IPI-International Pharmaceutical Industry

The Basics of FP7 -European Research Funding Explained

Carbon Neutral Solvents in a Carbon Neutral FuturePart 2:Practical Applications

Japanese Cardiac Safety RequirementsThe Rising of a New Regulatory Landscape

Challenges of the Clinical Trial Supply Chain For Stem Cell Products Special Preview:HCPC Europe’s 5th Annual Conference on Patients’ Adherence

Peer reviewed

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International Pharmaceutical Industry Supporting the industry through communication

INTERNATIONAL PHARMACEUTICAL INDUSTRY 1www.ipimedia.com

ContentsEDITOR’S LETTER

REguLaTORy & MaRkETpLacE

Balancing Innovation and Risk in the uS Medical Device Industry – current Situation and challenges aheadThe medical device industry has shown tremendous growth over the past twenty years. It has outperformed the pharmaceutical industry (based on compounded annual growth rate (CAGR)) and has been one of the most profitable industries in US commerce. Although it is dominated by large, diversified companies, many smaller, specialised device makers also flourish in this sector. In this observational study of the US medical device industry Saurabh Awasthi and Nikhil Bhanagar of Kinapse explain that while focus on innovative research and development (R&D) should be the top priority of device companies, the industry also needs to reassess their strategic focus while streamlining their regulatory and clinical operations.

The Basics of Fp7 - European Research Funding ExplainedThere are many sources of grants and funding available for research and development activities in the health, biotechnology and pharma sectors, but for European researchers and businesses there is one that surpasses all others in its scope and size; the grandly titled 7th Framework Programme for Research and Technological Development, or, as it is more commonly known, FP7. This article by Graham Hughes of Beta Technology will provide an introduction to the Framework Programme for those in the health, biotechnology and pharmaceutical industries interested in accessing this significant funding stream.

collaborating to Develop Technologies, products and Services – Working with Others to create, Enhance and Realise ValueCollaboration has become the smart way to start, grow and/or expand a business. Among the benefits are a greater potential for innovation, improved ability to harness technological complexity, and reduced costs of developmenti. Dominique Kleyn of London Genetics shows how these benefits may be achieved by companies working together, by companies working with academic institutions, and by academic institutions working together.

people: the Missing Dimension?Countless informatics projects are competently specified, acquired and delivered to an expectant user base – only to flounder in the hands of those very same users. How can we ensure that the solutions we deliver will get used and deliver the return promised? Simon Coles, the co-founder and Chief Technical Officer of Amphora Research Systems, explains that improving return on investment starts with people and the deployment of information systems to help people do their work; the extent to which the system is used effectively determines the ROI achieved.

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6EDITOR: Dr. Patricia Lobo [email protected]

DIREcTORS: Martin Wright Mark A. Barker

puBLISHER:Clive [email protected]

EDITORIaL aSSISTaNT:Linda [email protected]

BOOk MaNagER: Anthony Stewart [email protected]

BuSINESS DEVELOpMENT: George [email protected]

DESIgN DIREcTOR: Ricky Elizabeth

cIRcuLaTION MaNagER:Dorothy Brooks [email protected]

FINaNcE DEpaRTMENT: Martin [email protected]

RESEaRcH & cIRcuLaTION: Gramatikov [email protected]

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

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

The next issue of IPI will be published in Summer 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 Industry Supporting the industry through communication

Summer 20102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Dr patricia Lobo – Editor of IPI & Managing Director of LifeSciences Business Consulting speaks with Jean-Claude Marcourt, Vice-President and Minister of Walloon Economy

DRug DIScOVERy / DEVELOpMENT & DELIVERy

a generic approach to the Validation of Small Molecule Lc-MS/MS Biomarker assays In recent years, there has been a large increase in the use of both exploratory and validated biomarkers1 as they have been formally incorporated into the drug development process as indicators of the pharmacodynamic effect of drugs. In this article, Richard Houghton of Quotient Bioresearch discusses the benefit of androgynous assay validation.

Maximising protein yields with pichia pastorisThe yeast Pichia pastoris is widely used as host for heterologous protein expression for hundreds of different proteins. Recently, the organism received attention in the biologics industry when the first Pichia-derived biopharmaceutical protein received market approval by the FDA. Pichia expression cells can furnish yields of more than 10g/L of secreted recombinant target protein. Dr Roland Weis and Dr Thomas Purkarthofer of VTU Technology GmbH argue that there are many aspects and factors influencing expression levels which have to be tuned properly in order to obtain a high performance expression strain.

clinical perspectives of Stem and progenitor cells for Liver Regenerative MedicineBecause the liver is the site of many vital functions, impairment of only one protein within a complex metabolic pathway is usually highly deleterious. Treatments, and long-term management, are currently not efficient enough, and patients would greatly benefit from an innovative therapy that meets this medical need. Eric Halioua Etienne and Marc Sokal of Promethera Biosciences explain that cell therapy has been identified as the best alternative tool to overcome scarcity of organ donation. Several cell types are under investigation, and adult liver stem/progenitor cells represent an attractive cell source for liver regenerative medicine.

In Vivo Measurement of Human Skin penetration: alternatives for Measurement of cutaneous BioavailabilityIn the case of systemically delivered drugs, plasma or serum drug concentrations are traditionally used for assessment of pharmacokinetic (PK) parameters, and to establish bioavailability (BA). However, for topically administered drugs designed to exert a local effect in diseased skin, only a fraction of the administered drug usually reaches the systemic blood circulation, and active drug concentrations in the skin will be many times higher. Dr. Betsy Hughes Formella of Bioskin GmbH explains why the development and validation of appropriate methodologies to determine the rate and extent to which a topically applied drug reaches its site of action within the skin is one of the biggest challenges in dermatological research today.

