IPI - International Pharmaceutical Industry

www.ipimedia.com

International Pharmaceutical Indus-‘Supporting the industry through communication’

Encompassing Approaches For Valuation of Early Stage Life Sciences Technology

Centralizing ECGs For Efficient, Accurate, Cardiac Safety assessments in Clinical Trials

Braille labelling on medicines The clock is ticking!

Outsourcing solutions to cGMP In the manufacture of oral

solid dosage forms

Winter 2009 / 2010

Medical image management and EDC.Now working together.Real Value.

Global clinical trial solutions. Real-world results.

BioClinica brings together the power of industry-leading medical

image management with world-class EDC to deliver new value and

a breakthrough in eClinical services. Giving you increased quality

throughout the entire lifecycle of your trial and delivering real results.

Want to learn more about BioClinica?

Visit bioclinica.com/realvalue or call 888-392-7456.

www.ipimedia.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 1

ContentsEDITORS NOTE

REGULATORY & MARKETPLACE

Encompassing Approaches for Valuation of Early Stage Life Sciences TechnologyPharmaceutical companies seeking partnering strategies to bolster pipelines and drive long-term revenues are increasingly looking towards earlier stage compounds and technologies. Valuations are essential components of effective life sciences partnerships, however owing to the perceived uncertainty and risk associated with early stage life sciences technology, early stage valuations are a contentious area of valuation practice. Stephen Mayhew of Kinapse Ltd explores why meaningful early stage valuations require new approaches that integrate complementary evaluation practices to build robust valuation outputs.

Caribbean Region: A Clinical Trial DestinationIn their drive for development speed, pharmaceutical companies have increasingly turned to emerging countries in Eastern and Central Europe, Latin and Central America and Asia to supply greater numbers of patients and diversity. The Caribbean region, however, with a population of approximately 49 million (2009 estimate), also offers tremendous research opportunities in certain therapeutic areas. Garth Henry of Caribbean Clinical Trial Services Inc takes you on a tour of this glamorous region.

Göteborg – World Leader in BiomaterialsGöteborg, on the west coast of Sweden, is the site of numerous breakthroughs in research and development within medicine, and the city is today a leading cluster in biomaterials and cell therapy. Mrs. Sandra Nordström of Göteborg explores the potential of the region.

DRUG DISCOVERY, DEVELOPMENT & DELIVERY

Performing Automated Dynamic Light Scattering Using Plate Reader TechnologyDynamic light scattering (DLS) is a technique commonly used to measure the size of molecules in solution. However, traditional methods of DLS often prove extremely time-consuming and labour-intensive, as well as offering limited reliability and reproducibility. This article by Dr Thomas Jocks & Dr Dierk Roessner of Wyatt Technology Europe discusses the benefits of new plate reader technology, which has been developed to address the growing need for fast, automated and reliable DLS measurements. Advanced plate readers are revealed as the optimal instrument for applications where size, stability and aggregation of molecules are of interest.

8

16

20

22

6EDITOR: Dr. Patricia Lobo [email protected]

DIRECTORS: Martin Wright Mark A. Barker

PUBLISHER:Clive [email protected]

EDITORIAL ASSISTANT:Linda Stewart [email protected]

BOOK MANAGER: Anthony Stewart [email protected]

BUSINESS DEVELOPMENT: Figen Gunes [email protected]

DESIGN DIRECTOR: Stuart Docherty [email protected]

CIRCULATION MANAGER:Dorothy Brooks [email protected]

FINANCE DEPARTMENT: Martin [email protected]

RESEARCH & CIRCULATION: Gramatikov [email protected]

COVER PHOTOS: iStock#: 2409642 Vasiliy Yakobchuk

PRINTED BY: SW TWO UK www.swtwo.com

PUBLISHED BY: Pharma PublicationsBuilding K, Unit 104Tower Bridge Business Complex,100 Clements Road, London, SE16 4DG, UK

Tel: +44 0207 2375685 Fax: +44 0207 3947415Email: [email protected]

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 Spring 2010 and quarterly thereafter. 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.

2010 PHARMA PUBLICATIONS

International Pharmaceutical Indus-‘Supporting the industry through communication’

Winter 2009 / 20102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

ContentsDRUG DISCOVERY, DEVELOPMENT & DELIVERY(cont)

Non-Clinical Development of Pharmaceuticals: Consequences of the Recent Update of the General ICH M3 GuidelineIn December 2009 the updated ICH M3 guideline on non-clinical development and safety testing came into operation [“ICH Topic M3 (R2), Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals”]. Antoine Wellink of NOTOX addresses here the changes compared to the previous version, and the consequences for the design of a preclinical programme to support different phases of clinical development and marketing authorisation.

CLINICAL RESEARCH

Current Status of the Transition from Paper to Electronic Regulatory Submissions in the European Union.After many years of very slow progress, the last two years have seen a dramatic acceleration in the transition to electronic submissions; eCTD submissions are now accepted without paper in the EU centralised procedure, and more than 50% of EU national agencies are now accepting electronic submissions without paper. This article by Martin T. Moxham of iRegulatory Ltd summarises the current situation regarding acceptance of electronic regulatory submissions in the European Union.

Centralising ECGs for Efficient, Accurate Cardiac Safety Assessments in Clinical Trials Research has shown that some drugs have the potential to pose a significantly increased risk of arrhythmias or other serious cardiac conditions. Cardiac safety is therefore the primary reason for drug withdrawals from the market, labelling changes and delay or denial of regulatory approval for marketing. Amy Furlong, Executive Vice President, Cardiac Safety Operations at ERT shows how centralising the process of collection and standardisation of quality ECG data, and employing digital ECG systems and a core laboratory, not only reduces inconsistencies that may occur from site to site, but in addition helps to alleviate laboratory and site workloads.

Phase I: As Relevant as Ever?For many working in the industry, Phase I studies are viewed as representing a stage in the drug development cycle that must be done and is not necessarily considered to “add value” to a drug’s portfolio. More companies are looking to move into patients earlier for answers. This has led to new strategies and terms, Proof of Concept (POC) being one and microdosing another. The attraction of the latter is that companies can move into man quicker with an abbreviated preclinical package, thus claiming to be “in man” with their compound. Brian Sanderson of Chiltern (Early Phase) argues that although these new studies have their place, the more traditional Phase I studies have evolved over the years, with new thinking being applied along with a wealth of expertise available to add value.

LABS & LOGISTICS

Point of Care in Clinical TrialsPoint of care (POC) testing is diagnostic testing performed promptly and conveniently in the vicinity of the patient, avoiding the often lengthy procedure of sending samples to be processed in a central laboratory. Mike Wickham, Dave McComas & Charlotte Wickham of Woodley Equipment investigate how POC offers many benefits and opportunities over the conventional laboratory approach, making it an exciting, ever-developing alternative.

The Next Generation of Clinical Supply Shipment MonitoringManagement of cold chain clinical supplies presents sponsor companies with significant logistical challenges, especially considering the global nature of distribution to many less-developed regions and emerging markets. When investigational products are shipped, supplies are subject to various factors which may influence the way in which temperature-controlled shipping systems may operate. These variables include myriad external temperature ranges, supply routes, transit time, and stability of data and people. Nathan Kohner of Almac Group explains that a process for the efficient visibility of the success of temperature control increases detectability, and therefore reduces the risk factor.

MANUFACTURING

Outsourcing Solutions to cGMP in the Manufacture of Oral Solid Dosage FormsRegulation within the pharmaceuticals industry presents a dichotomy. On the one hand increasing regulatory pressure leads drug companies to investigate means of reducing the time, cost and risk associated with meeting ever-evolving guidelines, while on the other hand there is a perceived risk in outsourcing for fear of failing to properly meet complicated global requirements. Dr. Ingela Herrmann of Next Pharma explains why the outsourcing of OSD manufacturing solves not just a price, flexibility and value proposition, but also overcomes potentially costly GMP and other regulatory considerations.

46

50

56

26

40

32

36

FOCUS • INSIGHT • VISION

Want to see more?quotientbioresearch.com

[email protected]

tel +44 (0)1638 720500

quotient els advert 215x300:Layout 4 7/8/09 12:26 Page 1


ContentsMANUFACTURING, cont

Emulsions - Established and Promising Drug Carriers for Parenteral AdministrationIntravenously administered emulsions are today excellent carriers for lipophilic drugs which are often difficult to deliver (e.g. diazepam, vitamin A, vitamin E, propofol, dexamethasone palmitate, progesterone). In this presentation Anton Gerdenitsch of Fresenius Kabi evaluates the proposition that, when emulsions are carefully designed with respect to the target and route of administration, they may provide one solution to some of the delivery problems posed by new classes of active molecules, such as peptides, proteins, genes, and oligonucleotides. They may also extend the therapeutic potential of established drugs.

Considerations for Choosing a CMOThe development of a new drug is a complex venture that requires many evaluations and decisions prior to a commercial launch. Biotech and smaller pharmaceutical companies are increasingly choosing to outsource most, if not all of their drug manufacturing efforts throughout the development phase, including the clinical trials that lead up to commercial acceptance. Large pharmaceutical companies are also beginning to outsource clinical (developmental) phase products in order to cut down overhead. They see outsourcing as a way to improve asset management as well as gain access to emerging markets. This article by Hyaluron Contract Manufacturing focuses on elements to consider when choosing to outsource drug production.

PACKAGING

The DRUGS Don’t Work.... Or Do They? Why Brand-Switching is Bad for BusinessSwitching patients from one brand of medication to another is common practice among clinicians as they strive for fast and lasting improvements to health. While on the surface this appears to be a necessary measure, ‘brand-hopping’ often obscures the real and widespread issue – that patients aren’t taking medication as prescribed. The phenomenon of ‘non-compliance’ creates a complex lose-lose situation for all parties. Norman Niven, CEO of Protomed explores this in more detail.

Global Standard for Medication Adherence MonitoringThe world spends more every year on pharmaceuticals than the USA has spent in total on the war in Iraq. And whatever we think individually about the war in Iraq, most of us agree that much of the pharmaceutical spend is wasted. Chris Johnson of CYPAK writes on how products conforming to IEEE 11073-10472 and Continua Health Alliance will have a major impact on the way pharmaceuticals are packaged and delivered in future. For the first time patients will be provided with a standard system to manage their medications and record data for objective discussions with their carers. As adherence rates rise, hospital and care home admissions will fall and more chronic patients will use medications properly for the long term. All involved should benefit by adopting the international global standards.

Combating Drug Counterfeiting Using Advanced Packaging TechnologiesCounterfeit drugs are increasingly infiltrating the global pharmaceutical supply chain, threatening the health of patients and incurring a high cost to drug manufacturers. Packaging plays a key role in counterfeiting prevention. As a result, strict legislation is in force to ensure that pharmaceutical packaging cannot be easily reproduced. New technologies have been developed, enabling packaging manufacturers to produce secure packs and comply with regulations. This article by Richard Burhouse of Payne Security discusses the issue of counterfeit drugs, outlines current legislation and discusses the latest secure packaging technologies and their unique benefits.

Braille Labeling on Medicines – the Clock is Ticking!To safeguard the millions of blind and partially sighted patients in Europe, in 2005 the EMEA introduced legislation which requires labeling in Braille on the secondary packaging of virtually all pharmaceutical products; the only exceptions are products which are never handled by a patient. Anne Dallison of Design Cognition Ltd argues that this change will dramatically increase the safety and sense of security of the many Braille users in Europe.

Innovation in Malaria Drug Packaging: Coartem® and Coartem® DispersibleMalaria is highly preventable and treatable, yet it is still a major cause of disease and death worldwide, especially in tropical and sub-tropical regions where it stems from and causes poverty. There are approximately 881,000 malaria-related deaths every year. Drs Nadia elMasry and Chemtai Kipkeu show how Novartis Pharma AG is doing in the fight against malaria.

Blister machine technology in use for better compliance

According to a study from the University of London, after ten days 30 per cent of chronically ill people do not take their prescribed medication properly, and after four weeks every second patient struggles with compliance. To ensure consistent compliance, especially in the case of chronically ill and older people, 7x4 Pharma GmbH commenced a pilot project with the compulsory health insurance AOK Berlin in 2009 to supply patients with individually-packed blisters with their weekly medication. Oliver Naucke of Uhlmann Pac-Systeme GmbH explains the concept of - “7x4 Box - My week´s medicine”.

EXHIBITION PREVIEWS & REVIEWS

GENESIS 2009

ICSE/CPHI/PMEC/BIOPH

NEWS

ADVERTISERS LIST

82

84

90

92

98

101

104

78

62

66

72

76

Analytical Biochemical Laboratory BV (ABL BV) is an independent contract laboratory and a central laboratory serving (multicentre) clinical trials for pharmaceutical and biotechnological companies. ABL is a laboratory that operates world-wide, supporting clinical trials and pre-clinical drug development studies (PK-PD-and safety samples).

ABL is subdivided into two departments

Bio Analytical ServicesFocuses on the analysis of samples derived from pre-clinical and clinical studies.Available techniques include:■ LC-MS/MS■ GC-MS■ GC-FID, NDP and ECD■ HPLC with UV, fluorescence and electrochemical detection■ Immunochemistry (RIA, EIA, FIA)■ Clinical chemistry■ HematologyContact: Mr. E. Oosting MSc, technical director

E-mail: [email protected]

Clinical Trial ServicesOffers support services for the conduct of multi-site clinical trials ranging from sample logistics and source verification to data and project management.Contact: Mr. H.J. Trip, manager CTS

E-mail: [email protected]

By combining these two activities, ABL is able to optimize the overall efficiency, quality and data integrity while saving costs and time. We operate under a set of strict protocols and procedures to ensure transparency whilst not affecting the capability to adapt to the requirements and needs of the individual client.

Analytical Biochemical Laboratory BVW.A. Scholtenstraat 7P.O. Box 232, 9400 AE AssenThe NetherlandsTelephone +31 (0) 592 34 42 11Fax: +31 (0) 592 34 44 25www.abl.nl

Analytical Biochemical Laboratory BV

Clinical Research Organization


Editorial Letter

Browsing through the bumper crop of articles in this issue of IPI, they cover a wide range of topics – including Phase I clinical research, cold chain logistics, outsourcing, manufacturing and packaging, brand-switching, medication adherence monitoring, emulsions as drug carriers for parenteral administration, counterfeiting, regulation and legislation. Does this mark a sea change compared with the pharma scene ten years ago?

One important area has been development of vaccines, both preventive and therapeutic. However, among the vaccines on the market, there are significant gaps, for example to prevent diseases such as Gp A Streptococcus, Dengue, Leishmaniasis or Malaria, which are prevalent in developing countries such as Africa. This may be due to weakness of financial drive for pharma companies to invest in R&D where there is a high risk of no commercial returns or advance market commitment to purchase vaccines, although Government Charities may drive more R&D investment. Thermostability, cold-storage distribution and storage (see article by Nathan Kohner, page 50), vaccines delivery to various areas, technology transfer and regulatory gaps for different countries are some of the challenges faced when assessing vaccines for developing countries, which are also subject to high ambient temperatures and often inadequate cold storage (refrigerators).

GSK and Novartis are two big pharma companies dedicated to continuing research and investment in these disease areas in developing countries. In areas of the world such as Africa, where malaria is particularly rampant, the youngest are the most vulnerable to the disease since they have not built up the same natural immunity as adults. A child dies of malaria every 30 seconds, according to the World Health Organisation. About 300 million malaria cases worldwide each year result in more than one million deaths, most of them African children.

A new vaccine, called FMP2.1/AS02A, has

been developed as part of a longstanding research collaboration between the Walter Reed Army Institute of Research (WRAIR) and GlaxoSmithKline Biologicals (GSK). The vaccine comprises a form of the AMA-1 protein, invented and manufactured by WRAIR, and the AS02 Adjuvant System, developed and manufactured by GSK. The Adjuvant System is a compound that boosts the immune response to the vaccine. Previous studies in the U.S. and in Mali already have found the vaccine to be both safe and to produce strong immune responses in adults.

Since the late 1990s, Novartis has joined the fight against malaria. Working with partners in China, Novartis developed Coartem, the first of a new class of antimalarial medicine dubbed as ‘artemisinin-based combination therapy’, or ACT, a component that has been used for centuries in traditional Chinese medicine to treat fever. A second antimalarial compound with a different mechanism of action acts synergistically, mopping up any parasites that might have survived the initial assault. Combining both components in a single pill, Coartem is the first ACT to offer the convenience of a fixed-dose formulation, enhancing patient compliance. In clinical trials, Coartem achieved cure rates of up to 95%, even in areas of multi-drug resistance.

Since 2006, more than 62 million treatment courses of Coartem were delivered to more than 30 countries across Africa, helping to save an estimated 200,000 lives. In an effort to widen access to Coartem, Novartis forged a partnership, with the World Health Organization to make Coartem available at no profit for use by public health systems in developing countries (see article by Dr Nadia elMasry and Dr Chemtai Kipkeu of Novartis Pharma AG, page 84).

On the 8th February 2010, the first results from a large-scale study of key antimalarial medicines in ten Sub-Saharan African countries (released by the Promoting the Quality of Medicines (PQM) Program, a USAID-funded program implemented by the US Pharmacopeial Convention (USP), for three countries surveyed in the study

-- Madagascar, Senegal and Uganda) -- revealed that a high percentage of medicines circulating on national markets are of substandard quality and thus may contribute to the growth of drug-resistant strains of Plasmodium falciparum, the most virulent form of malaria. Substandard and counterfeit versions of antimalarial medicines are highly problematic throughout Africa, Asia and Latin America because of the direct threat they pose to the lives of individual patients as well as their contribution to the development of drug-resistant strains of these diseases.

Patient safety is a big issue for the pharmaceutical industry and Richard Burhouse of Payne Security (page 78) discusses the latest secure packaging technologies and their unique benefits in preventing counterfeiting and current legislation for secure packaging in the supply chain.

In the outsourcing manufacturing world, NextPharma, a leading contract manufacturing

organisation acquired Intervet’s cold chain logistics division (an MSD-Schering Plough business) in December 2009. When it comes to outsourcing solid dosage forms, Dr. Ingela Herrmann of NextPharma assesses cost-effectiveness and the problems associated with potentially costly GMP and other regulatory considerations (see page 56).

Do read and enjoy the varied selection of articles in this winter issue of IPI. There’s no enough editorial space to discuss all the articles but I’m sure you will be inspired and informed by them. Thank you from the IPI team -- and keep the articles rolling in to share with the IPI community..

Patricia Lobo, MSc, PhD, Managing Director & Senior Consultant for Life Science Business Solutions (LSBS). Email: [email protected]

Advanced Component Technology

Prefillable Syringe SystemsWest’s Daikyo Crystal Zenith® ready-to-use prefillable syringe system is available with an inserted needle or with an easy-to-use luer connection for infusion and injectable administration.

• Silicone-oil-free system

• Consistent breakloose and glideforce

• Reduces adsorption and improves drainability

Advanced ComponentsWest offers documented, validated processes for preparing components that help companies comply with international standards and current regulatory requirements.

• Patented barrier films and coatings

• Westar® ready-to-sterilize and ready-to-use component processing

• Minimize risk of drug/component interaction

When it comes to prefillable syringe solutions, West has the technology you need to mitigate risk and avoid delays.

www.westpharma.com

West Pharmaceutical Services Deutschland GmbH & Co. KGStolberger Str. 21-41

52249 Eschweiler, Germany49-24-03-796-0

Daikyo Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd.Crystal Zenith® technology is licensed from Daikyo Seiko, Ltd.

Westar® is a registered trademark of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.West and the diamond logo is a trademark of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.

Copyright ©2010 West Pharmaceutical Services, Inc.

Proven Prefillable Syringe Solutions

#5371

5371 CZ PFS IPI 303x213mm.indd 1 12/16/2009 8:34:00 AM


REGULATORY & MARKETPLACE

Encompassing Approaches for Valuation of Early Stage Life Sciences Technology

Pharmaceutical companies seeking partnering strategies to bolster pipelines and drive long-term revenues are increasingly looking towards earlier stage compounds and technologies. Valuations are essential components of effective life sciences partnerships, however owing to the perceived uncertainty and risk associated with early stage life sciences technology, early stage valuations are a contentious area of valuation practice. Meaningful early stage valuations require new approaches that integrate complementary evaluation practices to build robust valuation outputs that facilitate productive and mutually beneficial transactions, and form the basis for successful long-term partnerships.

Early stage valuations are an important – yet contentious – area of valuation practice

Life sciences companies are increasingly seeking externally-oriented strategies to augment pipelines, expand portfolios and drive long-term revenues. And with fierce competition in the market for late stage assets, early stage partnering has become an important component of life sciences business strategy, as evidenced by the significant proportion of early stage deals across the industry in recent years (Figure 1).

Valuations are essential components of effective life sciences transactions. However, despite the high proportion of early stage transactions, early stage valuations remain a contentious topic amongst life sciences professionals. A commonly cited reason for this is that the high degree of uncertainty and risk relating to the commercial applicability and useful lifetime of early stage technology (such as preclinical and early clinical phase R&D projects) invariably leads to differing perceptions – and hence lack of agreement – about early stage valuations.

However, research into valuation practices employed across the life sciences industry suggests that much of the contention surrounding early stage valuations arises from neither uncertainty nor risk per se, but from the commonly held view of the practice of valuation as a narrow, highly quantitative process which relies on numerous assumptions to generate value outputs. In many cases it is the inability to reconcile differing perceptions surrounding the assumptions used in valuation approaches that leads to contention over the resulting value outputs.

Meaningful early stage valuations require encompassing approaches that integrate complementary evaluation practices

Much of the contention surrounding early stage valuations can be minimised – and even avoided – by adopting more holistic perspectives in which valuation is considered not just as a narrow process, but as a broader, more encompassing, framework. A central tenet of this approach is the principle that an integrated suite of complementary qualitative and quantitative evaluation practices provides more widely accepted, balanced and transparent valuation outputs that facilitate productive and mutually beneficial transactions.

The value of early stage life sciences technology is often multi-faceted and depends upon the context of use. Value is

defined in terms of an ability to generate cash flows, either directly (which can be thought of as economic value), or indirectly through as yet unrealised opportunities (which can be thought of as potential value). Value may be derived from a unique ability to deliver benefit (termed independent value) as in the case of a novel therapeutic compound, or may exist in the capacity to lever the value of other assets (termed dependent value) as in the case of a novel discovery platform that speeds the identification of potential therapeutic candidates. Any approach to valuation must therefore consider both economic and potential components of value as well the context within which value is to be realised. This is illustrated by the valuation matrix shown in Figure 2, which defines the overall value of a technology in terms of its constituent independent and dependent economic and potential values. In the case of life sciences technology, economic value reflects the net cash flows attributable to the technology (e.g. licensing income, product revenues etc.) in its current state with no further investment other that that which has already been committed. Of the many valuation techniques with applicability to life sciences technology2 discounted cash flow (DCF) techniques that measure the net present value (NPV) of a technology are widely used to determine economic value. In contrast, the potential value of a life sciences technology reflects the range of investment opportunities that exist to generate cash flows from the technology, such as the potential to develop new product lines or expand into new markets. It is generally more challenging to apply DCF approaches to determine potential value because the increased uncertainty associated with realisation of potential value requires numerous assumptions to be made about key valuation parameters for which actual information is as yet unknown. This can result in unwieldy and controversial valuations. Options-based valuation methods are purportedly finding increased use on the basis of their ability to quantify the potential value of unrealised opportunities. However, research undertaken into valuation practices

0

100

200

300

400

500

600

700

800

900

2004 2005 2006 2007

Num

ber o

f dea

ls

Late stage deals (Phase II - licenced products)Early stage deals (discovery - Phase I)

35.1%

64.9%37.3%62.7%

42.8%

57.2%

46.2%

53.8%

No

of D

eals

0

100

200

300

400

500

600

2004 2005 2006 2007

Early stage deals(Discovery - Phase I)

Late stage deals(Phase II - licenced products)

Figure 1: Number of partnership deals by stage.Source: Windhover, Burrill & Company1

Figure 1: Number of partnership deals by stage.Source: Windhover, Burrill & Company(1).

Still counting on beads for

answers?

Biochip Arrays ...a 21st Century

Solution!

abc

Biochip Array Technology is a powerful tool for research, clinical trials and clinical laboratories.

Available test panels include:

Extensive assay development services

Contract test service available

t: f: e: www.randox.com

“revolutionising healthcare through continuously improving diagnostic solutions”

Biochip Array Technology - the way forward in multi-analyte testing

www.randoxpharmaservices.com

Reduce the R&D costs of your drug development

IPI Media - Pharma Ad - Beads - Oct 09.indd 1 2/10/09 15:47:45

Still counting on beads for

answers?

Biochip Arrays ...a 21st Century

Solution!

abc

Biochip Array Technology is a powerful tool for research, clinical trials and clinical laboratories.

Available test panels include:

Extensive assay development services

Contract test service available

t: f: e: www.randox.com

“revolutionising healthcare through continuously improving diagnostic solutions”

Biochip Array Technology - the way forward in multi-analyte testing

www.randoxpharmaservices.com

Reduce the R&D costs of your drug development

IPI Media - Pharma Ad - Beads - Oct 09.indd 1 2/10/09 15:47:45


employed across the life sciences industry suggests that options-based methods are used only to a limited extent, and that the majority of valuations tend to disregard the potential components of value. To realise the full value of early stage technology invariably requires further investment, therefore in order to derive meaningful early stage valuations it is essential that the valuation approach encompasses both economic and potential components of value.

Practicalities of encompassing approaches for valuation of early stage life sciences technology

To address the challenges associated with valuation of early stage life sciences technology, a series of six practical steps has been developed. The methodology encourages the use of encompassing approaches that blend complementary qualitative and quantitative evaluation practices to integrate the dependent and independent economic and potential components of value into meaningful outputs with practical relevance.

1. Identify the economic and potential value drivers

The term value driver refers to any

characteristic that confers benefit and as such represents a source of value. Economic value drivers reflect the net cash flows attributable to a technology as it currently stands. Cash flows are typically relatively straightforward to identify – cash inflows generally arise from subscription/licence income or sale revenues, whereas cash outflows are the costs associated with developing and maintaining a technology. In contrast, potential value drivers reflect the range of investment opportunities from which value could conceivably be realised (e.g. investment aimed at reducing development risk, expanding existing markets, creating new applications etc.), and are typically more difficult to identify.

Based upon analogous principles to the balanced scorecard3, the expansive perspective approach to valuation (Figure 3) retains the conventional financial perspective that recognises economic value, but also systematically incorporates other perspectives of value to build more balanced and widely accepted valuation outputs. The expansive perspective provides a means of rigorously interrogating a technology to gain insights into where the greatest value is located, as well as highlighting areas where

value can be created or strengthened. Because value is subjective, there is no

universal prescription for the perspectives to be incorporated for any given valuation. Notwithstanding this, there are certain organisational perspectives reflecting the interests of key stakeholders that are generally relevant for early stage life sciences valuations and which recognise the independent and dependent economic and potential components of value on the basis of their contributions to finance, innovation, human resources, reputation and marketing. Figure 4 illustrates how the valuation matrix and the expansive perspective can be integrated into an encompassing framework to identify the value drivers of early stage life sciences technology.

2. Evaluate the economic and potential value drivers

The economic components of life sciences technology value can readily be quantified using conventional financial valuation techniques2. Income-based approaches that take a view of the future cash flows attributable to a technology are generally considered to be the most ‘conceptually-correct’ valuation methods, however such approaches often depend on numerous assumptions which can be difficult to model in practice. Therefore, where possible (i.e. where financial information is available for sufficiently comparable technology) it is invariably good practice to augment income-based valuations using market-based comparables / benchmarking approaches. In contrast, potential value is often measured in non-financial terms and therefore in most cases must be monetised – i.e. translated into a corresponding financial value. This typically involves determining the payment cash flows necessary to obtain equivalent benefit to that which could be derived from the technology (as determined using market-based comparables / benchmarking approaches), and subtracting the investment cash flows required to realise the potential value. The monetisation of potential value depends upon subjective perceptions of willingness to pay to obtain equivalent benefit to that derived from the technology. This has clear consequences for the magnitude of the valuation output, which will be highest from the perspective of those that recognise the greatest benefits of the technology and vice versa. This is known as value discrimination and can have practical commercial implications for early stage valuations. For instance valuations are often used to help sellers (licensors) and prospective buyers (licensees) to establish financial terms for transactions such as technology acquisitions or licences.

Extent of realisation of cash flows

In isolation

Unrealised

RealisedIndependent

EconomicValue

IndependentPotential

Value

DependentEconomic

Value

DependentPotential

Value

In conjunction with other assets

Context of useFigure 2: The valuation matrix: The matrix provides a classification of the nature of value based upon a technology’s ability to generate cash flows and the context of its use; independent economic value reflects a technology’s ability to generate cash flows in isolation without further investment, such as in the case of a marketed therapeutic product; independent potential value reflects a technology’s ability to generate cash flows in isolation following subsequent investment, as in the case of a therapeutic compound in clinical development for an as yet unapproved indication; dependent economic value represents a technology’s ability to generate immediate cash flows in concert with other assets, such as a therapeutic compound approved for use in combination with another compound(s); dependent potential value represents a technology’s ability to generate cash flows in association with other assets following further investment, as in the case of a compound which is part of an unapproved combination therapy for a new indication. It should be emphasised that a given technology may simultaneously possess none, one, two, three or all four of the different characteristic components of value.

BiotechnologyCluster Bavaria

Germany's No. 1

Munich: Top Location in Germany

4 approved Biotech-Drugs

120 Biotech, 400 LifeScience companies

BigDeals with Pfizer, Novartis...

world leading production plant(Roche in Penzberg)

more than 30.000 employeesin business and science

Your gateway to excellenceBiotechnology in Bavaria and i.e.in the Greater Munich Area ismanaged and coordinated by BioM.Find out more about the companies,job opportunities, news:

www.bio-m.org

www.biotech-bavaria.de

anzeige_297x210mm_090429:Layout 1 29.04.09 17:09 Seite 1

BiotechnologyCluster Bavaria

Germany's No. 1

Munich: Top Location in Germany

4 approved Biotech-Drugs

120 Biotech, 400 LifeScience companies

BigDeals with Pfizer, Novartis...

world leading production plant(Roche in Penzberg)

more than 30.000 employeesin business and science

Your gateway to excellenceBiotechnology in Bavaria and i.e.in the Greater Munich Area ismanaged and coordinated by BioM.Find out more about the companies,job opportunities, news:

www.bio-m.org

www.biotech-bavaria.de

anzeige_297x210mm_090429:Layout 1 29.04.09 17:09 Seite 1


As a consequence of value discrimination, different prospective buyers (licensees) might be expected to have different perceptions of the value of a given technology based upon the nature of the benefits that they are able to derive from it. By recognising and exploiting value discrimination, sellers (licensors) have an opportunity to realise the greatest value by focusing their marketing activities towards identifying those prospective buyers who are able to derive greatest benefit from the technology.

3. Assess relationships between value drivers

The overall value of a life sciences technology is rarely simply the sum of all the independent and dependent economic and potential components of value, because certain value drivers are likely to be interdependent (and perhaps mutually exclusive). Furthermore, when evaluating potential value it is important to recognise that in practice many available investment opportunities will never be pursued (and hence the potential value of such opportunities will never be realised).

To illustrate this, consider the case of a technology that has the ability to modify

a therapeutic compound to enhance half-life. One value driver may be the technology’s capacity as an exclusive product improvement that expands the commercial scope of a single therapeutic compound, whereas another value driver could be its potential as a platform with applicability to a range of different products. Choosing to develop the technology as a unique product improvement would necessitate restricting its widespread availability (for obvious commercial and competitive reasons), whilst pursuing a platform approach with wide applicability would preclude the opportunity to benefit from the competitive advantages of exclusivity.

Therefore in addition to individual quantification of each value driver, it is important to assess the nature of any relationships between value drivers. Doing so will also allow the contribution of each value driver to the overall value of the technology to be determined under different scenarios.

4. Develop robust practical scenarios under which value is realised

Early stage valuations based upon forecasts of future income are frequently viewed with scepticism, which in many cases arises specifically because of an inability to reconcile differing assumptions used in early stage valuation approaches. An effective means of mitigating this scepticism is to focus on selecting a number of specific practical scenarios under which value could be realised, and developing these scenarios in a ‘bottom up’ fashion using the most relevant and accepted valuation parameters.

Income-based valuation approaches typically utilise numerous valuation parameters to generate forecasts of future income attributable to a technology. For example, consider an early stage compound where a key value driver is therapeutic potential. To forecast the timing of future cash flows, relevant parameters include clinical development timeframes, regulatory submission and review timeframes, commercial timeframes, patent lifetime, etc.; and to forecast the magnitude of future cash flows, relevant parameters include market size/share, pricing strategies, manufacturing and sales costs, etc. Moreover, the likelihood of realising the future cash flows under any given practical scenario will depend upon the technical risks associated with development, therefore the relevant risk parameters include probabilities of success (POS) for each development phase.

Much of the information relating to the relevant valuation parameters is unlikely to

exist for early stage technology, and therefore assumptions must be made as to the most appropriate parameter values. A common practical pitfall of early stage valuations is the use of unsubstantiated approximations for key valuation parameters. The main drawback with this practice is not that it creates uncertainty around the valuation output – uncertainty is almost unavoidable with early stage valuations – but that it compromises the perceived robustness of the valuation approach, which in many cases is the major source of contention regarding early stage valuations. In order to generate robust and meaningful valuations it is critical that the valuation parameters used are both realistic and justifiable, which means that all assumptions should be based upon the most appropriate and highest quality available data. Where direct data is unavailable, assumptions may be derived by benchmarking against relevant comparable technology, markets, companies or industries. Where assumptions are based on external data, the use of recognised data sources such as renowned experts in the field or reputable market intelligence providers is strongly encouraged to provide credibility and encourage acceptance of the valuation parameters used.

