. The rationale behind this new approach is to provide greater safety throughout the entire supply chain. Combatting counterfeit drugs through serialisation protects patients as well as companies whose reputation can be

adversely affected if their products are counterfeited. Serialisation combined with Track & Trace also offer potential for process optimisation, since clear mapping of distribution channels allows for easy tracking and tracing. Thanks to powerful IT systems with simple and efficient interfaces, caregivers can quickly check the origin and integrity of the drugs they are administering to patients. The fakes will be immediately identified and removed from circulation.

References1. Source: WHO http://

w w w . w h o . i n t / b u l l e t i n /volumes/88/4/10-020410/en/

Manufacturing

Alexander Ulbrich is project manager within the IT department responsible for the Serialization Project at Vetter. He began his career at Vetter in 2003 and since 2013 he is

team leader responsible for a team of SAP application consultants. Prior to Vetter, Alexander was with the technology group of Acterna (now JDSU) as system administrator member of the global Lotus Notes Core Team. After he finished his studies at the FH Reutlingen he began his working career in 1999 at Wavetek Wandel und Goltermann as a qualified engineer (FH) of Electronics.

Example of a software and hardware solution

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More than 370 leading suppliers (including 60 new companies) in pharmaceutical packaging and drug delivery technologies have already announced their participation at the 14th edition of Pharmapack Europe, taking place on the 11th & 12th February 2015 in Paris Expo, Porte de Versailles (Hall 5).

For pharmaceutical companies’ buyers and R&D managers coming from around the world, Pharmapack Europe is a unique showcase for technological innovations, especially those presented in the Innovation Gallery and the Pharmapack Awards.

Reflecting market trends, the internationalisation of the event is carrying on with more than 65% of exhibitors and 45% of visitors being international, coming mainly from European countries.

What makes Pharmapack Europe different is its unique content programme, always dealing with industrial issues. The main topics this year will be focused on regulation updates, new packaging materials, patient adherence & compliance, what’s new in injectables, oncology drug delivery & packaging, emerging technologies & innovation forecast and finally animal health packaging & drug delivery.

The dedicated session about animal health will be chaired by Martin Folger, head of pharmaceutical

development, Boehringer Ingelheim Vetmedica GmbH and animated by companies such as SIMV (Syndicat de l’industrie du medicament et réactif vétérinaires), Mazerolles Consulting and Primequal SA.

An infographic about the animal health product market and veterinary companies visiting Pharmapack Europe can be viewed below and on the Pharmapack Europe website: http://www.pharmapackeurope.com/animal-health-product-companies.

A whole day will be dedicated to

Serialisation, Track & Trace through a technical symposium hosted by Adents Pharma, Axway, Domino and Optel Vision on 11th February.

New Features will be Introduced This Year! The Learning Lab area on the exhibition floor will provide free conference presentations and the possibility for the exhibitors to talk about their latest innovations for 30 minutes. This open area will enable visitors to directly interact and share knowledge with exhibitors.

Pharmerging markets will be discussed through a networking breakfast and a special workshop on “Pharmaceutical Packaging Materials Registration in China”.

A dedicated workshop will be held on 12th February and hosted by Voisin Consulting Life Sciences, who will address “Combination products: CMC and Human Factors / user tests for regulatory compliance & market success”.

The organiser will also provide a new service to visitors in order to optimise their time and their visit. The International Meetings Programme will enable visitors to have private meetings with exhibitors based on their requirements. An area on the exhibition floor will be dedicated to networking to favour a performing business environment.

Finally, the 2015 edition will host two Pharmapack Awards ceremonies for two distinctive product categories:

• Health products: this award category will reward the pharmaceutical companies and suppliers they have worked with to develop a health product. It can be a new health product launch or improvement of an existing product in which packaging has been improved.

• Best innovative exhibitor: the exhibition will bring together the worldwide leaders in pharma packaging and drug delivery solutions. It will represent over 370 companies with at least as many innovations available on the show floor.

The awards will be delivered by a jury made up of decision-makers involved in R&D and purchase for packaging from pharmaceutical companies, and a special prize will be given by the event visitors, who will be able to vote prior to the show and at the event.

Pharmapack Europe has also launched a new website including a content library (infographics and articles): please visit: www.pharmapackeurope.com.

Packaging

Pharmapack Europe 2015: Innovation, Networking and Education on Pharmaceutical Packaging and Drug Delivery Solutions


Packaging

Beyond Item-level Serialisation:

Extending Traceability Schemes to

Secondary and Tertiary PackagingThe Case for Aggregation; The Legislative AgendaFalsified and counterfeit medicines are a chronic problem for the pharmaceutical sector, with a third of all shipments in the worst affected parts of the world estimated to contain fake medicines. Highly portable and often extremely valuable, medicines continue to be a favourite with those determined to fake products or subvert the system for illegitimate gain. Faced with this continued global threat, legislatures around the world are responding by tightening the supply chain to stamp out illicit goods.

Over the next few years, major markets and trading blocs, including the EU, the USA and Latin America, will enact legislation mandating that each patient pack will have its own unique identification number. Add to this schemes that are already either in force or being implemented in China, India, South Korea and Turkey and it is clear that there is significant momentum towards establishing item-level serialisation as the global standard

for proving the origin and source of each and every pharmaceutical pack. Against this backdrop, counterfeiters across the world will find it much harder to infiltrate legitimate markets. Even if the packaging and branding look authentic, item-level serialisation will help prove an item’s authenticity.

But moving unique products around the world presents its own problems. Items don’t move as single units, but in batches on pallets or in cases. Keeping track of what is included inside the secondary and tertiary level of packaging is the next major challenge for the pharmaceutical industry. Aggregation is about understanding how to accurately record serialised pack data and build that into a hierarchical structure that records detailed information about each pack’s progress through the supply chain.

The challenges of serialisation are well-documented; however aggregation requires an altogether higher level of data processing and joined-up thinking. Inserting the correct quantity of goods into

a box and applying a label is only half the battle. This paper will demonstrate that where serialisation is required, aggregation is a logical extension – even if not mandated – and one that delivers a range of benefits.