ContentsInjectable Hydrogel Drug Depots are coming of age for controlled DeliveryInjectable hydrogels form drug depots in situ after injection, and they enable localised and controlled drug delivery for a wide variety of active pharmaceutical ingredients (APIs). This overview article by Audrey Petit, Mike de Leeuw, Leo G.J. de Leede and Wim E. Hennink of InGell Labs describes the coming of age of a specific class of hydrogels, Physically Cross-linked Injectable hydroGels (PCIGs), and the benefits in commercialisation that the PCIGs offer over other injectable drug depots, both for marketed and novel APIs.

cLINIcaL RESEaRcH

cRO LeadershipAnthony S. Chilton, President and Chief Executive Officer of BASi, puts forward three key observations post the commercial impact of the economy in the CRO industry. These are the opportunities to internally review and streamline operations and cost centres, to diversify service offerings, and to build strategic partnerships with clients. The pharmaceutical industry will evolve and adapt through partnerships between CROs, and pharmaceutical companies will develop and create a stronger, leaner, more productive industry, to meet our mutual target of delivering effective medicines to patients.

Japanese cardiac Safety Requirements - the Rising of a New Regulatory LandscapeICH Guideline E14, which was released in May 2005 and adopted shortly thereafter in Canada, Europe, and the United States, has recently been adopted by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). This marks a considerable change in the regulatory landscape for companies wishing to market their drugs in Japan. The PMDA adopted the guideline in October 2009, and following an intervening ‘grace period’ it will become fully implemented on 1st November this year. Dr Rick Turner, Senior Scientific Director, Cardiac Safety Services at Quintiles, reviews this implementation.

cutting Edge Ecg Technology Reinforces the continued advancement of centralised cardiac SafetyContinual developments in technology are helping to provide solutions for the problematic issue of data inconsistency and inaccuracy in the analysis of electrocardiograms (ECGs). A new study of investigative sites conducted by the Tufts Centre for the Study of Drug Development (CSDD) revealed that over 50% of respondents predict that over the next five years the increased usage of the centralised method will be significant. In addition to being more economically viable for companies, a critical advantage of this approach is that it offers greater consistency for clinical trials, while significantly increasing data quality – explains Amy Furlong, Executive Vice President, Cardiac Safety Operations of ERT.

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LaBS/LOgISTIcS & cOLD cHaIN SuppLy

challenges of the clinical Trial Supply chain for Stem cell productsA high percentage of new therapies being announced and discussed in the news currently are based on stem cell products. Products derived from embryonic stem cells and adult cells are now beginning to enter the clinical trial phase of development. The clinical trial supplies for these products need to be conducted under similar regulations to conventional pharmaceuticals, which can be a challenge when many of the products are unconventional, and are stored at temperatures as low as -196oC. Within this article Rachel Griffiths from Biotec Services International assesses some of the present challenges and considers some possible solutions.

Opticooler: Optimal safety for temperature-sensitive airfreight shipmentsIPI Presents the Day-to-Day Running of Lufthansa Cargo’s newest container protection of sensitive goods in extreme conditions. Michael Breul, the Director of Lufthansa Cargo’s Competence Center, explains about the heating and cooling shipping containers and how they help when transporting temperature-sensitive airfreight consignments, regardless of weather conditions and within predetermined temperature ranges.

MaNuFacTuRINg

Bridging the gap between Early phase Development and commercialisationThe challenge of taking a drug candidate from discovery through to market should not be underestimated, as there can be many hurdles to face along the path. Some of these barriers will be unforeseen, but many can be anticipated and, through careful planning and consideration, they can be avoided, or at the very least, minimised. The aim of this article by Neil Jones of Patheon is to look at some of the challenges that need to be considered when outsourcing activities from early phase through to late phase development, then scale-up, and ultimately commercialisation.

carbon Neutral Solvents in a carbon Neutral Future. part 2: practical applicationsBogdan Comanita and Dave Aycock of Pennakem LLC propose a carbon neutral vision for the future of the chemical industry. This vision prompts for practical steps en route to a zero carbon footprint desiderate, by encouraging the strategic adoption of solvents from renewable resources. In this second part of the article, several examples are provided of carbon neutral solvents that are competing successfully with fossil-based solvents. This article shows the advantages related to the use of THFA, 2-MeTHF and THF obtained from renewable resources. In particular, 2-MeTHF is increasingly becoming a universal, carbon neutral solvent; its versatility creates an opportunity to reduce cost and carbon footprint at the same time.

product Lifecycle Management: create Value for your product and a Future for your companyThe iPod. Compact fluorescent bulbs. Cell phones. The razor blade. What do these items have in common? All are examples of products that have been re-engineered through a manufacturing concept known as product lifecycle management, or PLM. PLM’s purpose is to better serve the current and future needs of an existing manufacturer’s customer base by improving the quality of life of the end user, adapting the product to meet the changing needs of the market and helping to achieve better outcomes. Max Horn of Vetter Pharma-Fertigung GmbH & Co. KG argues that for pharmaceutical and biotechnology manufacturers, PLM is critical, considering the enormity of the expense, time and effort it takes to bring a drug to fruition.

Safe products and Technologies for the pharmaceutical Industry – Optimising your Manufacturing process, Drug Formulation and Drug Deliverytoday’s pharmaceutical industry is witnessing a shift towards biopharmaceuticals, as innovative biological therapies become an increasingly important branch of the healthcare sector. Sally Grosvenor of Novozymes Biopharma identifies the reasons why the industry must address regulatory concerns in addition to process and product efficiencies, which have the potential to translate to cost reductions in the manufacturing process, through developing industry partnerships, continued dialogue, and awareness of our customer’s challenges.

packagINg

Hcpc Europe’s 5th annual conference on patients’ adherence/compliance“People often miss taking prescribed medication, because of forgetfulness, changing medication schedules or busy lifestyles. It is estimated that between 40% and 60% of people do not take medication as prescribed, which can lead to worse health outcomes. Packaging of medications with reminder systems for the day and/or time of the week is an attempt to help people take long-term medications.” (Heneghan, Glasziou and Perera). Tassilo Korab of HCPC (Health Care Packaging Council) Europe gives a preview of what to expect at the HCPC Annual Conference, where top experts in healthcare will discuss the benefits of improved patient compliance and how it can contribute to more effective use of medicines and to better outcomes.