5. Use simulation tools to model chosen scenarios

An important feature of any early stage valuation approach is the ability to assess the extent to which changes to any one or more of the valuation parameters and assumptions impact the ultimate valuation output. Simple scenario analysis can be used to determine the effects of variations in individual valuation parameters. For example the impact of a 10% underestimation of market share can be explored by increasing the relevant market share parameter variable by 10% and recalculating the value. However, although such approaches recognise that different outcomes are possible, they are unable to predict the likelihood of any given occurrence. Calculation of more realistic outcomes requires numerous versions of a single model, each incorporating different parameter variables.

Highly sophisticated sensitivity analyses can be performed using simulation techniques such as Monte Carlo, which allow the effects of simultaneous variations in multiple valuation parameters to be explored. Monte Carlo applications allow a potentially unlimited number of scenarios to be developed from many different parameter variables, each of which is accounted for according to the probability of its perceived value.

Financial Value

ReputationValue

Human Resources

Value

Marketing Value

Innovation Value

Figure 3: The expansive perspective approach to valuation: The approach incorporates different perspectives of key groups of stakeholders to build balanced and more widely accepted valuations. Each perspective recognises different value drivers associated with a technology; the innovation perspective recognises value based upon a contribution to the application of new ideas; the HR perspective recognises value based upon the impact on employees; the reputation perspective considers value based upon the perceptions of external stakeholders such as customers, suppliers and society; the marketing perspective views value in terms of commercial activity in markets. The financial perspective recognises value based upon the ability to generate shareholder wealth. In this respect the financial perspective represents any direct economic benefit to the overall value of the business, and importantly, also integrates the components of value from each of the other different perspectives into an overall valuation output.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 13www.ipimedia.com

Stephen Mayhew, is a Manager in the Consulting Practice at Kinapse Ltd. He has over 15 years’ experience in life sciences organisations, focusing extensively on valuation, deal-making and asset and portfolio management. Stephen holds a BSc and a PhD in biochemistry, and an MBA with distinction from Imperial College Business School. Email: [email protected]

IndependantEconomic ValueIndependantPotentialValue

DependantEconomic ValueDependantPotentialValue

Figure 4: The encompassing framework to identify the value drivers of early stage life sciences technology.

6. Use value ranges to represent valuation outputs

Conventional valuation outputs are typically represented as discrete numerical entities. Outputs of this nature tend to infer a high degree of accuracy and precision, and as a result are often interpreted as definitive valuations. This can have practical consequences. For example, valuation outputs are often used to set target valuations for transactions, which parties use as a key basis upon which to build deal structuring, pricing and negotiation strategies. At the outset of a transaction, it is not uncommon for parties to have disparate perceptions of a technology’s value (with target valuations of sellers and licensors invariably being somewhat higher that those of prospective buyers and licensees). Parties tend to place a very high priority on achieving their target valuations and therefore disparate perceptions of value based upon narrow, misguidedly definitive valuations can prove difficult to reconcile. This frequently leads to deadlocked negotiations and can potentially compromise what may otherwise be successful and mutually beneficial transactions.

In certain cases – usually involving later stage technology assets where the benefits are well characterised and widely accepted – it is possible to generate discrete valuation outputs that are considered by both the seller and the buyer to be reasonably accurate and reasonably precise, and in such cases there usually exists broad agreement between the parties as to the technology’s ultimate value. However for earlier stage technology it is rare that all parties will be aligned in this regard. Therefore for early stage valuations, it is usually more helpful to represent valuation outputs as probability-adjusted value ranges – or value profiles – that encompass and reflect a range of valuations under different

practical scenarios. Expansive value profiles tend to be easier for parties to reconcile than narrow discrete outputs, and encourage more realistic expectations of what can be achieved when using early stage valuations to plan transaction and negotiation strategies.

Encompassing approaches towards valuation have implications for life sciences transactions

Encompassing approaches are necessarily more complex than conventional valuation methods that focus purely on financial components of value. In addition to the quantitative data and assumptions used in conventional valuation models, encompassing approaches also involve broad and often qualitative practices that consider different components of value from a range of different perspectives. This requires factoring information from all available sources into the valuation approach. Due diligence activities should therefore seek to identify all available information relating to the technology and to its potential uses, which can then be used to generate a comprehensive and inclusive valuation output. Parties seeking to realise value from transactions involving early stage technology are encouraged to focus on identifying and engaging potential transaction partners with the capacity to exploit the technology to its greatest commercial potential. Encompassing approaches therefore extend the perspective of valuation to more than simply a process for establishing financial terms for transactions, and seek to include and reflect the full scope of shared commitments pertaining to ensuing relationships. This encourages parties to adopt risk-sharing approaches to agreed valuations and long-term success, as opposed to the sole pursuit of near-term target valuations that may compromise longer-term outcomes. Diligence activities should therefore include both the typical

‘internal’ diligence activities relating to the technology and to potential transaction partners, as well as ‘external’ diligence activities involving a thorough market assessment. The latter are surprisingly uncommon, yet rigorous external diligence activities to identify potential partners who are best positioned to exploit the technology and for whom the technology represents strategic, technological and cultural compatibility is key to ultimately realising the full value from transactions involving early stage life sciences technology.

SummaryDevelopments in healthcare technology

and economics are continuing to change the business environment in which the life sciences industry operates. Early stage partnering represents an important component of life sciences business strategy and there is a high level of need for new approaches to valuation that account for the uncertainty and risk associated with early stage life sciences technology. By incorporating an integrated suite of qualitative and quantitative evaluation practices, encompassing valuation approaches repositiotn and expand valuation perspectives to provide more transparent, balanced and widely accepted valuation outputs that facilitate productive and mutually beneficial transactions and form the basis for successful long-term partnerships..

References:1. Lawrence, S. (2008) Partnerships

remain buoyant. Nature Biotechnology, 26(6), 602.

2. Bogdan, B. and Villiger, R. (2008) Valuation in life sciences: a practical guide 2nd Edn. Springer-Verlag, New York.

3. Kaplan, R.S. and Norton, D.P. (1992) The balanced scorecard: measures that drive performance. Harvard Business Review, 70(1), (Jan-Feb), 71-79.


TTP LabTech: Innovative Instrumentation for Life SciencesTTP LabTech is a global developer and manufacturer of automated laboratory equipment for the life science, biotechnology and academic industries. Our mission is to provide practical and innovative solutions and our strength comes from combining cutting edge science with first rate engineering to produce our instrumentation. We offer a portfolio of products that minimise assay volumes,

reduce material handling costs and put the discovery tools back in the hands of the scientist. TTP LabTech is a company with substantial technical breadth;

this has enabled us to be involved in the full life cycle of our products from the initial design concept and prototyping, to mechanical

and software engineering to the final manufacture and sale. These qualities mean that we offer the

best possible technical and mechanical support to all the equipment

that we supply.

Company Profile


In 2000 we first offered the concept of a benchtop screening engine, ‘Assay Developer’, as a working prototype. However, by involving several

new and innovative technologies it required too big a leap for most companies to make; as a result it never became a successful product. Since 2000, TTP LabTech has taken three of the key elements from ‘Assay Developer’ - liquid handling (mosquito®), compound storage (comPOUND®) and fluorescence detection (Acumen eX3®) and marketed these as independent modules. These instruments, which form the basis of our product portfolio, are now well established and have become market leaders. In addition to our current range, we are committed to extending our portfolio and bringing new and innovative products to market that will further facilitate the day to day life of research scientists.

About the companyTTP LabTech’s headquarters are located on Melbourn Science Park, near Cambridge, UK. The science park is owned by our parent company, TTP Group PLC. TTP group is privately owned and has around 300 employees, 75 of which form TTP LabTech. TTP has twice been awarded the Queen’s award for Enterprise, the second of which was for International Trade. This was granted in recognition of the impressive annual export revenue in 2008 and as TTP LabTech contributes a third of TTP Group’s turnover, with a significant proportion coming from overseas, it was somewhat instrumental in the procurement of the award.

The ongoing success of TTP LabTech and its product base has lead to the expansion of this company and the opening of offices in Boston, USA and Shanghai, China, complete with sales and technical support staff. Our products are marketed worldwide and we have dedicated distributors in Australia, Japan, Taiwan, Korea, Singapore and India.

ExpertiseKey to TTP LabTech’s strengths and commercial success is a core of highly qualified staff. Our workforce has proven expertise in most areas of technology including: electrical and mechanical engineering; software; control systems; physical and organic chemistry; biochemistry and cellular biology; materials science; optical engineering; and

Company Profilephysics. In addition to offering a multidisciplinary team, we also have extensive laboratory, pre-production and manufacturing facilities, all of which contribute to our first class range of products.

Business StrategyOur initial business model saw TTP LabTech as a company with two core activities: products and custom solutions - our consultancy arm that took on bespoke automation products. Recently, the company model has been restructured in line with the changing needs of the industries that we supply. We have curtailed our custom solutions offering and we are developing a new business unit offering contract screening services. This service is currently based on our industry standard Acumen screening platform and is being offered to pharmaceutical and biotechnology companies to help support their drug discovery programmes. The rationale behind this venture is that despite the increasing popularity of high-content screening, not all companies can justify the CAPEX investment in an instrument such as Acumen. This new screening service is intended to compliment our existing product business by offering customers an alternative route to accessing high content data.

Contact details: TTP LabTechMelbourn Science ParkMelbournHertfordshire SG8 6EEUKwww.ttplabtech.com


Caribbean Region: A Clinical Trial Destination

in urban areas and in hospitals in larger towns. There are also special clinics for certain diseases. Thus the potential patient population per site can be high. Many of the patients encountered in these centers and hospitals are treatment naïve. Furthermore, the region can provide an ethnically diverse patient population. A unique and strong patient-doctor relationship also leads to higher patient recruitment and retention and fewer dropouts in comparison to the U.S. and Europe.

The majority of investigators have received their specialized training in the U.S., Europe and Canada. They are motivated and eager to participate in clinical trials. Over the last decade Caribbean universities have recognized the importance of clinical trials and have improved their administrative and ethical framework required to attract, regulate and conduct studies. This is strengthened by a strong tradition of research and publication and the central role university research play in determining government health policies. The conduct of clinical trials will provide excellent research experience for the medical institutions and give patients the opportunity to try new treatments.

The regulatory climate is improving. All studies must be approved by Ethics Committees which are a part of regional university structures. In addition, approval is required by the Ministries of Health, which have regulatory oversight for import licences for investigational products. Clinical studies are conducted in compliance with GCP and ICH guidelines. In our experience with a sickle cell study, the time from ethics committee submission to receiving the import license took 8 weeks.

ChallengesInfrastructure and some components

of the healthcare system can provide challenges to conducting clinical trials in the Caribbean. In some medical institutions, internet ports are not widespread in the buildings. Hence it is important to ensure that the appropriate access is in place prior to patient recruitment. The transport of investigational drug and clinical supplies are dependent on the customs agent hired by

Brochures on the Caribbean Region emphasize the glorious beaches with clear turquoise waters, accommodations ranging from intimate guesthouses to seafront villas and naturally hospitable people. Each island has its own unique culture and natural beauty. They invite you to come and visit the magic of the Caribbean for yourself. What is not revealed in these glamorous brochures are the clinical research opportunities available throughout the region.

In their drive for development speed, pharmaceutical companies have increasingly turned to emerging countries in Eastern and Central Europe, Latin and Central America and Asia to supply greater numbers of patients and diversity. The Caribbean region, however, with a population approximately 49 million (2009 estimate), also offers tremendous research opportunities in certain therapeutic areas. Discovered by Columbus in 1492 and commonly known as the West Indies, there are 13 sovereign

states and 14 dependent territories linked to Europe and the United States in the Caribbean. In spite of the challenges due to global economic downturn, this region has remained mostly stable. In many of the Caribbean territories for business and science English is the official language of business and science. As with any emerging region, there is a wide range of regulatory, geopolitical and economic factors. As a result it is important to understand the advantages and challenges prior to selecting a country in the region for a clinical study.

AdvantagesThe governments’ focus on high priority

diseases and the strong interest of physicians in clinical trials facilitate the execution of studies in the Caribbean. Chronic diseases such as diabetes, obesity and cardiovascular disease are on the rise. HIV continues to be one of the major health concerns for the Ministries of Health, and there is significant local research in infectious diseases. Patient management occurs in community clinics


Garth Henry, a native of Trinidad, Garth Henry founded GPH Caribbean Clinical Trial Services Inc. in 2004. He is a graduate of the University of East Anglia, England in Biophysics. Garth started his career as a Research Coordinator at St. Bartholomew’s Hospital, London. His subsequent positions of increasing responsibility in the pharmaceutical industry include Director of Clinical Data Management and Director of Clinical Operations in Oncology. Email:[email protected]

the site. Utmost care must be taken when completing the required documentation to avoid delays. The choice of carriers for the shipment of patient samples from the region is limited. Miami is usually the first port of entry to the U.S.

Reimbursement for comparator medication varies according to the country’s formulary. New drug approvals tend to lag behind North America and Europe, so it is important when performing comparator studies to qualify countries in this regard. A common misconception of the region is that the islands are homogenous. However, there are important political, economic and cultural differences that must be considered. Economic disparities vary among the islands. As in industrialized countries, clinical trial agreements are carefully negotiated by the institutions.

Conclusion:Within 3 years, it is estimated that up

to 65% of FDA-regulated clinical trials for the top pharmaceutical companies will be conducted outside the U.S. The Caribbean Region has a rich history of science and research. Pharmaceutical and Biotech companies who are in search of a competitive advantage in startup time and enrollment should consider the opportunities available throughout the Caribbean Region. The region offers the medical expertise and study centers that can enroll patients in a timely fashion..References:Caribbean Internet Usage (www.internetworldsats.com)Outlook 2009. Tufts Center for the Study of Drug Development

JCS May_09b:JCS May 09 11/05/2009 23:59 Page 73


Mrs. Sandra Nordström, is a communications manager from Sweden. She obtained her Bachelor´s degree from Växjö University in Media, PR and Communications. Her studies included exchange programmes at both American and Australian universities and higher studies in journalism. Her employment history ranges from marketing and PR, to information and communication within the commercial and public industry. She has been employed at GöteborgBIO as Public Relations Officer during 2009.

World Leader in Biomaterials

implants. The procedures are taught to dental professionals at most universities worldwide, and the global dental implant market is valued at over €12 billion annually, and is still growing. This is enabled by the revolutionary research done by Professors Brånemark and Albrektsson and their co-workers over time.

Biomaterial specialisationNew materials, modification of materials

and characterisation of materials are other Göteborg specialties. Professor of polymer technology, Per Flodin of Chalmers, and co-workers developed the slowly biodegradable polyurethanurea, a material later manufactured by Artimplant for orthopaedic and dental applications. Today Artimplant is a public company located in Göteborg offering degradable implants for regeneration of body functions.

Another world-leading researcher is Professor Bengt Kasemo at Chalmers, whose work focuses on nano-scale surface phenomena and properties. Professor Kasemo and co-workers developed a unique method for surface analysis – the QCMD-technology, which is today marketed and sold to the biomaterial community by another Göteborg-based company, Q-Sense. Since 1999, when the first commercial system for measurements in liquid was launched, Q-Sense has become the leading supplier of acoustic resonator based instruments for analysis of various surfaces.

Professors Paul Gatenholm of Chalmers and Bo Risberg of the University of Gothenburg are also two very prominent scientists in the Göteborg biomaterial arena. Prof Gatenholm focuses on biopolymer technology while Prof Risberg allocates his time to Tissue Engineered Blood Vessels (TEBV). A company that originates from this research is Arterion. Arterion commercialises artificial blood vessels consisting of microbially-derived cellulose for revascularisation of patients with cardiovascular disease.

Stem cell technology is also a thriving research area in the Göteborg region, and

Göteborg, on the west coast of Sweden, is the site of numerous breakthroughs in research and development within medicine, and the city is today a leading cluster in biomaterials and cell therapy.

The city of Göteborg has an excellent record of achievements within the biomedical field. One key to Göteborg´s strength is its combination of high-calibre academic research capabilities and a well-established industrial base. Among its pioneers are Professor Arvid Carlsson, awarded the Nobel Prize in 2000 for his research in dopamine, Professor Per-Ingvar Brånemark, who introduced osseointegration as a method for attaching prostheses directly into bone, and Professor Jan Lindhe, who through his research of the biological mechanisms within the mouth has created both understanding of and treatments for diseases leading to tooth decay.

Strong research traditionBiomaterials research at the University

of Gothenburg and at Chalmers University of Technology has resulted in well over 150 PhD dissertations over the years. Two of these are by the noted Professors Tomas Albrektsson and Peter Thomsen. Prof Albrektsson was instrumental in the development of the first bone-anchored dental implant system and the first bone-anchored hearing aid implant system. Prof Thomsen focuses on the interface between material surfaces and cells using modern methods in cell and molecular biology.

Dental implants are today an accepted treatment for patients with missing teeth all over the world, and more than eight million people have so far received dental

one-third of the world’s stem cell lines are from Sweden, the majority of these being from Göteborg. The Göteborg-based company Cellartis has developed over 30 well-documented stem cell lines and is today one of the world’s largest stem cell providers.

Göteborg is also strong in clinical trials, thanks to its clinical research capabilities, outstanding international networks and university-affiliated CROs, such as A+Science.

Strong life science industryThere are some 170 companies and over

8000 employees in life science companies within the Göteborg Region. One of the largest employers is AstraZeneca, which has a large research site and global headquarters for cardiovascular and gastrointestinal research in the adjoining town of Mölndal. The biomaterial/cell therapy cluster includes leading companies in dental implants – Nobel Biocare and Astra Tech; human embryonic stem cells – Cellartis; polymers for implantable prostheses – Anatomica, Artimplant, Astra Tech, Cochlear and Integrum; and wound care and incontinence applications – Mölnlycke Health Care Group, Astra Tech, SCA, and Biopolymer products, to mention a few..

www.goteborgbio.se

World Leader in Biomaterials

The Göteborg region has a strong research tradition

with well above 150 PhD dissertations in biomaterials.

Göteborg is home to world leading scientists such as

Professors Albrektsson, Brånemark, Flodin, Kasemo

and Thomsen, to mention a few.

The Göteborg region has also a very strong life

science industry within areas such as dental

implants, bone anchored hearing aids, polymers

for implantable prosthesis and wound care

and incontinence applications.


PERFORMING AUTOMATED DYNAMIC LIGHT SCATTERING USING PLATE READER TECHNOLOGY

scattered. If the molecule was stationary then the amount of light scattered would be a constant. However, since all molecules in solution diffuse with Brownian motion in relation to the detector there will be interference (constructive or destructive) which causes a change in light intensity (see Figure 1). By measuring the time scale of light intensity fluctuations, DLS can provide information regarding the average size, size distribution, and polydispersity of molecules and particles in solution.

The faster the particles diffuse, the faster the intensity will change. The speed of these changes is thus directly related to the motion of the molecule.

The diffusion of the molecules is essentially controlled by the following factors;

Temperature – the higher the temperature the faster the molecules will move

Viscosity of the Solvent – the more viscous the solvent the slower the molecules move

The size of the molecules – the bigger the molecules, the slower they move

If the temperature and solvent are constant and known, the variation in the intensity of the scattered light is directly related to the “size” of the molecule. This number is referred to as the hydrodynamic radius, Rh.

The random pattern of light intensity changes into an Rh measurement by comparing the changes as a function of time. Thus two plots of the same data are essentially overlayed but with a small time

Dynamic light scattering is a technique commonly used to measure the size of molecules in solution. However, traditional methods of DLS often prove extremely time consuming and labor-intensive, as well as offering limited reliability and reproducibility. This article discusses the benefits of new plate reader technology, which has been developed to address the growing need for fast, automated and reliable DLS measurements. Advanced plate readers are revealed as the optimal instrument for applications where size, stability and aggregation of molecules are of interest.

Since the late 1980s commercial dynamic light scattering (DLS) detectors have been increasingly used in biophysical characterization laboratories. Early versions were designed to enable size measurements of proteins and other biomaterials in solution, with small sample volumes and in relatively low concentration ranges. The ability to perform such measurements in a comparatively straightforward way and with recovery of the sample soon established DLS as the method of choice for a wide range of applications such as stability, aggregation, complex formation and conformation studies in bio-molecular research. The technique was also extensively used in protein studies for screening proteins in order to predict if they were likely to crystallize.

Nevertheless, traditional DLS technology was associated with a number of shortcomings; limited reliability and reproducibility, cross contamination and

inefficient software. For more than 30 years, conventional DLS measurements were performed in the same mind-numbing and labor-intensive way, requiring analysts to stand or sit next to an instrument for hours, manually measuring one sample after another in a single cuvette. In addition, multiple measurements on the same sample were required to ensure the validity of statistics while the need to fill and eventually clean the cuvette made the method particularly labor-intensive.

A rapid screening method was required, featuring improved optics, lasers and software. The emergence of microarray technology for drug research and discovery presented even greater pressure. Plate reader technology was developed to address the growing need for rapid, automated and reliable DLS measurements. The idea to utilize disposable standard 96, 384 and 1536 well plates had been previously applied to other detection methods, such as UV and fluorescence assays, but never in a DLS instrument. The new automated plate reader DLS method can be compared with HPLC systems equipped with autosamplers whereas the cuvette-based technology is comparable to manual sample injection approaches.

TheoryDLS is also known as Quasi-Elastic

Light Scattering (QELS) or Photo Correlation Spectrocopy (PCS). It works by measuring the intensity of light scattered by the molecules in the sample as a function of time. When light is scattered by a molecule or particle some of the incident light is

DRUG DISCOVERY, DEVELOPMENT & DELIVERY

Figure 1: Constructive and destructive interference Figure 2:



repeat measurements scientific reasonable and economic reasonable. The samples can be easily recovered or the plate can be used for further screening. The industry standard microwell plates are disposable and so do not require cleaning of the optical cell. At the same time, it has the same sensitivity and the flexibility to act as a conventional DLS system – the user simply decides which mode the measurements should be performed in.

Moreover, sample analysis using the advanced plate readers allow the use of different amounts of sample: besides the standard volume of 50, 20, or 5µL, as few as 1.5 µL (oil coated) can be analyzed. The volume required per well depends upon the plate. For a 96 well plate standard format a minimum volume of 100 µL sample solution is used. For measurements using a 384 low volume plate design a minimum volume of 15 µL per well is used. Using 1536 well plates measurements with volume as low as 1.5 µL are done.

Batch DLS is a complementary biophysical tool to techniques such as SEC, AUC and FFF. Compared to separation methods, DLS measurements with the plate reader can be done in seconds to minutes: a 96 well plate can be easily screened in an hour or less, whereas the same number of samples in SEC would require more than two days worth of measurements. Another unique advantage of the instrument is that it is a non perturbing technique without interactions with any separation matrix or dilution. Thus, the aggregation state of a molecule can be detected accurately, which is imperative when looking at reversible aggregation. Additionally, the sample is easily recoverable or the microwell plate can be directly used for further analysis.

The plate reader is suitable for any application where molecular size, stability and aggregation are of interest. Applications include: characterizing proteins for size, homogeneity, aggregates and thermal stability over a wide range of formulation conditions; measuring the stability and size of liposomes, viral particles and drug delivery particles; determining aggregation constants and kinetics; optimizing protein crystallization conditions; monitoring folding of proteins and nucleic acids; and detecting and analyzing compound aggregates.

Detection of Aggregate FormationProtein drugs – especially antibody

preparations – are widely used as therapeutic agents. Many of them are physicochemically

delay between them. The correlation between the first and second plot is then noted. This correlation is then calculated for ever increasing time periods until no correlation is present (ie the changes in intensity are random in respect to each other). The faster the molecules are moving, the quicker the correlation becomes zero.

Once the correlation function has been plotted (normally on a log scale time base) this is converted into a size measurement by drawing in all the other factors that affect the signal such as the temperature, solvent viscosity, laser wavelength as well as the Rh. This process becomes more complex when multiple sized materials are present. This results in a correlation function that is a mix of the functions from each species present but strongly biased towards the bigger species (the larger the molecule the greater the scatter). It is possible to derive the individual correlation functions but there are an almost infinite number of ways of arriving at the final function unless some assumptions are made for the distribution of material. The mathematical impasse is overcome by assuming that either the distribution is monomodal (i.e. only one species is present) or that if more than one species is present the distribution of each of these obeys certain limits. Good DLS software will allow both of these results to be displayed. The theoretical limit of this technique is that species of less than 40% difference in size cannot be resolved. However, in practice a factor of two to three times can be required. If full resolution is necessary the sample must be physically separated by centrifugation, filtration, HPLC or Field Flow Fractionation techniques.

Hydrodynamic Radius RhThe hydrodynamic radius is the sphere

defined by the molecule rotating in all directions plus the hydration layer, modified by how easy it is to pass the solvent through that volume. It is a measure of how easy it is to move the molecule through the solvent.

Next Generation Plate Readers for Automated DLS

Next generation plate readers (for example the DynaPro Plate Reader, Wyatt Technology) screen samples directly in microwell plates. All standard plates for optical plate readers (like UV) can be used. The plate readers work with 96, 384, and 1536 well plates with normal or low volume design. There is no sample transfer needed which makes it a non-invasive, non-perturbing experiment. Cross-contamination due to using the same cuvette for multiple samples or transferring samples is eliminated. Sample measurements can be completely automated which makes measurements of several aliquots of the same sample, formulation buffers and

Figure 3: Determination of the Hydrodynamic Radius of a fluctuating particle in solution

Figure 4: Rh and related radii


Dr. Thomas Jocks, joined Wyatt Technology Europe in October 2007. He studied Biology at the University of Mainz. In his Ph. D. work at the University Hospital Eppendorf, Hamburg, he investigated the chemokine gene expression in inflammatory kidney disease. At Wyatt his main responsibility is in the field of scientific marketing. This includes activities like trade show presentations, authoring publications – frequently in cooperation with Wyatt users, analysis of current scientific literature or maintenance of WTE’s comprehensive literature database, only to name a few. Email: [email protected]

Dr. Dierk Roessner, Head of Analytical Services and Applications Scientist at Wyatt Technology Europe, earned his doctorate at the Institute for Technical and Macromolecular Chemistry at the University of Hamburg, Germany. He has been with Wyatt Technology for over ten years, where his focus has been the scientific support of potential and current users of Light Scattering (MALS and DLS) and Field-Flow Fractionation (Eclipse™) instrumentation. His academic and professional experience has allowed him to obtain an extensive understanding of various possible MALS, DLS as well as Field Flow Fractionation (FFF) applications for Protein, Biopolymer and Polymer applications.Email: [email protected]

controlled, if desired.

The applications of the technique are wide ranging and include many of the fastest growing areas of research – proteins, biomaterials, liposomes and micelles as well as the established uses for particle sizing and aggregation detection. Conscious of the numerous characterization challenges in the area of drug delivery systems and therapeutic antibodies as well as protein crystallization or particle analysis, the fields of application of automated DLS are countless..

unstable and prone to dimerization and aggregate formation. This raises new challenges for quality control and analysis. The following example shows a comparison of proteins derived from different sources (A and B) focusing on the detection of aggregates. Whereas protein from Source B does not have any aggregates in the nanometer size range, source A reveals a noticeable fraction of aggregates.

The following measurements principally demonstrate the problem of aggregate formation. Bovine serum albumin (BSA) is subjected to heat (60°C for up to 3 hours). It appears that this treatment exerts a time-dependent impact on the protein, which results in aggregate formation. This is indicated by an increase in average particle size (a) and accordingly in scattered light intensity (b). To demonstrate the convenience of automated DLS it should be

mentioned that the total measurement time of the 108 samples presented here was only 50 minutes.

SummaryDLS analysis is a widely applied,

non-invasive method for measuring the effective size of molecules in solution. This technique yields valuable information for the characterization of molecules and particles. It facilitates formerly laborious and time consuming measurements, e.g. screening for aggregates or determining optimal crystallization conditions for proteins.

Advanced plate readers are the instruments of choice for any application where molecular size, stability and aggregation are of interest. They read industry standard microplates with up to 1536 samples automatically and temperature-

Figure 5: Protein measurement using the DynaPro Plate Reader: Comparison of sources A and B in pH 5 buffer. Note the perfect well-to-well reproducibility of the measurements.

Figure 6: Treatment of BSA with high temperature leads to increasing aggregate formation.


NON-CLINICAL DEVELOPMENT OF PHARMACEUTICALS: CONSEQUENCES OF THE RECENT UPDATE OF THE GENERAL ICH M3 GUIDELINE

study to support an indicated treatment of one to three months is elevated from three to six months.

ADMEIn-vitro metabolism studies and protein

binding should now be performed prior to the first human clinical trial. Although this was not a prerequisite in the past, NOTOX always raised the option of performing these studies early in development in our discussions with clients on this preclinical programme design. We favour this approach because it can provide valuable information that is very useful in early drug development. The information is useful to help estimate the predictability of animal data. Furthermore, it may help in species selection for general toxicity studies and dose selection for clinical safety studies. As such this change in the guidance is quite useful.

Exploratory Clinical TrialsA new chapter in the guideline describes

a complete set of predesigned preclinical packages for different kinds of exploratory clinical trials. They are categorised as micro-dose trials, single-dose trial at (sub)-therapeutic dose and multiple-dose trials. Adapted toxicity studies and abbreviated preclinical programmes make it possible to shorten the time to clinical trial and can even reduce overall animal use in drug development. These exploratory clinical trials are used for an early investigation of PK profile, tissue distibition (PET study) pharmacodynamics (e.g. target receptor binding) or biomarkers in humans. Five different preclinical programmes are described supporting five different approaches for exploratory studies in human

In December 2009 the updated ICH M3 guideline on non-clinical development and safety testing came into operation [“ICH Topic M3 (R2), Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals”]. I will address here the changes compared to the previous version and consequences for the design of a preclinical programme to support different phases of clinical development and marketing authorisation. For some parts of the development programme no major changes were made, such as for safety pharmacology, genotoxicity, carcinogenicity, immunotoxicity and local tolerance. The most obvious changes and additions are a complete set of predesigned preclinical packages for different kinds of exploratory clinical trial, the extended guidance to the support of paediatric clinical trials, the non-clinical assessment of abuse liability, and guidance for the development of combination drugs.

Scope of the GuidelineBasically, the scope didn’t change: the

guidance applies to New Chemical Entities. Prior to and since the previous version, specific guidelines were developed for non-clinical safety of specific compounds and indications: biotechnology derived pharmaceuticals (ICH S6 guideline); advanced therapeutic products (e.g. gene therapy); anti-cancer products (ICH S9); paediatric indications. For these products and indications, ICH M3 only provides guidance to the timing of the necessary studies and in some cases guidance to the duration of repeated dose toxicity studies.

As it is an ICH guideline, non-clinical

development according to this guideline will support clinical trials and registration in the 3 main regions, US, EU and Japan.

General Toxicity StudiesThe guideline is extended with a helpful

recommendation and scheme for dose selection for the general toxicity studies. High-dose selection applying maximum tolerated dose (MTD), exposure multiples and maximum feasible dose are discussed with the aim to “prevent the use of doses in animals that would not add value to predicting clinical safety”.

In general, single-dose (acute) toxicity studies can be replaced by dose-escalation / range-finding studies preceding the RDT studies. These studies do not necessarily need to be performed in compliance with Good Laboratory Practice (GLP).

The duration and timing for Repeated Dose Toxicity (RDT) to support the conduct of clinical trials is slightly adapted compared to the recommendations in the previous version. The included scheme in the guideline with recommended duration of RDT studies now indicates in most cases an RDT with the same duration as the anticipated clinical trial it supports, up to six months. For clinical trials >six months, in general a six-month rodent study and six-month (EU) or nine-month (US, Japan) non-rodent study is sufficient. And in some cases a six-month non-rodent study is also appropriate for Japan and the US.

For the duration of RDT studies to support marketing authorisation, there is one change: the duration of an RDT non-rodent

‣ ‣ ‣ ‣


Antoine Wellink, graduated in Chemical Engineering at the University of Groningen. He has been consultant and senior project manager for several preclinical development programs.Since 2002 Antoine has followed several international courses and workshops on Drug Development and Regulatory Affairs, in special those on the non-clinical testing of biotech products. Antoine Wellink joined NOTOX as Head of Regulatory Affairs in 2007. In this position he is responsible for 3 regulatory affairs sections: Pharmaceuticals; Agrochemicals & Biocides; Industrial Chemicals. Within the pharmaceuticals section he acts as external and internal consultant in designing and managing pre-clinical research projects for the global, innovative (bio-) pharmaceutical industry.Email: [email protected]

of fixed combinations of medicinal products” in 2008, this topic is now covered in the ICH M3 document for the three main regions.

Three types of combinations are distinguished:

1.Two or more late stage entities. Defined as compounds with significant clinical experience (i.e. from Phase III studies and/ or post-marketing). Non-clinical combination studies are only recommended to support large-scale or long-term combination trials as well as for marketing.

2.One or more late stage entities and one or more early stage entities (defined as compounds with limited clinical experience, i.e. Phase II studies or less). Non-clinical combination studies are only recommended to support large-scale or long-term combination trials as well as for marketing. The clinical study of the combination should not be longer than the clinical experience of each individual compound.