The Data ConundrumSerialisation generates huge amounts of data, creating storage and data integrity challenges. Each item consists of two parts – a physical asset and a data asset. The association must remain linked from the moment a unique identity is assigned to a pack right through to the moment it reaches a patient.

This alone requires a modal shift in the manufacturing mindset, with each pack effectively a unique batch of one. Reconciliation, which has until now been a line side task completed once per batch, will in future need to extend right through the supply chain and be open to interrogation for the life of the product and beyond.

All serialisation schemes decree that

Photo 1: While some of the schemes in play include aggregation as a requirement, others do not

Photo 2: Print and apply labelling machines, such as this Domino M-Series, are a flexible option, suitable for use at bundle, case or pallet level

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Packaging

all product data must be uploaded to a national or supra-national database against which product IDs will be verified at the point of sale or dispensing. This in turn raises the question of data aggregation (or the establishment of hierarchical relationships at each stage of the packaging process).

While some of the schemes in play include aggregation as a requirement, others do not. However, it would seem to be a practicable extension of item-level serialisation, enabling, for example, the data for each pack in each bundle, and each case on a particular pallet, to be retrieved with a single scan.

Whatever the motivation, it is vital to start planning for aggregation early on in the manufacturing process. It is almost impossible to consider aggregation separately to serialisation. Just like building a house, it is best to start from

the foundations upwards as any attempt to retrofit aggregation after the fact is fraught with difficulties.

Pulling in the Right DirectionSuccessful aggregation strategies depend on multiple departments pulling in the right direction. It is no longer the case that products can be manufactured in a factory and simply handed over to the distribution department for despatch.

Now, the entire system of production can break down without cooperation between departments and disciplines. The fork-lift truck driver needs to be just as aware of the implications of pallet aggregation as the production manager or the IT department. Even the marketing team needs to be aware of how aggregation works, as designing the wrong GTIN identity can cause ripples throughout the entire supply chain.

The core challenge of putting a label on a box was resolved many years ago. The hidden challenge is what is going on behind the scenes to get the data to put it onto a box. How producers do all that effectively, taking account of all the stakeholders and without impacting negatively on transport or logistics, is fundamental to successful aggregation. In Domino’s experience, up to 80% of conversations in this area revolve around the practical problems of transferring serialised products from the primary packaging line to aggregated products in the secondary and tertiary stages.

The actual mechanics of label application are relatively simple. The problem-solving comes down to discussions on what sort of relationships pharmaceutical manufacturers have with their respective supply chain; recognising who is important, and finding a way to integrate aggregation within their existing set-up. Many manufacturers are comfortable with the technical and mechanical aspects of label application; it is the higher level of consultancy, solving the end user problems of serialisation or aggregation that manufacturers are looking for.

The cost of failure is high. Manufacturers can apply 20 labels a minute, but if a company has a breakdown which means that it has to manually search and de-aggregate 20 pallets, then any speed advantage is irrelevant. What is more, if a pallet or batch has

to be de-aggregated, then it generates a huge range of complications in terms of decommissioning serialised numbers. One bad case in the manufacturing process can create a whole world of problems.

There is also a blurring of the lines of demarcation between good manufacturing practice – traditionally confined to the production hall – and good distribution practice, which, if not recognised and embraced, can compromise aggregation. Drawing up a protocol that reflects the requirements of each discipline will avoid the traditional disconnect between how products are treated while still within the manufacturing arena and how they are handled once in the distribution stream.

The Benefits of AggregationProperly implemented, aggregation will save pharmaceutical companies time and money. Automated packaging lines have the ability to pack and label cartons efficiently and accurately. Combine this with a system that enables finished batches and shipments to be interrogated instantly to locate any pack, at any time, anywhere in the supply chain, and the appeal of aggregation is instant and abundant.

Supply chains can be long and complex, with security only as strong as their weakest point. From a brand protection perspective, the ability to spot-check the location of each pack with pinpoint accuracy is compelling, while those charged with delivering supply chain efficiencies will find much to interest them here too.

In terms of data management, much has been said and written about the technical and logistical challenges of recording and storing the vast volumes of data associated with item-level serialisation. Aggregation is a very tempting prospect in this regard; the possibility is that a single pallet code might be all that is required to hold the data associated with each one of the potentially thousands of packs it contains.

The correctly-assigned hierarchical relationships and robust code data encryption associated with a well-planned aggregation environment make this a very realistic scenario, effectively minimising or even eliminating the requirement for a big database.

Photo 3: The smaller the footprint of the print & apply labelling machine, the easier it is to integrate the technology into existing production lines

Photo 4: It is almost impossible to consider aggregation separately to serialisation

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Is Aggregation Mandatory?Is aggregation mandatory? The simple answer in most legislatures is ‘no’. In the EU member states for example, the Falsified Medicines Directive (FMD) does not specifically state the requirement to initiate aggregation in the pharmaceutical manufacturing process. But the pharmaceutical sector is a global industry, so what is not mandatory in one region, may well be in other markets. It doesn’t matter where a product is manufactured, but where it is sold. In many cases, pharmaceutical companies have no idea of the final destination point of their products at the point of manufacture.

The EU is introducing the Falsified Medicines Directive, Brazil operates under ANVISA, Argentina with ANMAT, the US with the senate bill (Drug Quality and Security Act), South Korea with MHW, and China with the CFDA. Any country might integrate a mandate for aggregation as part of its crackdown on counterfeit goods.

Taking the EU FMD as a particular reference point, its rules apply to all branches of the pharmaceutical industry including research-based manufacturers, generics producers, contract packers, parallel traders’ importers, wholesalers and distributors. Any organisation intending to supply into the EU either prescription-only medicines (POM) or over-the-counter (OTC) products, included in the scope by risk assessment, will not be able to do so unless it is fully serialisation compliant.