child-resistant packaging - Offering safety, security and convenienceMedicinal drugs are the leading cause of non-fatal poisoning in children in middle-income and high-income countries. Young children are particularly susceptible to the ingestion of poisons, because of the inquisitive nature of a young child. They are more likely to put items in their mouths and often are unaware of the consequences. Sandra Luciano of AMCOR observes that, although child-resistant packaging cannot be a substitute for other safety measures CR/SF packaging improves consumer trust of a pharmaceutical brand by helping to reduce the chance of a child gaining access to medications.

pREVIEWS & REVIEWS

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Editor’s LetterIt’s a Bug’s Life as Big Pharma feels the ‘Lemons’ Squeeze, IPI looks beneath the peel

Just as our pharmaceutical industry wrestles with the now all-too-familiar litany of reimbursement pressures, products losing patent protection, generic competition, depleted pipelines, the soaring costs of R&D and declining interest from investors, along comes a forearm smash in the shape of an academic “research” study purporting to show that, “85% of Big Pharma’s new medicines are ‘lemons’ and pose health risks to users.” According to its author, Donald Light, Ph.D., professor of comparative health policy at the University of Medicine and Dentistry in New Jersey, US, the pharmaceutical industry is a “market for lemons”, and Big Pharma “spends a fortune to sell those lemons to the public.”

Dr Light talks about the “Risk Proliferation Syndrome”, referring to Big Pharma as having grossly maximised the number of people exposed to new drugs with relatively low effectiveness, but a heightened risk of adverse and often severe side effects. Light suggests that new medications should enter the market using a controlled, limited launch, enabling evidence to be gathered about the drug’s effects, positive and negative, instead of “hyped drug launches” based on clinical trials that were designed in the first place to minimise evidence of harm and are then published in the medical literature to emphasise only a drug’s advantages.

Given that the modern life science industry has been built on the milestone achievements of the last century, with the development of antibiotics and vaccines to combat the scourge of infectious diseases worldwide, it’s astonishing to hear the industry now jibed as a market for lemons. Light is said to have based his conclusions “on a wide range of data from independent sources and studies”, mostly from regulatory submissions, but his suggested remedy of a limited launch

for new products could be welcomed by the industry.

In the meantime, Big Pharma isn’t throwing in the sponge just yet, as it presses on with new initiatives. Take GlaxoSmithKline, for example: while eschewing a classical merger bid with AstraZeneca, Andrew Witty, GSK’s boss, with a vision of fresh pastures in the ‘tiger’ economies of Asia and Latin America, has set up a development board with an annual budget of £500m, and is beefing up GSK’s vaccines business. While setting aside £1.57bn to settle major legal claims, GSK has five compounds in Phase III trials, and recently commenced Phase III clinical trials in order to develop a herpes zoster vaccine for the prevention of shingles. The Phase III zoster vaccine trials will study more than 30,000 patients globally and will evaluate the efficacy, safety and immunogenicity of the candidate vaccine.

A new study, published in the journal Thorax and led by researchers from Imperial College London, found that in the first two years following the introduction of pneumococcal conjugated vaccine, PCV7, hospital admissions for bacterial pneumonia decreased by a fifth amongst children aged under 15 years. The vaccine protects against seven different strains of Strep. pneumoniae bacteria. The admissions rate for empyema - a rare but serious complication of bacterial pneumonia - decreased by 22 per cent.

Is it possible that the threat of infectious diseases in the 21st century will propel the industry forward as it has in the past, with the unmet demand for novel antibiotics and vaccines? These could come from some unlikely sources, such as ants and frog skin. Scientists working at the University of East Anglia found that fungus-farming ants use multiple antibiotics as weedkillers to maintain their fungus gardens, by inhibiting the growth of unwanted fungi and bacteria. The

antibiotics are produced by actinomycete bacteria that live on the ants in a mutual symbiosis.

The research, led by Dr Matt Hutchings, led to the discovery of a new antifungal compound that is related to a clinically important antifungal, nystatin, opening up the exciting potential for ants and other insects to provide new antibiotics for medical use.

In a separate study, a team from the United Arab Emirates University found that frog skin may be an important source of new antibiotics to treat superbugs. With drug-resistant bacterial strains, such as MRSA, becoming an increasing problem, and a lack of new treatments in the pipeline, researchers are turning to new sources, having so far found 100 bacteria-killing substances in 6,000 species of frogs examined. The research aims to modify the substances to make them less toxic and suitable for use as human medicines, with the prospect of having some in clinical trials within five years. An important environmental aspect of the work points to the importance of preserving frog diversity, as certain frog species, including those that may contain potentially valuable medicinal substances, are in jeopardy worldwide due to loss of habitat, water pollution, and other problems.

We have a mine of interesting articles in this issue of IPI, from research and development to manufacturing and logistics. Thanks to all our authors for their contribution. Looking ahead, having just come back from a visit to Moldova to review the health system over there, we aim to give you an update of clinical research in Eastern Europe. In the meantime, whatever the future holds for our industry, the answer must be more than a lemon.

Dr Patricia Lobo, Senior Consultant, Life Science Business Solutions.


REGULATORY & MARKETPLACE

Balancing Innovation and Risk in the uS Medical Device Industry – current Situation and challenges ahead

The medical device industry has shown tremendous growth over the past twenty years. It has outperformed the pharmaceutical industry (based on compounded annual growth rate (cagR)) and has been one of the most profitable industries in united States (uS) commerce. although it is dominated by large, diversified companies, many smaller, specialised device makers also flourish in this sector. Various medical device firms are leveraging technological advancements to drive innovation and to bring safer and more effective products to the market.

Amid innovation and continuous growth, the device industry faces regulatory uncertainties. The Food and Drug Administration (FDA) is revising the existing medical device regulations and is increasing scrutiny of devices to ensure the safety of patients. Since 2002, the number of regulatory submissions and product launches per year has been declining, hence threatening the impressive growth rate of the device industry.