3.More than one early entity. In case a full preclinical programme has been performed with the individual components, an additional non-clinical combination study is recommended to support combination clinical trials. A 90-day combination toxicity study in one species generally covers for a marketing authorisation application..

volunteers. NOTOX has prepared standard study designs for these non-clinical studies and we offer the abbreviated programmes for all described exploratory trials.

Reproduction ToxicologyIn general, the need for reproduction

toxicity studies prior to clinical studies depends on the population to be exposed. These studies are described in the specific guideline for reproduction toxicity, ICH S5(R2).The inclusion of Women of Childbearing Potential (WOCBP) is the most critical consideration on this topic. In the former guideline, the requirements differed for each of the three regions, though they are more comparable for the EU, US and Japan in the updated version. In certain circumstances, WOCBP can now be included in early clinical trials without non-clinical developmental studies, which applies to all regions. In most cases, fertility and embryo-foetal development should be assessed before large-scale or long-duration clinical trials (Phase III) and pre-postnatal development before marketing approval.

Juvenile Toxicity Studies / Paediatric

IndicationsSince the implementation of the Paediatric

Regulation on 1st June 2007 in the EU, for all new medicines a “paediatric investigation plan” (PIP) has to be approved by the EMEA’s Paediatric Committee. The incentive in return is a half-year additional market exclusivity. For orphan drugs, the incentive is even a two year additional exclusivity above the ten years of regular market exclusivity in the EU. Besides the release of a new EMEA guidance for non-clinical development to support clinical trials in paediatric populations, this topic of growing interest and concern is also addressed extensively in this updated version of the general ICH M3 guideline.

Toxicology studies in juvenile animals to support the development of pharmaceuticals for paediatric patients are aimed at obtaining information on potential safety concerns that cannot be adequately addressed in human adults or in regular preclinical studies. These cases focus especially on effects on growth and development, and on immature systems such as the nervous system, the pulmonary system, the skeleton, kidneys, reproductive system and immune system. Additional differences in safety profile between paediatrics and adults can also be caused by metabolic, pharmacokinetic and pharmaco-dynamic differences.

The necessity and design of these studies will highly depend on the information

on safety which might be available from experience in adults, and depends on results from clinical trials and general non-clinical studies. This information is generally available in cases where the pharmaceutical was originally developed for adults, and treatment is planned to be extended to treatment of paediatric patients. When this information indicates a cause for concern in paediatrics or when the safety profile in paediatrics cannot be predicted well enough with this information, toxicity studies in juvenile animals are warranted.NOTOX has adopted the development of pharmaceuticals for paediatric indications and offers these juvenile studies in rodents and non-rodents. The design of our studies is tailor-made and will depend on specific target population (age, gender), indication, duration of treatment, route of administration and concern for specific target organs. Our non-clinical programmes will be in line with the EMEA “guideline on the need for non-clinical testing in juvenile animals of pharmaceuticals for paediatric indications” and in line with the recently updated (R2) ICH M3 guideline. In general, when development for paediatric patients is an extension to use in adults and if additional testing is warranted, results from a juvenile toxicity study in one appropriate species is sufficient to support a paediatric clinical trial. In case paediatric patients are the primary patient population, a more extensive preclinical programme will be necessary.

Abuse LiabilityNon-clinical abuse liability is a new chapter

in the updated ICH M3 guideline. Until now, the topic was covered by regional guidelines, like the EMEA “Guideline on the non-clinical investigation of the dependence potential of medicinal products”. The necessity of non-clinical testing of abuse liability should be evaluated for all drugs that produce central nervous system activity, regardless of the therapeutic indication. Identification of early indicators of abuse potential can be obtained by PK/PD profiling and receptor binding, structure similarity with known drugs of abuse, in vivo pharmacology studies investigating CNS activity, and clinical signs in preclinical studies. When the results of these studies give rise for concern or in case the compound has a novel mechanism of action on the central nervous system, specific non-clinical studies are recommended to support large clinical studies (Phase III).

Combination Drug Toxicity TestingIn addition to the release of EMEA’s

“Guideline on the non-clinical development

Amsterdam’s universities and research institutes are the

foundation of the city’s growing life sciences and drug

development community. They perform cutting-edge

research and train a highly educated workforce.

In addition, Amsterdam’s research centers provide the

pharma and biotech industry with an endless range of

opportunities for partnerships.

The Life Sciences Center Amsterdam streamlines access

to novel therapeutic approaches, diagnostics and expert

centers. The Center is the technology transfer hub to

innovative products, technologies, bio banks, data bases,

patient cohorts and mouse models from the Academic

Medical Center Amsterdam (AMC), the University of

Amsterdam, VU University & VU University medical

center, Sanquin and the Netherlands Cancer

Institute-Antoni van Leeuwenhoek Hospital (NKI-AvL).

Scientific excellence exists in oncology, neurosciences,

autoimmunity, infectious diseases and cardiovascular

diseases.

www.amsterdambiomed.nl/lsca

Both a knowledge and a business center, Amsterdam

has a strong international orientation and is well

connected to markets and customers worldwide.

More than 70 dedicated Life Sciences companies

have already chosen to set up office in the Amsterdam

Metropolitan Area, including multiple university spin

offs. Financial, business and supply services abound,

the area holds all the ingredients for your life sciences

business to be successful.

The Amsterdam BioMed Cluster is the unifying force in

the region’s life sciences. The Cluster stimulates

entrepreneurship by exploiting synergy between

knowledge institutions, businesses and government,

and opens up the regional knowledge- and technology

base to national and international partners interested in

doing business with us. Whether it concerns lab space,

partner search requests, company profiles, or specialized

knowledge we are there to point you in the right

direction.

www.amsterdambiomed.nl

Find your life sciences partner in theAmsterdam BioMed Cluster

At the heart of European life sciences, Amsterdam offers a longstanding tradition of biomedical research... and more

advertbiopmed09 21-09-2009 14:03 Pagina 1


Hyglos GmbH - New solutions for diagnostics and therapy of human pathogenic bacteria and toxins

Hyglos GmbH is certified according to EN ISO 9001:2008 as well as EN ISO 13485:2003 + AC:2007.

For further information please contact Hyglos at +49 (0)941 - 942 62 0 or by email: [email protected]

Hyglos GmbH Josef-Engert-Str. 11 93053 Regensburg Germany

Hyglos GmbH is a Bavarian biotech company located in the Biopark Regensburg, one of the most important biotechnology centres in Germany. The owners of the company are investors coming from science and industry (Hyglos Invest GmbH and Institut Mérieux).

Hyglos’ core competency is to exploit the principles of bacteriophage biology and the expert use of the proprietary phage-protein technology for pharmaceutical, diagnostic and research applications. This technology enables the production of state-of-the-art molecules for the effective binding and lysis of bacteria and bacterial components. Such molecules are perfectly suitable for the use in the fields of human and food diagnostics as well as the selective decolonisation of pathogenic bacteria e.g. Staphylococcus aureus.

Hyglos’ products and services are supplied worldwide to well known pharmaceutical and biotech companies, research institutes and universities. Furthermore, Hyglos collaborates with companies such as bioMérieux SA, a world leader in the field of in-vitro diagnostics. Already in 2008, bioMérieux launched VIDAS® UP for the detection of E. coli O157:H7, the first assay in a new ground-breaking generation based on Hyglos’ phage-protein technology.

Company Profile

Hyglos offers the following products and services:

Products:EndoTrap® (highly efficient endotoxin removal)•EndoGrade® (endotoxin-free proteins and •reagents)Components for food testing assays •Bacteria Capture Kits (sample preparation in •food diagnostics)

Customized Services:Endotoxin Detection Service •Endotoxin Removal Service (with EndoTrap® •technology) From Gene to Protein Service (from gene •synthesis to protein purification/modification)

Hyglos_Anzeige 210x297_DRUCK.indd 1 18.09.2009 11:30:52 Uhr


Current status of the transition from paper to electronic regulatory submissions in the European Union

during the period 2003-2007. Probable reasons for this delayed uptake of electronic submissions in Europe were competing priorities (including new legislation affecting other aspects of the European regulatory framework), the lack of a legal basis for electronic submissions, legal requirements for a paper copy as the “official” archive copy in many EU countries, and budgetary constraints on investment in the necessary IT infrastructure. Notwithstanding this, a target date of end 2009 for eCTD implementation was adopted at the European Heads of Agencies meeting in Reykjavik, Iceland, held on 23rd - 24th February 2005 [4].

The period of slow progress drew to a close in December 2007, with the announcement from the EMEA that electronic-only submissions would be implemented for the centralised procedure in 2008 [5]. Since then, there has been a dramatic acceleration in electronic submissions implementation in Europe.

Current StatusWith regard to the EU centralised

procedure, it has been possible to make electronic-only submissions since 1st July 2008 [6] (paper submissions are still accepted, but are not recommended). Up until 31 December 2009, electronic submissions could be in either eCTD or NeeS format, but since 1 January 2010 eCTD has been the only permitted electronic format [7].

The situation with regard to other European procedures (mutual recognition [MRP], decentralised [DCP] and national procedures) is fragmented and in a state of flux. There is no reliable central source of up-to-date information with regard to electronic-only submission implementation in individual EU member states, but a recent special press release [8] (November 2009) from the European Heads of Medicines Agencies network (HMA) provides a useful snapshot. As of the date of this press release, it was anticipated that 19 countries (of 31 in total) would be able to accept

This article summarises the current situation regarding acceptance of electronic regulatory submissions in the European Union. After many years of very slow progress, the last two years have seen a dramatic acceleration in the transition to electronic submissions; electronic Common Technical Document (eCTD) submissions are now accepted without paper in the EU centralised procedure, and more than 50% of EU national agencies are now accepting electronic submissions without paper.

BackgroundThe concept of electronic regulatory

submissions is not new, and has been evolving in Europe since the late 1980s. A significant milestone was the adoption in 2003 of the ICH guideline on the electronic Common Technical Document (eCTD) [1], which is the electronic counterpart of the Common Technical Document (CTD; a harmonised structure and format for regulatory submissions) [2].

The eCTD [1] is essentially a CTD in portable document format (PDF); it contains multiple PDF files in a folder structure that reflects the hierarchical CTD heading structure, together

with indexing information in extensible markup language (XML) format. An eCTD is organised into numbered sequences. The initial sequence (0000) represents a complete new submission. Subsequently, each time that changes are required (e.g. responses to questions, variations and renewals etc), a new sequence is submitted containing only the changes. The XML index file submitted with a sequence contains machine-readable information on how the PDF files in the present sequence relate to corresponding files submitted in previous sequences, thus providing so-called “life cycle management” functionality.

The benefits of switching from paper to eCTD are tangible, as follows:

Huge reduction in printing and shipping •costs;Time saved by not having to generate •paper copies;Ease of review (extensive hyperlinking •and bookmarking for easy navigation);Ease of archiving;•Facilitation of product life cycle •management and regulatory compliance;Positive impact on the environment.•

In Europe, the “non-eCTD electronic submission” format (NeeS) has emerged as an alternative to eCTD format for non-centralised applications [3]. A NeeS submission is essentially an eCTD without any XML indexing. Unlike an eCTD sequence, a NeeS submission is “free-standing” and does not provide any machine-readable information on how the contents relate to previous submissions i.e. there is no built-in “life cycle management” capability. With NeeS, it is left to staff at the agency to review the covering letter and contents of the submission in order to discern how the documentation being submitted in the present submission relates to documentation already on file from previous submissions.

Progress in Europe towards phasing out paper submissions and moving towards electronic submissions was very slow

CLINICAL RESEARCH

IPI 2 9/3/09 01:29 Page 43


In the PIM XML format, duplication is avoided, since the text making up each product information statement is stored only once and effectively re-used in multiple documents. The avoidance of duplication makes managing revisions much easier and less error-prone. PIM also makes management of translations easier by facilitating the use of computer-assisted translation tools, with the benefit of enhanced speed and consistency of translation. Finally, PIM improves the quality of product information, by assuring compliance with the authorised EMEA templates for product information (QRD) and improving consistency across multiple forms, strengths and presentations.

The development of PIM at the EMEA has been prolonged (well over five years), but a formal Statement of Intent [13] and related Q&A Document [14] has now been released (September 2009). This document proposes the following timetable for full implementation:

1Q2010: EMEA to commence •migration of all centrally authorised product information to PIM format (in consultation with MA holders).3Q2010: end of pilot phase, start of full •implementation (subject to specified criteria being met [15]).By end 4Q2011: EMEA to complete •migration of all centrally authorised product information to PIM format. PIM will be “strongly recommended” from this point onwards.

The implementation timetable depends on successful completion of the pilot phase (for which a number of criteria have been established [15]). Given the history of delays in PIM development to date, further delays are to be expected. In particular, experience with migration to PIM is limited at present, and it remains to be seen whether the EMEA has made realistic assumptions with regard to timelines and budgets for completion of this step.

The implementation of PIM in the pharmaceutical industry will be associated with significant challenges, because it represents a step change in how product information is managed. In particular, companies will have to make a significant investment in new information systems and revised business processes. Instead of being held as discrete word-processed files in a file system or document management system, product information will be held in a structured form in a database system, with suitable workflow, security, version control

electronic submissions (in place of paper) on 1st January 2010, as summarised in the following table.

Electronic submission formats in the EU: NeeS vs eCTD. Although eCTD is the only electronic format acceptable for centralised submissions [7], the NeeS format [3] is currently accepted as an alternative for MRP, DCP and national submissions. NeeS is supposed to be a transitional format to assist the industry in implementing electronic submissions. However, at the time of writing (January 2010), no date has been proposed for its withdrawal, and it is unlikely to be withdrawn in the near future.

The most recent EU Telematic Implementation Group (TIGes) survey published in September 2009 (for the year 2008) [9] revealed that eCTDs accounted for only 5% of electronic submissions made in the EU in 2008; in this survey, 61% of electronic applications were described as “NeeS” and 34% as “Other”. The majority of the eCTDs were centralised applications, reflecting the EMEA’s proactive approach to eCTD.

The popularity of the NeeS format may reflect the fact that a draft EU NeeS guideline was published in January 2008 [3], whereas the corresponding eCTD guideline was not published until May 2009 [10]. It also reflects that fact that NeeS has advantages in a number of situations, as discussed below.

Many companies have large portfolios of existing authorised products for which the original submissions and all subsequent variations have been done on paper. In order to switch to eCTD format for future maintenance submissions for such legacy products, it is necessary to prepare a “baseline” eCTD sequence containing the current approved documentation set (covering at least administrative, labelling and pharmaceutical quality aspects covered in CTD Modules 1, 2.3 and 3, since these account for the bulk of variation activity). This provides the necessary foundation for future eCTD life cycle management.

However, the cost and resource associated with preparing eCTD baseline sequences for legacy products is not always justifiable, especially for older products of low commercial value and for which variations are infrequent.

Furthermore, many of these legacy products are maintained as individual national authorisations, with responsibility

for maintenance devolved to company local offices or local consultants. eCTD publishing requires specialised software and trained operators, and is usually done by specialised central groups within pharmaceutical companies. In contrast, preparation of NeeS submissions on a small scale does not require specialist publishing software or special skills, and can be done relatively easily by local office staff or consultants.

Whilst the NeeS format is suitable for legacy products in the circumstances discussed above, eCTD is advantageous for new products because it has integrated life-cycle management features that make it easier to keep track of changes with time. Detailed guidance is available on life-cycle management aspects of eCTD in the MRP and DCP [11].

Electronic product information: PIMAnother standard that has been under

development in Europe is PIM [12], which is an XML format for exchange of product information, including the Summary of Product Characteristics (SPC), Patient Information Leaflet (PIL) and package labelling. PIM submissions can be included within eCTD sequences, or exchanged independently of eCTD.

PIM is being implemented initially for the centralised procedure, to meet the needs of the EMEA for improved quality and more efficient review of product information (including review and approval of translations).

During the evaluation of marketing authorisation applications, the product information needs to be reviewed, revised and approved, a process which may involve multiple rounds of communication and negotiation with the applicant. Typically, product information documents cover multiple forms, strengths and presentations (pack sizes), and they must be available in each of the languages of the European Union. Consequently, a full set of product information may comprise many hundreds of documents containing a very large amount of duplicated information. Up until now, product information has been stored as a set of word-processed documents. Whenever a particular statement in the product information is changed, the change must be made in all documents where this statement appears (and the translations of the statement also need to be updated). Consequently, implementing changes is resource-intensive and error-prone.


Dr Martin Moxham, is the Managing Director of iRegulatory Ltd, a UK-based regulatory affairs consultancy. On completion of his PhD studies in Biochemical Pharmacology at the University of London, he began his career in pharmaceutical regulatory affairs in 1992 with SmithKline Beecham. Subsequently, he held various managerial positions within Merck Generics UK, Akos International Consultancy and Mitsubishi Pharma Europe Ltd before founding iRegulatory Ltd in 2001. He has a special interest in IT in pharmaceutical regulatory affairs, including electronic submissions. Email: [email protected]

11.Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human. Best Practice Guide on the Use of the Electronic Common Technical Document (eCTD) in the Mutual Recognition and Decentralised Procedures. April 2008. http://www.hma.eu/277.html

12.European Medicines Agency. Product Information Management (PIM). http://pim.ema.europa.eu/

13.European Medicines Agency. Implementation of Product Information Management (PIM) in the Centralised Procedure: Statement of Intent. EMEA/132166/2009. September 2009. http://pim.ema.europa.eu/PDFs/EMEA%20PIM%20Statement%20of%20Intent%20-%20Final.pdf

14.European Medicines Agency. Implementation of Product Information Management (PIM) in the Centralised Procedure: Statement of Intent. Questions and Answers relating to Strategic and General Aspects of PIM Implementation. General-EMEA/127652/2009. September 2009. http://pim.ema.europa.eu/PDFs/Statement%20of%20Intent%20QAs%20-%20Final.pdf

15.European Medicines Agency. Stability Criteria for PIM in the Centralised Procedure: Criteria for moving from pilot to regular operation for both new applications and post authorisation procedures. Version 0.2. Undated. General-EMEA/546925/2008. h t t p : / / p i m . e m a . e u r o p a . e u / P D F s /Stability%20Criteria%20for%20Moving%20out%20of%20PIM%20Pilot%20-%20Final.pdf

and the ability to export and import PIM files.

In the same way that implementation of eCTD has seen the evolution of specialised “regulatory publisher” roles within regulatory affairs departments, the implementation of PIM is likely to see the introduction of a new “product information specialist” role. This role will require specialist skills in pharmaceutical product information, together with an understanding of the concepts of managing information in a structured format.

Currently, it is unclear as to the extent that pharmaceutical companies will embrace PIM. The EMEA does not currently have the legal power to make PIM mandatory, and it will be “strongly recommended” only [13, 14]. Consequently, it seems likely that the uptake of PIM will be confined to large pharmaceutical companies, who have the most to gain from the efficiency improvements that will result from the management of product information in a structured form.

ConclusionsRapid strides have been made since •2008 towards full implementation of electronic submissions in Europe;eCTD has now been fully implemented •for the EU centralised procedure, with no requirement for paper submissions;More than 50% of national authorities •now accept electronic submissions (NeeS or eCTD) without paper copies, for MRP, DCP and national submissions: the remainder can be expected to follow suit within the short- to medium-term;Use of the eCTD format is mostly •associated with centralised applications, with the NeeS format being the preferred format for MRP, DCP and national submissions;A timetable for implementation of •PIM XML product information for the centralised procedure has been proposed, but the likely extent of uptake of PIM by the industry is uncertain and the possibility of further delays cannot be ruled out..

References:1.International Conference on

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Electronic Common Technical Document Specification. Version 3.2.2. 16 July 2008. http://estri.ich.org/eCTD/eCTD_Specification_v3_2_2.pdf

2.International Conference on

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (M4). Harmonised Tripartite Guideline. 13 January 2004. http://www.ich.org/LOB/media/MEDIA554.pdf

3.EU Telematic Implementation Group - electronic submissions (TIGes). Guidance for Industry on Providing Regulatory Information in Electronic Format: Non-eCTD electronic Submissions (NeeS). Final Draft. Version 1.4, January 2008. http://esubmission.ema.europa.eu/doc/eGuidance_Document_1.4.pdf

4.Heads of Medicines Agencies (HMA) of the European Economic Area. Summary Report of Meeting in Reykjavik, Iceland 23rd – 24th February 2005. 28th February 2005. http://www.hma.eu/uploads/media/23.feb.2005_01.pdf

5.European Medicines Agency. eSubmission: What’s New. http://esubmission.ema.europa.eu/new.htm

6.European Medicines Agency. EMEA Implementation of Electronic-Only Submissions and eCTD Submissions in the Centralised Procedure: Statement of Intent. EMEA/563366/2007. 22 January 2008. http://esubmission.ema.europa.eu/doc/EMEA_eCTD_Strategy_Announcement_%20FINAL.pdf

7.European Medicines Agency. eSubmission: EMEA Implementation of Electronic-Only Submissions and Mandatory eCTD Submissions in the Centralised Procedure: Statement of Intent. EMEA/572459/2008. December 2008. http://www.ema.europa.eu/pdfs/human/regaffair/57245908en.pdf

8.Heads of Medicines Agencies (HMA) of the European Economic Area. Special Press Release. November 2009. http://www.hma.eu/uploads/media/e_readiness_HMA_nov_09.pdf

9.EU Telematic Implementation Group - electronic submissions (TIGes). eCTD Implementation Survey Report By the Czech Presidency of the EU – 2009 (Covering the period from January 2008 to December 2008). http://www.hma.eu/uploads/media/eCTD_Implementation_Survey_Report-v3_0.pdf

10.EU Telematic Implementation Group - electronic submissions (TIGes). Guidance for Industry on Providing Regulatory Information in Electronic Format: eCTD electronic Submissions. Draft for Testing. Version 1.0. May 2009. http://esubmission.ema.europa.eu/doc/eCTD%20Guidance%20Document%201.0%20FINAL%20FOR%20PUBLICATION.pdf

Centralizing ECGs for efficient, accurate cardiac safety assessments in clinical trials

not cost effective. This article will discuss the regulatory requirements in relation to ECGs and will highlight the benefits of a centralized versus a decentralized approach.

Regulatory OverviewRecent concerns over the cardiac

effects of new pharmaceutical products have triggered greater regulatory scrutiny for all new compounds and final drugs prior to reaching the marketplace. While there is no legislative mandate in relation to ECG assessment across clinical trials, the requirement to conduct a Thorough ECG Trial (TET) for new compounds has been mandated by the US Food and Drug Administration (FDA) with limited exceptions.

Centralizing the process of collection and standardization of quality ECG data and employing digital ECG systems and a core laboratory, not only reduces inconsistencies that may occur from site to site, but in addition helps to alleviate laboratory and site workloads.

Despite the many benefits associated with a centralized system, a large number of clinical trials (Phases I to IV) continue to use a decentralized ECG study model typically carried out across multiple investigator sites using local ECG machines. The basis for this adoption of a decentralized approach includes a lack of regulatory guidance and a widespread perception that centralization is

Research has shown that some drugs have the potential to pose a significantly increased risk of arrhythmias or other serious cardiac conditions. Cardiac safety is therefore the primary reason for drug withdrawals from the market, labeling changes and delay or denial of regulatory approval for marketing. As a consequence of these well documented concerns, biopharmaceutical organizations, contract research organizations (CROs) and medical device companies are required to provide quality electrocardiogram (ECG) data in the primary stages of drug development to ensure the most comprehensive and accurate assessment of a new drug’s effect on the electrical functions of the heart.

ExCard Research GmbH www.excard.deBerliner Straße 5 D-16540 Hohen Neuendorf ph. +49(0)3303-217490

Standard-ECGsDigital and paper•Manual and automatic •interval measurementsECG interpretation by •CardiologistsIndividual heart rate •corrections

Holter-ECGs12-channels, high-resolution•Online Safety-ECG extraction•Heart rate variability•Complex QT-analysis•Arrhythmia analysis•Pharmacodynamics•

ExCard Research provides everything you need for planning, preparation, organisation and analysis of your ECG studies for cardiovascular safety.

Cardiovascular safety is at our heart


This is a result of the introduction of the ICH E14 guideline which was developed to assess QT/QTc prolongation in new drugs to determine cardiac safety risks.

The ICH E14 guideline recommends that a TET should be performed and if any cardiac safety concerns are raised, Phase III trials will require more robust or intense ECG collection. Unlike many other clinical trials, the TET typically uses a centralized system, which has proven to greatly improve the accuracy and reliability of ECG data in clinical trials. This centralized approach uses standardized digital ECG machines for collection and a centralized high resolution data analysis supplied by a core laboratory.

Why Centralization?Traditional ECG data collection methods

use a decentralized model, typically carrying out ECG studies across multiple investigator sites using local ECG machines. However, there are significant limitations associated with this approach. The use of different instrument types at different sites means that Interval Duration Measurement (IDM) data are often inconsistent since not all instruments use the same algorithms for calculating the resultant data. As a consequence, the over read of the ECG output is not consistent across investigational sites and additional fees are required for professional cardiologist over reads on a site by site basis. In general, data are collected at the beginning and end of the trial, which provides very little information about the cardiac effects of the chemical entity under investigation.

As individual monitoring sites are responsible for performing and acting upon the interpreted ECG data, the transfer of information can result in transcription errors and other unexpected results due to differences in site investigators’ ability to adequately interpret the data. From a purely clinical standpoint, Viskin et al.1 did a study that was published in Heart Rhythm in June 2005 to look at the competency of non-cardiologists, cardiologists, electrophysiologists and QT experts in assessing the QT interval measurement in a small sample of ECGs. The findings were striking in that non-cardiologists and cardiologists were found to be essentially equal in their inability to assess the length of the QT interval with an accuracy rate of 21% and 22% respectively. Electrophysiologists faired better at 62% and QT experts were correct 96% of the time. For the majority of clinical trials being conducted today, whether

the investigator interprets the ECG or has a local cardiologist do the work for them, it is highly unlikely that accurate clinical signals will be detected. These factors, coupled with the lack of consistency amongst cardiologists in their ECG interpretation, makes analyzing any data obtained very difficult. A centralized approach has been found to efficiently overcome all the above shortcomings.

The Vital Role of Centralizated ECGs A centralized approach uses digital ECGs

and a core laboratory which handles much of the work done by clinical trial sponsors, CROs and individual monitoring sites. The core laboratory typically provides investigator sites with all standard ECG equipment having first ensured that it has been tested to full functionality and is programmed for the correct demography capture for the particular study.

The use of digital ECG data collection at the core laboratory speeds up the analysis process and generates much cleaner data by using a high resolution digital methodology eliminating the common transcription and misinterpretation errors which normally occur when following a decentralized approach. In addition, some core laboratories employ systems that automatically check for missing visits or any changes in demography. Each ECG is evaluated by a qualified cardiologist at the

core laboratory to ensure maximum data quality, integrity and consistency.

In the ICH E14 document, centralization is recommended in cases where cardiac safety concerns are raised. As such, the guideline further highlights the superior results generated by this approach. However, approximately two-thirds of ECGs collected in clinical trials are still obtained using traditional decentralized paper methods. The continued use of decentralized systems is partly due to limited regulatory mandates in this area and the misconception that centralized systems are more costly.

Cost ImplicationsCurrently, there is much debate about

estimating the true costs of centralized versus decentralized ECGs. Quantifying the number of ECGs that will be required in advance of a study program is particularly difficult, making it harder to estimate the true costs of centralized versus decentralized ECGs. Staffing costs, the number of investigator sites and the number of ECG machines needed are unknown and vary based on the specific study design.

Additionally, much of the collection, transcription and interpretation of ECG data is carried out by the sponsor and the individual monitoring site when using a decentralized model. This means that many companies


Amy Furlong, Executive Vice President, Cardiac Safety Operations - Amy has been Executive Vice President of Cardiac Safety at ERT since December 2005 and previously served as Senior Vice President of Regulatory Compliance. She holds a Bachelor of Science degree in Biology and a Master of Science degree in Quality Assurance and Regulatory Affairs from Temple University’s School of Pharmacy. Amy has more than 10 years of clinical research experience, specialising in regulatory compliance and computer system validation. Email: [email protected]

using this approach see the use of a core laboratory in a centralized system as an unnecessary additional expense. However, added costs in a decentralized model include fees which are paid to the site, including a technical fee for the ECG acquisition and a professional fee for evaluation of the ECG. These fees are based on standard medical reimbursement rates (CPT codes). In many settings, where a qualified cardiologist is not available, the site needs to employ the necessary qualified expertise which can generally cost from $75 to $250 per ECG.

Centralized ECG trials involve the rental, storage and shipping of the ECG machines to each investigator site. A typical ECG device can weigh anything between seven to 10lbs and can be of substantial size, which means they can be expensive to transport and store. Furthermore, the maneuvering and preparing of the instruments ready for use can be time consuming and difficult for inexperienced users. The average rental cost of such a machine generally varies between $100 and $150 per month. Reducing the acquisition fee, which includes the amount of rental paid for the ECG instrumentation, is one way of lowering costs. This point is further explored below.

However, the added value of digital ECG collection, improved accuracy and reliability can actually help sponsors reduce costs. By eliminating errors in collection and transcription of ECG data, sponsors can reduce the amount of retesting that must be carried out. In addition, the centralization of ECG analysis eliminates these unnecessary over read fees and also allows a reduction in the standard site fee payments for the technical fees. For example, analysis of blood tests in clinical trials was originally decentralized and required the management of site-specific laboratories with multiple normal ranges, data quality issues and high costs due to site specific requirements. When blood work is performed in a centralized manner by experienced core laboratories, an efficient, consistent and high quality service is offered. Also, since the use of centralized equipment is an integral feature of a core laboratory, sponsors should not technically have to pay extra for machine rental.

The Future of CentralizationAlthough centralization provides clear

advantages over the decentralized model, there is still a clear need for innovative new instruments which can help sponsors increase accuracy, reliability and cost effectiveness, while overcoming the perceived

challenges of decentralization. The issue of large, heavy and expensive instrumentation could be tackled with the introduction of highly compact ECG machines that have a much smaller footprint than existing systems. A number of new highly-compact ECG machines on the market have already made several strides towards this goal, being a fraction of the size of traditional machines and still provide full ECG functionality. These smaller machines are easy to maneuver and are less expensive to ship and store.

Advances in software allow these new instruments to integrate into existing computer systems allowing key data, such as demographics and algorithms, to be automatically downloaded prior to a trial. The ability to download these data is a substantial benefit in terms of both staff time and cost, especially to sponsors involved in studies involving non-cardiac drugs where the investigator site is not familiar with ECG systems.

Traditional ECG machines produce a paper printout of all the key ECG data which are then transcribed and the results analyzed. However, errors are common during transcription which leads to inaccurate results and has a detrimental effect on the overall validity of the trial results. Eliminating the need for this printout by enabling the machines to upload the data directly onto the core lab computer system would eliminate transcription errors and increase the overall accuracy and timeliness of the data, as well as saving staff time and cost in the process.

Regulators are increasingly requesting that studies submit digital ECG data to a central digital system, also known as a data warehouse, to assist with regulatory inspections. All data stored on the system can then be accessed by regulators to quickly and efficiently analyze the quality of the data. Even though this is not a mandatory requirement as yet, most clinical trial sponsors are currently complying with it. A centralized digital ECG system makes this request easy to comply with as all data are already stored centrally and simply have to be transferred to the database as required.

ConclusionAn increase in concern over the cardiac

safety of drugs has resulted in heightened regulatory scrutiny for all new compounds and has put greater pressure on the pharmaceutical industry to monitor the potential effect of new drugs on the electrical functions of the heart. Although the use of the decentralized ECG study model is still

widespread across the industry, it suffers from a number of limitations including poor accuracy, reliability and efficiency of ECG data. The introduction of the centralized model of ECG has provided the industry with significant improvements in a number of key areas including data quality and data capture in addition to reduced workloads for sponsors and the ECG site, thus lowering cost while increasing data quality.

By utilizing new ECG solutions, clinical trial sponsors can benefit from a more cost effective and efficient system that will help them to ensure patient safety and regulatory compliance by reducing site burden and increasing accuracy, reliability and usability. Although there are no plans at the moment to enforce centralization as standard within the pharmaceutical industry, the ICH E14 guidance highlights centralization as a more robust method of ECG data collection. Though the advantages of a centralized ECG system are clear to see, demonstrating the real value of this approach remains a challenge. However, it is evident that when all the costs are added up, the advantages of centralization are unrivalled by decentralized systems..

Reference:1. Viskin, et al; Inaccurate

Electrocardiographic Interpretation of Long QT: “The Majority of Physicians Cannot Recognize a Long QT When They See One”; Heart Rhythm, June 2005

C

M

Y

CM

MY

CY

CMY

K

PharmaFocus Phone.pdf 18/09/2009 10:14:06


Phase I: As Relevant as Ever?