But aggregation comes as part of that. One cannot demonstrate the complete traceability that many are hoping item-level serialisation will bring without knowing where a unit pack is as part of a consignment. It must be traceable through the distribution network; whether as a serialised pack or aggregated pallet. Many consignments are also destined for multiple destinations. A shipment of 100,000 cartons may be destined for two or three overseas markets. Not knowing which pack is contained in which box, the distributor has no way of complying with serialisation. Part shipments can either be physically separated on the pallet by hand, or a much more efficient method is to control the data via aggregation, enabling producers to be able to identify and report on exactly what is contained inside each pallet or shipment.

The legislative framework for introducing serialisation into the EU FMD starts in 2018. That is enough time to put the issue on a back burner. But if pharmaceutical producers focus all their efforts on serialisation, and not on aggregation, then it will be virtually impossible to bolt on a solution later. So many variables are involved in a serialisation operation that, even if manufacturers lay out a perfect strategy, they will miss some areas. If not factored in at the outset, aggregation is unlikely to succeed.

By default, therefore, aggregation is mandatory, not through any written part of a directive, but through the practicalities of the distribution network. If goods need to be shipped around the world, the end user, the customs officials and the importer are all going to want to know which goods are contained in each shipment.

The Cost of Getting it WrongIf manufacturers label a pack incorrectly, it will cost them a few pence. If they label a case incorrectly it might cost them a few thousand pounds. But if a pallet leaves the factory with the incorrect information, the cost can run into millions of pounds of lost revenue.

Decommissioning serialisation numbers in manufacturing areas is complex enough; doing so in a distribution environment is fraught with problems. What distributors are trying to do is manipulate a data asset that originated elsewhere, in another environment, which is extremely difficult to do.

Any rejects need to be verified and double-checked with the manufacturer before they are decommissioned from the serialisation chain. This involves checking to see if the pack belongs to the manufacturer, if they have been incorrectly packaged, damaged, mis-read, or if they are counterfeit.

Once a tamper-evident seal is broken on a pallet, security is compromised and the batch has to be re-manufactured rather than re-packaged. Reconciling the non-reads leads to a whole raft of inefficiencies and problems. In the pharmaceutical industry, manual hand-packing is the norm for almost 80% of all palletisation processes. That creates an enormous risk, as human error is always

a factor in labour-intensive processes, but automating the aggregation process eliminates a huge element of risk.

Speed is critical in a manufacturing environment - time is money as they say. But the flip side is the cost of getting the manufacturing process wrong. Most manufacturing facilities measure their efficiency with an overall equipment effectiveness (OEE) rating. It not only measures the speed of the manufacturing line, but the equipment up-time, the percentage of good units over bad and any maintenance needed.

The prevailing wisdom is that serialisation will adversely impact the OEE for most drug production lines by around 10-20%. That is going to cost millions of pounds in production time for the average drug producer. Any percentage improvement on the OEE rating is a massive gain, with the potential to recoup any investment in automated aggregation lines in a very short space of time.

But some OEE issues are going to be completely new to the manufacturing sector. What happens, for instance, when there is a data loss and the serialisation code does not match the pallet or the batch? The only solution is to conduct a manual check on the pallet contents, considerably impacting on the OEE performance of the manufacturing or distribution facility.

Many pharmaceutical companies are still aggregating items on hand-packing lines or by case-level packing. If there is a problem, the label cannot simply be peeled off and replaced. The speed of labelling is not as critical an issue as it is to be accurate. If, for instance, an error occurs on every third pallet, it will lead to an immediate 30% drop in a manufacturer’s OEE rating.

If manufacturers are labelling at case level, and building a pallet manually, there are major implications for productivity and profitability levels. If just one of the cases is labelled incorrectly, the pallet production is exposed to a whole new set of complexities, potentially compromising the entire shipment.

Good Manufacturing Practice v Good Distribution PracticeThe fact that the GxP status quo needs to change to accommodate serialisation

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Packaging

and aggregation is an indicator of just how disruptive these changes are. But, drawing on the generally accepted definition of disruptive innovation as a force for good, there are potentially positive outcomes. Technology is making convergence a fact of everyday life; managed properly, it can go a long way to overcoming the inefficiencies associated with operating in silos. Looking specifically at the pharmaceutical sector, there are opportunities to transform the traditional hand-off from production to warehousing and warehousing to distribution into a seamless operation with an impeccable audit trail.

Print & Apply LabellingThe same principles apply to equipment capabilities for aggregation as they do for serialisation; printers need to have on-board capability to apply unique information to each aggregated ‘unit’. Establishing hierarchical associations between the unit-of-sale packs in a bundle, bundles in a case, cases on a pallet and so on, enables any party authorised to handle the product on its journey through the supply chain to interrogate precisely which items the batch contains in a single scan.

While speed is not such a significant requirement in code application at aggregation stage, quality and legibility most certainly are; a pallet code is effectively the key to the unique data associated with every single item on the pallet. Just as users have a choice of technologies at item level, so too are there options at secondary and tertiary level. Print & apply labelling machines are a flexible option, suitable for use at bundle, case or pallet level, while

for direct printing onto cases, large-character continuous inkjet systems offer a label-free solution.

Print & apply systems have been around for many years, but their footprint and speed continues to improve. An effective and increasingly popular method of label application in the pharmaceutical sector is the corner wrap, where a label is applied to one edge of a box, and wrapped around to stick to another side of a pack. Corner wraps are highly recommended by the Healthcare Distribution Management Association (HDMA) in the US and the distribution channel generally ends up dictating the look, feel and position of the corner labelling solution.

The smaller the footprint of the print & apply labelling machine, the easier it is to integrate the technology into existing production lines. The control and positioning of the label is critical for an efficient and reliable manufacturing process. Many pharmaceutical manufacturers may be working with two or thee partners to introduce serialisation, so it is vital to understand the mechanics of the equipment they are working with.

As pallets are normally stored in cramped and badly-lit conditions, it is also important that labels are easily legible by hand-held scanners. Corner labels are large enough and accessible enough to be read with comparative ease, providing the aggregation information needed for easy recognition and distribution. Again, any savings in time can be of enormous value to shippers and pharmaceutical companies, so providing the means to read and convey information is as important as correct labelling.