In our observational study of the US medical device industry, we analysed the trend of regulatory submissions

over the past ten years and assessed the performance of various medical device firms. Our analysis indicates that companies with a higher than average Premarket Approval (PMA) product portfolio outperformed companies with a pure focus on 510(k) products, both in terms of gross profits and sales growth. However, despite better performance and substantial clinical value, the volume of PMA submissions has plummeted more than 50% since 1999.

In light of these developments, we believe that while focus on innovative research & development (R&D) should be the top priority of device companies, the industry also needs to reassess their strategic focus while streamlining their regulatory and clinical operations, where applicable.

Overview of the Medical Device Industry: Facts and FiguresMedical devices encompass a broad range of products, from simple devices, such as surgical staplers, to sophisticated electronic devices, such as cardiac pacemakers to life-supporting implantable devices, such as artificial hearts. All device firms are required to adhere to the regulatory guidelines for product development issued by the FDA1. These

guidelines mandate that companies submit different levels of clinical and technical data based on a three-tier risk classification system, shown in Table 1, in order to receive approval to market their products.

Using innovations in computer and electronic technologies to their advantage, the industry has seen improvements in both the effectiveness of the form and the robustness of the function of medical devices. Invasive products and equipments that were considered unsafe a few decades ago now account for more than two-thirds of the industry revenue. Orthopaedics and cardiovascular products have been extremely successful commercially, showing high growth rates among various product segments2.

Figure 1 shows the impressive growth of the medical device industry over the last 25 years.

The device industry comprises companies of different size and product scope. It is dominated by diversified companies with billions of dollars in revenues (the four top companies, defined by annual revenues, produce over 50% of the revenues). Some of the big companies, such as Medtronic and Boston Scientific, specialise in only medical devices, while others, such

Figure 1: Growth of the Medical Device industryFigure 2: Market share of top companies by annual revenues in 2008

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as Johnson & Johnson and Abbott, have a substantial presence in the pharmaceutical arena as well.

Almost all top companies (defined by annual revenues) have realised mid-to-high single digit growth rates consistently over the past few years. Figure 2 shows the big players and their % market share (2008).

Regulation of Medical Devices in the uS – a Decline in SubmissionsMedical devices are regulated by class, primarily via a 510(k) Premarket Notification or a Premarket Approval (PMA). The vast majority of devices cleared in the US market undergo the 510(k) Premarket Notification process – a submission claiming that the product is “substantially equivalent” (SE) to existing marketed products (also known as predicate devices). The PMA process, which is far more stringent and rigorous, requires applications supported by clinical data demonstrating the safety and efficacy of the device. The time- to-approval of a Class III PMA device can range from eight to twelve months, as compared to a shorter time window of three months for a

510(k) device.As shown in Figure 3, the number of

original PMA applications has declined by almost 52% since 1999, while the number of PMA supplements per original PMA application has been increasing over the last few years. The total number of 510(k) submissions has seen a similar trend as PMA submissions, declining by 13% since 19994.

pMa vs. 510(k) – assessing Impact on company performanceFor our analysis of the performance of the Medical Device industry, we selected nine diversified companies with annual revenues greater than US $3 billion, using data from 2004 to 2008. The criterion for selecting these companies was the availability of publicly available information on all performance parameters.

All companies were rated on a scale of 1 to 5, where 5 indicates the best performance in each category, for five distinct parameters:• Gross profit ratings: calculated based

on the average gross profit as a percentage of annual revenues over the last five years.

• R&D expenditure ratings: calculated based on the average R&D expenditure as a percentage of annual revenues over the last five years.

• PMA ratings: calculated based on the number of PMA products developed per dollar spent on R&D over a period of five years.

• 510(k) ratings: similar to PMA ratings, these were calculated based on the number of 510(k) products developed per dollar spent on R&D.

• Growth rate ratings: compounded annual growth rate (CAGR) was calculated for the period of five years for each company. The CAGR values were used to calculate the growth rate ratings.The results of our analysis are depicted

in Figure 4, and show that the companies with above average ratings for both gross profit and R&D expenditure were also leaders in PMA submissions. Two companies had below average R&D

Figure 3 (above): Original PMAs and PMA supplements per original PMAs and 510(k) submissions over the last 10 years

Figure 4 (left): Gross profit ratings against R&D expenditure ratings

Figure 5 (opposite page): Comparison of companies with differ-ent portfolios against average ratings

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expense ratings, yet still performed better than the average. This finding may be attributed to a balanced portfolio of both PMA and 510(k) products. The two companies that performed below the industry average had a portfolio of mainly 510(k) devices, with no, or few, PMA products over the period of five years.

We further analysed the submission portfolio of these companies to identify the distribution of R&D expenses across PMA and 510(k) devices over the last five years.

Figure 5 shows three classifications of company portfolios: 1) a higher that average PMA portfolio, 2) a primarily 510(k)-oriented product portfolio and 3) a mixed PMA and 510(k) product portfolio (Table 2). We observed that the companies with a higher than average PMA product portfolio outperformed companies with primary focus on 510(k) products with respect to higher gross profits and better sales growth (Table 3).

The Innovator’s DilemmaBased on our analysis, we observe a

strong correlation between the type of product (and thus regulatory submission) and the financial performance of the device company. Companies that focus on PMA submissions have shown better growth rates and higher gross profits over companies that primarily focus on 510(k) devices. However, the overall trend has been a sharp decrease in PMA submissions over the past decade (Figure 3).

We believe that tighter FDA scrutiny and complex regulatory guidelines may have had a negative impact on PMA productivity. Although companies are increasing R&D investments in their PMA pipelines, the soaring cost of conducting clinical trials and complex regulatory guidelines seem to be impeding the ability of device companies to produce PMA devices

The FDA is increasing its oversight by launching several initiatives to monitor the safety and efficacy of medical devices. For example, under its recently announced “Post-Market Transformation Initiative”5, the FDA will proactively identify potential device safety and efficacy deficiencies

or other issues after market approval and thoroughly assess these issues before communicating their findings and recommendations to healthcare professionals, the public and the device industry.