The effects of disease on drug pharmacokinetics and hence pharmacodynamics can affect both safety and efficacy. This information is required for the SPC or drug label. Most small molecule drugs undergo hepatic metabolism and clearance and/or renal clearance. Therefore, disease states of these organs can affect drug exposure leading to toxicity. Renal function as measured by creatinine clearance can start to decline in the fourth decade of life at a rate of 8mL/min/1.73m2/decade in approximately two-thirds of elderly persons.2 Drug utilisation in this age group is also high, with a high incidence of chronic illness requiring long-term therapy. Thus, knowledge of any dose adjustments in those with end organ compromise is important to aid compliance and to assure long-term safety. Such dose adjustments can usually be calculated from simple single-dose pharmacokinetic studies, comparing the PK in those with renal and hepatic impairment compared to those with age-sex matched healthy volunteers.3,4

First in man (FIM)Some are of the opinion that not much

has changed in Phase I dose escalation studies. A recent review5 which looked at 105 published studies from 1995 to 2004 concluded that there was little consensus in the design of such trials. The average trial was placebo controlled, double-blind, and included 32 subjects at five dose levels, yet with great variation in cohort size. The parallel single-dose design was the most common and the most conservative. The use of the crossover designs, both grouped and alternating, were considered more novel approaches. Since these designs allow the drug to be administered more than once to each subject, they allow more information to be obtained from fewer subjects and importantly, enable intra-subject comparability at the different dose levels. The use of these crossover designs coincides with the drive by the industry to achieve more out of such studies.

There has been an emergence of multi-functional protocols or “umbrella protocols”, particularly in Phase I. These involve the combination in a single study of the traditional single ascending dose study

For many working in the industry, Phase I studies are viewed as a stage in the drug development cycle that must be done and is not necessarily considered to “add value” to a drug’s portfolio. More companies are looking to move into patients earlier for answers. This has led to new strategies and terms, Proof of Concept (POC) being one and microdosing another. The attraction of the latter is that companies can move into man quicker with an abbreviated preclinical package, thus claiming to be “in man” with their compound, which helps satisfy business metrics, company performance statistics and shareholders. There is no doubt that these new studies have their place, though the more traditional Phase I studies have evolved over the years with new thinking being applied along with a wealth of expertise available to add value.

Not Just Phase ISome use the term Phase I to

mean clinical pharmacology and vice versa. However, these terms are not interchangeable. Phase I is a specific area of clinical pharmacology focusing on the first administration in man of new chemical and biological entities. Primarily, this involves administration to healthy volunteers except

in the case of specific therapies such as cytotoxic drugs where the risk:benefit ratio does not allow healthy subjects to be involved.

A significant amount of clinical pharmacology work occurs in New Chemical Entities (NCEs) during the drug development lifecycle. Drug/drug interaction studies, which study the effects (usually pharmacokinetic though sometimes pharmacodynamic) of one drug on another are performed in all stages of clinical drug development, even when a drug is in Phase III. These are determined by the pharmacology of the drug, in particular the route of drug metabolism and transportation in the liver and the gastro-intestinal tract. This is an area of advancing scientific knowledge, and of increasing regulatory concern due to the increase in poly-pharmacy that comes with an ageing population with associated multiple pathology. This is one area where clinical pharmacology in healthy volunteers has direct relevance to prescribers.

At the first in man or Phase I stage, the new chemical entity formulation is usually crude (often a simple oral solution, made with bulk drug). Considering that up to 40% of NCEs fail in Phase I due to inappropriate pharmacokinetics,1 companies do not want to invest large sums of money in a drug which may still fail. The counter-argument to this is that the crude formulation may be the reason for the inappropriate pharmacokinetic profile, while a refined formulation might demonstrate a more appropriate profile. Again, clinical pharmacology has a pivotal role here in demonstrating that refined “market image” formulations have appropriate pharmacokinetics for successful self-administration by patients that will allow the drug to achieve a Marketing Authorisation. Bioavailability (BA) and bioequivalence (BE) studies, both as initial formulation pilot pharmacokinetic studies and subsequent regulatory BA/BE crossover studies, can provide this information. In the case of a molecule that may have several formulations, small pilot pharmacokinetic studies (sometimes as part of the initial first in man study) are used to ascertain the optimal one for full development.

with the first in man multiple-dose tolerance study. Food effect crossover legs have been added as well. The advantages are that such studies require only one regulatory approval and ethical review, there is consistency in the inclusion/exclusion criteria and they are quicker to perform. In addition, all parts of the study can be managed by the same project manager and team and be conducted by the same centre and the same investigator, promoting operational efficiencies and saving time. However, these studies require control mechanisms to be in place to assure participant safety when moving from the single-dose to the multiple-dose section of the study; specifically, what data will be available to select the dose regimen for the multiple dose, what decision criteria will be applied, who will apply these criteria, and how this data is assured to be accurate? The key is to be as flexible as possible and use algorithms to clearly define the different possible scenarios.

Traditionally, such dynamic changes during a Phase I study were handled by protocol amendments, though the approval of these can restrict the speed of research. With the use of pre-defined algorithms detailed in the protocol, changes in dose levels and sampling numbers, for example, can be instituted without further regulatory review. Of course, this must all be explained

in clear terms to the study participants in the information sheet and consent form, which can result in large and sometimes “user-unfriendly” documents, that require a high level of explanation from research staff in order to ensure that proper informed consent is achieved. Using pre-approved consent updates during the study to cover the pre-planned changes described by the protocol algorithms is a technique that has to be employed in order to ensure that informed consent is maintained throughout the study.

“Healthy” patients in Phase I?In recent times there has been the

emergence of using certain groups of patients in what were traditionally the first in man studies (excluding cytotoxics). These are usually patient groups who are otherwise healthy with minimal end organ dysfunction caused by their disease; Hepatitis C patients for example. Some of these patients chronically infected with the Hepatitis C virus have no symptoms or signs; all that might be present is a mild derangement in serum ALT and positive viral serology. In these patients, liver and renal function are normal and thus any new chemical entity is likely to be handled in the same way as in normal healthy subjects. Their viral serology can be used to assess any potential benefit of new anti-viral molecules and thus give

very early Proof of Concept as well as safety in the target population. Such studies can have a key role to play in taking the decision to move into Phase II and full development. For small companies, such data allows them to out-license the drug to a partner. In this respect, clinical pharmacology is being used to assist in business and development decisions rather than solely for regulatory requirements.

Translational/experimental medicineAnother area that has grown in interest

in the past few years is that of translational medicine or experimental medicine. Both terms have been used frequently to mean the same area. This involves the use of innovative measurements (referred to as biomarkers), models and designs in studying human subjects for establishing proof of mechanism and concept for new drugs. It also can be used to explore the market differentiation for successful drug candidates and for terminating the development of unsuccessful ones.6

BiomarkersThe biomarker chosen must be valid

and meaningful for the target therapeutic area. Biomarkers can be as simple as measuring blood glucose and serum insulin in response to new anti-diabetic agents, measuring routine coagulation parameters


in healthy subjects in response to new anti-coagulants targeted for thrombo-embolic disease and the use of bacterial lipo-polysaccharide ex vivo to “spike” human blood to demonstrate a reduction in TNFα response when comparing certain anti-inflammatory agents to placebo in healthy subjects. Others are more complicated. Examples include the use of forearm blood flow measurements to assess vascular response to endothelin antagonists and euglycaemic hyperinsulinaemic clamp studies for assessment of anti-diabetic agents.

Newer challenge agent models have been developed to look at anti-inflammatory effects in the skin; for example, the use of urate crystals intradermally to recruit neutrophil infiltration of the skin with an inflammatory response which can be assessed by laser Doppler and local biopsy. Skin blisters are formed using a vacuum chamber, are de-roofed and urate crystals applied to the skin to provoke the inflammatory response. Comparisons can be made between responses seen with active drug versus placebo.7

MicrodosingMicrodosing is another relatively new

development which has been put forward by many as a potential way of reducing development time, gaining early proof of concept and reducing the traditional attrition rate seen in early drug development. Essentially, microdosing is a human ADME study performed before a new drug candidate moves into Phase I (sometimes referred to as a “Phase 0” study). The drug is administered in a sub-pharmacologically active dose and the study utilises ultra-sensitive analytical techniques, such as accelerator mass spectroscopy (AMS) and positron emission tomography (PET), in order to assess the pharmacokinetics and the potential pharmacodynamic responses.

PET scanning is an exciting new development which can be used to demonstrate receptor occupancy of a new drug, for example dopamine and 5-HT receptors.7 It can detect the displacement of labelled receptor ligand by the ‘cold’ new molecule, thus demonstrating receptor interaction. The use of AMS allows the pharmacokinetics of the microdose to be assessed to show potential appropriate

human ADME.8 The word “potential” is used here because the technique relies on the compound having linear kinetics in the pharmacologically active range.

Can Phase I studies add value in drug development today?

Absolutely. Adding value starts even before the study actually begins. Phase I is a discipline in its own right. As in other areas, there are experts in Clinical Pharmacology/Phase I who can help a sponsor plan, implement and interpret data that provide answers for a drug; even if that answer demonstrates that the drug in question or its current formulation could not be moved into full development. In the majority of cases this is usually due to inappropriate or variable human pharmacokinetics. Getting these answers quickly and reliably is where having a good Phase I project team and project manager pays dividends. They coordinate all the elements that make up a Phase I trial: protocol and Informed Consent production, regulatory and ethics submissions, start up, recruitment and screening, coordination of clinical scheduling and activities (in conjunction with the medical and nursing


Dr. Brian Sanderson, Medical Director, Chiltern (Early Phase) Ltd., Ninewells Hospital & Medical School, Dundee. He joined Drug Development Solutions (then DDS Medicines Research) in 1998 as Deputy Medical Director and in February 2002 was promoted to CEO & Medical Director. He led the management buyout of DDS Medicines Research to form Drug Development Solutions Limited in September 2005 prior to the acquisition of DDS by Chiltern in February 2008. Brian has developed an interest in first into man administration and biomarker measurements in healthy volunteer trials. He has been Principal Investigator or Co-Investigator on over 350 Phase 1 studies and is an Author of over 60 Phase 1 study reports. Email: [email protected]

staff within the Clinical Pharmacology Unit (CPU)), data collection and management, as well as report production. Not to mention coordination with other possible external parties such as laboratory, monitors, drug supply and other study-specific suppliers. An experienced investigator is also required. He/she can often help prevent issues during the study by using their experience to advise the client how to maximise the benefits they can get from such studies and to avoid potential pitfalls. This is in addition to their traditional role as being the person responsible for subject safety during the study.

Location for Phase I studies is a factor as well. There has been a move to conduct more FIM studies in hospital-based CPUs, primarily because of safety concerns and to ensure rapid access to emergency medical services in the case of Serious Adverse Events (SAEs). Access to a hospital crash team who can assist the CPU medical team manage ill subjects in the unit has become a prerequisite for many pharmaceutical companies placing work in CPUs. However, there are other non-emergency benefits of hospital-based CPUs which apply not only to FIM studies but to other clinical pharmacology studies as well, such as:

There is ease of access to specialised •diagnostic techniques and experts within the hospital itself for some of the biomarker assessments previously mentioned. Teaching hospitals have senior •medics who are key opinion leaders in therapeutic areas and are able to collaborate with the Phase I CPU in helping refer small numbers of patients for Proof of Concept studies, which are becoming a part of the Phase I programme rather than Phase II. Access to hospital labs with their array •of assays and experts can help the CPU medics interpret results from studies and help give the sponsor guidance to any findings. Referral into the hospital for “non-•emergency” adverse events; for example, having a dermatologist consult to give an opinion on possible drug-related skin rashes can be achieved more quickly if the CPU is hospital-based.

Timelines are always critical in early phase studies. The conduct of Phase I studies is a global activity with different countries having different approval timescales. In the UK, for example, we are fortunate to benefit not only from years of experience with

Phase I studies following the growth of CPUs in the 1980s, but also a favourable ethics and regulatory climate exists. This means that there can be a parallel submission for both ethics and regulatory approval in which valid submissions are reviewed and approved within a 14- 21 day time frame in most cases. Data published by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the period April 2008 to August 2009, demonstrated that the average time for application review for Phase I healthy volunteer studies, including FIM but excluding those required by the Expert Advisory Group (since they were considered to be of “higher risk”) ranged between 9.8 days and 15 days 9.

Looking at all of this together, one can see that Phase I or Clinical Pharmacology is not like other stages of clinical drug development. More so than ever before, there are developments in this area with new approaches and study designs coming to the fore. Out of the box thinking is needed by pharmaceutical companies and CROs alike to help deliver maximum value to drug development pipelines in order to ascertain at the earliest possible opportunity whether any drug is suitable for full development or not. Key to this is innovation, planning, careful site selection, and good project management. These buzz words have become more associated with the new trends of POC, microdosing and biomarker studies, yet they equally apply to the more traditional phase study. These will produce added value if planned and managed by the right CPU with an experienced team and in the right location..

References:1.Dimasi JA (2001): “Risks in new drug

development: approval success rates for investigational drugs”, Clinical Pharmacology and Therapeutics 69, pp297-301

2.The Merck Manual of Geriatrics, Ch 97, Ageing and the Kidney: http://www.merck.com/mkgr/mmg/sec12/ch97/ch97b.jsp

3.EMEA Committee for Human Medical Products (CHMP) (2004): “Notes for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function: CHMP/EWP/225/02”. Available via www.emea.europa.eu/pdfs/human/ewp/022502en.pdf [Accessed January 10th 2007]

4.US Department of Health and Human Services, Food and Drug Administration, Centre for Drug Evaluation and Research (2003): “Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic function: Study Design,

Data Analysis and Impact on Dosing and Labeling”. Available via http://www.fda.gov/downloads/Drugs/Guidance Compliance Regulatory Information/Guidances/ucm072123.pdf

5.Buoen C, Bjerrum OJ & Thomsen MS (2005): “How First-Time-In-Human Studies are being performed: A survey of Phase 1 Dose-Escalation Trials in Healthy Volunteers Published between 1995 and 2004” J Clin Pharmacol 45:1123-36

6.Littman BH & Williams SA (2005): “The ultimate model organism: progress in experimental medicine”, Nature Reviews 4(8) p613-8

7.Newbold P (2004): “Challenge Agents and Microdosing”, Presentation at the Institute of Clinical Research conference “From Concept to Reality”

8.Wilding I (2005): “The art of the possible”, Scrip Magazine 146 p19

9 . h t t p : / / w w w . m h r a . g o v . u k /H o w w e r e g u l a t e / M e d i c i n e s /Licensingofmedicines/Clinicaltrials/UK clinical trial authorisation assessment performance/index.htm

Your research is too important to be left to others!

www.bmglabtech.com


www.bmglabtech.com


www.bmglabtech.com


Point of Care in Clinical Trials

trained clinicians and other non-laboratory staff can carry out testing otherwise performed in the laboratory.

CONNECTIVITY - Connectivity of POC devices provides even greater convenience, meaning patient and quality control results can be input into a central database where they can be collated, accessed and shared by those who need them. Several methods are implemented by different POC devices, including USB and wireless connections, this eliminates the need for manual transcription, thus reducing errors. Inputting these results into a central database also means they can be used for data mining and research purposes. Usernames and passwords can help eliminate the risk of non-authorised personnel gaining access to patient records.

SAMPLE QUALITY - With samples being tested immediately, their quality is no longer compromised by time and environmental conditions that are exerted when a sample is transported to a central laboratory.

QUALITY ASSURANCE - Special POC testing schemes have been set up by the Clinical Pathology Accreditation (CPA) accreditation scheme and the National External Quality Assurance Scheme (NEQAS) to ensure the quality of the results generated by the POC devices and their users.

With all the above points considered, POC testing, when used in conjunction with the traditional centralised laboratory approach, becomes a very powerful, effective tool in diagnostics.

Appropriate Governance and Quality Assurance

In taking laboratory testing outside the confines of the CPA accredited laboratory and out of the hands of the qualified laboratory staff, POC testing becomes an area that requires strict governance and application of quality assurance. This is an issue that is highlighted in the Review of NHS Pathology Services in England (The Carter Report), chaired by Lord Carter of Coles. The report represents a thorough and informed appraisal of pathology and the direction in which this key diagnostic service

Point of care (POC) testing is diagnostic testing performed promptly and conveniently in the vicinity of the patient, avoiding the often lengthy procedure of sending samples to be processed in a central laboratory. This gives rise to the alternative names of near-patient and bedside testing. The requirement for POC testing is increasing, with the global POC testing market predicted to rise from $12.8 billion in 2008 to $17.8 billion in 2014 (Life Science Intelligence, 2009)

Looking back through history, POC testing has been around from the very start. In Ancient Egypt, patients’ urine was analysed at the bedside for abnormalities, and in India around the same time, the practice of tasting urine to detect glucose first arose. Later in the 1600s, this technique reoccurred when Thomas Willis associated sweet-tasting urine with diabetes. During the 1960s, as technology advanced, it became necessary for samples to be sent to centralised laboratories for analysis by qualified scientists using large analytical equipment and a variety of complicated scientific procedures. Now however, with further advancement of analytical technologies, such as solid phase chemistry and integration of microprocessors, analysers are becoming smaller and more compact, meaning we can take diagnosis back to the patient’s bedside; to the point of care.

POC testing can be implemented using disposable testing kits, such as dipsticks and cassettes; handheld analysers and monitors; or small benchtop analysers, all of which require little or no maintenance. This equipment can be applied to a range of different tests such as blood gases, electrolytes, coagulation, pregnancy assessment and drugs of abuse testing,

covering a variety of fields including biochemistry, haematology and virology.

Why POC?In certain settings POC offers many

benefits and opportunities over the conventional laboratory approach, making it an exciting ever-developing alternative (Figure 1).

SPEED - The most significant advantage of POC testing is the marked decrease in turnaround time. The testing procedures themselves can produce results in minutes and sometimes seconds. It eliminates the need for samples to be sent to centralised laboratories whereby clinicians have to wait for the specimens to be processed and results returned. A faster patient diagnosis means faster implementation of treatment and all-round better management of the patient and their condition. This is particularly important for a rapid response to critical values.

PORTABILITY - POC devices are often small and portable and sometimes battery-powered, giving particular advantage when used out in the community or on large hospital sites. Even the larger POC analysers are small enough to be installed in areas such as GP surgeries, thus providing greater accessibility for the people who use them.

CONVENIENCE – Clinicians, through the use of POC, spend less time organising the necessary logistics involved when sending samples to a laboratory. Time isn’t wasted filling in forms and organising the shipping of specimens or looking for results once completed.

DECREASES LABORATORIES’ WORKLOAD - Pressure is taken from overworked laboratories as appropriately

LABS & LOGISTICS

Benefits of POC

Speed Portability Convenience

Decreases laboratories’workloadConnectivity

Sample quality

QualityAssurance

Figure 1


Mike Wickham, is the Managing Director of Woodley Equipment Company. Mike is a Chartered Scientist and Fellow of the Institute of Biomedical Sciences with 36 years experience specialising in Haematology, Blood Transfusion and Point of Care devices for all disciplines. Email: [email protected]

Dave McComas, is the Biomedical Technical Manager at Woodley Equipment Company. Dave is a Biomedical Scientist and Fellow of the Institute of Biomedical Sciences with a BSc in Biology and an MSc in Biomedical Sciences specialising in Haematology, Blood Transfusion and Point of Care devices for all disciplines. Email: [email protected]

Charlotte Wickham, is a Biomedical Specialist in the Technical Service Department at Woodley Equipment. Charlotte is a trainee Biomedical Scientist with an MSc and BSc in Biomedical Sciences with Forensic studies, specialising in Haematology, Biochemistry and Point of Care devices for all disciplines. Email: [email protected]

should develop to meet the requirement for high-quality patient care. The Carter Report calls for POC testing to be covered by CPA regulations. In response to this the CPA organisation have set out several external quality schemes for POC testing that relate to each area of testing. The Institute of Biomedical Science (IBMS) has suggested future integration of CPA and NEQAS to create an independent strengthened accreditation service, which also extends to POC testing.

The IBMS, in conjunction with The Royal College of Pathologists, have published a set of guidelines on POC testing to direct POC users in the appropriate implementation of POC technologies. The guidelines advise that POC testing should be overseen by a CPA accredited laboratory who would have the relevant knowledge and experience to ensure quality assurance is implemented correctly. To meet the needs of clinical governance it is recommended that all the laboratory disciplines are under the guidance of a POC testing committee. NHS POC testing committees typically include managers with an understanding and authority for implementing a POC program, members of the hospital laboratory such as the POC testing manager (quality manager), pathology services manager and a co-ordinator of the laboratory’s quality assurance schemes, as well as various other individuals who are using the POC testing devices in the hospital or general practice. In general practice the committee will be under the guidance of the local Primary Care Trust (PCT). The POC guidelines recommend that POC committees based in hospitals and those in local primary care involve members from both sectors to ensure an overview of POC devices across the divisions.

These POC committees are designed to ensure that the cost and clinical need for a POC test are first considered before purchase and implementation; that internal quality schemes are in place to ensure the device and the user are performing to an acceptable standard, and participate regularly in the relevant external NEQAS schemes and that performance in these schemes is reviewed. It is essential to monitor POC testing to ensure devices are well maintained by qualified Biomedical Scientists; users are kept up-to-date with training and that Standard Operating Procedures (SOPs) are written and adhered to, to appropriate standards. It is also important that any results obtained by patients using devices at home, that are indicative of an infectious disease, are

reported to the Health Protection Agency (HPA).

As mentioned, the POC testing device operators are required to be adequately trained to maintain a high-quality service. The user should be trained using SOPs and not be allowed to perform tests that will alter clinical management until the trainer is satisfied with the user’s competence and this is documented. When training is complete the user should be registered, and sign to accept legal responsibility for the results they generate. It is also important to keep the user’s skills up to date with Continuing Professional Development (CPD). In the situation where a device is used by a patient to self-manage a condition, it is important the individual is not only trained appropriately in the use of the device, but also in how to correctly interpret the result and the application of this to self-management. The SOPs should be written to the standard of CPA and NEQAS and according to the IBMS guidelines, must include the following points:

Clinical background•Analytical principle•

Health and safety including:Information on COSHH (Control Of •Substances Hazardous to Health)Safe disposal of waste•Control of infection•Adverse incident reporting•Pre-analytical considerations•Equipment•Reagents, standards, controls and •quality assuranceTest procedure•Sample analysis•Calculation of results•Assay performance•Maintenance•Record-keeping•

POC testing in Clinical TrialsResults generated by POC devices can be

utilised in clinical trials as decision-makers prior to administering treatment, or results can be used as actual trial data. Companies exist that can supply POC equipment and reagents to sponsors and CROs on a global scale. It is essential that these companies are suitably equipped to provide an efficient and reliable service as this is a highly specialised area of expertise. Biomedical scientists with a high level of knowledge and experience are required to provide global training and technical support. It is important to have a well-equipped service department with qualified engineers to ensure equipment is fully calibrated and maintained. Experience

PDP IPC CorpAdCurves.indd 1 12/2/10 16:20:28

in logistics is also essential to maintain the supply of sensitive reagents worldwide. Reagents need to be kept at correct stable temperatures throughout the shipping process, so it is vital to work with the correct logistics companies who can move equipment and reagents across borders and through difficult countries whilst ensuring the cold chain is maintained and documented..

References:Worldwide Markets and Emerging

Technologies for Point of Care Testing, Life Science Intelligence, 2009

PDP IPC CorpAdCurves.indd 1 12/2/10 16:20:28


The Next Generation of Clinical Supply Shipment Monitoring

3200 monitor results being processed and reviewed per year using a sample average excursion rate of 4%. However, many sponsors now require that all monitor results are returned and archived. At Almac Clinical Services this leads to around 40% of dispatched monitors being returned, or around 32,000 results per year based on figures above.

The retention period for GMP data at Almac is ten years. Therefore, a system for handling these results must be capable of maintaining 320,000 records. Each record may contain up to 16,000 data points (the current maximum memory on most temperature monitors) giving a total potential data volume of 5.2 billion individual temperature readings. This is assuming that there is no increase in monitoring or return of temperature monitor results, an assumption which is likely to be proved incorrect if recent years are anything to go by. The monitoring requirements and return rate of the results within specification results has increased year on year since 2005. The volume of information from temperature-monitored shipping is set to increase for the foreseeable future.

Speed of ReturnTime is always precious when

distributing clinical supplies. Depending on trial design, the potential impact of a delay of available drug at a site can range from an inconvenience to the study subject, to lost enrolment in a trial, or even missed patient dosing in the most extreme case. A shipment arriving with a temperature excursion showing on the temperature monitor cannot be administered at the site until the recorded data has been reviewed by a delegated individual. This individual is almost always not at the site or even in that country. Getting the data from the consignee who receives the shipment to the individual who will review the data as quickly as possible is critical.

The majority of monitors currently used to record temperature during transport

Management of cold chain clinical supplies presents sponsor companies with significant logistical challenges, especially considering the global nature of distribution to many less developed regions and emerging markets. When investigational products are shipped, supplies are subject to various factors which may influence the way in which temperature-controlled shipping systems may operate. These variables include a myriad of external temperature ranges, supply routes, transit time, and stability of data and people. A process for efficient visibility of the success of temperature control increases detectability and therefore reduces the risk factor.

Temperature monitoring of shipments is an area in which there has been rapid development. The‘Temptale’ style of device has been the most commonly used electronic monitor for many years, but a new generation of units have appeared on the market. These new monitors have improved communication methods, such as RFID or USB compatibility. They also boast more sophisticated internal and analytical software. The criteria used by

quality departments to judge a product’s usability, based on stability data, can be programmed directly into the monitor. This reduces the number of quality reviews of temperature excursions, while improving accuracy and turnaround times. Improved communication via general standards such as USB and the ability to program at the point of use are opening new opportunities for the development of handling the temperature-monitoring of clinical trial shipping. How can these technologies be used and are they really necessary?

Volume of InformationThe volume of information flow of

temperature-monitoring results from clinical trial shipping is staggering. Including all of the distribution centres of Almac Clinical Services, a conservative estimate of 60- 70,000 temperature-monitored shipments were sent in 2009, using well over 80,000 monitors as sometimes more than one monitor is included in a shipment. The majority of sponsors only require that temperature monitor results that have recorded an excursion are downloaded and returned for analysis. As an illustrative example , this would result in around

◼

◼

◼

◼

◼

◼

◼

◼

◼

◼

◼

◼


Support review of excursions for •product usabilitySupport archiving of GMP data, and•Enable effective KPI review and process •improvement.

The system that was previously in use was sufficient, however we had the opportunity to replace it with a purpose-built system that is ideally suited to management of multiple clinical trials from very large to very small, and offers the full range of services that our clients wanted. The end result was the Shipping Temperature Electronic Monitoring System (STEMS).

The first obstacle that had to be overcome was getting the monitor results returned to Almac Clinical Services without having to send the monitors back using an express courier. Not only does this add time and cost to the process, the consignee also has extra effort to arrange the collection with the courier. Online collection of data has been available for some time using USB-enabled devices. It was decided that this would be the main method for data collection as it was established and intuitive to the end user. Now the consignee is able to take the monitor to their computer and upload the results to our server without the need for any dedicated hardware or software. Nothing could be simpler or faster.

As soon as the information from the monitor is on Almac Clinical Services’ server, the streamlined communication is straightforward. All the predefined interested parties are immediately notified of the results of the temperature monitor. This means that any required corrective actions can be started at the soonest possible moment. Similarly, for shipments that arrive within temperature specification, recipients of the notification can have that warm fuzzy feeling knowing that everything has arrived ok and to plan. This communication process takes the old model of following up after an event has occurred, to the new model as close to a live system as is practical in airfreight temperature-controlled shipping.

The notification of an in specification shipment is nice to have, however, where there has been an excursion, there must be review of results and a decision made on the usability of the product. The excursion could have just skimmed past an upper or lower limit for a fraction of an hour, or could have been exposed to extreme temperature in some handling error, for example. Determining how significant the temperature excursion during transport

that can be reviewed at a later date require specific hardware to access the results. The monitors must be returned to a central location for downloading for the result to be linked with the shipment information and then sent to the individual responsible for the review. This can be a lengthy process if the shipment has been delivered to a remote location. A typical time for the return and review process is five days, and it can be as much as two weeks. For the duration of this period the shipped product is not able to be used at the site, and takes up valuable temperature-controlled storage space. Meanwhile a patient dose or enrolment may be delayed for a similar length of time. In this age of high-speed data communication, why are we shipping temperature data round the world on small electronic devices with a clear negative impact on efficiency of a study?

Low Speed, High CostThe length of time taken to communicate

the results of shipping temperature records can be detrimental to a trial or patient. It also has a high cost. The courier charges on a monitor return range from £30 or so with an express courier to hundreds of pounds from the most remote sites. A conservative estimate for illustrative purposes is around £45. For example - a study requiring 750 shipments, based on the increased trend for

100% return of all monitors regardless if the shipment has gone out of specification , we would estimate @40% return rate. Avoiding shipping costs associated with returning these devices would save £13,500 across the 750 shipments. This may not seem a very significant cost in terms of a clinical trial, but this is just to move a string of numbers from one location to another. The total cost of report compilation and review in terms of lost time far outstrips the return cost.

The cost of report compilation and review in a trial involving 600 shipments from UK to Spain has been estimated at 2,304 staff hours (Cold Chain to Clinical Site: The Shipping Excursion. Ray Goff, Pharmaceutical Outsourcing, Vol. 9, Issue 4). These lost time hidden costs are often overlooked and not factored in to the overall cost to a trial. A streamlined method of result communication has the potential to reduce the monetary costs of returning monitors to base, as well as time invested in staff hours.

Practical ImprovementAlmac Clinical Services decided it was

time for a change in temperature monitor results handling. There are certain key areas that were most suitable for radical review:

Return results to base without physical •return of the monitorStreamline the communication routes•

Global SOPs for all temperature ranges

At pick-up we supply the appropriate packaging and refrigerants to meet your shipment’s unique requirements

Qualified packaging material and validation reports

Individual priority treatment of every consignment

Unparalleled end-to-end global solutions

40 years’ experience

In-transit temperature monitoring for controlled ambient temperatures, e.g. 2-8°C, -20°C, etc.

Comprehensive guidance concerning country-specific import requirements

Consultation on specialty packaging solutions

Refrigerated trucking services

GMP-compliant depot storage facilities in Australia, China, India, Latin America, Russia and South Africa

Expedited customs brokerage

We have a global network of over 140 company-owned offices in 50 countries, operating 24 hours a day, 7 days a week.

Our service features:

For global listingand contact informationvisit www.worldcourier.com

Cold Chain ManagementWorld Courier is the sole premium logistics provider that offers a cold chain transport service.

Network | People | Technology

Ad_CCM_210x297_1009_final.indd 1 06.10.2009 12:42:15 Uhr


Nathan Kohner, obtained a BSc (Hons) degree in Mathematics at Edinburgh University. He joinedAlmac Clinical Services Temperature Controlled Distribution Team in 2005. Since then, Nathan has been a driving force behind, Almac Clinical Services temperature -controlled shipping strategy and was responsible for the introduction of the QB shipping system and designed the Shipping Temperature Electronic Monitoring System ( STEMS). With his background and experience, Nathan often lends himself as a guest speaker at key pharmaceutical and biotech conferences. Email: [email protected]

actual readings can be reviewed over time on specific transit routes to assess whether the risk of excursion is too high with the current method of control. Processes can be adjusted in response to this information, then the impact of the change can be quantified by the readings subsequently recorded in the system. Couriers, insulated shipping units, airlines, customs, weekdays, even individuals, can all be reviewed and analysed for trends and potential improvements. Add in a root cause tool and there is no end to the level of insight into the strengths and weaknesses of the temperature-controlled supply chain. The information gathered by STEMS will be more than just an archive of results; it will drive the future development of Almac Clinical Services’ temperature-controlled shipping solutions.

Temperature monitoring of clinical trial shipping is a fast-changing environment. The demands from sponsors on monitoring requirements are ever-increasing, demanding more detailed monitoring and faster access to results. Ultimately the prime goal of all this caution around temperature monitoring is to protect the patient enrolled in the trial, and to protect the trial to give new effective medications the best chance of getting to market for future patients. At Almac Clinical Services we are striving to make the process of temperature-monitored clinical trial shipments safer, faster and more efficient. STEMS is the next step in our journey towards total temperature control..was, and whether it negatively affected the

product, are now the primary goals of the clinical trial project managers. The decision-making process for temperature excursions is usually restricted to a specific group of people who have the necessary training and knowledge to make the decisions. Therefore, only a restricted group are allowed access to the specification reports to review the data and record whether the product within a particular shipped box is usable or not. This trained group of individuals are notified to log directly into STEMS, and from there are able to review all the recorded temperature data, enabling them to make a decision on the usability of the product. The decision is then recorded and archived in STEMS. Notification of this decision is essential and requires immediate communication in the same way as the communication of the in spec/out of spec status. Again, the people who need to know are immediately informed automatically by STEMS.

The net result for an individual shipment that has had a temperature excursion recorded during transit is that the monitor result is sent to the responsible individual and reviewed for impact on the product.

Notification of the decision made is sent out to the people who need to know urgently. All of this can happen within minutes of the shipment being delivered. This is a giant leap forward from the previous process that would take anything up to several weeks depending on compliance. The STEMS process enables super-quick communication of results in a fully validated, 21 CFR Part 11-compliant system.

The communication of shipping temperature results and review of excursions covers the in-line part of the process. The new STEMS system also provides effective archiving and trend analysis tools. Archiving information is a critical part and legal requirement of running a clinical trial. Confirmation of the shipping temperature conditions can be very useful, for instance at the end of a study when returned stock from sites may need to be used for another purpose, such as continued compassionate use. A full temperature history of the specific product is the best way to be sure that it has not been negatively affected by extreme temperature during its lifetime. Trending of temperatures during shipping opens up a whole area of process improvement. The

With an air cargo container that actively regulates it’s own temperature and certified hand-ling partners, your valuable drugs will be better taken care of. In that way you secure their functionality and your financial return. Year after year. At Envirotainer we offer unique air transport solutions for healthcare products. Worldwide. www.envirotainer.com

First class transportation for your drugs.