The Business Challenge – or the Business Opportunity?This paper has identified that while serialisation is in itself a challenge that is currently exercising pharmaceutical manufacturers ahead of impending legislative deadlines, it is one that is best dealt with in conjunction with aggregation. Project engineering new equipment into existing lines is the essential first step for the packaging hall. But beyond that, the critical success factor is gaining senior stakeholder engagement to establish a robust serialisation and aggregation infrastructure in the short term.

As stated before, aggregation is not just a challenge for the manufacturing hall, but needs to encompass logistics teams, warehouse managers, IT personnel, marketing teams and pack designers, to create a ‘one world’ vision.

Whilst serialisation has the potential to increase the trust in the brand and manufacturer for medicines of all description, aggregation has the ability to get them to patients in an efficient and orderly manner. There is not much time left for implementation. Although aggregation is not written into the most pressing legislative deadlines, logic dictates that it will become a requirement sooner rather than later. Implementing serialisation without at least planning for a subsequent aggregation deployment could prove to be a very costly and time-consuming strategy.

Successful implementation of automated aggregation lines can offer significant benefits. For those manufacturers who want to gain a leadership position ahead of the deadlines, now is the time to plan to go ‘beyond compliance’ well before it becomes a legal requirement to do so.

Craig Stobie has worked for Domino for over 18 years in technical, operations service and commercial roles. Craig has a broad view of the legislative and commercial pressures

facing the healthcare sectors and is well versed in current and impending global legislation.Email: [email protected]

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Packaging

On its way: New ISO Standard on Interoperability of Anti-counterfeit Systems, Based on Unique Identifiers

Identification systems based on unique identifiers are no longer restricted to individuals' ID cards, car plates or telephone numbers. For many years now, object identification has been established in the world of things, using unique identifiers on sales items and their packaging, as well as other sales and transport units. This is seen as a major step forward in consumer safety, in particular in uncovering counterfeit and illicit trade activities.

Whereas in the pharmaceutical industry early birds long ago introduced unique data matrix codes to their individual packaging, the new hype is fostered by legislation. It is expected that more than 70% of all countries will require prescriptive medicines to carry unique codes within the next years. Many countries have already introduced such legislations. Other industries, for example the semiconductor industry or suppliers of technical parts, also face the challenge, as governments try to ensure the safety of, e.g., cars and aeroplanes. Legislation also aims to get a stronger hold on counterfeiters and fraudsters; to combat illicit trade, tax evasion and the support of illegal and terrorist organisations by what has become a counterfeit industry.ISO 16678 has outlined functional units and principles of systems based on unique identifiers. It has been established that interoperability of such systems is key to future deployment, which is enabled by internet connectivity. This international standard ISO 16678 was finalised and published by June 2014, and is now available to everyone via the national standards institutes such as BSI, DIN and others. I have now proposed to continue and extend this substantial work of the international standards community. Nominated as the project leader, I have suggested a new work item to ISO. The international committee 247 of ISO will bring about more clarity on the landscape of interoperable architectures, to foster vast deployment of object identification systems.

If interoperability rules are not successfully established, companies, as well as customs and other public authorities, will be faced with diverse unique code systems to cope with. The

intention is to avoid such nightmares in our production and logistics environments.

I have been involved in printing variable codes and numbers on tax bands, labels and vignettes, in the labels and security business. I have been instrumental in the development of software for variable data management and camera workflow. Together with a team of experts, we have developed a system that mainly targets brand protection and anti-counterfeiting, but also allows for other uses of the unique codes, e.g. consumer communication and education. In my opinion, automation of processes on an inter-organisational level is one of the core challenges of the digital era, but the problem of interoperability in logistics, security and safety environments is given by the fact that any transaction shared with third parties already creates new information as such. For example, it may be interesting for a company just to know the amount of checks, verifications or trace points of the competitor’s product. Further, ownership of attached information, such as product and batch attributes, is not always clear - the NSA scandal has added to the public awareness about what may be achieved by mass data analysis. Finally, few unique code applications are alive today, as compared to their future deployment. One can say that for ten or more years we have been part of the beginning only, which has been characterised by RFID hype and slow growth of printed codes. Today and finally, variable code printing has matured, and at the same time the

use of smartphone cameras is paving the way for quick deployment of security by unique identifiers and consumer communication.

The new ISO guideline will build on the functional units of identification systems, as outlined in ISO 16678:

• Object examination function• Trusted query processing function• Trusted verification function• Attribute data management system• History function• Response formatting function

Among other things, it will differentiate between input- and output-oriented interoperability. The types of typical transactions may influence the architecture of choice, which may range between loose interoperability and systems integration. For data privacy and the mentioned risks of data leakage, corporations are more prone to maintain ownership of their data and just share

EU legislation poses a challenge to pharmaceutical manufacturers. Flap-label: Securikett®


Packaging

Dr. Marietta Ulrich-Horn holds a PhD in Social and Cultural Anthropology at the University of Vienna, and a Master of Business Administration at the Carlson School of Management in Minnesota

and the Wirtschaftsuniversität Wien. Marietta is co-founder and CEO of Securikett. The company holds own patents in tamper evident and authentication technology and labels, and in 2010 has launched Codikett®, a web based system using unique identifiers. Since 2011 Marietta is Austria’s delegate to the ISO TC 246 and 247 committee, as well as to the CEN TC 261. There she works on standards for authentication, security management and the interoperability of coding systems.

them on demand.

Inbound transactions may include, but are not limited to

• establishment of trace logs per item or group of items, such as are assembled in a packaging hierarchy

• counting the number of verifications per item

• registering users by their authentication credentials or by their IP addresses

Outbound transactions may include

• verification queries • product and general information

requests • download of a confirmation of the

checking procedure• specific information requests by

privileged user groups

The new guideline, to be hosted by the ISO TC247 committee, will strongly focus on security aspects, which is the core topic of the committee. It is recommended that the reader should study the already-published document ISO 16678, as it gives advice on how to raise the robustness of identification systems against misuse and how to raise the level of trust. The guideline aims to leave competition open to current and future solutions in object identification systems. By interoperability, the development of technologies present and to come shall be maintained. It will allow for the evolution of best practice at affordable costs.