Another FDA initiative, which invoked criticism from the industry, was the “Medical Device User Fee and Modernization Act (MDUFMA) of 2002”6. Upon implementation, this legislation increased the regulatory review fee for sponsors of all device submissions. As depicted in Figure 3, the number of PMA and 510(k) submissions declined sharply after this legislation went into effect. In terms of overall submissions, a decrease to 9,348 in 2008 from 10,175 in 2002 was observed.

In addition, enhanced focus on health outcomes is placing demands on the medical device industry. Products that do not show a distinct advantage over competing technologies face delays in third-party healthcare coverage, creating an extremely costly post-FDA approval hurdle before the manufacturer can accomplish full commercialisation. This has begun to contribute to a decline in the development of technologies that do not have an obvious clinical or economic advantage, in turn reducing overall PMA submissions

Other factors have also contributed to the decline in PMA submissions. A hostile product liability environment has discouraged innovation over the years. Concerns over litigations on high-risk Class III devices have led many companies to abandon or divest higher-risk businesses. The “Medical Device Safety Bill of 2008” had provisions for shielding such devices from product liability lawsuits filed in state courts. However, the law was never enacted7.

The amount of venture capital (VC) funding available to medical device start-up companies has declined. Such smaller companies have traditionally been seeds of innovation. However, with limited VC support, they are often aligning themselves with larger companies, leading to a decrease in discovery and development of high-impact and ground-breaking technologies.

The Road aheadDespite the present reluctance towards PMA products, device companies cannot overlook their steady and long-term advantages. As we have shown in our analysis, companies with a strong PMA portfolio or a balance of PMA and 510(k)

Classification Risk Examples

Class I Low risk Scalpels, crutches

Class Il Moderate risk Endoscopes, infusion pumps

Class Ill High risk Stents, tissue grafts

Table 1: Three-tier device classification

Portfolio Classification PMA Ratings 510(k) Ratings

Higher than average PMA Higher than average Higher or lower than average

Higher than average PMA and 510(k)

Higher than average Higher than average

Primarily 510(k) Lower than average Higher than average

Table 2: Definition of classifications of company portfolios

Portfolio Classification Average Gross Profits (as % of sales)

Average CAGR

Higher than average PMA 76.53% 13.93%

Higher than average PMA and 510(k)

74.21% 10.91%

Primarily 510(k) 52.48% 8.12%

Table 3: Comparisons of gross profits and CAGR across companies



products are also the top performers in the industry. In the coming years, a step-up in innovation will be dictated by improvements in government policies and legislation on one hand, and company initiatives on the other hand.

Recently, the FDA has taken proactive steps to encourage innovation in the medical device industry. The introduction of the “Medical Device Innovation Initiative”8 (2006) aims to foster the development of safe and effective medical devices through a variety of regulatory process improvements. As part of this programme, the FDA is providing device makers with guidance documents outlining the scientific, clinical, and technical issues that should be considered in early stage development. This will help companies to minimise design changes in late stage development, leading to a more efficient development process and faster time to market. Additionally, in the recent reauthorisation of the MDUFMA (2008), the submission fees for devices have been significantly reduced. For PMA devices, the standard fee has been reduced by 34%, while for small businesses the fee has been cut by 57%. Other submissions have also seen reductions of similar scale.

Irrespective of the regulatory environment, device companies must continue to focus on innovation if they wish to continue to grow. Operational efficiency must be improved in order to remain competitive. We believe that the industry needs to focus on the following areas to realise higher R&D productivity, better growth, and operational excellence.

• Focus on Innovation – A Balanced Portfolio: Based on our analysis, companies investing in PMA based products have shown a better than average performance over the years, suggesting that there is a clear need for device companies to ensure a certain level of resource investment in PMA products. In addition, by focusing on high-growth therapeutic areas such as cardiovascular and orthopaedics, the companies can realise higher growth rates in the future. This will require executives to make decisions on accurate market, payer, and product development-related data on a portfolio level, while product development leaders effectively manage their teams’ efforts. One area that will require more focus than in the past is comparative effectiveness research. Focus on health outcomes and comparative

effectiveness needs to be included at the start of the product development process and maintained throughout its lifecycle.

• Cost Consciousness – Improving Operational Efficiencies: Clinical operations and manufacturing, the two large cost drivers for the device industry, are also critical avenues for cost savings. Leveraging the manufacturing capabilities of emerging markets such as India and China can help the industry contain costs. The containment in costs will help companies enhance their R&D productivity. Further, outsourcing of functional activities such as regulatory documentation and clinical trial data management can help companies remain lean and focused on their core expertise. With the increase in clinical trials required for PMA submissions, more data will need to be collected, consolidated, and presented to reviewers. The pharmaceutical industry has gone through a decade of streamlining clinical and regulatory functions and processes, and the medical device industry needs to do the same. Streamlining operational capabilities and outsourcing non-core activities will allow innovative medical device companies to focus critical resources on high-value and high-impact PMA products.

In summary, medical device companies need to focus on more PMA products in order to sustain their growth agenda. This will require closer cooperation with regulators early in the product development lifecycle, and companies will need to utilise resources more effectively to drive innovation in key areas. The increased cost of clinical trials and meeting regulatory requirements can be offset by an effective outsourcing strategy, by developing a robust marketing plan, and by making intelligent portfolio decisions n

References:1. US Food and Drug Administration

(FDA). Device Regulation and Guidance. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance

2. K Kruger, “The Medical Device Sector”, in The Business of Healthcare Innovation, ed. RL Burns (New York: Cambridge University Press, 2005)

3. Company Annual Reports (2005-2008)4. Christy Foreman. Center for Devices

and Radiological Health (CDRH).