Outsourcing solutions to cGMP in the manufacture of oral solid dosage forms

primarily in the developing world. The European Union’s GMP (EU-GMP) enforces more compliance requirements than the WHO GMP, as does the FDA’s version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Singapore and others having highly developed/sophisticated GMP requirements. In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as “The Orange Guide”, which is named so because of the colour of its cover; it is officially known as The Rules and Guidance for Pharmaceutical

Manufacturers and Distributors.There are many considerations in the

application, compliance and adherence to cGMP processes. Not least of these is the acknowledgement that different plants, producing varying products will have specific requirements under cGMP by which to comply. That is not to suggest that there must not be an overarching policy and process by which quality and standards are maintained. While such a statement sounds simple enough, in reality pharmaceutical companies looking to outsource must satisfy themselves that theory and practice are one and the same thing.

This consideration is exacerbated when a product is outsourced along many or all of the links in the value chain. Contract pharma companies must be able to deliver – and prove delivery – of a consistent and regulatory compliant process at every stage. Given the breadth of potential regulations, such as US FDA, EMA (formerly EMEA) and so forth, encountered globally, cGMP is a platform rather than a panacea for compliance.

Remember that GMP guidelines are not prescriptive instructions on how to manufacture products. They are a series of general principles that must be observed

Regulation within the pharmaceuticals industry presents a dichotomy. On the one hand increasing regulatory pressure leads drug companies to investigate means of reducing the time, cost and risk associated with meeting ever-evolving guidelines, while on the other hand there is a perceived risk in outsourcing for fear of failing to properly meet complicated global requirements.

Outsourced pharmaceutical manufacturing has been a rapidly growing segment of the industry. In 2004 the global market was valued at about $25 billion. It is now estimated to be approaching $50 billion – a rise that outstrips overall growth in the pharmaceutical sector and is a clear indication of a trend towards outsourcing.

Similar percentile growth applies to outsourced clinical trialling, where the market value has risen from $9.3 billion in 2001 to $36 billion in 2010. Such growth is also to be increasingly seen in cold chain and logistics operations.

Even those in the industry who are sceptical of the high degree of regulation and legislation would concede that one of the key factors in the successful move to outsourcing resources ever further up the value chain is the consistency of quality standards. An imperative to successful outsourcing therefore is compliance with current good manufacturing practice (cGMP) and other global standards. Contract pharmaceuticals companies recognise this, but there remains differentiation in exactly how quality, traceability and validation processes are applied and managed. This is particularly true when an holistic approach is taken within the development cycle and across the entire value chain from research and development, through transfer and manufacturing and into packaging, storage and distribution.

GMP is just the startGMP is enforced in the United States

by the US Food and Drugs Administration (FDA), under Section 501(B) of the 1938 Food, Drug, and Cosmetic Act (21USC351). The regulations use the term cGMP to describe these guidelines. Courts may theoretically hold that a drug product is adulterated even if there is no specific regulatory requirement that was violated, as long as the process was not performed according to industry standards. By June 2010, the same cGMP requirements will apply to all manufacturers of dietary supplements including those with OSD.

The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred countries worldwide,

MANUFACTURING

©WhiteBoxA

gency-Salon

deProvence

Come and Visit us at BioPh- ICSE/CPHIParis, October 5/7 2010Booth # 4BIO33

Lyofal Encart Presse V2:Mise en page 1 2/02/10 16:26 Page 1


clients that the outsourcing be more flexible in terms of batch sizes and lead times than they can achieve themselves.

A measure of how great that investment can be is to consider the cost of merely repurposing an existing production line. Assuming no major changes to the hardware of the equipment, revalidation alone costs anything between $50,000 and $100,000 typically. Where new equipment is involved, there is not only the significant capital equipment investment, but the costs of installation, commissioning and validation remain further cost elements. Financially, the establishment and subsequent transfer of product is a major consideration in electing to outsource. To put this into perspective, my own company, NextPharma, has invested more than 25 million Euros in new plant and machinery over the past five years.

Most production equipment manufacturers now incorporate facilities and features to assist in validation and compliance with cGMP. For example, control systems can now have electronic signature systems to not only prevent control tampering, but also to log activity within the control itself. Critical controls may also have dual redundancy to provide secure backup and prevent system failures. It is important as part of the cGMP approach to embrace these technological aids wherever possible, since they reduce the costs of validation and also the risks of drifting from process norms.

Another scenario affecting OSD forms is in economical small batch production as part of the transfer process. Again, legislative considerations such as cGMP

during manufacturing. When a company is setting up its quality programme and manufacturing process, there may be many ways it can fulfill GMP requirements. It is the company’s responsibility to determine the most effective and efficient quality process.

If one considers the facet of outsourcing drug development, there is more than regulatory compliance at stake. The industry norm is for a CDA (confidentiality agreement) covering typically five to ten years to be agreed before any work commences. However, increasingly companies with new chemical entities (NCEs) seek outsourced development assistance and in these cases, where the contract company has extensive experience, intellectual property and development risks may be shared. In all cases compliance, confidentiality and customer confidence are all of paramount importance.

Manufacturing considerationsClearly, in oral solid dosage (OSD) forms

where the chemistry and manufacturing processes are mature, the key drivers in outsourcing tend to be the improvement of quality, greater flexibility in manufacturing and, most significantly, price. It is a misconception outside the industry that pharmaceuticals businesses are wealthy and cash rich. The industry knows the reverse to be true, and adding value while reducing costs are the bywords of modern manufacturing. Consolidating as much of the value chain as possible in controllable, reliable and flexible outsourcing companies holds many advantages.

A further factor has been the demise of blockbuster drugs, the last of which is likely to have gone by 2014 – representing

about $64 billion released into the generics marketplace. As a result many big pharma companies have had to consider the redeployment of existing plant, where the transfer costs and the price of validation can be prohibitively high. The trade-off between using existing, but sometimes inappropriate, plant, or outsourcing to a contract manufacturer that has state-of-the-art manufacturing equipment and also takes responsibility for validation, traceability and legislative compliance, is compelling.

Because OSD forms have changed little over many years, the assessment of the benefits of outsourcing lie with factors other than the ability to make the products. GMP parameters must be adhered to, including all the associated processes such as validation of the production facilities, batch recording, product marking and so forth, but the primary evaluation criteria are always likely to price and quality.

OSDs can require dry, wet and alcoholic granulation, tablet pressing and coating. Clients demand support with full regulatory and analytical expertise and capacity to make a broad range of tablet sizes, shapes and coatings. More than any other classical process, the manufacturing of tablets requires a degree of craftsmanship and experience.

To deliver a tenable alternative to in-house manufacture requires the outsourcing company to offer better than the product owner currently delivers. This is likely to entail investment on the part of the contract manufacturer in not only advanced machinery, plant, systems and controls, but also in maintaining quality and GMP processes. It is also a perquisite for most

Biovian_ad_A4_130109.fh11 13.1.2009 15:18 Page 1

Contract Manufacturing of Biopharmaceuticals

Microbial fermentation

Mammalian cell culture

Protein purification

Gene therapy vector production

Formulation

Fill & Finish

Lyophilisation

Analytical quality control

Cell bank preparation and storage

Biovian cGMP services


Dr Ingela Herrmann, MBA ESCP Europe, is a qualified pharmacist who worked for ten years for Roche. While there, she orchestrated the launch of the company’s Cenexi’s business within the outsourcing market in the role of marketing director. Previously, Ingela Herrmann was Project director for Roche’s new Products within the French market, and before that was the company’s QA manager. She then spent three years as account manager with Catalent before joining NextPharma Technologies in France in May 2009.Email: [email protected]

up thinking must preempt the linked processes.

One benefit in adopting a comprehensive approach is that while specific cGMP compliance may be assured at any single point in the process – be it tablet pressing, blister packing and so forth – it is also vital that the active ingredients, transfer process, packaging, cartooning, storage and distribution marry to deliver the whole solution. Having a central repository for quality, tracking and tracing data is a key to success. In this way documentation can be consistent, the approach to GMP unified, and certification simplified.

If outsourcing, the contract manufacturer should be able to bring to the table a wealth of experience and prior knowledge by which to facilitate project management. It is further intellectual property that goes with the deal whether that is simply manufacturing or other services upstream or downstream.

In conclusion, the outsourcing of OSD manufacturing solves not just a price, flexibility and value proposition, but also overcomes potentially costly GMP and other regulatory considerations. If manufacture is retained in-house, pharmaceuticals companies must consider the investment required to meet increasingly stringent regulations while retaining profitability..

are increasingly steering companies towards outsourcing this part of the drug development cycle.

Returning to the concept of taking responsibility for the entire value chain, the benefit of having a single outsource is significant when it comes to cGMP. As stated earlier, specific technical requirements are best handled by experts in the relevant field – OSD manufacturing technicians know all about the requirements of the manufacturing process for that form. However, it is also important to retain consistency of GMP approach across all the stages in manufacturing and logistics. A suitable outsourcing partner can assist in this regard because the expertise and experience comes as part of the package.

With effective GMP practices established, manufacturers should be able to respond quickly to transient needs. For example, the recent global Swine Flu scares have necessitated responsible manufacturers quickly putting both preventative and reactive countermeasures in place – albeit, properly set up safety systems would already disallow contamination from any disease.

Packaging controlOn which note, packaging has greater

implications under cGMP. While packaging design for OSDs has changed little in recent times – blisters predominate still and look likely to continue to do so – the requirement for control has increased dramatically. In spite of blister domination in most markets, there remain a large number of varieties of other OSD packages, any of which can be requested by a manufacturer. These include: blister packs (PVC/PVDC/PP/COC/Aclar/ALU-ALU foils); tubes for chewable and effervescent tablets; sachets (up to two formulations in one sachet); glass or plastic bottles for dry syrup; tamperproof closures; as well as carton boxes (secondary packaging). For dedicated solids such as hormones or betalactams, there are blister packs (PVC/PVDC/COC/Aclar/ALU-ALU foils); flow packs (blister in alu sachets) and standard sachets. All of these pack types require control.

One of the speculative trends a few years back was for all pharmaceutical products to be radio frequency identification (RFID) coded. This was driven in the USA for a time by large retailers, notably those such as Walmart, but endorsed by the likes of both the FDA and the packaging body the PMMI. In practice, the failure of the electronics industry to be able to develop inexpensive

devices – the quest continues for the ten-cent chip – has seen the RFID concept sit on a back burner as far as the pharma industry is concerned.

However, a number of factors have prompted some countries to assess how security and control might be improved. Factors influencing these decisions include bioterrorism concerns and counterfeiting issues. In Europe, for example, France is likely in future to demand the use of data matrix coding as used within the automotive industry for some time, and now increasingly used by the transport, leisure and tourism sectors.

Cold chain considerationsBeyond manufacturing and packaging,

cGMP also applies within the cold chain. Warehousing and storage facilities must be properly and traceably regulated for example. Controlled temperature storage and distribution services are supported by state-of-the-art technology appropriate for the pharmaceutical industry. While OSDs mostly require dry, humidity-free storage, some speciality drugs can require controlled room temperature storage down to minus 80°C. Picking, packing and shipping systems also need to ensure the correct product reaches its destination according to requirements.

Reliable outsourced businesses meet current good distribution practice (cGDP) and storage practice (cGSP) regulations. Such pre-wholesaling businesses deliver directly to pharmacies, hospitals, doctors, sales representatives and wholesalers. By outsourcing, smaller pharma companies can take advantage of economies of scale.

Logistics services include importation, receipt of goods, storage, order administration, processing of returns, pick, pack, ship/dispatch, accounting, invoicing and debt collection. All of this must be supported by sound information technology (IT) systems – ideally with seamless communication between sites. Again, it is control over batches, storage and handling under cGMP and cGSP/GDP that determines compliance for the client.

Project managementOverlooked at one’s peril is the need to

properly manage the entire value chain. Compliance with standards, whichever they are, will not mitigate for poor project management. This is never more so than where a complete development to distribution channel is established. Joined

For US inquiries please call +1-215-321-6930.For EU inquiries please call +49-751-3700-0.www.vetter-pharma.com

More than Filling.

One of 400 Million pre-filled systemsworldwide – filled by Vetter per year.

Expertise of over 25 years in aseptic contract filling

Support from clinical development to market success

Platform for lyophilized products:dual-chamber cartridges, dual-chamber syringes and vials

Making your product the best it can be.


Reason Drug Sample

Solubilisation of low water-solubility drugst

Diazepam, vitamin A, vitamin E, propofol, dexamethasone palmitate, progesterone

Stabilisation of hydrolytically susceptible compounds

Lomustine, physostigmine salicylate

Prevention of drug uptake by infusion sets Diazepam, Perilla Ketone

Reduction of irritation, pain, or toxicity of intravenously administered drugs

Amphotericine, diazepam, propofol

Potential for sustained release dosage forms

Barbiturates, dexamethasone palmitate, physostigmine salicylate

Possible directed drug delivery to various organs

Cytotoxic agents

Emulsions - established and promising drug carriers for parenteral administration

Emulsions – HistoryLipid emulsions were developed after

World War II to serve as an intravenous source of both calories and essential fatty acids. The first approved IV-emulsion, Intralipid®, was developed more than 40 years ago for parenteral nutrition. It consists of an O/W-emulsion of 10 or 20% soybean oil droplets (70-400nm in size) stabilised by a monolayer of egg yolk mixed with phospholipids (1.2%) and glycerol (2.25%) as an osmotic agent.

The wide and clinically well-accepted usage of this emulsion for parenteral nutrition later raised the possibility of using the internal oil core of this emulsion for solubilising water-insoluble drugs. The past decade has seen enormous activity in drug delivery and targeting research using emulsions as carriers of a wide variety of drugs.

Emulsions – Relevance in today´s medicine

Intravenously administered emulsions are today excellent carriers for lipophilic drugs which are often difficult to deliver (e.g. diazepam, vitamin A, vitamin E, propofol, dexamethasone palmitate, progesterone).

Emulsions are in general heterogeneous systems in which one immiscible liquid is dispersed as droplets in another liquid (simplified definition).

Normally one of the two immiscible liquids is water, and the second is an oily substance, often a long chain triglyceride (e.g. soybean oil). Hence, an emulsion in which the oil is dispersed as droplets throughout the aqueous phase is termed an oil-in-water (O/W) emulsion. All pharmaceutical emulsions designed for parenteral administration are of the O/W type. Emulsions do not form spontaneously. Energy input through shaking, stirring, homogenising or spray processes are needed to form an emulsion.

Over time, emulsions tend to revert to the stable state of the phases comprising the emulsion. Surface active substances (surfactants or emulsifiers) can increase the kinetic stability of emulsions greatly so that, once formed, the emulsion does not change significantly over years of storage.

Emulsions – Fundamentals - Composition

Normally one of the two immiscible liquids is water, and the second is an oily substance, often a long chain triglyceride (e.g. soybean oil). The most frequent emulsifiers used in parenteral emulsion formulation are phospholipids (generally from egg yolk sources). The main functions of the emulsifiers are to form a thin film in the interface and lower the surface tension, thus preventing flocculation and coalescence of the dispersed phase. Additives are needed to adjust to physiological pH and tonicity. Glycerol is most recommended as an isotonic agent, and can be found in almost every parenteral emulsion. The pH is adjusted to the desired value with an aqueous solution of NaOH or HCL. The pH of an emulsion should generally be adjusted between 7 and 8 to allow physiological compatibility and maintain emulsion physical integrity by minimising hydrolysis reactions of the components.

Table 1: Reasons for using medicated emulsions.


container the production unit runs different filling lines, which are adapted to a wide range of container types and formats.

Emulsions - SummaryEmulsions are today well-established

drug delivery systems of poorly water-soluble drugs. Fat emulsions are established and promising drug delivery systems which can solubilise considerable amounts of lipophilic drugs, control the in vivo disposition of incorporated drugs, and deliver drugs selectively to a target site. If emulsions are carefully designed with respect to the target and route of administration, they may provide one solution to some of the delivery problems posed by new classes of active molecules, such as peptides, proteins, genes, and oligonucleotides. They may also extend the therapeutic potential of established drugs..

Emulsions - Example:Propofol (2,6 di-isopropylphenol) is not

soluble in water.

It is presented as an oil-in-water-emulsion with 1ml of emulsion containing 10mg propofol (1%) or 1ml emulsion containing 20mg propofol (2%), respectively.Propofol is a highly effective short-acting hypnotic without analgesic properties. It is used for induction and maintenance of general anaesthesia and for sedation of mechanically-ventilated intensive care patients. Propofol emulsion appears as a highly opaque white fluid due to the scattering of light from the tiny (~150nm) oil droplets that it contains. It resembles milk, and is jocularly called “milk of amnesia” by medical professionals.

Emulsions – Relevance in medicineEmulsions are able to control the in vivo

disposition of incorporated drugs, and deliver drugs selectively to a target site. Emulsions are promising to improve the therapeutic index of drugs by increasing their efficacy and/or reducing their toxicity. Fat emulsion drug delivery systems offer today a wide variety of possibilities for preparing better-tolerated intravenous formulations of selected drugs, while either maintaining the same characteristics concerning pharmacokinetics and tissue distribution, or enhancing the site-specific delivery in targeted organs.

Emulsions – OutlookIf emulsions are carefully designed

with respect to the target and route of administration, they may provide one

solution to some of the delivery problems posed by new classes of active molecules, such as peptides, proteins, genes, and oligonucleotides. They may also extend the therapeutic potential of established drugs.

Emulsions – Manufacturing – The Challenge

Intravenous emulsions, like all parenteral products, are required to meet pharmacopoeial requirements. The emulsion must be sterile, isotonic, non-pyrogenic, non-toxic, biodegradable and stable. Furthermore, the particle size of the droplets has to be controlled accurately and needs to be within certain limits. To comply with these requirements, careful selection of the excipients and of the manufacturing process needs to be performed.

Emulsions – Manufacturing - Fresenius Kabi

Intensive research efforts at Fresenius Kabi for more than 30 years have been concentrated on the design of special injectable emulsion formulations that led to sucessful marketed products such as the emulsion of 1% propofol, a highly effective anaesthetic agent.

Emulsions – Manufacturing – Preparation process

In Graz emulsions are produced in state-of-the-art equipment under full cGMP-conditions, utilising batch sizes ranging from 5 litres to 6000 litres and fully automated high pressure homogenisers. In the first step the drug substance is dissolved in the oily component (e.g. soybean oil). This oily phase is then dispersed together with the emulsifier (e.g. Lecithin) in water for injection using an Ultra-turrax mixing device. The excipients (e.g. Glycerol and sodium oleate) are added under constant heating and stirring, forming the so called pre-emulsion.The pre-emulsion is afterwards homogenised via high pressure homogenisers.

Emulsions – Manufacturing – FillingFor filling the emulsions into the final

Anton Gerdenitsch, Master degree in Chemistry followed by Master degree in Economics. His main areas are Biotechnology and Biochemistry. Joined Fresenius Kabi in 2008 as Director Contract Manufacturing, from Sanochemia Pharmazeutika AG where he was Director Supply Chain Management and Logistics. Email: [email protected]

Copyright © Fresenius Kabi

Type Pre-filled syringes

Ampoules Vials Bottles IV-bags Multi-chamber bags

Speciality Devices

Size 1-50ml 1–20mL 1–100mL 50–1,000mL 40–5,000mL 100–5,000mL 1mL–200L

Material GlassPlastic

Glass Plastic

Glass Plastic

Glass Plastic

Non-PVC Non-PVC Various


At Moorfields Pharmaceuticals we are able to supply specialist unlicensed products and have capabilities to manufacture sterile liquid products for third parties, currently supplying numerous customers throughout the UK and overseas.

Moorfields Pharmaceuticals offers same day solution for trials

By focusing on smaller volumes and specialist requirements such as same day delivery, Moorfields Pharmaceuticals is offering a very dedicated service for the production of sterile, liquid pharmaceuticals for use in contract manufacturing and clinical trials.

Moorfields Pharmaceuticals concentrates on batch sizes of between 1 and 25,000 for vial presentations which it manufactures in a state-of-the-art facility built originally to fulfill the needs of the world-famous Moorfields Eye Hospital. The company has built on its heritage to provide the UK’s widest range of ophthalmic specials and has invested in leading edge manufacturing techniques which include a Rommelag 3012M blow-filling system. With the ability to produce as few as 5,000 ampoules this aseptic processing system is recognised as the superior solution for preservative free, ophthalmic drugs and sterile liquids for Phase 1 clinical trials.

Company Profile:


Specialists in ophthalmic and sterile liquid products

www.moorfieldspharmaceuticals.co.uk Tel: +44 (0)20 7684 9090

CASE STUDY:

Flexible response to trial recruitment delays

A small scale trial involved the manufacture of sterile syringes for a double blind, five way cross-over study for 20 patients over five weeks. This was complicated by the fact that two of the drugs had a limited stability of 24 hours and the remaining three had only five days expiry. In addition to this, the syringes for each day’s dosing had to be at a location over an hour away by 10am each day.

To ease some of the manufacturing intensity, Moorfields Pharmaceuticals agreed with the sponsors that the longer dated syringes could be produced a little in advance and only those with a 24 hour shelf life would be prepared on the morning of dosing. All syringes were held at the Moorfields site and delivered on a daily basis according to the randomization list.

After a smooth start, the trial ran into difficulties with recruitment. This impacted on the dates for dosing and hence the dates for manufacture to take place. Moorfields Pharmaceuticals worked closely with the customer to meet their changing needs and the new time frames and as a result the study was completed without problem.

Company Profile


Considerations for Choosing a CMO

of the needs of its product(s). There is considerable effort in the development of the active pharmaceutical ingredient (API). The safety, efficacy, dosing and numerous other tests and decisions that must go into this process are overwhelming. The evaluation of the formulation/filling CMO should be rigorous. How the product is “made” is presented to the FDA, and if the documentation is not sufficient, approval can be delayed and more studies may even be required prior to drug acceptance (or even clinical trial entry).

The stage of development that a drug is in becomes an important factor in the decision-making process. For example, if the company is a small start-up then it might not have the ability to hire a CMO that requires a six-month lead time and has a very rigid structure to its production schedule. If the product is in a Phase I or II trial it may require and allow more flexibility than a product in Phase III or commercial, where all aspects of development have already been determined. The filling equipment of a CMO can be a big issue if not evaluated correctly. For example, if a company has only a litre of product to fill and chooses a CMO that has only a commercial line that involves two litres of product (in hold up and line loss), then this is a poor match.

Assessing Company NeedsCompanies need to consider their risk

tolerance level; doing activities in parallel can create financial losses if there are manufacturing delays. How these delays impact your product and the CMO’s ability to accommodate changes in receiving the materials — such as the API — can make a big difference in early stage drug development. The cost to manufacture a product with a CMO is a critical consideration when it comes to selecting a CMO. However, this cost is significantly less than the cost of the clinical studies and the financial loss incurred in not achieving product goals.

ConfidentialityConfidentiality is rated a high priority

amongst biotech and pharmaceutical companies when choosing a CMO. You need to evaluate how the potential CMO

The development of a new drug is a complex venture that requires many evaluations and decisions prior to a commercial launch. Biotech and smaller pharmaceutical companies are increasingly choosing to outsource most, if not all, of their drug manufacturing efforts throughout the development phase, including the clinical trials that lead up to commercial acceptance. Due to the low success rate of drug commercialisation and the high cost of facility build out, validation, staffing and support needed to manufacture one product, the investment community does not support the building of manufacturing facilities to produce and fill a speciality drug until commercial acceptance is imminent. Many times, the investors of the drug, during the development phase, will not be the entity commercialising the product.

Large pharmaceutical companies are also beginning to outsource clinical (developmental) phase products in order to cut down overhead. They see outsourcing

as a way to improve asset management as well as gain access to emerging markets. We will focus on elements to consider when choosing to outsource drug production. Considerations can vary from active pharmaceutical manufacturing, formulation development, methods development, formulation and filling of the drug product, analytical development and testing, stability, packaging and distribution for clinical sites and storage of the finished product. Elements of the outsourcing process that should be considered when selecting a CMO are quality, timeliness, flexibility, technical expertise, facility/company size, confidentiality, facility compatibility, capacity, customer service and price. Since there are multiple CMO relationships that can be evaluated, this article will focus on choosing a formulation/filling CMO; the considerations presented can apply to other relationships as well.

Assessing Product NeedsThe first step in selecting a CMO is for a

drug developer to conduct an assessment

Ludger Ltd, Culham Science Centre, Oxfordshire OX14 3EB, UKTel: +44 870 085 7011 Email: [email protected]

www.ludger.com

We can design and execute appropriate glycoprofiling programmes for carbohydrate structure analysis of your therapeutic

(during product development and for regulatory submissions),perform glycoprofiling QC for product lot release, and transfer the optimised methods to your labs.

Glycoprofiling modules include:sialic acid profiling (to compare levels of NeuAc vs NeuGc),

quantitative monosaccharide analysis, and Level 1 and Level 2 profiling of N- and O-glycans by a range of

orthogonal HPLC and MS methods combined with detailed exoglycosidase sequencing.

Glycosylation can significantly affect the performance, consistency and cost of your biopharmaceutical.

L u d g e rSpecialists in biopharmaceutical glycoprofiling

Safety - e.g. levels of immunogenic non-human glycosylation

Efficacy - e.g. glycans affecting mAb Fc receptor functions, Fab glycosylation

Regulatory Compliance - e.g. IND submissions

Product Consistency - e.g. batch consistency during scale-up

Half Life and Stability - e.g. sialylation of EPO and FSH

Demonstrating Comparability - e.g. biosimilars vs innovator’s product

Patent Issues - e.g. patent infringement

We provide glycoprofiling products and analytical servicesto help you optimise, measure and control your product’s glycosylation

so you can deal effectively with:

G0 G1 G2 G2S G2S2


ensures confidentiality. The CMO should have a system in place that avoids the use of client names/initials, locks information in a secure area and sends the client separate passwords for electronic access to documents, under a separate cover. The issue of confidentiality can be critical when it comes to formulation development, because the formulation may provide a barrier to development. This issue is important for both the drug developer and the CMO. A drug developer would like to have a formulation/filling CMO with experience in handling drugs similar to the one they want manufactured; however, the CMO must also be diligent in maintaining confidentiality with any special/proprietary process. A confidentiality agreement is a must and it should, without question, be two-way. A CMO that signs only a one-way agreement is letting you know that it does not value its expertise.

Experience and ExpertiseWhen evaluating formulation/filling

CMOs, it is important to consider the following:

CMO compliance with the latest US •and European regulationsEquipment and facility status•Problem mitigation – knowledge and •experienceSystems to transfer production, if •required

Training, experience and personnel•

When choosing a CMO, the formulation complexities of the solution, filling, type of container (syringe, vial or other), final product processing (labelling, kitting, etc.), and volume required will dictate the size, experience and level of technical manufacturing expertise necessary. Consider the requirements of the product in regards to process scale-up, validation and/or stability testing, transfer issues, compound formulation, safety concerns and any regulatory implications. The regulatory and technical environment in CMO services is constantly changing. For example, many CMOs are utilising disposable technology to reduce cleaning requirements and the potential for cross-contamination, as they provide naive surfaces for every lot of production. Determine if the CMO is knowledgeable about and keeping up with the latest industry trends.

Facility SizeMatching your product to the facility size

is important. Facility infrastructure typically increases along with facility size. Many think “bigger is better” but this is not always true in drug development and processing. In early phase trials the quantity of the drug product available is often very small. Matching the equipment and the handling experience with the product is essential in

order to ensure a successful outcome. The phase you are in with a drug will dictate the capacity requirements of the formulation and fill. For larger, later stage production activities the output of the facility is critical to ensure success. It is important to evaluate the product’s requirements and determine the best fit.

The ideal CMO is one that can grow with a product’s success, but this is difficult — if not impossible — to find. CMOs that manufacture high volume commercial products typically lack the equipment and personnel to manage a developing product that requires low hold-up volume, flexibility in scheduling and development in manufacturing. Companies that specialise in small volume early stage products will have sufficient staff to assist with the transitions that occur throughout the development cycle. Evaluating the structure that you require for your stage of production is an important aspect in choosing the CMO that will meet your current and potential future requirements.

Client Satisfaction/Project ManagementA CMO committed to client satisfaction

and quality provides an environment in which both parties can grow and develop. There needs to be a strong sense of partnership and a high level of commitment from the CMOs you are evaluating. Once the


are listening. Learning from the experience of others can save time and money, and bring your product to market on schedule. Contact the CMO and be prepared to fill out a survey or send an RFP that relays all relevant information about the product.

The Site VisitA drug sponsor should always visit the

CMO’s site during the evaluation process. This visit gives the drug developer a good overview of how the CMO works. Touring the facility shows if it is a clean and functioning facility. This is the time to explore many of the considerations listed above. Evaluate, among other things, whether the staff grasp the scope of your project, quickly, and determine whether the engineers and chemists have familiarity with the product class. Drawing on a CMO’s experience can save time and potentially deliver a better outcome. For instance, drug or device sponsors believe that filling their product in a vial is the best administration method for a clinical setting. However, this practice can lead to errors in dosing and loss of extremely scarce product, consequently determining the path forward in container stability. Being open to advice from a CMO on which container to fill your product in might save you time and cost, and perhaps improve the clinical outcome. There are always some engineering challenges. It is important to develop confidence in the

CMO should have an understanding of the regulatory environment in which a product will be evaluated. If a product is being developed or manufactured by a CMO that is not aware of the regulations needed for the agency (FDA, EMEA) filing then there is a risk that they will not prepare adequate documentation for submission. This could lead to delays in approval and/or the request for additional studies.

In the early stages of drug or device development, parameters will be adjusted to meet efficacy targets better and/or overcome processing hurdles. The CMO making these adjustments should have a formal change control system that allows the client to present this documentation to the FDA (or other agency) during later stage filings. Gauging a CMO’s ability to make changes in an efficient and compliant manner is essential to the selection process.

Getting the ListFinding a CMO is simple — Google them.

Ask some industry colleagues who they have used and you have an ideal way to create your “short list” of CMOs to consider. Word-of-mouth is one of the most credible forms of advertising because people put their reputations on the line every time they make recommendations, but have nothing to gain except the appreciation of those who

project begins, the project manager is your in-house advocate. They are the liaison between you and other departments. Communication — early, often, and honest — is the only way to deal with these complex programmes. The CMO should provide a contact person from project management who should be ready and able to answer all questions quickly and accurately. The client and CMO must realise that they are partners in the production, learn to trust each other and work with each other to overcome any and all hurdles.

Many times the drug sponsor views the CMO as the expert with its product. A CMO may have expertise in a product class but each sponsor’s product is unique and should be treated as such. The sponsor needs to be the expert. Every detail of the formulation and filling process known by the sponsor should be communicated clearly and in writing to the CMO. Having the CMO re-develop the path may lead to errors and many times result in additional work, incurring extra costs, and increasing the time to completion. It is best not to assume anything; when issues arise, keep an open line of communication to promote a successful completion of the project.

Compliance/QualityMost companies need a CMO that can

operate under a variety of regulations. The

systems, and equipment maintenance and calibrations.

Also, look at measurements/metrics for monitoring and controls, deviations (the number and significance of them), technical transfer controls, capabilities, test methods and validations, material controls and inspections, supplier and material qualifications, purchasing controls, and laboratory controls. Determine the GMP compliance history, and SOP (Standard Operating Procedures) records. From this review a drug developer will be able to determine if a CMO has the technological knowledge, compliance record, and experience to provide solutions to problems and be able to complete documentation in a timely fashion.

The ContractIn a recent conversation with a

drug developer, we heard the following (paraphrased) statement, which summarised succinctly how many pharmaceutical and biotech companies think about selecting a CMO: “In choosing a CMO we looked at various factors that were relevant to the phase we are now in with developing our therapeutic. One of the most important factors was the regulatory aspect. We needed a CMO that had the specific capabilities, experience and production environment to meet our product’s specific

requirements. We needed a CMO that had the staff on hand to support our product from an analytical perspective. The inherent nature of our drug made it difficult to work with. It was important to have a CMO that uses its equipment on a regular basis and that if a piece of equipment needed maintenance then in-house personnel could repair it vs. waiting a week to have an outside vendor repair it. We also needed a CMO that had the analytical and lab support on-site. Finally, price was an important factor. The first three considerations were the most important, and once the CMO was able to meet those then we looked at price. It is important to factor in the cost of the tech transfer, which varies from CMO to CMO. Initially, we looked at 20 different CMOs and then were able to pare this group down to a shortlist of realistic contenders. The CMO we finally selected and contracted with worked with us on all aspects of the manufacturing project.”

Making the final decision on which CMO to select to manufacture a drug has two main aspects. First, evaluate a CMO for compliance, facility, experience, and capabilities. If these attributes of a CMO are positive then the second aspect to consider is the “personality” factor. Relationships vary between sponsors and CMOs. If you have a complicated product you will need to rely on the experience and expertise of the CMO to overcome the challenges, and being able to work together in this process is crucial. Consideration of all the elements presented above will lead to choosing the best CMO amongst all that are being evaluated ..

”A previous version of this article appeared in the October 2008 edition of Contract Pharma.”

Hyaluron Contract Manufacturing (HCM) is a scale-up process developer and aseptic filler of syringes, vials and custom containers from pre-clinical to commercial scale. HCM offers traditional filling, BUBBLE-FREE FILLING® and lyophilization. HCM excels in scale-up of difficult formulations including: emulsions; viscous gels; suspensions, liposomes, and proteins. HCM has been inspected by the FDA and is ISO certified.

competency level of the CMO. Devoting a minimum of four hours to the site visit will provide the opportunity to visit with most relevant departments such as Project Management, Engineering, Quality, Sales and Corporate. If you leave a site visit with confidence, then the next step would be to conduct an in-depth audit.