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EU legislation poses a challenge to pharmaceutical manufacturers. Flap-label: Securikett®


Packaging

The pharmaceutical industry, as we knew it, appears to be over. The high guaranteed margins in a relatively stable market are no longer assured. During the forthcoming years, cost pressure, streaming in the supply chain and improved speed to market will make for a challenging operating environment for the companies in the pharmaceutical industry. All this is in addition to ensuring that the complex regulatory and legal framework in every country are met.

Besides, it is even more important to take into consideration that the pharmaceutical industry should work hard on the implementation of security of the supply chain. Intentional adulteration by different players, cargo issues and counterfeiting are some of the main relevant risks that turn up when it comes to security. In this case, a lean supply chain becomes even more important, to prevent the accumulation of “waste” within.

To successfully protect against these risks, proactive supply chain security must deliver actionable intelligence to mitigate those risks. Once implemented, this decision-based approach, utilising information delivered in real time, allows for efficient business practices that not only protect a brand but also the many partners and people connected to that brand.

Many regulations coming from different countries have been developed in order to fight against counterfeiting. Thus, most of the pharma big players have been working during the past years to implement projects linked to serialisation, despite the uncertainty regarding concrete rules, data and specific regulations, etc. On the other hand, the dead lines in each region vary notably: Turkey, India, China, Argentina, EU, etc. In fact, this is the reason why companies are delaying the facing of serialisation projects, and moreover, the investment to support them, although they know the serialisation capability will be a compliance requirement and it will be something that will give some of the organisations a competitive advantage. Besides, the consolidation of CMOs as

important players in the industry will be particularly relevant, due to the fact that they will offer serialisation as a crucial service to their clients. These contract manufacturers, especially the medium ones, will be in a disadvantageous position, as they do not have the financial muscle that others have.

Concerning Europe, companies are thinking about the requirements being introduced in Europe. They perhaps expect that the time taken to transpose and apply the rules relating to the launch of the products in the EU market will give them a breathing-space for implementing the required equipment and procedures of serialisation. But the reality is that there are already needs in other regions of the world.

The serialisation programmes should take into consideration several aspects, including:

• Master data: clearly companies will require a new master data structure for the level of aggregation needed. Also, the compliance to different country mandates will modify the procedures to collect the master data.

• Master data exchange: there will be a number of diverse serial numbers coming from each government agency, CMOs/CPOs producing for other companies, wholesalers and distributors, pharmacies and hospitals, etc. The exchange of data will be so huge that processes should be sufficiently clear and well-designed to support it. Moreover, if it comes to security, obviously the protection measures within the supply chain should be mapped carefully.

• Potential investments to serialise: one of the most relevant decisions is which technology the companies should implement in their lines to comply with quality requirements. Also, the amount of investment compared to the volumes that will be produced has emerged as a difficult trade-off. On the other hand, a few packaging providers

have detected a business opportunity in supplying pre-serialised packaging for covering the current demand whilst pharma are making decisions about this topic.

Above all these important but tactical considerations, the strategy to adopt embraces a difficult decision: to be one of the early adopters in the industry, taking the risk of wrong investments and mistakes. Certainly, any company that has managed to act as leader of the sector will have an advantage in selling to those countries that currently have serialisation regulations.

The next deadline for serialisation is 2015 in China, with the well-known 128C code, different from the expected data matrix that is likely to be implemented in Europe. This code is becoming a nightmare for the people responsible for serialisation in companies, due to technical problems related to length and grading. Apart from that, there is a complete process defined by the China Food and Drug Administration, the CFDA, that I will try to summarise in the following lines.

The requirements included in the Chinese regulations are:

• Single box, bundle, shipper case and pallet have to be serialised.

• All information related to the entire supply chain of prescription medicines (Essential Drug List) should be communicated to China DES, the China Drug Electronic Supervision System. The drugs will be registered by electronic monitoring on the Electronic Monitoring Network by the medicine manufacturer, including details from the manufacturer, warehouse, distributors and point of sale.

• Drugs manufacturers can apply directly to get the EDMC (Electronic Drug Monitoring Code) or they can proceed via a local agency.

• The codes requested for each packaging unit – folding carton,

Serialisation: The Great Challenge for the Pharmaceutical Industry – Considerations on China

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Packaging


bundle (if necessary), shipping box and pallet – will be based on a calculation of the quantities to be used in the supply chain within a certain period, including normal waste and loss factors.

• The aggregation of the different package levels has to be marked off.

• Drug distributors shall also manage the Electronic Monitoring Network access formalities.

• Distributors may consolidate the EDMC on the outer package upon stock-in and stock-out of the drugs. Besides, they have to scan the EDMC of the drugs received and verify the EDMC of the drugs to be shipped.

In summary, the process will be as follows:

• The producer fills in the network registration form and submits to China CFDA.

• Pharmaceutical manufacturers get the digital certificate from China to use for master data updates, to obtain the serial number and to upload the reports required.

• Serial numbers will be given by the CFDA to the manufacturer to use in the production.

• The company (directly or indirectly) manufactures applying the serial numbers: unit package, bundle, shipping box and pallet. It is important to keep the aggregation within the hierarchy; moreover, whether the product will be serialised externally in a contract manufacturer, or if the producer gets the packaging already serialised from the supplier.

• A report enclosing the codes used during the production has to be uploaded into the Electronic Monitoring Network before shipping. The aggregation relationship must be kept and included in this report. The FDA will send permission to ship the goods.

The type of code used by the Chinese government is the 1D linear 128C barcode; different from the data matrix used by other countries and probably by the EU. The 1D barcodes contain data in the lines and spacing of parallel lines, while 2D barcodes can have

patterns of squares that hold much more data than linear barcodes in a much smaller space. Most of the countries with serialisation regulatory requirements are recommending the use of the 2D data matrix for these reasons: the small real estate needed on artwork and the large amount of data that can be encoded – 2335 alphanumeric characters and 3116 numeric. Type 128C can only encode digits (00-99) and FNC1, but this is enough for China as there are no alpha characters contained in the 20-digit EDMC. The China code does not require a specific lot number and expiry date, which allows the pre-printing of barcodes offline so that they can be subsequently applied to any product produced at any

time, but nonetheless, the international GB/T 14258 – 2003 (ISO/IEC 15416) will be complied with.