Office of Device Evaluation (ODE) Update (December 2008)

5. CDRH Initiatives. Medical Device Postmarket Transformation Initiative (2006). http://www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHInitiatives

6. Device Regulation and Guidance. Medical Device User Fee and Modernization Act. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/

7. Rep. Frank Pallone. Medical Device Safety Act of 2008. http://www.govtrack.us/congress/bill.xpd?bill=h110-6381

8. CDRH Initiatives. Medical Device Innovation Initiative (2006)

Saurabh Awasthi is a Consultant in Kinapse US He has extensively worked with Regulatory Affairs groups and has supported various consulting initiatives including organizational restructuring, program management, resource management and performance management. Saurabh holds bachelors and masters degrees in Biotechnology from the Indian Institute of Technology, Delhi (IIT Delhi), and a masters degree in Chemical Engineering from Carnegie Mellon University, Pittsburgh, PA. Email: [email protected]

Nikhil Bhatnagar is a Senior Analyst in Kinapse India office. He has supported various consulting projects including organisation redesign, change management and project management, and has worked with different R&D functions of leading pharmaceutical companies. Nikhil holds bachelors and masters degrees in Biochemical Engineering and Biotechnology from the Indian Institute of Technology, Delhi.e Email: [email protected]



The Basics of Fp7 - European Research Funding Explained

There are many sources of grants and funding available for research and development activities in the health, biotechnology and pharma sectors, but for European researchers and businesses there is one that surpasses all others in its scope and size; the grandly titled 7th Framework programme for Research and Technological Development, or, as it is more commonly known, Fp7. The high priority given to the European R&D effort by the European commission is demonstrated in this seven-year, €50 billion initiative to maintain leadership in the global knowledge economy. This article will provide an introduction to the Framework programme for those in the health, biotechnology and pharmaceutical industries interested in accessing this significant funding stream.

Objectives of Fp7FP7 is the key mechanism by which the European Union intends to meet the requirements of the Lisbon Strategy, which commits Europe to become “the most dynamic competitive knowledge-based economy in the world”. To do this it has sought to group all European research-related initiatives within this single programme, and so meet the stated goals for growth, competitiveness and employment. In order to maximise the benefits of the research programme, it is complemented by the Competitiveness and Innovation Framework Programme (CIP), which provides funding to support innovation activities in small and medium-sized enterprises (SMEs) through direct business support in the European regions. In addition, education and training programmes, plus structural and cohesion funds will be used to maximise the impact of the research by creating the infrastructure for dissemination and implementation of results.

FP7 is intended to complement

national research programmes across Europe, and so all funded activities must demonstrate a “European added value”, and are performed at a transnational level by consortia of European and international research groups. This approach reflects the ambition to tackle major research challenges in a coordinated way.

Fp7 StructureAt its highest level, the programme is broken down into four main categories: Cooperation, Ideas, People and Capacities. Under each of these categories there are specific programmes that correspond to the main areas of EU research policy.

The Ideas category is concerned with “frontier research”, with the purpose of opening new opportunities for scientific and technological advance. It intends to promote excellence, dynamism and creativity in European research, and attract high quality researchers from across the world to Europe. Grants are awarded to individual scientists or research teams, and the scope of the work is open rather than being directed along any particular theme.

The People category aims to strengthen the human potential in European research and technology by stimulating the participation of researchers in European programmes. It targets researchers at all stages of their careers in both the public and private sectors, supporting them through initial research training through to life-long learning and career development. Equal opportunities are also encouraged.

The Capacities programme is designed to enhance research and innovation capacities throughout Europe, and so support the development of the knowledge-based economy. It uses a number of different funding vehicles to support the coherent development of polices across the member states, identify and develop regional synergies and infrastructures, and complement the activities of the Cooperation programme.

The Cooperation programme is allocated two-thirds of the overall FP7 budget, and supports collaborative research across Europe and the world in a diverse range of themes from social science to space. It is within this programme that the research themes of most interest to the health, biotechnology and pharma industries are found. Although the bulk of the research is carried out within collaborative projects, there is also funding for coordination activities, Joint Technology Initiatives (specific public-private partnerships with focussed and strategic research agendas) and Technology Platforms (research themes with special industrial relevance).

collaborative ResearchThe objective of the collaborative work programmes is to establish excellent transnational research projects and networks, to ensure that Europe is at the forefront of the various research agendas. It uses a range of funding schemes, such as collaborative projects, networks of excellence and coordination and support actions. There are ten research themes covered, each with an allocated budget spread over the seven-year duration of the FP7 programme. This budget is spent on a yearly basis according to the strategy determined by the programme committee (PC) for each theme.

The programme committee is made up of EU officials and nominated members and experts from all of the EU member states, and consults widely with sector opinion leaders and expert researchers to determine the major topics to be funded each year. These topics are normally grouped under the structure of the call prospectus, which is made up of major and minor research “pillars”. After negotiation of the yearly call prospectus by the PC, it is officially launched and is open for research consortia to submit proposals based upon the pre-defined topics. In this way the research agenda is managed to meet the needs of the



European people based upon long term strategic plans and shorter term “current issues”.

Project proposals are invited from researchers working in the fields indicated by the call prospectus. To ensure collaboration between research teams across Europe, there are strict eligibility terms that must be met before a proposal can be submitted. The basic requirements are three different legal entities from three different EU member states or associated countries, though normally consortia are made up of anything between five and 15 legal entities, possibly more. Legal

entities can be any type of organisation – academic , research institute, charity, NGO, large company or SME, to name a few.

The calls are highly competitive, and only the very highest quality proposals are chosen. The success rate is in the region of 20%. Selection is performed by independent experts with knowledge of the research areas of the call topics. Very few unsuccessful submissions go to appeal. Once selected, the successful consortia are invited to negotiate and sign a grant agreement with the Commission, which is a legal document setting out the

terms and conditions for funding. Because of the large sums of money involved (up to €12million for large projects) financial probity is rigorous, and recipients are regularly audited by the Commission or by appointed auditors.