The AuditAuditing potential CMOs will provide

answers to many of the questions posed in this article. Evaluating three CMOs is recommended, and spending two days at the site is ideal. Being prepared for the audit will guarantee a better result. The more a drug developer knows about its product and the GMP regulations the more prepared it is to make a wise choice.

During the audit you will review documentation systems and discuss the project in more depth. All information and discussions should be viewed from a quality standpoint. First, learn about the company’s history, size, services, financial stability, future plans for growth and technological innovations. Then determine the training of personnel and the expertise level of the staff. Find out about the quality assurance and quality control systems, manuals, reviews and methodology; also determine certifications, document management, procedures and problem solution


A Trading Division of Dechra Ltd

®

www.dalespharma.com

CONTRACT MANUFACTURE

Contract manufacturing capacitynow includes our facility in Denmark!


THE DRUGS DON’T WORK ... OR DO THEY? WHY BRAND-SWITCHING IS BAD FOR BUSINESS

Switching patients from one brand of medication to another is common practice among clinicians as they strive for fast and lasting improvements to health. While on the surface this appears to be a necessary measure, ‘brand-hopping’ often obscures the real and widespread issue – that patients aren’t taking medication as prescribed. The phenomenon of ‘non-compliance’ creates a complex lose-lose situation for all parties; one I will explore in more detail in the following article.

Playing medical musical chairs Before investigating the implications of

brand-switching for the pharma industry, we must consider the process that provokes medical professionals to prescribe a new medication. Put simply, the adage ‘if it ain’t broke, don’t fix it’ applies here. As long as patients display signs of improved symptoms, clinicians have no reason to review their prescription. However, when medication appears not to have the desired effect, whatever the root cause may be, GPs and prescribing nurses take the natural course of action and try another route. That said, the true reason behind ineffective medication is not always as obvious as it seems.

The root of medication ‘malfunction’The failure of any drug to have the

desired effect can be due to three main parties: the manufacturer, the prescriber, or the person administering the medication (be it the patient, carer or nurse). Let’s look at each in turn.

A winning formula?The most readily accepted explanation

for drug inefficacy among typically often-overworked medical professionals is that the product isn’t delivering on its promise. In spite of extensive clinical trials proving a product’s efficacy, there are no guarantees that one plus one will equal two when it comes to the complex workings of the human system.

We only need look back to the thalidomide tragedy of the fifties and sixties to see that drug trials conducted in a controlled environment can never account for all potential outcomes. Modern clinical research is now much more stringent, minimising the likelihood of ineffective or dangerous drugs ever reaching the patient. That said, medication is still frequently withdrawn from the market due to perceived inefficacy or health risks. Senile dementia drug Cyclandelate is one example, withdrawn not due to negative effects, but due to its lack of efficacy.

Even the most tried and tested medication can have varying levels of efficacy from patient to patient. So if medication appears not to be doing its job, clinicians will logically

recommend an alternative. If the reason for drug inefficacy doesn’t lie with the product itself, human error provides an alternative explanation.

A matter of fallibility not inefficacyNo matter how experienced the clinician,

the possibility of human error is inevitable, and research indicates the incidence of incorrect prescribing can be surprisingly high. Latest findings in a study of 1329 elderly patients in the Republic of Ireland revealed over 18 per cent were prescribed inappropriate medicines by their GP(1).

The report concluded that these prescribing errors were largely unnecessary and avoidable. This underlines the fact that the suspected inefficacy of a drug can

Packaging


commonly be attributed to straightforward human fallibility on the part of the clinician, the patient or both. An error of judgement on the clinician’s part, or a patient’s omission to accurately report on their symptoms and any over-the-counter (OTC) medication they are taking, can all impact the compatibility of patient and product.

Thinking outside the boxOnce a pharmaceutical product is

approved, one of the greatest challenges in ensuring its efficacy is in preventing ‘off-label’ prescribing by clinicians. Few drugs are approved for use in all conditions, rather, they are trialled and approved to treat specific problems, or work in certain timeframes. In reality, clinicians often discover through experience that drugs approved to treat one disease have other uses, for example, a headache remedy could help ease arthritis symptoms. Alternatively, they may allow patients to take a drug designed for short-term use over a long period. Prescribing outside of approved conditions can created unexpected effects, or conversely, mean that medication fails to deliver the expected results.

The truth about self-administrationIn spite of stringent clinical trials on

any drug, once it enters the market and is prescribed, its efficacy and commercial

success can depend greatly on the patient’s (unpredictable) behaviour. In a highly controlled research environment, medication is taken in the quantity specified, at the agreed intervals, and in isolation from any other medication that could produce unpredictable effects. In the real world, self-administration is exposed to an assortment of ever-changing conditions which can dramatically impact a drug’s efficacy.

Forgetfulness, apathy and the chaos of modern life can all result in a patient failing to take medication as instructed. This can be as simple as skipping doses, taking it in the wrong quantity, or at the wrong time of day. Commonly, patients stop taking medication when the symptoms disappear, or take them in combination with previous prescriptions or OTC drugs without knowing the potential side-effects. Whatever the reason, patients may report that a drug is not working, when in fact, it simply hasn’t been given a level playing field.

Everyday errorJust as patients’ judgement can lapse

when it comes to taking medication, medical professionals are subject to the same challenges (i.e. lack of time or knowledge, or straightforward distractions) when administering drugs. Recent research (2) revealed that seven out of ten care

home residents have been given the wrong medication. This shocking figure refers to patients receiving the wrong drug or the wrong dosage. As with self-administered medication, a lack of results can be interpreted as being the fault of the drug, when in fact, it is simply not being taken as instructed.

What does this mean for pharma?We’ve established that the actions of

patient, carer or prescriber can have as great an influence on drug efficacy as the makeup of the product itself. But whatever the reason for incorrectly ‘writing off’ a particular product, the net result is the same: prescribers recommend an alternative (brand-switching), unnecessarily occupying medical professionals’ time and slowing the patient’s recovery: a negative result for patient and health professional.

From a pharma manufacturer’s perspective, however, drug wastage isn’t seen as a significant problem. After all, if a product is prescribed and perceived not to be working, the purchase has already been made and the threat of returns that impacts sales of other consumables does not apply. Also, since brand-switching is so common, there is an underlying assumption that as patients transfer from one brand to another, any lost business will ‘come back around’ in the longer term.

If at first you don’t succeed, try, try againIn truth, brand-switching is a vicious

circle. Let’s look at this in context. A GP may prescribe brand A, instructing the patient to take it three times daily after meals. The patient half-listens to the instructions and takes the drug haphazardly, skipping doses and taking it as and when he/she remembers. On returning to the GP two weeks later, the patient reports little improvement, and the doctor drops brand A in favour of the longer-established (and more expensive) brand B. A self-perpetuating cycle like this can go on and on, creating a lose-lose situation where no brand is given a fair opportunity to function.

Giving innovation a chanceClinicians are creatures of logic and

habit, favouring familiar, tried and tested, long-standing brands that offer predictable results. When new drugs come on the market, pharma companies have already invested hundreds of thousands on R&D, before spending further hundreds of thousands on sales reps and marketing to get new products recognised and to galvanise health professionals to try them.


Norman Niven CEO, Protomed has thirty years experience of primary and secondary healthcare as former director of BUPA Care services. From his roots a s a pharmacist, Norman has applied his industry knowledge and entrepreneurial streak to develop the total medication management system Biodose. As a member of HCPC Europe (healthcare Compliance and Packaging Council), he now helps raise awareness of the role of packaging technologies in patient compliance.

Ultimately, the adoption of new medication brands is based on a fragile bond of trust between health authorities’ procurement departments and sales reps, trust that the product will deliver on its promise.

Typically, new products have a narrow window of time in which to ‘prove themselves’, so if and when a product fails to have the desired effect, the likely outcome is that prescribers will default to ‘old faithful’ brands, which are typically more expensive. This subsequent effect on drug budgets means that this is bad news for both public and private healthcare institutions.

One chance at a first impressionThe biggest loser in this scenario is the

new kid on the block. The innovative new drug which hasn’t been given a fair chance, and without further persuasion and marketing spend, is unlikely to make it back into that clinician’s radar of preferred products. When patients are prematurely switched away from a product, the manufacturer misses out on the prescriber’s potentially lifelong loyalty. Had the drug been taken correctly, the results reported accurately by the patient and monitored closely by the clinician, the new brand may have rightly earned its stripes in the GP’s eyes. Consequently, positive word-of-mouth marketing could lead to a steady stream of revenue, quickly offsetting the considerable initial NPD investment.

Winner takes all?On the surface, the newly-adopted brand

B should be the victor here. However, both clinicians and patients demand results, and in spite of the many possible behavioural causes of the drug’s inefficacy that may never come to light, if brand B also appears not to work, it will become another victim of brand-switching. The worst-case outcome of this self-perpetuating cycle is that brands are withdrawn from sale, with pharma manufacturers forced to swallow the bitter pill of major financial loss and the damage to reputation that comes with it.

Brand-switching is equally detrimental for medical authorities. For public health organisations, brand-switching equates to waste; waste of already scarce funds spent on medication that may be unnecessary and that doesn’t deliver results. The consequence? An avoidable burden on a health service looking to improve recovery rates and make optimum use of health professionals’ time. In the private sector, the switching cycle eats into medication budgets, pushing private healthcare

premiums higher and in turn creating a more difficult selling proposition.

The antidote to switching We’ve established that drug inefficacy

is only one of numerous potential catalysts associated with unnecessary drug-switching. Looking behind the issue, incorrectly administering medication and failing to accurately report on the results is a more likely reason why patients hop from one brand to another without success. A clear solution to this unconstructive and costly trend is to increase patient compliance; that is, to ensure medication is taken or administered as and when directed so its effects can be evaluated objectively.

Ignorance is no longer an excuseThe question here is, how can we

ensure patients or carers administering medication are following instructions on when and how to take it? In the last decade, monitored dosage packaging systems such as Biodose® have become increasingly sophisticated. The concept is quickly catching on in the UK among pharmacists, who are now equipped to provide prescriptions for care home residents or directly to patients, in foolproof, pre-measured pods, labelled with date, time and patient data. With most elderly patients taking over five different medications simultaneously (1), pro-compliance packaging is going a long way to minimising the human error that leads to premature brand-switching. Plus, microchips embedded in drug packaging can also record when each day’s pod is opened, alerting GPs, carers or family members if medication isn’t taken correctly. This presents massive potential for reducing non-compliance and offers a major opportunity to the pharma industry.

The route to long-term loyaltyBased on the success of the compliance

monitoring model in a pharmacist-to-patient channel, the pharma industry can adopt this approach to add value to their brands and encourage clinicians’ loyalty. Imagine a pharma company funding the use of compliance-monitoring packaging with new or ailing medication brands and promoting this to medical professionals. From a clinican’s perspective, the benefits of monitored dosage systems are vast. The fact that it increases the likelihood of patients following instructions, but also alerts the GP or nurse in the case of non-compliance, increases the probability of the product’s efficacy and the patient’s recovery. On this basis, knowing that a particular brand of medication is supplied to patients (via

pharmacists) in high compliance packaging would go a long way to influencing medical professionals’ decision over which drug to prescribe.

Bottom line benefitsIf medication is taken properly, and its

perceived success rate increases, the need to switch brands declines. The upshot? New drugs will be given a greater opportunity to ‘prove themselves’ among medical practitioners, and greater efficacy will engender long-term loyalty. Ultimately, this will help pharma products achieve the holy grail of branding; the switch from a high-maintenance, revenue-sapping ‘dog’ to a self-funding, profit-building ‘cash cow’.

In shortThe complex thought and behavioural

processes that influence the prescribing-administering-reporting-recovery cycle can mark the death-knell of any pharma brand, not to mention wasting valuable resources and impacting patient welfare. Yet technology offers pharma companies a potentially lucrative route to long-term brand loyalty and increased market share. Looking at it this way, who wouldn’t consider the opportunity to go from a lose-lose to a win-win situation?.

References:1‘Potentially inappropriate prescribing in

an Irish elderly population in primary care’, British Journal of Pharmacology, November 2009.

2 Research by University of London’s School of Pharmacy – published Oct 09.

Vienna School of Clinical ResearchBUILDING BRIDGES THROUGH TRAINING AND EDUCATION

The Vienna School of Clinical Research (VSCR) is an international non-profit organisation dedicated to continuing education of physicians and other experts who are involved in clinical research. The VSCR has trained more than 4000 experts from 90 countries over the last 8 years. Since 2001, approximately 20 different course modules have been developed, involving an international faculty of around 150 experts from more than 40 different countries. The courses cover topics relevant to clinical trialists including GCP, trial design and methodology, evidence based medicine, biostatistics, clinical epidemiology, ethics, publication, project management and health outcomes research.

This educational programme aims at optimising clinical research by minimising risks and cost while maximising the scientific value as well as ethical and quality standards. Based on a partnership between public bodies (City of Vienna, Austrian Government, European Commission), academic centres (15 universities in Europe, US and Africa) and the private sector (pharma and other industry), the VSCR promotes international dialogue and exchange, thus building bridges across stakeholders.

Vienna School of Clinical ResearchKoelblgasse 10, A-1030 Vienna

Tel: +43 (0)1 7134051-0Fax: +43 (0)1 7134051-99

Email: [email protected]: www.vscr.at

Vienna School of Clinical Research

Upcoming Courses in Vienna

07 – 11 Sept 2009 Systematic Reviews to Support Reimbursement Decisions and Evidence Based Medicine

11 – 16 Oct 2009 Health Outcomes Research: Pharmacoeconomics, the Economic Evaluation of Health Care

19 – 21 Oct 2009 Advanced Good Clinical Practice

29 Nov – 04 Dec 2009 Health Outcomes Research: Drug Pricing, Reimbursement Policy

07 – 11 Dec 2009Publication Masterclass: How to Publish Abstracts, Posters, Review Articles, Observational Studies and Case Studies


Global standard for medication adherence monitoring

activities around three focus areas: fitness and wellness, chronic disease management, and ageing independently.

The Continua mission is: “To establish an eco-system of interoperable personal health systems that empower people & organizations to better manage their health and wellness.” The 22 founding members stated: “We can enable a personal health eco-system where many diverse vendors can combine their products into new value propositions with significant health benefits for people worldwide.”

The Continua Use Case for medication monitoring was developed under the chairmanship of Cypak (www.cypak.com) with input from healthcare providers such as Kaiser Permanente, Partners, and the National Health Service. Pharmaceutical companies such as Pfizer contributed, as did service providers like Tunstall, Philips, and technology companies like Cypak and Panasonic.

After approval of the Use Case by Continua, the technical work passed to IEEE. IEEE draws on the expertise of a global membership of over 375,000 engineers and is the leading international body responsible for developing and maintaining over 1300 international standards, including Wifi, Bluetooth, and most of the interoperable norms at the heart of today’s information technology. The IEEE 11073 working group is chartered to develop standards for Personal Health Devices, including medication monitoring which is titled 10472. A major benefit of working with IEEE for medication monitoring is to utilise the same common basis – called 11073-20601 – for all monitoring devices. This means the same common core is used for blood pressure monitoring, ECG, glucose monitoring, fitness devices, oxymeters, and many other device specialisations. Systems can be built easily on a single platform to measure both medication adherence and efficacy.

IEEE standards are open standards that can be used by any member company to build compliant devices. In the case of

The world spends more every year on pharmaceuticals than the USA has spent in total on the war in Iraq. And whatever we think individually about the war in Iraq, most of us agree that much of the pharmaceutical spend is wasted.

We are increasingly convinced that many prescribed medicines are not taken properly. The National Institute of Clinical Excellence (NICE) published a thorough review in 2009; the Cochrane Collaboration presents similar evidence regularly; the World Health Organization supports the broad conclusions. People differ on the exact extent of the problem – we have not been measuring systematically – but most are now convinced that the opportunity to improve patient compliance for prescribed medication is massive. Healthcare costs are rising above 10% of GDP, and a significant amount is directly attributable to the raw pharmaceutical spend. Incidental costs caused by non-compliance are even higher. According to recent back-of-the-envelope calculations done by the New England Health Institute (NEHI), the cost of non-compliance in the USA alone approaches 300 BILLION dollars annually, with two thirds due to avoidable hospitalisation. Payers will take action.

Pharmaceutical companies are also convinced. Apart from the pressure to provide an evidence base to support their pricing, they know that over 90% of their marketing spend goes to acquire new clients. When said clients, many with long-term chronic therapies, stop taking their medicines within three months, pharma knows that improving adherence is a vital marketing necessity.

Patients too look for change. The majority trust that medicines work but many forget to take them on schedule, worry about side-effects and efficacy, and want help. Patients are the big winners from improved adherence - they can manage their conditions better with a bigger chance to live outside hospitals and care homes for longer. Monitoring medicine intake and communicating more closely with their support network are the first steps. The technology now exists to support patients

in managing their own medication, and to build a record of adherence that is of value to themselves, their care professionals, and concerned family. A complete picture of many patients will provide data to analysts, insurers, and pharmaceutical companies – data that has been sadly lacking up to now and which will build a more reliable picture of efficacy in future.

Today adherence data is not captured. The professional rarely has a scientific way to determine whether a patient is compliant. The anecdotal evidence provided by the patient is notoriously imprecise. Memory is fickle and the “white-coat syndrome” well documented.

Standards are needed because over 40% of patients take multiple medications – often from several different sources. Adherence support should work in the same way for all medication, just as we can step into any car and drive it. Doctors and pharmacists have one computer system on their desk and need the data from all their patients to be presented in a similar way. Communication depends on standards and there are potentially many people to communicate with - family members, care visitors, pharmacists, family doctors, and clinical specialists. Many different systems will read adherence data, either a special device in the home, a normal mobile phone or customised PDA, or a computer screen linked to a specific clinical network. Standards for adherence data enable integration with the care network. International standards are needed when people travel and to enable manufacturers to develop affordable systems in which innovations can be integrated quickly and easily.

The drive for standards for medication adherence monitoring began in the Continua Health Alliance (www.continuaalliance.org). Continua was founded in June 2006. It is a unique combination of healthcare organisations, information and health service companies, device manufacturers and health technology providers. Today Continua has over 200 members and many established global leaders. It organises its


Chris Johnson, leads medication monitoring activities in Continua Health Alliance and IEEE 11073-10472. He is Vice-President Cypak and Director of the Healthcare Compliance Packaging Council. Email: [email protected]

Some healthcare providers expressed a desire to have absolute certainty that a “dosage event” means that a patient actually swallowed the pill after taking it out of the package. The group resisted this on two grounds. Firstly, patient cooperation is essential to improving adherence and outcomes and patients are more likely to cooperate when not compelled. With up to 70% of patients not complying in some studies, it did not seem productive to drive the standard in a direction that would perhaps result in a rejection of the whole concept of adherence monitoring. Secondly, the technology for detecting that a substance is ingested is in a very early stage – RF tagging of pills, for example – and consumer reaction often not tested at all. Instead of striving for absolute certainty, the groups chose to adopt the Continua model of providing vital sign monitors alongside medication monitors to highlight problems in 99% of cases with patient choice paramount.

Some optional features of the 10472 standard are added because they are easy to add reliably to an electronic system. Tampering, for example, is easy to detect and record with an electronic system. Storage of drugs beyond licensed temperatures and humidity ranges is equally easy to detect. The expiry date is easy to detect when you have a real time clock. All these optional features have value for adherence – patients should take medicine that is effective.

Products conforming to IEEE 11073-10472 and Continua Health Alliance will have a major impact on the way pharmaceuticals are packaged and delivered in future. For the first time patients will be provided with a standard system to manage their medications and record data for objective discussions with their carers. As adherence rates rise, hospital and care home admissions will fall and more chronic patients will use medications properly for the long term. All involved should benefit by adopting the international global standards..

11073-10472 several companies are already offering technology platforms to deliver the basic level of interoperability. Cypak (www.cypak.com) has already made a public announcement.

IEEE made an agreement with ISO, the International Standards Organization, to take the 11073 specifications to full international status. This process started for medication monitoring in 2009 and should result in a fast track acceptance globally. The final vote on content was passed in October 2009 with a 97% approval, and substantial changes are not expected before ratification. Ratification will confirm conformance with IEEE and ISO editorial standards and processes, and prepare for publication in 2010.

The active participating organisations – around 50 in total – built a simple patient-centric system. The main actors in improving compliance are the patients themselves, while the other actors, both family and professionals, are enabled to support when given patient permission. 10472 may also be used in future situations where high adherence might be considered mandatory, for example when public health concerns are critical (tuberculosis, HIV, anti-virals) or when the costs of non-compliance are very high (transplant surgery and cancer treatments). However, in many cases patient cooperation is vital to manage long-term use of medication whether for contraception, psychiatric illness, or management of chronic conditions such as hypertension and diabetes.

Patients prefer to be mobile, continuing their normal work and social lives while managing their condition. The standard assumes that many medication monitors will be integrated electronically into a variety of packaging that travels with the patient. Low power, local storage, and low cost are high on the list of priorities.

Typically a 10472 device will be powered for its lifetime by a small battery, have a memory to record dosage events, and a clock for accurate time-stamping and reminders. Dosage events can either be fixed quantities or variable. Optionally the patient is able to record a personal diary as a series of events, a time-stamped indication of subjective feelings such as level of pain or moments of faintness. The data captured is customised to fit the therapy – and the patient. The result is an accurate record of patient compliance and subjective reactions that can be used for an objective discussion around side-effects and adherence with healthcare professionals and

other carers.

The 10472 standard is designed for automatic use with a wide variety of packages, including carded blister packs, plain blisters, bottles, syringes, inhalers, and the personalised pharmacy-packed multi-dose containers that are making a big impact in chronic care. The standard is flexible and does not place limitations on the chosen packaging. A report card may also be constructed for use alongside standard packaging. Instead of dosage events being captured automatically, the patient indicates a dosage event or symptoms on the report card. The emphasis is to capture relevant data in a standard format – a shared language that is understood worldwide.

Extensive discussions decided which elements should be included in the core standard, which elements should be optional but in a standard format, and which should be left to manufacturers’ own invention. Technological companies argued long and hard to include pharmaceutical nomenclature in the core standard, before accepting the medical advice that currently there is no universal and appropriate nomenclature. Each 10472 device will, however, have a unique identifier even when a device is refilled. The unique identifier can be used in a local healthcare system to tie an adherence device to a unique context such as patient identifier and individual patient prescription according to local nomenclature standards.

A similar discussion took place around reminder systems, and again it was decided to leave the exact user implementation to the creativity of individual manufacturers while ensuring that basic standards for recording time and adherence intervals are established. Adherence is not an automatic problem for every patient when a dose is missed. Many therapies are designed to accommodate non-compliance, while others are dependent for their success on a rigid adherence. 10472 specifies optional parameters that can be programmed by the pharmacist or manufacturer to define when a patient or professional should be alarmed by an actual level of non-compliance. The exact implementation of a reminder scheme is also flexible. In extreme cases the 10472 can be online to a monitoring centre and trigger intervention 24/7. In other cases a periodic review of adherence is sufficient. Some trials report good results with an SMS reminder scheme, others with patients programming their own alarm. 10472 is a solid basis for a wide variety of implementations.


Combating Drug Counterfeiting Using Advanced Packaging Technologies

authorized repackager shall repack again in a tamper-proof packaging.

New secure packaging technologies have been developed to facilitate easy regulatory compliance.

Secure Packaging as an Anti-Counterfeiting Measure

Defeating the counterfeiters demands a multi-level approach, an element of which is secure packaging. However, in order to ensure optimal security of pharmaceutical packaging, both overt and covert technologies need to be used.

Latest technological advancements have seen the introduction of a multi-level range of solutions with which to ensure the security of pharmaceutical packaging in order to safeguard the supply chain and authenticate products within the global pharmaceutical market. The solutions incorporate sophisticated covert technology for use by customs agencies, authorized distributors and other parties with access to high tech readers or secure databases. They also feature advanced overt identification capabilities for users who have to rely on the evidence of their own eyes.

The new technologies offer the flexibility to be adjusted to the specific security issues and needs of each company. On that basis, they can incorporate a blend of features, from overt counterfeiting deterrents such as holograms and security seals, to invisible markers that can be placed anywhere on the package. These countermeasures can be fully integrated into wider solutions, such as electronic readers and secure database systems used by manufacturers, distributors or government agencies. The result is a suite of solutions that is effective at all stages of the supply chain, virtually anywhere in the world.

Overt TechnologiesOvert features enable instant

authentication of packaging through visual inspection by the user without requiring

Counterfeit drugs are increasingly infiltrating the global pharmaceutical supply chain, threatening the health of patients and incurring a high cost to drug manufacturers. Packaging plays a key role in counterfeiting prevention. As a result, strict legislation is in force to ensure that pharmaceutical packaging cannot be easily reproduced. New technologies have been developed enabling packaging manufacturers to produce secure packs and comply with regulations. This article discusses the issue of counterfeit drugs, outlines current legislation and discusses latest secure packaging technologies and their unique benefits.

The World Health Organization (WHO) estimates that 30% of medicines in some areas of the developing world and 50% of drugs bought from illegal online pharmacies may be counterfeit. The problem, however, is not confined to less developed countries or the Internet. Whilst the scale of the threat is hard to quantify, WHO has suggested that 1% of prescribed drugs in the developed world may be counterfeit. WHO estimates that the counterfeit drug market will continue growing by approximately 13% a year and global trade of fake medicines will be worth £75 billion by 2010.

There is no doubt that counterfeiters are becoming more sophisticated and capable in the way they package their products. In addition to manufacturing fake drugs, counterfeiters are seeking to infiltrate the legitimate supply chain. By doing so, they can steal genuine shipments and divert them to alternative markets, where they can resell them to their own benefit. ‘Third shift’ packaging production by irresponsible contract manufacturers has also been identified as a threat to the security of the global drug supply chain, where contractors undertake additional, secret production runs and sell the resulting genuine packaging to counterfeiters. In response, global regulatory bodies have introduced stringent legislation to ensure maximum security of pharmaceutical packaging.

Regulatory OutlookThe WHO Expert Committee on

Specifications for Pharmaceutical Preparations has stressed the importance of implementing a quality assurance program. In the relevant report1, the committee focuses on the role of packaging in relation to the stability of pharmaceuticals and the potential for counterfeiting. It is specified that the design of the packaging must contribute to preventing tampering with, or the counterfeiting of, the enclosed medicinal products. Packaging must also carry the correct information and identification of the product.

The US Food and Drug Administration (FDA) enforces rule 21 CFR Part 2112, which specifies current good manufacturing practice for finished pharmaceuticals. Within this framework, the rule mandates that tamper-evident packaging should be used for over-the-counter (OTC) human drug products. According to the regulation, a tamper-evident package has one or more indicators or barriers to entry which, if breached or missing, can reasonably be expected to provide visible evidence that tampering has occurred. It should not be able to duplicate the packaging using commonly available materials or processes.

In 2003, in response to the increasing number of counterfeiting incidents, the US FDA formed a Counterfeit Drug Task Force3. The force aims to create a comprehensive system of modern protective measures against counterfeit drugs. One of the measures is to ensure the security of packaging by using tamper-resistant tapes, holograms and colour-shifting inks and dyes.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published a white paper4 on the anti-counterfeiting of medicines. It is clearly stated in the document that packaging should be adequately marked to prevent reproduction. In cases of tamper-proof packaging that needs to be repackaged, the


expert knowledge. Optically variable features such as holographic devices within the design and colour shift inks are the most common and effective overt security features, enabling packaging to be validated both quickly and easily.

HolographyEasily identifiable holograms, showing

the pharmaceutical manufacturer’s logo for example, are primarily used as first level identification devices and are designed to enable successful authentication at point of inspection. Additional features, such as nanotext and hidden images, can be used as second and third level techniques for trained and equipped specialists.

High security holograms cannot be reproduced by using conventional printing methods available on the market. In addition, tiny holographic markers can be printed in a predetermined position on the packaging. These markers are clearly visible when viewed with a magnifier, but invisible to the naked eye.

Whilst holograms offer a high level of overt security on their own, they can also be used in combination with other security devices to provide another hurdle for would-be counterfeiters to overcome, including colour shift inks.

Colour Shift InksColour shift inks appear as two or more

distinct colours when viewed from differing viewing angles. Such features are easily verified by tilting the item carrying the colour-shift in order that the different colours can be seen. Different colour combinations are available and both strong opaque and subtle transparent effects can be created to compliment the existing design of the packaging.

Currently, only a limited number of security suppliers produce colour-shift inks since the process to create the colour-shift pigment is highly specialized requiring particular technical knowledge and bespoke equipment. Supply of colour-shift inks is tightly controlled to ensure that the products are used only in genuine circumstances and under strict codes of conduct including end use agreements.

Covert TechnologiesThe level of packaging security can be

further increased with the introduction of covert and forensic features. Covert techniques such as infra red (IR) and ultra violet (UV) pigments, microtext and

microscopic tagging are invisible and difficult to detect and replicate without specialist detection equipment. As a result, they provide a higher level of protection. Forensic solutions include molecular markers and biological tracers. These features can only be identified using laboratory equipment, offering complete confidence in packaging authentication.

UV Inks and PrintThe images printed with a UV ink are only

visible under a UV light. UV inks are available in different frequencies. Depending on the formulation of the ink, the investigators will need to use either a long wave or short wave UV light in order for the printed images or text to become visible. Images and text can be printed in a variety of UV colours ranging from blue to yellow to red. Even UV ‘picture’ images can be printed in full colour or black and white, with grey scale or ‘flesh tones’ that are again only visible under a UV light source.

The level of security with UV inks and print is defined by the limited access to the inks and their component pigments with a genuinely secure range of inks only available under restricted use measures. By combining the colours to create photographic images, the level of security is further increased due

to the highly specialized origination and printing techniques required.

Sophisticated printing capabilities also allow for the creation of fine line designs as well as colour and UV microtext prints, similar to those used in bank notes.

Colour and UV Microtext PrintMicrotext print creates text characters

which cannot be seen with the naked eye and can therefore be hidden within larger overt images such as text and pictures without the knowledge of the consumer or potential counterfeiter. These complex designs are hard to reproduce and can be further validated using a magnifying lens or microscope to examine the detailed features and sophisticated print. Such equipment is inexpensive, readily available and pocket sized, making microtext print a very user friendly technology. Due to the need for specialist printing equipment, materials and technical knowledge, this technique is extremely difficult to copy. As the technology is covert, many counterfeiters simply do not attempt replication and create the overt image without the inclusion of microtext print.Microtext can also be printed using a UV ink. In that case, the finished image is only visible under UV light and with a magnifying lens. The invisibility of this


Richard Burhouse, joined Payne Security’s parent company, Filtrona in 2000 on a Graduate Management Development Program and has held various commercial roles within its Coated & Security Products business. Previously Richard was Marketing Manager for secure track & trace technology company FractureCode Corporation, Copenhagen, Denmark. Richard serves on the board of International Authentication Association and holds a Bachelor of Science Degree in Chemistry and Business, a Post-Graduate Certificate in Management and is a Chartered Marketer, CIM.Email: [email protected]

h3009e.pdf 2. US Food and Drug Administration,

CFR - Code of Federal Regulations Title 21 FOOD AND DRUGS, CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES, SUBCHAPTER C--DRUGS: GENERAL, PART 211 -- CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS, Subpart G--Packaging and Labeling Control, Sec. 211.132 Tamper-evident packaging requirements for over-the-counter (OTC) human drug products, http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.132&SearchTerm=packaging

3. US Food and Drug Administration, FDA Counterfeit Drug Task Force Reports, http://www.fda.gov/Drugs/DrugSafety/ucm169825.htm

4. European Federation of Pharmaceutical Industries and Associations, WHITE PAPER

ON THE ANTI-COUNTERFEITING OF MEDICINES, November 2005, http://212.3.246.100/Objects/2/Fi les/Counterfietingwhitepaper20052.pdf

5. Anti-counterfeiting Packaging Technologies in the U.S. Pharmaceutical and Food Industries, January 2007, BCC Research, http://www.reportbuyer.com/pharma_healthcare/general_industry/a n t i _ c o u n t e r f e i t i n g _ p a c k a g i n g _technologies_u_s_pharmaceutical_food_industries.html

variable line width, guilloche designs, crystal patterns and special rasters.

Security Tear TapeFinally, in addition to the different

overt and covert security techniques and technologies that can be used to protect products, the carriers that these security devices feature on also offer an opportunity to “out fox” the counterfeiter. Using materials that are available from a relatively small numbers of sources makes it even more difficult to create a convincing “pass-off”.

One such example of this is in the use of security tear tape in combination with shrink sleeves as an anti-tamper solution around bottle caps. The tear tape is an ideal medium to integrate a brand protection solution into product packaging. It can carry a variety of sophisticated brand protection features available from overt and covert authentication and tamper evidence technologies.

The tear tape technology provides solutions for authentication, tamper evidence and product coding. It is virtually impossible to remove the tear tape without destroying it, thereby preventing opening packs, refilling and resealing them without detection. In addition, the removal of the tear tape from the original packaging can be designed to damage the pack surface, leaving behind a void/ tampered message on the pack. This means that the original tear tape cannot be reused by the counterfeiters. As a consequence, counterfeit products are prevented from infiltrating genuine batches.