In relation to the EDMC print specifications, the 20-digit 128C code should meet the requirements explained in the chart above.

This code can be applied directly to the folding carton or by a label.

All drugs commercialised in China may fulfil these requirements by the end of December 2015. Linked to this idea, it is important to point out the modifications that the companies should make in the

packaging lines; furthermore, the reason why should be asked if it comes to lines that are used to package more than one format. In particular the equipment to print the codes in the lines will have actually to be adapted because they will need to be very precise to reach printing quality. It will imply additional time for line changes and should be taken into consideration for making adequate decisions.

As explained before, China is currently the great forthcoming challenge for the pharma companies, but we may not forget that the Delegated Acts of the Directive 62/2011 will turn up in the first quarter of 2015. After that, the companies operating in the European

Union will have three years to adapt and implement solutions regarding IT systems, printing packaging and any regulatory changes: all of this under a global and unified corporate strategy to drive and manage the programme execution and guarantee that a coherent approach is taken to meeting the deadlines. As in other areas, if this programme will not have a complete approach, the identification of solutions and synergies would not be possible.

In the end, there are some important aspects to consider:

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• The organisation has to fully understand the serialisation requirements of every impacted market. From the experience up to now, there will not be a common solution in every region. Even inside the region, some differences may arise that can imply some slight but necessary solution approach.

• Analyse exactly if the current technical status and existing systems will need to be changed, and in what economic and structural level. Determine the full scope of your current business operating environment.

• Serialisation programmes are complex and consume a wide

range, and usually a huge amount, of resources. Indirect business benefits should be identified in order to decide if additional functionality implementation is needed.

• A change management risk analysis will be desirable in order to know the impact of such implementation and the consequences for the organisational culture and structure, as well as revenues.

In the end, in these serialisation projects, a 360º approach will be necessary in order to take into account all the players that can support this purpose in every step, as well as those whose

involvement may contribute to a leaner, more effective and more successful implementation.

Packaging

Marga Romo is International Development Manager in Nekicesa and responsible for the expansion in Europe and North of Africa for her company. She has experience in sales and marketing in the

pharmaceutical packaging sector, focusing on innovation areas such as serialization. Email: [email protected]

- - -

- - -

- - -

- - -

-- - -

- -

Data Matrix isa 2D data matrix code

and human readable textseems like the most likely

code to be required in Europefrom 2017 and on

Print quality is a critical factor

Unique,machine-readable code to verify product’s authenticity

China is implementing the code-128 (20 digit 1D Barcode)

High levels of consistency need to be achieved in order to avoid rejection

What will be the coderequired?

By Dec. 2015, all drugs for China will need serialization and reporting.

Databasegenerationand control

of the database

Print ontheproduct

Control of the resultsand Quality

FIRST

SECOND

THIRD

FOURTH

SERIALIZATIONProcess

2009 2011 2015 2017

Nekicesa starts serializing Directive 2011/62/eu Delegated Acts Mandatory

World’s Overview

2010Item Level Serialization

Serialization and Aggregation 2013

Standard and code: GS1 2/ D Barcode

2011 -2013Item Level Serialization

Serialization and Aggregation -

Standard and code: GS1 / 2D Barcode

-Item Level Serialization


Standard and code: Custom / 1D BarcodeItem Level Serialization -


Standard and code: GS1 / Any

(California)

To be determined Mandatory from 2017

CURRENT SITUATION

NEKICESA’S SERIALIZATION SOLUTIONS

Capable of printingover 100 types

of codes

for the generation of databases in txt or xls format.

NOT JUST PRINTING A CODE

Verificationequipment

Nekicesa provides hard- and software for every step of the process

Codificationfor both conventional and UV printing.

Devices Inline check Software Calculation

011000010110010110000101100001100110011000

of the control digit with dif-ferent algorithms (Module 10, Module 15,…).

according to GS1 standards and other non standard codes (more than 100)

of 100% of our production, detecting neither printed cartons nor invalid position of the code.

for 1D and 2D codes, according to ISO/IEC 15415.

✓

of all medicines are counterfeited

15%up to

between 2005-2011

92%rose by

Counterfeiting

10.500Billion

folding carton will be serialised in Europe

2017By

Facts & Figures serialization and brand protection

Legislation compliance

Why should you serialize?

Supply chainSinergies and efficiency

Brand Protection

AnticounterfeitingSupply Chain

Patient Safety

Timeline for compliance in the EU is three years after the forthcoming publication of the Delegated ActsFrom 2017 on, all medicines with destination the EU market, will be required to carry the unique code identifier

Every code printed in the packaging will be backed by a software and all codes should be conciliated.

Updating of lines and installation of serialisation-capable coding equipmentor Chosing the most reliable packaging partner to provide your company with pre-serialized packaging

1st

2nd

3rd

Main concerns on serialization

European Union

Legislation on Serialization

2017The composition,

format and carrier of the unique identifier will be fully harmon-

ised across the EU

2D barcode will contain:

1. Manufacturer code2. Serialisation number3. National reimburse-

ment number 4. Batch number

5. Expiry date

Medicine authenticity will be guaranteed by an end-to-end verifica-tion system

✓The delegated acts shall set out the modalities for the verification of the safety features by the manufacturers, wholesal-ers, pharmacists and per-sons authorised

✓Medicines at higher risk of falsification will be additionally checked at wholesaler level

✓

MEDICINE

Printing quality

Easily Readable

Reliable database management

Packaging lines speed

Investment in new technologies

Nekicesa prints codes using the latestprinting method for serialization

Verification 100% online. Only allowing codes with quality of reading from A to C

We create or manage any database that your company needs with the ultimate software

We serialize the package, so you won’t be affected by a speed reduction on your packaging lines

Instead of introducing serializing technolo-gies in your own lines, Nekicesa will pro-vide you with already serialized packaging

Conciliation

Nekicesa conciliates all the codes used, and those returning errors

1

2

3

4

5

6

What’s your role in serialization as a

Pharma/CMOcompany?