Encouraging participation by SMEsParticipation of SMEs in FP7 projects is particularly encouraged, as they are seen to be the mainstay of European technological and intellectual growth over the next decade, and the Commission is seeking to support them as much as possible. This is particularly so in the



health theme, where SME involvement lags behind some of the other themes. Consequently there have been a number of initiatives to make the research programmes more attractive to SMEs:• Covering areas of research where

SMEs are more active, and widening the scope of the call topics in these areas to allow greater flexibility in project scope.

• Increased funding – up to 75% of research and development costs for SMEs, as well as 100% management and training costs.

• Making the rules for intellectual property rights more suited to the needs of SMEs.

• A new fund to cover the financial risks of working in consortium-led projects.

It is important to note though that it is still rare for SMEs to lead projects – it is still more likely that they will be part of a consortium led by an academic group – but they are encouraged to play a more significant role and should now reap more rewards from participation.

Benefits of participationThe benefits of accessing a high value funding scheme such as this should be obvious. The level of funding is such (€3 – 12 million per project) that even within a large consortium, a significant amount of financial support should be available for R&D activities, though it should be remembered that the recipient must still fund 25% of these, and that only a proportion of overheads are normally covered. It is also important to note that the funding is intended to support genuine additional research activities only, and should not be sought simply to maintain cash flow or standard business activities. Working within a high class consortium of academic institutions and other organisations, such as other SMEs, regulatory bodies and patient groups, could potentially strengthen future research capabilities. It will almost certainly lead to further collaborations both within the same consortium or even with wider networks of organisations accessed through it. Working alongside other consortium members can also allow access to shared intellectual property and resources that may enhance a participant’s own capabilities, and so provide a better competitive advantage in the longer term. It is notable that the Commission has taken a much more open attitude to IPR rules recently, and agreements about the use of background

and foreground IP are left for the individual members of the consortium to work out together. Finally, there are many opportunities for publicity and promotion of a participant’s skills and expertise on an international stage through academic publications and dissemination activities from the project, an aspect that is strongly encouraged by the Commission, and is promoted through its own CORDIS website.

Though the benefits of participation are attractive, embarking on a FP7 project must be undertaken with a good understanding of the risks and realities that are inherent within a highly competitive international funding scheme. It is highly recommended that new participants seek expert advice before starting out.

Relevant Themes There are a number of themes within the Cooperation programme that might provide suitable project areas for health, biotechnology and pharma industry participants. It is worth researching the work programmes of each carefully, to find the topics that most closely align with research interests and capabilities. The most obvious and relevant one for most is health, which covers all aspects of health research, from generic tools and fundamental techniques, through translational medicine, to health systems and disease prevention. E-health related projects may also be found within the ICT work programme and the nanosciences/nanomaterials theme can cover the development of new materials and manufacturing processes relevant to medical treatments or diagnostics. Medically related biotechnology subjects may also be found within the environment and food themes. In many of the themes recently there has been an effort to give the subjects a wider scope so that they are more attractive to the SME participants – in recognition of the fact that SMEs cannot easily adapt their R&D efforts to match the requirements of tightly defined subjects. It is worth looking at some of the older call prospectuses available on the CORDIS website to understand the range of topics and the requirements for participation. http://cordis.europa.eu/fp7/dc/index.cfm?fuseaction=UserSite.FP7CallsPage&callstate=closed

getting SupportThere is a vast resource of material available to potential applicants for FP7 projects, but as a result it can be a

bewildering experience for first-timers. To obtain simple downloadable fact sheets explaining the basics of FP7, the European Commission’s research website http://ec.europa.eu/research/fp7/index_en.cfm is a good starting point. However, for more detailed information, CORDIS, the official European R&D website http://cordis.europa.eu/home_en.html is the natural starting point, as it contains within it the FP7 website http://cordis.europa.eu/fp7/home_en.html, which carries the relevant information on the individual thematic areas, provides access to the call documents and applicant guides at the appropriate time of year, and offers advice in the form of FAQs .

To supplement the online information, all the EU member states employ one or more National Contact Points (NCPs) to provide specific FP7 support services. The NCPs are nominated experts in each thematic area and are responsible for a wide variety of support actions, such as publicising the yearly calls, helping applicants define and match project ideas to the call topics, liaising directly with the European Commission, identifying and matching trans-national partnerships (consortium building), and signposting applicants to other sources of advice and help. The advice and support is free, confidential and impartial, and therefore worth seeking out. NCPs also have access to the programme committee members, and will take suggestions for subjects or programmes to be considered in future calls n

Graham Hughes - Beta Technology Graham is the United Kingdom National Contact Poi nt for Health for the European Framework Program. In this role he is involved with promoting the Framework Program in the UK and abroad, supporting organizations who want to take part in the Program and liaising with the European Commission to represent the interests of UK companies taking part. The NCP service is free, impartial and confidential and is funded in the UK by the Technology Strategy Board. Email: [email protected]



collaborating To Develop Technologies, products and Services – Working with Others to create, Enhance and Realise Valuecollaboration has become the smart way to start, grow and/or expand a business. The media regularly reveals many stories of companies working with others to create value in new technologies, products and services. among the reported benefits are a greater potential for innovation, improved ability to harness technological complexity, and reduced costs of development1. These benefits may be achieved by companies working together, by companies working with academic institutions, and by academic institutions working together.

A case in point is the academic consortium led by London Genetics Limited, an expert in pharmacogenetics established in 2007 to lead on industrial collaborations for London’s medical universities. Together, its seven member institutions can apply their genetic knowledge to improve efficiency and reduce risk in clinical development (www.londongenetics.com).

The shift towards working with others demands carefully crafted development programmes, contracts and IP strategies, to extract the maximum potential from shared resources and harness the spill-over benefits from a partnership approach to best effect. In this short review we explore various ways of working together to create, enhance and realise this value.