ConclusionThe pharmaceutical packaging

counterfeiting threat is continually developing and new secure techniques have been developed to combat it. Overt, covert and forensic technologies are applied to ensure that packaging cannot be reused or misappropriated. Anti-theft, tamper evidence and authentication solutions enable inferior and potentially harmful counterfeit products to be reliably intercepted and stolen genuine products recovered. By implementing the new security techniques, robust and reliable protection from tampering, copying and brand infringement is enabled and counterfeiting becomes a difficult and costly process..

References:1. WHO EXPERT COMMITTEE ON

SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS, Thirty-sixth Report, http://apps.who.int/medicinedocs/pdf/h3009e/

printing technology enables it to be used without affecting other design elements. Although the text size is slightly larger than with standard microtext print, the UV invisible ink considerably enhances security. Multi-colour responses to UV light are available that further increase the level of security.

Added security is ensured by incorporating taggants on packaging to ensure reliable identification of the product and its source of manufacture.

Taggant AuthenticationTaggant authentication technology

provides a highly secure method for on-site or in-field applications. Pharmaceutical companies can integrate taggants to quickly protect and authenticate packaging in the market, through using most standard printing and coating techniques. Authentication is a key factor for the technology, which can reliably identify and distinguish genuine packaging from counterfeit ones.

The most highly secure taggant systems can only be verified with special handheld readers, that are in turn only available from a secure source, thus ensuring that any potential counterfeiter is not aware of the presence of an authentication technology. Handheld readers are relatively low cost, lightweight authentication tools that enable quick and easy authentication in different environments. Company personnel or authorized agents can simply and accurately determine whether packaging is authentic.

In general, overt and covert design features complement each other and are jointly used on packaging for maximum security.

Combining Overt and Covert Technologies

Security Design and Print. Security print techniques using highly defined print lines to create complex designs that are difficult to originate and print are also highly effective in the fight against counterfeiting. Sophisticated overt and covert security design features, created using the latest software, can be built into each design, protecting pharmaceutical packaging from counterfeit.

A wide variety of fine design techniques can be combined to build bespoke security solutions into packaging protection and authentication requirements. These include engraved images, relief images, warp grids,

B O B S T G R O U P . C O M

ACCUBRAILLE

Delivered by Express Braille Getting Braille onto cartons has never been faster than with ACCUBRAILLE and a BOBST folder-gluer. Taking just minutes to set, ACCUBRAILLE needs only a single low-cost tool, and keeps pace with your gluer even at 100,000 boxes an hour. But, if that isn’t enough, ACCUBRAILLE can also be used on any of the four carton panels, right up to creases or edges, and Braille embossing on your folder-gluer instead of your diecutter means an end to dot definition drift over the length of the run.

ACCUBRAILLE : Revolutionary Braille embossing.

Annonce_AccubrailleI.indd 1 07.05.2009 10:21:06


Braille labelling on medicines – the clock is ticking!

packaging industry, trade associations, regulatory bodies and blind associations from across Europe. The group has been working for over three years to determine and agree standards, including the Braille font style (Marburg medium) and measurement of Braille cell dot height that can be applied across the whole of the EU. One of the main issues for the team has been reaching agreement on the cell dot height that the blind associations feel will be sufficient to meet the needs of the blind users and also industry believe is commercially achievable. The final standard will hopefully be available before October 2010.

The Alphabet Braille is an alphabet created out of

raised dots which allow blind people to ‘read’ the written word by ‘touch’:

Currently there is no EU standard for the font style of Braille dots or their height – this will change sometime next year with the publication of the CEN standards. Meanwhile people are having to make their own decisions as to what is acceptable.

There are many examples of packs incorporating Braille on sale with varying degrees of quality and readability – both of the Braille and the underlying text. Historically there has been reluctance by some in the pharmaceutical packaging industry to allocate the time or money to incorporate Braille onto their packs. The approaching deadline means that this view has to change or the licence holders will risk having products taken off the market.

Developing updated labels which meet the new requirements is both time-consuming and complex. It requires specialist input in many cases to ensure that the regulatory requirements are properly met and that

Twelve-year-old Louis Braille, born 200 years ago, could have had no idea that his invention would change the lives of millions of blind people all over the world. Despite the enormous technological changes which have taken place since, there is still no other way in which a blind person can “see” a label or what is written on a piece of paper. There can be very few innovations which have stood the test of time in this way.

To safeguard the millions of blind and partially sighted patients in Europe, in 2005 the EMEA introduced legislation (Article 56(a) of Council Directive 2001/83/EC) which requires labelling in Braille on the secondary packaging of virtually all pharmaceutical products; the only exceptions are products which are never handled by a patient. This change will dramatically increase the safety and sense of security of the many Braille users in Europe.

Under the Directive, Braille labelling is required on all submissions for new medicinal products made since that date (with time allowed for implementation). In addition a requirement was set out that Braille labelling should be present on ALL products by October 2010 (with the exception listed above), including herbal products. Much has happened in the last five years, but this requirement has not gone away, and it is raising the blood pressure of many product licence holders – particularly in small and medium-size pharma companies.

What is required? The guidance states that:

“The name of the medicine as set out in section 1 of the SPC must appear in Braille on the package..... In some circumstances where different pharmaceutical forms and strengths of the same medicine are available it is recommended that this information is also included and this will be considered on a case-by-case basis. Inclusion of the generic name in addition to the invented name where relevant is encouraged, particularly for medicines which are available on prescription.”

There is a special exemption for small products:

“In the case of small volume packages (up to 10 ml) with limited space capacity, alternative means of providing Braille information may be considered, e.g. use of contracted Braille system or certain defined abbreviations or addition of supplementary “tab” label.”

The original intention was that the Braille labelling would be added to the product details as part of the routine changes needed during a medicinal product’s life. But now that the time for compulsory implementation gets closer, a further consideration applies…

“However, towards the end of the transitional provisions, the original marketing authorisation should be updated to comply with the Braille provisions prior to the submission of the change of ownership application.”

So if you have not made the required change to your product licence, and you want to sell or transfer it to someone else, you will have to update the label first!!! Be warned …

Staff at Pharmaceutical Development

Services Ltd and Design Cognition Ltd have been working with many clients to make sure they keep their Marketing Authorisations up to date and in compliance with the Braille labelling requirements. We take the implementation of Braille labelling on products very seriously. Design Cognition’s Chief Technical Officer, Annie Dallison, volunteered to be a member of The European Committee for Standardization (CEN) working group on Braille standards. Annie, as a leading industry expert, already had over eight years of experience in the application of Braille on pharmaceutical packaging, developing processes, and establishing and setting standards for blue chip companies, making her an ideal member of the working group.

This CEN working group is made up of dedicated representatives from the


the revised labels comply without adversely affecting the legibility of the textual copy. Significant improvements in processes and equipment have been made in the last five years and Braille can now be applied onto numerous media types.

So who is affected and

what should they do? All holders of Marketing Authorisations within the EU should check whether the secondary packaging of their products has been updated to include labelling in Braille. If the packaging has not, urgent action is needed. Developing Braille-compliant packaging is a long process. You are recommended to:

Develop an understanding in your •business of the requirements and how they affect your particular products. Develop a strategy and priority list for implementation and minimise impact on costs.

Identify artwork studios that have the •appropriate processes, software & technical skills to develop the required ‘layered’ artwork.

Check that you have robust •organisational processes in place to manage the approval and version control of Braille artwork within the Quality System of your organisation, under full CAPA (Change and Preventive Action) control. Remember that the change process will be inspectable by regulatory authorities during GMP inspections and will give an accurate demonstration of the change management processes within your company. You need it to reflect well on the organisation – do you need a Quality Systems audit?

Check, for example, if your current •

carton suppliers have the capability to work with Braille – they need converters ‘geared-up’ to make the ‘formes’ and emboss the quality of Braille correctly and consistently.

Prepare updated packs. As many •products do not have large areas of unused space, it is important to ensure that any changes in layout introduced to accommodate the Braille do not adversely affect legibility. Remember that most ‘sighted’ approvers will not be able to read and approve Braille!

Submit the changes as variations to •MHRA (or other authorising body) bearing in mind the requirements of the original guidance. The applications should be made to the Product Information Unit and will attract a fee, whether or not other changes are made at this time.

Await regulatory approval, making •adjustments as needed, before ordering updated packaging components.

Work with your supply chain •components – manufacturers, suppliers, packing facilities distributors – to ensure that the quality of Braille is maintained at all stages and that the patient receives a quality product, correctly and legibly labelled.

As usual, the maxim “get it right first time” is extremely important; the MHRA process can take some time, and is likely to be put under heavy strain as slow-to-adopt companies get organised in the nick of time.

One further complication is the position of parallel importers. The guidance states:

“in all cases where Braille is present on

the (outer) packaging of a medicinal product, the parallel importer/parallel distributor should ensure that the same Braille text is provided in the language(s) of the destination member state and that the original Braille text will not cause confusion.”

With no universal Braille standard, and many products available with different European names, the requirement for all parallel imports to be labelled in the language of the final user will be extremely challenging. Most QPs will not even be able to tell what the Braille on the imported pack actually says! This has the potential for a major compliance and patient safety problem.

In summary, for anyone with medicinal products on the European market without labelling in Braille, prompt action is needed to ensure that the products continue to meet the current quality standards and do not become at risk of being removed from the market for non-compliance with the Braille labelling directive. Assuming normal regulatory approvals, action is needed in the next few months to maintain compliance..

Anne Dallison, is the main technical contact within the company. She has over 30 years experience of the Packaging Industry with a very thorough understanding of all packaging materials and formats. She has worked in many sectors of the industry including: food & confectionary, pet care, homecare, veterinary, homebrew, healthcare and pharmaceuticals (all categories from general sales to prescription medicines).Anne has a passion for the industry, demonstrated by the number of year’s service she has given and actively gets involves in helping to apply regulations that are imposed upon the industry (e.g. Braille). She is highly respected by her peers and was awarded fellowship of the IOM3 Packaging Society (of which there are only 6 females across the whole of the UK) earlier this year and is also accredited as a ‘Chartered Environmentalist’.Email: [email protected]


Innovation in malaria drug packaging: Coartem® and Coartem® Dispersible

therapeutic drug levels during the middle third of the life cycle, when they are most sensitive to treatment [17,18]. This anti-malarial has been an important component of the crusade to roll back malaria.

The development of a dispersible formulation of Coartem® adapted for use in infants and young children demonstrates a patient-centric approach. Ahead of a call from WHO for child-friendly medicines, Novartis, working in partnership with Medicines for Malaria Venture (MMV), started the development of a new formulation of Coartem® for infants and young children: Coartem® Dispersible. The choice of which paediatric formulation to develop was carefully considered. Both syrups and powder for reconstitution, which are used for existing paediatric anti-malarial formulations, have several disadvantages: they are bulky to supply and store, and once opened/reconstituted, the stability and hygiene of the formulations can no longer be guaranteed. Accurate dosing of syrups, which are typically delivered in a multi-dose format, is difficult in the field. Consequently, a report from the Expert Committee on Selection and Use of Essential Medicines hosted by WHO, recommends the avoidance of oral liquids [19]. Novartis recognised an unmet medical need and responded with the delivery of a child-friendly formulation specifically designed to meet the needs of these vulnerable patients, supported by a rigorous clinical development programme. The development of Coartem® Dispersible represents a significant advance in the successful treatment of this population.

Novartis also has an ongoing commitment to the education of healthcare workers and the communities they serve. Initiatives include training courses – for example, a malaria case-management programme for nurses in Zambia – and the development of educational materials for healthcare workers and mothers/caregivers. These have been translated into several different African languages, and are distributed free of charge to the countries that request them. In addition, Novartis

Malaria is highly preventable and treatable, yet it is still a major cause of disease and death worldwide, especially in tropical and sub-tropical regions where it stems from and causes poverty. There are approximately 881,000 malaria-related deaths every year [1], with nine out of ten deaths occurring in sub-Saharan Africa and 85% of deaths in children under five years old. This equates to a child dying of malaria in Africa every 30 seconds [2]. In 2008, it was reported that 109 countries were endemic for malaria, with 45 of these countries being within Africa [1]. There were an estimated 247 million episodes of malaria in 2006, with 86% of cases reported in the African region [3].

In addition to the human cost of malaria, the economic burden of the disease is vast. It is thought that malaria causes an average loss of 1.3% of annual economic growth in countries with intense transmission [4]. Malaria affects productivity – adults with malaria cannot work, and children with malaria cannot attend school. Up to 40% of African health budgets are spent on malaria each year [4].

Effective control and treatment of malaria also presents enormous logistical challenges. Many at-risk populations live in extreme poverty in remote rural areas. Poor and rural families are the least likely to have access to preventative measures such as insecticide-treated nets [5] that are fundamental to malaria control, and are less able to afford treatment once infection has occurred [5].

The key to reducing the burden of malaria is an integrated approach that combines preventative measures, such as long-lasting insecticide-treated bed nets and indoor residual spraying, with improved access to effective anti-malarial drugs.

Novartis’ commitment to the fight against malaria

The Novartis anti-malarial treatment Coartem® (Artemether/Lumefantrine) is the first fixed-dose artemisinin-based

combination therapy (ACT) prequalified by WHO [6], and the first ACT to be approved by the US Food and Drug Administration (FDA). The efficacy and safety of Coartem® has clearly been demonstrated in a clinical development programme spanning over 14 years and enrolling approximately 5000 patients [7,8]. Coartem® has consistently achieved 28-day PCR-corrected cure rates of over 95% in the evaluable populations, in randomised, controlled trials conducted in malaria-endemic areas [9–13]. It has demonstrated a favourable safety and tolerability profile [9–14], and when used first-line, in parallel with preventative measures, results in dramatic reductions in malaria-related deaths [15,16].

Coartem® has made a remarkable journey, from discovery of artemether in China to the delivery of a curative treatment to some of the world’s poorest communities, serving those most vulnerable to malaria – infants and children. From the outset, Novartis has worked in collaboration with government bodies, research institutes, and multilateral organisations to bring Coartem® to those who need it most. A landmark private-public agreement between Novartis and the World Health Organization (WHO) was unveiled in 2001, and in a ten-year pact, Novartis agreed to make Coartem® available without profit for distribution through WHO in malaria-endemic developing countries. This broad partnership has provided millions of children and adults with access to an effective high-quality treatment for malaria. Since 2001, Novartis has delivered more than 300 million treatments of Coartem®, without profit, helping to save an estimated 750,000 lives. Coartem® consistently achieves 28-day PCR-corrected cure rates of over 95% even in areas of multi-drug resistance; over 35 independent studies have confirmed the efficacy and safety of this anti-malarial in a wide range of geographical areas and in a variety of populations [7]. The simple, three-day regimen of Coartem®, means two asexual life cycles of P. falciparum are exposed to treatment (as recommended by WHO), while the twice-daily dosing helps to ensure that the parasites are exposed to


During the development of the packaging for the new formulation of Coartem® – Coartem® Dispersible – Novartis commissioned several independent studies in African communities. Research in Kenya and Uganda was conducted by Dr. Ane Haaland (Communications Specialist, University of Oslo) and James Moloney (MPhil, University of Oslo), in partnership with the Kenyan and Ugandan Ministries of Health, and the Child Health and Development Centre (Makerere University, Uganda). Additional research was conducted in Malawi and Tanzania. All studies involved a variety of community members, including health workers, community health workers, caregivers and potential patients. The research in Kenya, Tanzania and Uganda

regularly brings together the managers of national malaria control programmes across Africa to share best practice in community awareness, health worker training, stock management and distribution, and health impact measurement.

The key role of packaging for malaria drugs

Packaging for anti-malarials must fulfil a number of criteria: it must protect the drug from humidity and physical damage under the conditions that prevail in malaria-endemic countries, be easy and hygienic to store, and be acceptable and understood by end users from a variety of cultural backgrounds who may have low levels of literacy.

Developing and testing Coartem® packaging

Drug packaging for anti-malarials has not traditionally been tested with end users in malaria-endemic countries. However, Ministries of Health and health workers appreciate testing, as it helps ensure that the packaging is practical in the environment in which it will be used and is understood by patients and rural health workers. Novartis invested in user testing of the Coartem® packaging for the public market over a period of several years, allowing the development of packaging for Coartem® that is relevant and accessible to health workers and patients in African countries.

Figure 1: Coartem® and Coartem® Dispersible packaging. The packs are colour-coded according to different body-weight groups.


significance of completing the full treatment course. This is particularly important in areas where there are varying levels of education, illiteracy is common, and the disease is most prevalent. The Coartem® packaging is also colour-coded to denote the different dosing regimens recommended for different body-weight groups, which aids identification of the correct dose for each individual patient, and facilitates the recognition of the Coartem® product. By providing specific packs that contain a full three-day course of treatment for different body-weight groups, the need to score tablets or split packs is avoided.

The user-friendly packaging of Coartem® ensures proper dosing and patient compliance. Ensuring that a patient takes the full course of an anti-malarial drug is beneficial not just for the patient, but for society as a whole. If patients do not take anti-malarials correctly then this can present a major problem, as drug levels will potentially be sub-therapeutic and thus will not be adequate to cure the infection. Exposure of parasites to sub-therapeutic levels of anti-malarials could lead to the development of parasite resistance [21]. Appropriate dosing advice is vital for promoting compliance, reducing the emergence of resistance, and preserving the effectiveness of ACT.

Coartem® DispersibleThe majority of malaria deaths are in

children [1], but until recently there were no anti-malarials specifically formulated for this critical group. Novartis, working in partnership with Medicines for Malaria

was co-sponsored by Medicines for Malaria Venture.

Questionnaires, demonstrations and role-plays were employed to gather information on how health workers were using current Coartem® packaging and their impressions of the new packaging in development in partnership with WHO. Most participants were already familiar with Coartem® tablets, which they perceived to be effective and well packaged with clear instructions. During these sessions, a wide variety of feedback was obtained not only on the design of the packaging but also on the images used. For example, respondents felt it was important that a baby depicted on the pack intended for the smallest children looked ill, ‘so we believe that they have malaria’, but not so sick as to suggest that the mother had left it too long before getting medical help. In addition, respondents commented on hairstyles and head-dresses, style of dress, the colours used, and the way the mother was holding her baby. A middle ground had to be found to avoid cultural bias and make the images acceptable to different communities across Africa.

During field testing of the packaging, it became apparent that when educating patients on the need to complete the full course of Coartem®, health workers often failed to explain why this is important. Novartis responded to this by enhancing the educational features of the packaging and encouraging (in their training materials) health workers to use the pack as an

educational aid with mothers and patients. The usefulness of depicting a diminishing population of parasites with each dose – to explain why it is important to complete the course – was assessed by semi-structured questionnaires and observation in Tanzania and Uganda [20].

Coartem® – responding to the requirements for anti-malarial packaging

Coartem® supplied to the public market has an innovative packaging design that was developed in partnership with WHO to address the challenging requirements of anti-malarial packaging (Figure 1). The foil blister packs produced on stiff card protect the tablets from humidity and damage during transport, while the enclosure of each tablet in a separate blister provides hygienic storage. Clustering of tablets within the blister pack reminds the patient or caregiver how many tablets should be taken at each dose. Each pack contains one full three-day course of treatment, and different packs are produced for different body-weight groups, with a pictorial representation of the patient in each body-weight group. Consequently, each patient receives exactly the amount of medication required, reducing wastage and promoting correct dosing.

In addition to written instructions, the Coartem® packaging incorporates illustrations designed to increase the understanding of the treatment regimen, remind the patient of how many tablets to take at each time point, and to help explain the

Figure 2: Explanation of pictorial guides for health workers on the Coartem® Dispersible pack


Venture, developed a dispersible formulation of Coartem® expressly tailored to the needs of children. Coartem® Dispersible is as efficacious as the crushed tablet formulation [10], with a similar safety profile. It is sweet tasting, easy to administer [10] and affordable. Coartem® Dispersible is the first dispersible ACT developed for children with uncomplicated P. falciparum malaria.

The Coartem® Dispersible packaging was created to further build on the legacy

Figure 3: Summary of levels of adherence to the three-day Coartem® regimen across different countries [18–21]

of the existing pack for standard Coartem® tablets. The packaging was enhanced on the basis of independent field testing with rural African health workers, patients and community members, including mothers. As literacy levels vary, the packaging was illustrated as much as possible. There are clear, three-step instructions on how to make up the dispersible formulation and give the dispersed tablet(s) to the child. Colour-coding of the different Coartem® packs according to the recommended dosing regimen for each body-weight range has been maintained with Coartem® Dispersible.

Key features of Coartem® Dispersible packaging include:

further development of the patient •illustrations to assist with the identification of the correct pack (Figure 2)images of malaria parasites decreasing •in number as the three-day course progresses, to indicate how the drug works and the reason why it is necessary to complete the full courseenhanced clarification of when to take •the tabletssimple instructions and illustrations to •indicate how to make up the dispersible formulation

The packaging serves as an educational tool that the health worker can use to teach

the caregiver how and when to administer the dispersible Coartem® tablets, and serves as a visual aid for the caregiver once at home. It is thought that educating the mother of a sick child may be the biggest factor in compliance with anti-malarial therapy. Ultimately, the packaging supports best practice in both local health service provision and patient use of Coartem®

Dispersible. Evidence for adherence and

acceptability of Coartem® packagingFeedback from the field testing was

utilised to create user-friendly packaging that promoted adherence to the three-day, twice-daily regimen. Several studies have confirmed excellent adherence to Coartem® under field conditions [22-25]; these data are summarised in Figure 3. In addition, data from a study in Tanzania indicate that the illustrations and design of the Coartem® packaging encourage patients to take their medication appropriately.

A study conducted in Malawi evaluated adherence to Coartem® using electronic containers that record the date and time of opening. Overall, 92% of study participants took all doses out of the electronic container, indicating excellent adherence [22]. Another study conducted in Bangladesh reported similarly high rates of adherence. In this study, adherence was assessed by counting remaining tablets and conducting interviews. Among the 160 study participants, 93.1% were judged to be adherent [23]. Examination of the 140 available blister packs revealed that the final sixth dose was missed most frequently; 64% of non-adherent patients missed their last dose [23]. The most frequent reason given for discontinuation of treatment was the improvement of condition. Once symptoms resolve, patient adherence to a treatment regimen can reduce. To try to counteract this possibility, illustrations were included on the Coartem® Dispersible packaging, which show a decrease in parasite numbers with each dose, to help explain to patients why it is so important to complete the full course of treatment. Adherence to the Coartem® regimen has also been examined in the context of home-based management of malaria in febrile children in Nigeria and Uganda [24]. Treatments were dispensed by community medicine distributors and administered by caregivers. Used at this community level, adherence to Coartem® was 81% in Uganda and 93% in Nigeria [24].

A further study, designed to prospectively examine the adherence to and acceptability of Coartem® administration in Tanzania, provides further evidence of excellent

adherence to the dosing schedule [25] and demonstrates that end users find the design of the Coartem® packaging useful in helping them to correctly adhere to the Coartem® regimen. Following microscopic confirmation of P. falciparum infection, the first dose of Coartem® was taken under supervision, with the remaining five doses taken unsupervised at home. Patients were randomised to receive a home-based assessment close to the scheduled time for one of the unsupervised doses, but were blinded to which follow-up visit they had been allocated. The full six-dose regimen was taken by 98% of patients, with 90% of doses being taken at the correct time. Only 1.7% of participants reported missing a dose [25]. Patient responses to a questionnaire indicated that the clustering of tablets for each dose of Coartem® within the blister packs was a helpful aid to remembering how many tablets to take at each dose. In addition, 91.8% of patients found the dosing pictogram useful. Illustrative instructions for the timing of drug administration provide a useful reminder of the dosing schedule in rural areas where few individuals have a clock or wristwatch [25].

Enhancing patient compliance by packaging solutions

The effort that Novartis has put in to the development of the Coartem® Dispersible pack was recently acknowledged by the Healthcare Compliance Packaging Council (HCPC) Europe.

The HCPC-Europe’s 2009 Conference involved an international forum of experts discussing the role of packaging in the context of patient adherence. Innovative packaging solutions containing elements that help and encourage patients to take their medication appropriately were presented, and the annual HCPC-Europe Compliance Pack Award was given to a pack that offered the most comprehensive support. Out of a large number of entries, the jury (HCPC-Europe’s Board and Advisory Board members) short-listed three outstanding packaging solutions for the award. The jury based their decision on the pack’s design (use of colours, icons, reminder aids and readability), ease of use (accessibility, compact, portable, longevity/re-closable, and life-time appeal), intuitiveness of use, leaflet presentation, practicality and sustainability.

Coartem® Dispersible was the winner of the 2009 HCPC-Europe’s Drug Packaging Design Award. This award symbolises an “innovative solution for what might appear to be a complex unsolvable problem”.


Dr. Nadia elMasry PhD, MBA, is the Global Brand and Country Liaison Manager for the not-for-profit Novartis Malaria Initiatives, based in the company’s Headquarters in Switzerland. With over 14 years’ experience in the pharmaceutical industry, Dr. elMasry is currently responsible for the development and implementation of medical marketing activities and communication/education materials for healthcare professionals and patients across Africa.Email:[email protected]

Dr. Chemtai Kipkeu, is the Medical Advisor for Novartis in Kenya. She is a medical doctor by training and has a clinical research background. Dr Kipkeu provides medical support for Novartis within the east and central African region.Email: [email protected]

ConclusionsNovartis is a committed partner in the

fight against malaria. Coartem® consistently achieves 28-day PCR-corrected cure rates of over 95%, but however efficacious the anti-malarial, its impact will be diminished if not taken correctly. In order to facilitate adherence, Novartis has taken a patient-centric approach to developing the Coartem® and Coartem® Dispersible packaging. Faced with the considerable challenge of creating packaging suitable for use in rural Africa, which could be understood by and be acceptable to health workers, caregivers and patients from different cultural backgrounds and with variable levels of literacy, Novartis conducted extensive field tests of packaging concepts. The result is an innovative packaging solution that is fit for use in rural Africa.

Since 2001 Novartis has provided 300 million Coartem®/Coartem® Dispersible treatments on a not-for-profit basis to the public sector of malaria-endemic developing countries..

References:1. WHO World Malaria Report 2008 [http://

www.who.int/malaria/wmr2008]2. African Malaria Day Fact Sheet (WHO)

[http://www.rollbackmalaria.org/docs/AMD/factsheet.htm]

3. Roll Back Malaria. Key malaria facts [http://www.rollbackmalaria.org/keyfacts.html]

4. WHO Malaria Factsheet No. 94. Updated January 2009 [http://www.who.int/mediacentre/factsheets/fs094/en/index.html]

5. Roll Back Malaria Partnership. Africa Malaria Report – 2003. Chapter 2: Insecticide-treated nets [http://rbm.who.int/amd2003/amr2003/pdf/ch2.pdf]

6. WHO List of Prequalified Medicinal Products [http://apps.who.int/prequal/]

7. Makanga M, Krudsood S. The clinical efficacy of artemether/lumefantrine (Coartem®). Malar J 2009, 8(Suppl 1):S5.

8. Falade C, Manyando C. Safety profile of Coartem: the evidence base. Malar J 2009, 8 (Suppl 1):S6.

9. Lefèvre G, Looareesuwan S, Treeprasertsuk S et al. A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 2001, 64:247-56.

10. Abdulla S, Sagara I, Borrmann S et al. Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African

infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. Lancet 2008, 372:1819-1827.

11. van Vugt M, Wilairatana P, Gemperli B et al. Efficacy of six doses of artemether/lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 1999, 60:936-942.

12. van Vugt M, Looareesuwan S, Wilairatana P et al. Artemether/lumefantrine for the treatment of multi-drug resistant falciparum malaria. Trans R Soc Trop Med Hyg 2000, 94:545-548.

13. Hatz C, Soto J, Nothdurft HD et al. Treatment of acute uncomplicated falciparum malaria with artemether/lumefantrine in non-immune populations: a safety, efficacy and pharmacokinetic study. Am J Trop Med Hyg 2008, 78:241-247.

14. Falade C, Makanga M, Premji Z et al. Efficacy and safety of artemether-lumefantrine (Coartem®) tablets (six-dose regimen) in African infants and children with acute, uncomplicated malaria. Trans R Soc Trop Med Hyg 2005, 99: 459-467.

15. Barnes KI, Durrheim DN, Little F. Effect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu–Natal, South Africa. PLoS Medicine 2005, 2(11): e330.

16. Chizema-Kawesha E, Mukonka V, Mwanza M et al. Evidence of substantial nationwide reduction of malaria cases and deaths due to scale-up of malaria control activities in Zambia, 2001–2008. World Health Organization, Zambia 19–23 January. Impact Evaluation Mission Report.

17. WHO Guidelines for the treatment of malaria 2006. Available at: http://who.int/malaria/docs/TreatmentGuidelines2006.pdf

18. White NJ. Antimalarial pharmacokinetics and treatment regimens. Br J Clin Pharmac 1992, 34, 1-10.

19. Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children, WHO Headquarters, Geneva, Switzerland, 15-16 December 2008. Available at: http://www.who.int/selection_medicines/committees/expert/17/application/paediatric/Dosage_form_reportDEC2008.pdf

20. Haaland A, Moloney J. Testing comprehension and acceptability of parasite symbols to strengthen adherence to antimalarial treatment in Tanzania and Uganda [abstract 1055]. Am J Trop Med Hyg 2008, 79(Suppl 6):310.

21. White NJ, Pongtavornpinyo W, Maude RJ et al. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance. Malar J 2009, 8:253.

22. Bell DJ, Wootton D, Mukaka M et al. Measurement of adherence, drug

concentrations and the effectiveness of artemether-lumefantrine, chlorproguanil-dapsone or sulphadoxine-pyrimethamine in the treatment of uncomplicated malaria in Malawi. Malar J 2009, 8:204.

23. Rahman MM, Dondorp AM, Day NP et al. Adherence and efficacy of supervised versus non-supervised treatment with artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Bangladesh: a randomised controlled trial. Trans R Soc Trop Med Hyg 2008, 102:861–867.

24. Ajayi IO, Brown EN, Bateganya F et al. Effectiveness of artemisinin-based combination therapy used in the context of home management of malaria: a report from three study sites in sub-Saharan Africa. Malar J 2008, 7:190.

25. Kabanywanyi AM, Lengeler C, Kasimu P et al. Adherence and acceptability of artemether-lumefantrine as first-line anti-malarial treatment: evidence from a rural community in Tanzania. Malar J 2010. In press.

Serving the pharmaceutical industry with confidence

www.breconpharm.com

Commercial contract packaging

Clinical trial services

Stability packaging & testing

Storage & distribution

Analytical services

QP release of non-EU products

Manufacturing Phase I/II

Brecon Pharmaceuticals Ltd, Wye Valley Business Park, Hay-on-Wye, Hereford, HR3 5PG, UK · T +44 (0)1497 820829 · E [email protected]

Commercial contra

vicClinical trial ser

St bilit k i

ct packaging

es

& t ti

Stability packaging

Storage & distribu

vicesAnalytical ser

QP release of non-

Manufacturing Pha

g & testing

ution

s

-EU products

ase I/II

Brecon Ph

alley Businessmaceuticals Ltd, Wye VVahar

s Park, Hay-on-Wye, Hereford, HR3 5PG

G, UK · T +44 (0)1497 820829 · E sal

m.comes@breconphar

MC 8/9/08 12:51 Page 1


Oliver Naucke, is Head of Marketing at Uhlmann Pac-Systeme. Most of his career has been spent working in sales and marketing for machine manufacturing companies. Ten years ago he assumed the position to manage a broad range of innovative marketing instruments as well as corporate public relations. Oliver Naucke is meanwhile responsible for brand management of the whole Uhlmann Group worldwide. Email: [email protected]

Blister machine technology in use for better compliance

According to a study of the University of London, after ten days 30 per cent of chronically ill people do not take their prescribed medication properly, after four weeks every second patient struggles with compliance. To ensure consistent compliance, especially in the case of chronically ill and older people, 7x4 Pharma GmbH commenced a pilot project with the compulsory health insurance AOK Berlin in 2009 to supply patients with individually packed blisters with their weekly medication: “7x4 Box – My week´s medicine”.

Better medicinal care by centrally blistering medicines in individual unit doses: that is the target that 7x4 Pharma wants to attain. The costs that drain the healthcare system due to non-compliance are substantial. In Germany alone, some 4,000 tonnes of prescribed medicines land in the rubbish each year. And the indirect costs are even higher: experts estimate that expenses related to incorrect treatment, which results in longer hospital stays or an earlier move from home into nursing care, amount to some 10 billion Euros annually. The costs of this non-compliance already match those of major widespread diseases and, in view of the growing number of older people and the associated cases of illness, will rise even further.

Against this background, compliance is of great significance: “We can simply no longer afford to neglect compliance. There is no money available for follow-up costs”, says Edwin Kohl, owner of 7x4 Pharma, referring to the motives for his development of the individual weekly blister system.

“7x4 Box – My week´s medicine”While in Sweden the unit dose packaging

of medicines is carried out just in separate tubular bags that need considerable time and effort to check and revise the correct filling, Edwin Kohl favours ultramodern, fully validated technology: the packaging of a weekly blister for the seven days of the

week and the four times of day – morning, noon, evening and night – when medicine is to be taken.