PHARMA COMPANIES AND CMO’S ROLE

MEDICINE

?

Serialization Underpinnings

Factory Distributor Re- Packer Wholesaler Pharmacy Patient

Serialize Pack

Pack Data

2D ScannerData Flow

Material Flow

------ -----------

--

---

---

---

-- -- -- --> > > > >

>

----

>

>> >

>

Trusted Partner in Serialization of the folding carton

Implementing Serialization

in folding cartons

Nekicesa is already serializing, allowing pharma companies to be more

efficient in their packaging lines

yearsexperience

Always innovating to offer the best solutions to our clients, we have been serializing for over 5 years now.

Latest technology in serialization in our lines. Including soft-ware and hardware dedicated to the management of data-

bases, the printing and the verification of codes.

Experienced professionals control every step of the process and carry out the reconciliation of the figures

Client custom made serialization solutions. In any part of the folding carton and leaflet, over 100 types of codes

RPC Formatec_Anzeige IPI_September2014_Pfadtext.indd 1 16.09.2014 10:09:15


News

New Study Supports the Effectiveness of 3-D MammographyA new study supports the effectiveness of 3-D mammography, which researchers found has the potential to significantly increase the rate of identifying cancer in women with dense breasts who are screened using the digital technology. Using digital mammography along with tomosynthesis, which provides a 3-D view, researchers detected 80% of the 132 cancers in women with dense breasts, compared to 59% detection when using mammography alone. The study, which included more than 25,000 women, was presented in Chicago at a meeting of the Radiological Society of North America.

"Tomosynthesis could be regarded as an improvement of mammography and would be much easier than MRI or ultrasound to implement in organised screening programmes," Per Skaane, lead author of the study and an M.D. and Ph.D. from Oslo University Hospital in Norway, said in a statement. "So the intention of our study was to see if tomosynthesis really would significantly increase the cancer detection rate in a population-based mammography screening programme."

In the study, 257 malignancies were detected using full-field digital mammography (FFDM) and a combination of FFDM and tomosynthesis. Of the 257 cancers, 211, or 82%, were detected with FFDM plus tomosynthesis, a significant improvement over the 163, or 63%, detected with FFDM alone. "Our findings are extremely promising, showing an overall relative increase in the cancer detection rate of about 30%," Skaane said. "Stratifying the results on invasive cancers only, the relative increase in cancer detection was about 40%." Not only did the use of tomosynthesis increase the rate of cancer detection in women with dense breasts, it also helped improve detection for women in the "fatty breast" category. The combination of tomosynthesis with FFDM bumped the cancer detection rate up to 84% from 68%.Source: FierceMedicalDevices

Leukaemia Drug Approved by FDA Ahead of ScheduleUS health regulators on Wednesday approved an Amgen Inc drug that helps the immune system fight a rare type of leukaemia, more than five months ahead of the expected decision date. The drug, blinatumomab, which will be sold under the brand name Blincyto, was approved to treat a form of acute lymphoblastic leukaemia (ALL) for which there are few treatment options once a patient has relapsed. The initial approval is for patients whose cancer has returned after treatment or did not respond to previous treatment, such as a stem cell transplant or chemotherapy.

Dr Anthony Stein, professor of haematology at City of Hope outside Los Angeles, who worked on clinical trials of blinatumomab, called the approval "very important" for patients. "It's a very promising therapy and there are new trials trying to move the drug into an earlier stage of treatment," Stein said.

The US Food and Drug Administration had given blinatumomab both its breakthrough designation, used for what it sees as potentially important new medicines, and a priority review, which typically cuts the approval decision time to six months from the normal 10 to 12 months. The action date under the priority review had been May 19, 2015. "Blincyto is being approved under the FDA's accelerated approval programme, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect ... reasonably likely to predict clinical benefit to patients," the agency said.

The programme provides earlier patient access to promising new drugs while the company conducts further clinical trials to confirm the effectiveness of the medicine. In a clinical trial used for the approval decision, 32 per cent of patients achieved complete remission for nearly seven months after receiving the drug via infusion for four weeks.

Source: BioSmartBrief/Reuters

Cardiff University-trialled Leukaemia Drug NHS-approved In December 2014, a u-turn by health watchdogs means leukaemia patients in Wales and England will get NHS access to a new cancer drug trialled in Cardiff. Those with the most common form of the blood cancer – chronic lymphocytic leukaemia (CLL) – will now be able to have access to the drug Gazyvaro.

Cardiff University trials showed it can reduce the risk of death by 59% by preventing cancer cells multiplying. Officials initially rejected the use of the drug. The National Institute for Health and Care Excellence (Nice) has provisionally approved the medicine following further analysis and the cost of the medicine being cut. "NICE's reversal on access to Gazyvaro means that clinicians will have an important new treatment option to help fight this common form of blood cancer," said Prof Chris Fegan, who led the trials at Cardiff University.

"Many patients with CLL often suffer from other medical conditions such as diabetes and heart disease, making them unsuitable for more aggressive treatments. Gazyvaro is a tolerable option that can not only keep these patients in remission for significantly longer, but offers a survival benefit over the current standard,” added Fegan.

Source: BioSmartBrief/BBC

Experimental Multiple Sclerosis Treatment Under DevelopmentServier will team up with GeNeuro to develop and market the experimental multiple sclerosis treatment GNbAC1, the first drug intended to addressing a causal factor of the disease, the companies said.

GNbAC1 is a humanised monoclonal antibody designed to stop progression of both relapsing-remitting and progressive forms of MS without hampering a patient’s immune system. Current MS treatments address forms of relapsing-remitting MS, which affect about 90% of patients at onset of the disease, by targeting the patient’s immune system, with the aim of reducing the frequency of relapses. But such treatments do not always impact overall disease progression, and raise the risk of infections and cancers — downsides that GNbAC1 is designed to combat.

GNbAC1 has successfully completed Phase IIa, showing encouraging signs of efficacy on a first small cohort of patients as well as an optimal safety profile, according to GeNeuro and Servier. GNbAC1 targets MSRV-Env, the envelope protein of MS-associated retrovirus, the expression of which is reactivated and expressed in MS lesions from an early stage in the disease. The protein has been shown to be both pro-inflammatory and an inhibitor of remyelination.

GeNeuro has agreed to oversee development of GNbAC1 until completion of Phase IIb, after which Servier can exercise the option to license the product for all markets excluding the US and Japan.

“With all further development costs in MS funded by our


News

partner, GeNeuro has a clear path forward with a manageable geographic focus on two of the world’s major markets,” GeNeuro Chairman Jesús Martin-Garcia said in a statement.

Source: BioSmartBrief/GEN

Eleven More Countries Adopt Cambridge Structural Database System National ProvisionThe Cambridge Crystallographic Data Centre (CCDC) announced that National Affiliated Centres covering Australia, Croatia, Finland, Hungary, FYR Macedonia, Norway, Russia, Serbia, Slovenia, Spain and Sweden secured countrywide access, granting all of their academic institutions unlimited and open use of the Cambridge Structural Database System. These agreements expand the CCDC’s national access initiatives to 17 countries, adding to those already in place in Brazil, Israel, Taiwan, The Netherlands, Switzerland and South Africa. Through local and web applications, academic researchers and educators enjoy immediate access to the CSD, the definitive resource for experimental organic and metal-organic crystal structure information.

“Providing all academic institutions in these countries with unfettered access to the CSD System aligns directly with both our open access philosophy for academia and our not-for-profit and charity status,” said Colin Groom, the Executive Director of the Cambridge Crystallographic Data Centre. “We will continue to expand this programme around the world to ensure researchers, educators and students benefit from the CSD and the associated software packages for knowledge-based modelling of molecular structure and interactions.”Source: B3Cnewswire

Imaging Companies in Europe Shoulder-to-shoulder with Life ScientistsFor the first time, leading imaging companies Leica, Nikon, Zeiss, FEI, Olympus, SVI and Photometrics jointly founded an open Industry Board linked to the upcoming European research infrastructure for imaging, “Euro-BioImaging”. The mission of the Board is to facilitate interaction between the imaging industry and its academic users, enabling timely understanding of the users’ needs. This has the potential to directly boost innovation in biomedical sciences and strengthen the position of companies which can respond faster to new developments on the market.

As a pan-European research infrastructure, Euro-BioImaging will be composed of imaging facilities, called Nodes, distributed throughout Europe. These facilities will open their doors to all life science researchers, granting access to state-of-the-art imaging instruments and hosting training activities. Christoph Thumser from Leica, the first Chair of the Board, said that “imaging companies are very motivated to establish closer interaction with users and to contribute to training activities, ensuring the best use of instruments,” adding that all other companies from the field of bio-imaging and medical imaging are welcome to join the Board. “Euro-BioImaging Nodes are for us the perfect test sites for novel instruments and technologies – their highly-skilled technical staff can test robustness and technical operation of the instruments while working on a wide range of samples and research applications from visiting Euro-BioImaging users,” Peter Drent from Nikon, Vice-Chair of the Board, added.

Plans for establishment of Euro-BioImaging came from the scientific community in Europe, but are now adopted by governments of 17 European countries and EMBL, all of which

are interested in its implementation and construction. It is expected that the first generation of Nodes is selected next year by countries, soon opening access to researchers. Jan Ellenberg from EMBL, the scientific coordinator of Euro-BioImaging’s preparatory phase, emphasised that “it is very important that researchers and imaging facility staff have a clear communication line to a wide range of companies in the field, because their ability to do research depends on the availability of suitable products, be it lenses, lasers or dyes, or large instruments like the most advanced super resolution or electron microscopes”. “Only if this communication can efficiently function in both directions, researchers will have necessary tools and material to do cutting edge research. The Board is therefore a very important tool for boosting innovation in biomedical research,” Jan Ellenberg said.

With the formation of the official Board, companies have created a platform to officially interact with Euro-BioImaging, its users and technology providers. The Board is now actively inviting other bio- and medical imaging companies to join this open initiative and participate in the imaging revolution in Europe.Source: Olympus

MHRA has Approved Genetic Test for the UKThe UK drugs regulator has approved the £125 personal genome testing kit – which its manufacturers 23andMe claim offers individuals “more than 100 reports offering health, trait and ancestry information” – for sale in the UK from 2nd December 2014.

The MHRA says 23andMe had met the minimum standards it uses for regulating personal genome services – but warned people to check the CE mark of this and other personal genome tests, as ‘no test is 100% reliable’.

California-based 23andMe submitted applications to the FDA in July and September 2012. But in November the following year the FDA effectively banned the company from marketing its gene testing service in the US, because 23andMe had failed to provide evidence to back up its claims. The FDA concluded that 23andMe could not market its test – which it deemed to be a medical device – without regulatory approval. In its letter, the FDA said the company had subsequently failed to address the regulatory issues the FDA raised – including ‘particularly concerning’ questions around genetic testing for the breast cancer BRCA gene. The FDA said 23andMe had “failed to provide adequate information to support a determination that the personalised genome service is substantially equivalent to a legally marketed predicate for any of the uses for which you are marketing it”.

Despite the objections by the US regulator, the UK MHRA has given the test the go-ahead. In the UK commercial testing products – but not the testing services themselves – are subject to medical devices legislation. The MHRA has asked 23andMe to implement an enhanced vigilance system in order to further monitor the safety and performance of the product whilst on the UK market. 23andMe says its test results have an error margin of +/- 4 per cent. Mark Thomas, professor of evolutionary genetics at University College London, said: "For better or worse, direct-to-the-consumer genetic testing companies are here to stay. One could argue the rights and wrongs of such companies existing, but I suspect that ship has sailed.”Source: Pharmafile


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ipi - dec 2014 - volume 6 issue 1

Documents

issue of ipi

global life sciences

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