Reliable medication – every weekThe way the system works is as easy

as it is convincing: as up to now, the GP and respective specialists prescribe medications on the basis of 7x4 Pharma’s list of medications filed in the practice administration system. The doctor also puts the dosage instructions on the prescription. The patient takes all his prescriptions to a pharmacy that offers the 7x4 Box blister service. The pharmacist checks the medication of the patient for contraindications, interactions and double prescriptions and separates the forms of medicine such as liquids, drops or suppositories that are unsuitable for blistering from the solid, oral forms. He then forwards to 7x4 Pharma the prescription covering products included in the list of available medications giving the patient’s data, the prescribed dosage and the desired commencing date to take the medicine. 7x4 Pharma produces the blister and delivers it to the pharmacy via the wholesaler. The patient either picks up the blister or has it delivered by the pharmacist in the case of ill-health.

Up to 400 medicines to treat the major widespread diseases

First the products are packed in continuous blister strips, then dosed into the 7x4 Box as required by the patient and finally the weekly blister is automatically sealed and equipped with a cover card printed with the essential information. During the course of this complex production process, use is also made of Uhlmann Blister machines, which have been modified to the customer’s requirements for the packaging of such a variety of different products in continuous blister strips.

Three different feeding systems, for example, operate alternately on each blister machine: depending on the type of product, a SimTap feeder, a flood feeder or a linear

feeder. The latter, which only has a few product-related format parts so changeovers are quick, is ideally suited to the processing of the up to 400 products.

After passing through the feeder, a VisioNIR system checks that the product has the correct active substance and is intact. Should the system establish breakage or even the wrong active substance, a suction station is responsible for removal from the blister web. A further camera check then follows – to be absolutely sure that the product really has been rejected.

The blister is sealed with a foil that is printed inline with a matrix code. To enable the tablets to be mechanically pushed out more easily and to ensure that no pieces of foil end up in the 7x4 Box weekly blister, the lid foil over the pocket is lasered. The web is cut into strips, rolled up and is ready to be used to fill the weekly blisters..

EUROMEET INGMonaco 2010

2 2 n d A n n u a l

March 8-10, 2010Grimaldi Forum, Monaco

Please contact the DIA in Europe on +41 61 225 51 51 or email: [email protected]

A neutral, global forum for 3,000 professionals from the biopharmaceutical industry, contract serviceorganisations, academic research centres, regulatoryagencies, health ministries, patient organisations andtrade associations.

Download the programme or register online!www.diahome.org > click on the EuroMeeting2010 icon

Exhibiting Opportunities Available

EUROMEET INGMonaco 2010

2 2 n d A n n u a l

March 8-10, 2010Grimaldi Forum, Monaco

Please contact the DIA in Europe on +41 61 225 51 51 or email: [email protected]

A neutral, global forum for 3,000 professionals from the biopharmaceutical industry, contract serviceorganisations, academic research centres, regulatoryagencies, health ministries, patient organisations andtrade associations.

Download the programme or register online!www.diahome.org > click on the EuroMeeting2010 icon

Exhibiting Opportunities Available


Genesis Conference 2009 Review

only measure being taken though as set out by Lord Drayson. The patent box tax breaks to incentivise companies to manufacture products based on intellectual property originating in the UK is expected to help ‘UK plc’ retain more of the economic value from its innovation base. Questioned about the security of such measures beyond a general election, Lord Drayson provided convincing reassurance that UKIIF in particular was committed to being a 10-year fund and would remain intact.

... and what about the international scene?

An international perspective cannot be ignored in the biopharma and medical technology sectors however if our companies are to be successful and the world class innovation being fostered in the UK is to be translated into true benefits for patients. An opportunity for Genesis delegates to hear how the world’s leading life science cluster, Massachusetts, USA, is supported and nurtured was presented by Susan Windham-Bannister, Director of the Massachusetts Institute for Life Sciences and Tom Sommer, Chief Executive of MassMEDIC. Investing not just in new companies and research programmes, we heard how the Governor’s $1Bn life science fund took a very strategic role in funding the next generation of talent through competitive post-doc programmes. Leveraging of the impressive PR machinery available via the Governor’s office to raise profile of those companies receiving funding was key to attracting further capital to those companies. Perhaps, more surprisingly, was to hear how the Institute for Life Sciences invested significant sums in upgrading infrastructure such as water and drainage systems. On the face of it such infrastructure seems unconnected to supporting life sciences, however when one understands the barriers a poor infrastructure presents to attracting global companies to locate in that area, one can see why this investment is just as key. Of course, investing in infrastructure to underpin economic development and success is a match to the business case made by the Genesis headline sponsors, London First, here in the UK. We heard from MassMEDIC how the responsibility to nurture the sector did not fall solely to public sector, but indeed his work at MassMEDIC

The Genesis Conference was established by London Biotechnology Network to provide an accessible biotech and life science forum for innovators to meet investors, partners, advisors and policy makers. Initially serving the London-centric community, Genesis has subsequently grown to be much more of a UK Showcase event that attracts significant overseas interest. The competitive advantages of being held in London, the bio-business heart of Europe’s most dense region of life science companies and research institutes are manifold when it comes to assembling a high quality delegate list from across the sector. In return for London First taking steps to support the sector such as a reduced cost entry for R&D companies and investors, securing top level UK and international speakers and a keeping to a high quality but economic exhibition format, the sector’s key players rewarded Genesis by turning up in significant and well engaged numbers.

Key messages .... The tone of the event was set during the

plenary session – innovation, practice and international views all being presented. We heard from Karol Sikora (Cancer Partners UK), of the need for change in the way cancer is treated if we are to meet the challenges of the 21st Century. Not just from a technical perspective, but a need to embrace innovation in the way we fund and personalise treatment for cancer patients in the UK and worldwide. In a first for Genesis, we heard from a patient and carer’s perspective what hope the excellent

research into new medicines gives those with ‘heart sink’ disorders. This very personal and impassioned point of view was presented by Kathy Oliver, founder and co-director of the International Brain Tumour Alliance. On the one hand, it was sobering for the delegates to hear first-hand of the news ‘your son has a brain tumour’ affects a parent. However, the hope the research undertaken can give those parents and sufferers, the energy tapped into by Kathy’s lobbying for access to innovative medicines and hearing the impact new treatments are already having, brought the reasons why many of the delegates are in the biotechnology sector and the spur to deliver into sharp focus.

Lord Drayson, Minister for Science & Innovation, took centre stage for a very engaged speech and Q&A on how the UK Government is supporting life science innovation in the UK. Whilst the funding of basic research was left for others to discuss, the Minister focussed on the incentives announced in the Pre-Budget Report to encourage private sector investment in UK technology and innovation. The hot topic of the report was, unexpectedly, an update on the UK Innovation Investment Fund (UKIIF). The Minister discussed the rationale behind the fund of funds structure and the £250M cornerstone contribution from across Government departments and research budgets. That same day Hermes and European Investment Fund were announced as the Fund of Fund managers. The fund is expected to invest in world class innovation from the UK and be technology sector agnostic – following the best opportunities for impact and return. The UKIIF was not the

EXIBITION REVIEW


environment in which they operate. This is in no way to suggest that many of the companies do not need a global reach, they do. Simply highlighted here is that our sector has and will continue to benefit from the tendency of these innovative academic institutes, hospitals and businesses to co-locate in clusters of excellence. The remaining question perhaps is not one of whether there remains a ‘cluster effect’ to success, but more a question of how the management of such clusters can evolve to match the innovation demonstrated by their constituents.

Although slightly clichéd now, the life sciences industry is now globalised. There are many more players from many more locations looking for deals and markets which at first glance is a very positive thing. This brings it own challenges however in areas such as identification of partners and managing supply chains. Whilst new management processes can address some of the logistics, knowledge sharing will, by its nature, remain a people driven process. This accessibility of peers is a large contributor to the cluster effect on business success. So, in short, there is likely to remain a role for local clusters even in the globalised world. The way in which those organisations that facilitate the networking and knowledge sharing operate may need to evolve however. The light touch of being able to open doors for our members via links with other leading cluster organisations such as the Institute for Life Science in Massachusetts and MassMEDIC is not perhaps a revolution, but a necessary evolution for Genesis that renders it fit for purpose to add value to our members in the 21st century..

demonstrates how the industry itself can take the lead in shaping its success.

Building international collaborations through inter-cluster collaboration

As explained above, supporting the life science sector is a key driver for the ethos of Genesis. This was exemplified at this year’s conference by the next step in forging relationships between the UK’s Golden Triangle Partnership (GTP) and Massachusetts by the signing of a Memorandum of Understanding between MassMEDIC and the three UK clusters of the Golden Triangle – ERBI, OBN and London Biotechnology Network.

Michael Charlton, Chief Executive of Think London, introduced the need for global collaboration in delivering success in innovative medicines reaching patients as well as the need for such links in securing long term economic success. The leader of inward investment support in London explained that the innovation engine provided by the GTP region means the input end of the R&D pipeline is comparable to any leading clusters worldwide, such as Massachusetts or San Diego. The clinical trial capability and expertise revolves around breadth of expertise in nearly all disease areas with a clear focus on providing quality and timely outcomes in drug development. He set out why London serves as an ideal touchdown pad for no-UK companies to explore their UK and European markets and partnerships.

Global Industry on the Genesis doorstep

A great deal of time was spent discussing the strength of, and indeed support innovation. Further along the chain, however, is the need for the multinational Pharma and Medical Technology industry players to link with our academic institutes and nascent life science companies in order to truly drive the pipeline towards revenues. The industry is often described as a ‘deal driven’ sector due to its reliance on alliances and licensing deals to progress programmes. This reliance is demonstrated by the vast number of successful global and local biopartnering events in which our members engage. That said, events and structures are one thing, but a huge part of the success of deal execution and subsequent success of the project revolves around the softer people factors. Thus, relationships are key and a high presence of the multinationals in the South East of the UK, literally on the doorstep of Genesis, assists innovation in being propelled along the R&D pipeline. Examples of multinational companies with a presence in the Golden Triangle of which Genesis is the focal networking event in the calendar are as follows:

Is there a role for life science clusters in a globalised industry?

If Genesis examined anything, it is maybe the question of how a cluster group such as London Biotechnology Network can contribute to the sector. From blue sky research through clinical development and market entry, the success of the biopharma and medical technology companies, including the leading edge providers of technology, clinical trial and professional services, will be impacted by the quality of the business

Abbot Laboratories Genzyme Philips

Actellion Gilead Roche

Almirral GlaxoSmithKline Sanofi Pasteur MSD

Amgen Huntleigh Healthcare Schering Plough

Astellas Pharma Ipsen Servier

AstraZeneca Johnson & johnson Shire

Baxter Healthcare Lundbeck Siemens Diagnostics

Boston Scientific Medtronic Smiths Medical

Bristol Myers Squibb Merck Sharp & Dohme Stiefel

Cambridge Consultants Mitsubishi Pharma Europe Takeda Global R&D Centre Europe

Chugai Pharma Europe Napp Pharmaceutical Group Toyama Europe

Eisai Europe Novartis UCB Celltech

Elan Pharma Olympus Keymed Unilever

Eli Lilly & Co Ono Pharma United Therapeutics

Eppendorff OSI Vertex

GE Healthcare Pfizer Wyeth

You work hard to explain your complex ideas inunderstandable terms.

Shouldn’t you expect the same from your advisors?

We clarify intellectual property issues with straightforward advice.

Birmingham 0121 236 0484 • London 020 8889 6622 • [email protected] • www.forresters.co.uk

Patent and Trade Mark Attorneys.


BioCity Nottingham

Ibuprofen to the MRI scanner – Nottingham’s long past in medical discoveries is one of the many reasons the city was identified as

one of the six ‘Science City’s’ in the UK. However, the city hasn’t rested on its laurels and continues to see the Sciences at the forefront of its economy.

BioCity Nottingham, one of the UK’s largest bio-incubator facilities in the country continues to grow and support many businesses that are at the leading edge in Life Sciences in disciplines including drug discovery, pharmaceutical development and medical devices amongst others. Over 60 companies and 500 people now work within BioCity which is able to

provide high quality laboratory and office accommodation for a range of companies from Spin-Outs to high growth companies. On-site

support for businesses is a key selling point for BioCity and with partners from legal firms to patenting experts

and even dedicated banking and finance services.

Company Profile

around life sciences and drug development. The £25 million Centre for Biomolecular Sciences is a state of the art campus dedicated to solving the global healthcare challenges of the future. The centre brings over 300 scientists together across seven different scientific disciplines to tackle key health priorities for the UK in drug discovery, cancer research, stem cell science, bacteriology and regenerative medicine.

With two science parks in the city, Nottingham Science Park and University of Nottingham Innovation Park (UNIP), Nottingham is able to offer a wide range of technology and office space from incubation facilities to grow-on space. MediPark is the latest science park currently being planned to further strengthen Nottingham’s profile as a leading medical technologies location in Europe. The park is currently in planning stages and aims to bring together Nottingham’s medical and science communities into one unique site close to the Queen’s Medical Centre, one of Europe’s largest teaching hospitals.

Companies that are based in Nottingham are also able to access a wide range of business support services. The regional Healthcare and Bioscience Innovation Network (I-Net) helps bring together businesses, colleges, universities, public sector representatives and individuals to form collaborations and share knowledge. The city is also the home of the East Midlands Medilink which provides specialist business support to help local businesses establish,

grow and develop. The Invest in Nottingham BioMed team are also at hand to assist businesses that are looking at

Nottingham as a potential business location across a range of areas including providing information

on the sector, identifying suitable premises, developing links with the Universities

and support networks as well as areas around recruitment and

training.

Developing international links is also on the agenda for BioCity, following the recent collaboration with three Biotechnology centres in the US. The collaborative partnerships with the Virginia BioTechnology Research Park in Richmond, Virginia; the Commercialization Centre for Innovative Technologies (CCIT) in New Jersey and the MU Life Science Business Incubator at Monsanto Place, Columbia, Missouri, provides valuable support to Nottingham’s growing life science sector.

Support for companies in the Life Science sector has recently been strengthened with the launch of the Mobius Life Science Fund. At a time when many private venture funds shy from seed funding in this area, the Mobius Life Sciences Fund will provide the crucial bridge in finance and expertise which will enable early stage companies to succeed further down the line.

The universities in Nottingham are also very strong in the life sciences sector and regularly work with industry leaders in the sector. The £2.3 million Nottingham Trent University Interdisciplinary Biomedical Research Centre manages a worldwide research project into pioneering new vaccine treatments for cancer patients. It’s one of the major centres of its kind in the UK and covers range of sciences, including cell biology and pathology, immunology, cancer, neuroscience, food microbiology, pharmacology and toxicology and DNA technology.

The University of Nottingham also has extensive experience working with industry in areas

To find out more about what is happening in Nottingham’s ever growing Life Science and Bio Medical sector visit www.investinnottingham.co.uk or contact Ken Nettleship, BioMed Project Manager on +44 (0) 115 915 5350.

Company Profile


delegates. The modular seminars featured sessions on biopharmaceuticals and biosimilars, API sourcing, CROs and clinical trials, API demand and the rise of generics, in-licensing and out-licensing, and CMO selection and partnerships.

The CPhI Innovation Awards attracted high-quality entrants once more, with 28 projects being submitted to the judges, which were whittled down to just six finalists. Puleva Biotech Exxentia won the Gold award for its Hereditum probiotic bacteria derived from human breast milk that can be used in infant nutrition products. The Silver award went to Cambrex for its continuous flow microwave assisted organic synthesis technique. And the Bronze winner was Novozymes Biopharma for its albumin fusion technology, albufuse, which can increase the half-life and bioavailability of protein drug candidates.

This year, the shows will be returning to Paris for the first time since 2006, and will be held from Tuesday 5 to Thursday 7 October. Organisers UBM International Media expect the quartet of co-located events to rival the 25,000+ attendees in Madrid. The 2006 events in Paris hosted more than 22,000 attendees.

The shows continue to evolve. CPhI is

A return in confidence across the global pharma ingredients and services sector was reflected by the buoyant CPhI Worldwide, ICSE, P-MEC and BioPh, which were held in Madrid last October. Provisional figures from organisers UBM International Media showed a 5% increase in visitors over the previous year in Frankfurt, and the total attendance, including exhibitors, was more than 25,000 – only 300 short of the previous year’s record numbers. Across the four exhibitions, CPhI for ingredients, ICSE for contract services, P-MEC for Pharma machinery and equipment and BioPh for biopharma, more than 1800 companies exhibited – up by more than 100 on the 2008 event – and 114 companies made their debut in Madrid.

“Our provisional figures show the steady return of confidence in the pharma services sector,” said CPhI Event Director Annemieke Timmers. “Exhibitors were positive about enquiry volumes and quality. Although we had expected them to be cautious, the underlying business mood was actually upbeat. This year’s rise in both overall and first-time exhibitor numbers is further confirmation of the business value generated by CPhI and its co-located events.”

Haf Cennydd, Event Director for ICSE, P-MEC and BioPh, added: “Footfall in ICSE and P-MEC reflected strong year-on-year gains in pre-registrations, together with high levels of interest for the 2010 events.” The co-located shows have grown rapidly. Since its 2001 debut in London, ICSE exhibitor numbers have increased dramatically, from 14 to 287, reflecting the growing importance of the pharma contract services sector. And from an initial 16 in 2006, P-MEC’s exhibitor numbers have more than tripled to 50.

The biotech BioPh event made its debut in Madrid, reflecting the growing convergence of the pharma and biotech business models in drug innovation, production and market delivery. BioPh proved a great success – the event itself drew more than 800 dedicated visitors, and there was a lot of cross-over from the other shows as well. In addition, the Bio Pharma brokerage event, which was organised in association with Parque Cientifico de Madrid, provided great synergy with BioPh, and is very likely to return this year.

Another first was the Pre-Show Seminar series on the Monday before the exhibition itself opened, which attracted more than 350


celebrating its 21st anniversary this year, and to mark the occasion it will have a new zoned layout to make it easier for visitors to find the exhibitors they’re looking for. Six zones will be home to businesses from different sectors of the pharma ingredients industry, giving more logical on-site navigation and leaving visitors with more time to talk to exhibitors and less time walking between them. The colour-coded zones will feature APIs, custom manufacturing, intermediates, fine chemicals, excipients and general exhibitors such as purification and contract research.

ICSE will have two new zones this year: the Contract Research Zone and the Packaging Zone. The Contract Research Zone replaces the Clinical Trials Zone, as it will not only cover clinical trials, but also preclinical and contract research companies. The Packaging zone will be open to all companies that provide packaging solutions within various stages of pharmaceutical processing. P-MEC is also evolving. It now covers every aspect of pharma and biotech

equipment and technology, from packaging machinery, through laboratory and analytical techniques, to track and trace technologies.

Following the success of the pre-show event last year, the multi-track Where Pharma Meets modular seminars will return. Although these are yet to be finalised, sessions will likely include topics such as biosimilars, API sourcing, clinical trials CROs and CMO selection and partnerships. The breakfast briefings and Speakers’ Corners will also return, along with the brokerage event, and of course the CPhI Innovation Awards will be presented again. Full details about the 2010 events will be posted on the website over the next few months.

Eliane van Doorn, UBM International Media’s Group Director Pharma Ingredients Events, said, “The industry has seen some significant business challenges since our last visit to Paris. Back in 2006, it was the second time P-MEC had been held, after its launch the year before in Madrid. In 2009, we also launched a new show in Madrid – BioPh – and will also move to Paris with the

momentum of newly-launched features. One of the dominant changes since 2006 has been the strong convergence of the bio and Pharma business models, especially in ingredients and contract services,” she added. “We expect this to be a strong continuing theme, with CPhI Worldwide strengthening further as the senior networking platform for pharma production interests.”.

Coming next….Coming next in UBM’s Pharma events

family, on 21 – 23 April in Tokyo, is CPhI Japan, with the co-located shows ICSE, BioPh and P-MEC Japan.

CPhI Worldwide, with ICSE, BioPh and P-MEC, are staged by Netherlands-based UBM International Media. Worldwide locations of annual sister events for the Pharma sector included China (June), South America - Argentina (August) and India (December). See: www.cphi.com, www.icsexpo.com, www.bioph-online.com and www.p-mec.com.


Scarab Genomics Introduces it’s NEW White Glove IS Detection Kit for detecting transposable Insertion Sequence Elements

Scarab Genomics has now launched the White Glove IS Detection Kit to test for the presence of transposable Insertion Sequence (IS) elements in a DNA of interest. Numerous IS elements are naturally present in the genomes of E. coli strains commonly used for protein and plasmid production, but are not present in the Scarab Genomics Clean Genome® strains. IS element transposition is known to be stimulated by the cell stress response and can lead to the “hopping” of IS elements into plasmid DNA and or into other regions of the bacterial chromosome. The transposition of IS elements into an expression vector can interfere with the expression of a foreign protein in E. coli. IS element transposition can also contaminate pDNA isolated for vaccine purposes. To alleviate these undesired transposition events, Scarab Genomics previously produced the Clean Genome® E. coli strains. These strains are devoid of all known IS elements thereby creating the ideal hosts for the production of foreign proteins or plasmid DNA. The White Glove IS Detection Kit can be used to detect the presence of IS elements in the genomes of commonly used E. coli strains. The kit can also be used to determine which elements have transposed from these genomes into a plasmid of interest propagated in these strains. Scarab Genomics.

For Further Information please visit: www.ScarabGenomics.com

The US FDA says its new screening system will expedite the importation of genuine drugs and help inspectors focus their efforts on “high risk” products.

At present, customs officials only examine a fraction of the 20m shipments that reach US ports each year, with products being selected in what is essentially a random fashion, albeit one based on officer expertise and experience. The new web-based system, called Predict (Predictive Risk-Based Evaluation for Dynamic Import Compliance Targeting), assigns drug, food and cosmetics imports a risk rating based on contents, supplier and point of origin. High risk imports are flagged for inspection, enabling customs officials to focus their investigations on imports that have been problematic in the past such as, for example, heparin or those that contain melamine. Food and Drug Administration (FDA) Commissioner Margaret Hamburg set out the scale of the challenge facing customs inspectors in relation to pharmaceuticals which, increasingly are, coming sources outside the country. Dr Hamburg explained that: “Up to 40 per cent of the drugs [US citizens] take are imported” and that “up to 80 per cent of the active pharmaceutical ingredients in those drugs come from foreign sources.” She went on to say that while systems are in place to try and ensure the safety of imports “clearly our nations’ traditional approach – relying on FDA inspections to catch problems at the border or in foreign facilities – needs a significant overhaul.”

Global collaboration on inspection

While the launch of Predict was the focus of Hamburg’s address at the Center for Strategic and International Studies (CSIS) last week, she also touched on the new collaborative approach the FDA and other drug regulatory agencies are adopting . She explained that, in addition to setting up offices new offices worldwide over the last 12 months, the FDA now has agreements with more than 30 agreements with counterparts worldwide to share data on facility inspections. “If our British counterparts share with us critical information about inspections… we can use that information and not re-inspect,” said Hamburg, citing the FDA’s work with the EC and the TGA on API plant inspection as a further example of the approach .


The pharmaceutical biggie GlaxoSmithKline announced its proposed launch of final clinical trials for an anti-malaria vaccine in seven African countries to kick-off in January.

“This is the most advanced vaccine, and the only one today that has been shown effective against malaria in infants and children in Africa,” said Joe Cohen, who created the vaccine after two decades of work for GlaxoSmithKline. Studies in Mozambique on children under five found that the vaccine, called RTS,S, was 30-35 percent effective against benign cases of malaria and 50 percent effective against severe cases, over a period of about three years. “With 30-35 percent effectiveness, that would prevent 100 million cases of illness a year ... and suggests that several million lives could be saved,” Cohen told AFP, noting that malaria spells death for nearly one million children every year. In Mozambique, the vaccine also reduced the number of hospitalizations from malaria, said Christian Loucq, director of the Malaria Vaccine Initiative, which is financed in part by the Bill et Melinda Gates Foundation. The clinical trials will take place at 11 sites in Kenya, Malawi, Mozambique, Gabon, Ghana, Burkina Faso et Tanzania. About 16,000 children will take part in the study, which includes African scientists, and the first trials should begin in January in some countries, Loucq said. “This is a vaccine designed to activate the immune system in such a way ... that it destroys the parasite very quickly when it is in the blood or the liver, before it reaches the red blood cells,” Cohen explained. The phase III trial, the last step before seeking regulatory approval, would allow sales of the vaccine possibly in 2012, if the results are conclusive. Developing the vaccine has cost some 500 million dollars i.e. 392 millions euros, Cohen and Loucq said. Source-AFP - TAN

Caprotec bioanalytics Announces Commercial Launch Of Three New caproKits(TM) For Applications In Proteomics And Drug Development Berlin, Germany and Burlington, MA, January 26, 2010

Caprotec bioanalytics GmbH announced today the commercial launch of three new caproKits(TM), enabling the discovery, identification and characterization of proteins belonging to the groups of metallo-proteases, histon-deacetylases and GDP/GTP binding proteins. The three new kits are the Marimastat caproKit, SAHA caproKit and GDP caproKit, respectively and increase the number of commercially available caproKits to a total of seven. The company’s caproKits are based on the proprietary Capture Compound Mass Spectrometry (CCMS) technology, a novel and direct way to investigate small molecule - protein interactions resulting in a significant functional reduction of proteome complexity. Capture Compounds(TM) enable direct isolation and identification of proteins including membrane proteins out of complex biological samples.The new and existing caproKits target different areas of research ranging from signal transduction (cAMP, cGMP, Stauro and the new GDP caproKit) to epigenetics (SAH and the new SAHA caproKit), and proteases (Marimastat caproKit). Additional caproKits for applications in these and other research areas are under development and will be released in the coming months. “Our new caproKits are innovative and effective tools for researchers in the field of proteomics needing a solution for targeted reduction of sample complexity,” stated Dr. Hubert Köster, CEO of caprotec bioanalytics. “Our most recent scientific publications in Molecular and Cellular Proteomics and Toxicological Sciences provide powerful testimonials for the capabilities of our CCMS technology.“

For further information please contact:Dr. Hubert Köster, CEO, caprotec GmbH, Phone: +49 (0)30-6392-3990orDr. Christian Jurinke, President, caprotec Inc., Phone: (781) 685-4992, [email protected]


PAREXEL enhances EARLY PHASE BIOMARKER capabilities THROUGH ALLIANCE WITH PROTEOME SCIENCES

Boston, MA and Cobham, UK — PAREXEL International Corporation (NASDAQ: PRXL), a leading global biopharmaceutical services provider, and Proteome Sciences plc (LSE: PRM), a leading provider of protein biomarker discovery, validation, and assay development services, today announced the formation of an alliance focused on enhancing PAREXEL’s biomarker capabilities for early phase clinical development. PAREXEL is using Proteome Sciences’ PS Biomarker Services™ protein and peptide biomarker capabilities to support biopharmaceutical companies in making earlier assessments of new compounds in development. Proteome Sciences will assist PAREXEL early phase experts in helping biopharmaceutical companies advance biomarker discovery and qualification within clinical trials. This expanded capability allows PAREXEL to offer its customers mass spectrometric and pharmacokinetic assays for protein and peptide compounds. Christopher Pearce, Chief Executive of Proteome Sciences said: “We are very pleased to have PS Biomarker Services selected by PAREXEL as a preferred provider of protein and peptide biomarker services. We believe that the current regulatory requirements for biomarkers in drug development and diagnostics coupled with the need for fast, flexible and cost effective workflows have meant that specialist services will be increasingly required. Our ISO 9001:2008 facility in Frankfurt, Germany was designed to provide expert protein biomarker discovery and validation and for the development of rapid mass spectrometric-based assays to service the growing requirements of the biopharmaceutical industry.”

For more information about PAREXEL’s early phase capabilities visit: http://www.PAREXEL.com/Early_Phase.html.

Repros Submits Response to FDA Regarding Androxal® Indication for Treatment of Hypogonadal Men Wishing to Preserve Fertility

THE WOODLANDS, Texas--(BUSINESS WIRE)--Repros Therapeutics Inc. (NasdaqCM:RPRX) today announced that the Company, as requested by the FDA during the Type C meeting held on January 25, 2010, has sent a revised indication statement to the FDA’s Division of Reproductive and Urologic Products for the use of Androxal® in the treatment of men wishing to preserve fertility while being treated for their hypogonadal state. The Company also provided a literature review supporting the Company’s belief that administration of exogenous testosterone at doses resulting in morning testosterone levels within the normal range render a significant number of men oligospermic (sperm counts less than the generally accepted level of male fertility). The Company also submitted the final clinical study report investigating the fertility impact of Androxal compared to a topical testosterone in men previously treated with testosterone for hypogonadism. Previously, the Company noted that the FDA suggested it will respond to Repros’ submission in a timely fashion following receipt of Repros’ materials. Repros will provide an in depth review of the outcome of the Type C meeting held with the FDA on January 25, 2010 during its BIO/CEO presentation today at 2:30 p.m. Eastern Standard Time. There will be a live video webcast of the event and subsequently archived for at least one month on the Company’s website http://www.reprosrx.com under the “Events” heading on the home page. To ensure a timely connection to the webcast, it is recommended that users register at least 15 minutes prior to the scheduled start time to ensure adequate time to download any software that may be necessary.

For more information, please visit the Company’s website at http://www.reprosrx.com.


Subscription Offer

Guarantee you receive your copy of IPI: International Pharmaceutical Industry, 4 issues per year. Pharma Publications is delighted to be able to offer its readers a great one year’s subscription offer.

Subscribe now to receive your 20% discount

POST: Complete the form, detach and post to Pharma Publications, Building K, Unit 104 Tower Bridge Business Complex, 100 Clements Road, London, SE16 4DG, UK

TEL: +44(0)207 2375685

FAX: Complete and fax this form to + 1 480 247 5316

EMAIL: Your details to [email protected]

Please tick the relevant boxes:

UK & N. Ireland £80 inc p&p Europe €90 inc p&p USA $120 inc p&p I enclose a cheque made payable to Pharmapubs

I wish to pay by credit card (MasterCard or Visa)

Card number

Valid from Expiry date

Security code

Name:

Job Title:

Company:

Address:

Post Code:

Tel:

Fax:

Email:

Signature:

For Advertising opportunities, contact on +44 (0) 207 2375685 or Email: [email protected]

Advertisers Index

IBC AirBridgeCargo Page 29 Amsterdam BIO Page 5 Analytical Biochemical Laboratory BVPage 11 BioM biotech Cluster Development GmbHIFC BioClinicaPage 96 & 97 BIOCITY NOTTINGHAM Page 99 BIOTRINITY 2010 Page 59 Biovian OyPage 93 BIOWIN – The health Cluster of WalloniaPage 44 & 45 BMG LABTECH GmbHPage 81 BOBST GROUPPage 89 Brecon Pharmaceuticals LtdPage 23 Caprotec Bioanalytics GmbHPage 17 Caribbean Clinical Trials Services, INC.Page 71 Dales PharmaceuticalsPage 91 DIA – 22nd Annual Euro MeetingPage 55 Envirotainer ABPage 39 ERTPage 36 Excard research GmbHPage 95 ForrestersPage 21 Göteborg BIO – Business Region GöteborgPage 33 Health Protection AgencyPage 30 & 31 HYGLOS GmbHPage 67 Ludger Ltd. Page 57 LYOFAL S.A.S.Page 51 MARKEN Page 19 MediLingua Medical Translations B.V.Page 64 & 65 Moorfields PharmaceuticalsPage 27 Notox B.VPage 41 Oxford Global – The 2nd Annual Drug Development Congress 2010Page 49 PDP Courier Services LtdPage 3 Quotient BioresearchPage 9 Randox Laboratories LtdOBC Swiss World Cargo Page 14 & 15 TTP LabTech Ltd. Page 61 Vetter Pharma International GmbHPage 75 Vienna School Of Clinical Research Page 7 West Pharmaceutical servicesPage 47 Woodley Equipment Company Ltd. Page 53 World Courier

For more information concerning ABC’s flight schedules, charter opportunities and rates for this unique product to Russia, Central Asia and the Far East.

Please contact AirBridge Cargo sales at +31-20-654-9030 or check the website www.airbridgecargo.com for details.

AirBridge Cargo and Maastricht Aachen Airport are pleased to announce their cooperation to provide a scheduled freighter service from the heart of the Dutch hightech corridor to the expanding markets of Russia. Including a twice weekly service from Maastricht Airport (MST) to Moscow Sheremetyevo (SVO) with continuing connections to the Far East, serviced by its fl eet of 6 Boeing 747-400F/200F aircraft, AirBridge Cargo offers daily freighter service from the Netherlands to Russia, Central Asia and the Far East.

From Maastricht airport, located less than an hour’s drive from Holland’s high-tech logistics hotspots in Venray, Venlo and Tilburg, AirBridge Cargo offers a twice weekly export connection to Moscow. With special attention to secure and expedited handling, your valuable (VAL) and vulnerable (VUN) shipments move quickly to and from the aircraft. The proximity of the airport and lack of congestion to and at the airport will minimize lead and transit times, keeping your cargo in motion and keeping it secure!

Russia’s High-Tech Cold Chain Logistics to the Kazakh region

“They act cool, but we deliver cool”

SWISSWORLDCARGO.COM

CONSTANT CLIMATE FOR YOUR CARGO – WORLDWIDE: SWISS °CELSIUS–If your cargo needs to be kept warm or cool, Swiss °Celsius is made for you – our quality product for freight shipments, which are sensitive to temperatures and critical in terms of time factors. With temperature-controlled transport between -20 °C and +20 °C in special containers, we deliver your cargo to over 70 destinations all around the world. We care for your cargo.

AZ_SWC_Celsius_A4_hoch_.indd 1 03.09.2009 16:51:44 Uhr

Documents

IPI - International Pharmaceutical Industry