In all collaborations there will be key considerations in terms of input (sharing resources and crafting collaboration programmes to create new value), and output (harnessing spill-over benefits and structuring contracts to enhance and extract maximum potential)2. Both of these aspects are important elements of making a partnership work. Without taking account of all potential resources and all potential benefits you may not harness the maximum potential value. Similarly, without constructing a suitable programme and describing this in a suitable contract you

may not manage to extract the results you have achieved3.

For example, most universities now use a standard set of collaboration contracts developed in response to the Lambert Review of university industry collaborations in 2004. Companies can select from a menu of partnering options offering different degrees of collaboration. These range from a less collaborative approach requiring exclusive ownership of all arising IP to a more collaborative approach requiring non-exclusive rights to use output in a specified field/territory (see www.ipo.gov.uk/whyuse/research/lambert). The former might be suitable if a firm wanted to validate proprietary biomarkers and was relying on its collaborator to work under instruction and at arm’s length; the latter might be suitable for a partnership intended to discover new drug targets or elucidate a mechanism of action.

Working together to build relationships, select projects and structure deals allows a business to more quickly tap into new markets, grow sales and become more competitive in today’s collaborative environment. A broad range of developments may be covered by such collaborations, including the opportunity to prepare for development of new methods, technologies, processes and specialist resources. Similarly, a broad range of outcomes may be secured, including shared insight into unmet needs, access to finance and a route to market for new products. A recent example in drug discovery was announced in June by the Medicines for Malaria Venture and AstraZeneca - MMV has employed scientists to screen 500,000 compounds from AZ’s library against Plasmodium falciparum, and AZ will progress promising leads at its R&D facility in Bangalore, India. In his launch message, David Brennan, AstraZeneca’s CEO, said: “Our experience with infection research, and indeed with all of our R&D efforts, has taught us that we will only

find solutions to today’s global health challenges through collaborative efforts”4.

To reflect this outward-facing approach to R&D in industry and in academia, R&D organisations have also had to change, becoming more complex, multi-disciplinary, matrix structures5. In both cases, small teams operate with accountability and decision-making ability to encourage agility and enterprise. Centralised functions are used to marshal scarce resources and disseminate learning through the company. Shareholders and funders are demanding more of their research teams, requiring excellent science with impact and a greater diversity of funding from different sources6.

Trusting relationships are critical to taking forward a collaborative deal, as commercial negotiators weave their way through a complex set of decisions (see Figure 1). For example, is this a fee-for-service arrangement (tending towards more highly defined outputs) or are we seeking a true collaboration (tending towards more highly defined inputs)? Will the deal structure be fixed in advance or do we need flexibility to manoeuvre arrangements once the contract has been signed? Is it best to plan one big deal or should we consider a sequence of smaller deals? Can the relationship stand the inclusion of additional partners or should we stick with single partner deals? Where is the best balance between commercial and scientific considerations? Can we make commercialisation rights reciprocal by perhaps sharing access to background IP or segmenting arising IP (see Figure 2)?

Despite the difficulties, there are many examples of successful collaborative deals and consortia that bring added value to development of new products and technologies. Collaborations appeal to organisations at many stages of development, not only large or well-established groups. A good example of industry and academia working together



in an early-stage yet well-established group is the International Serious Adverse Events consortium, set up in 2007 to “bring together DNA-variants useful in predicting the risk of rare, drug-induced serious adverse events that present significant health issues for certain patients” (www.saeconsortium.org). This challenge demands a highly co-ordinated, collaborative effort involving many parties, and seems to work best where partners all have a common desire to do something together that they would not be able to do on their own.

Another example illustrating this principle is provided by Genizon, when it chose in 2008 to partner with University College London to refine its schizophrenia GeneMap in well-validated patient cohorts using DNA samples. As a result, known and novel pathways of disease were revealed, potentially accelerating the development of antipsychotic treatments

with fewer side effects (www.genizon.com, www.londongenetics.com). Big pharma is also active in this area, as AstraZeneca showed when it sponsored a student to investigate mechanisms of taxane-induced cardiac arrest and death in breast cancer at Hammersmith Hospital’s oncology lab. As a result, science moved forward with the publication of a review of the emerging roles of forkhead box (FOX) proteins in cancer (Myatt SS, Lam EW. Nat Rev Cancer, November 2007). In 2007, Oxford Gene Technology tested its family of CytoSure oligonucleotide arrays at North West Thames Regional Cytogenetics Laboratory, and was then able to launch validated products to detect abnormal chromosomes (www.ogt.co.uk, www.londongenetics.com).Another example is given by GSK when it used novel models of disease to support drug selection and development through an Alternative Discovery Initiative at

Imperial College London (www.imperial.ac.uk/corporatepartnerships/partners/successes). Nearly 50 projects were approved for funding in a number of therapeutic areas, and new IP and testing methods were developed.

Overall, we conclude by suggesting that working with others does indeed allow organisations to accelerate development programmes and create, enhance and realise greater value from their R&D n

References:1. Lambert, R (2003) Review of Business-

University Collaboration, accessed 31st July 2010 at www.hm-treasury.gov.uk/d/lambert_review_final_450.pdf. Final report of the review by former Financial Times editor Richard

2. Chesbrough, H (2003) Open Innovation: The New Imperative for Creating and Profiting from Technology, Boston: Harvard Business School Press.

3. Jones, A (2007) Minimizing leakage of value from R&D alliances, Nature Reviews Drug Discovery, Volume 6, pages 712-719.

4. “AstraZeneca and MMV Join Efforts in the Fight Against Malaria” press release published on 28th June 2010 at www.astrazeneca.com/media/latest-press-releases.

5. Tralau-Stewart, C et al (2009) Drug discovery: new models for industry - academic partnerships, Drug Discovery Today, Volume 14, Issues 1-2, pages 95-101.

6. Pharma 2020: Challenging business models. Which path will you take? Report accessed on 31st July 2010 at www.pwc.com/gx/en/pharma-life-sciences/pharma-2020.

Dominique kleynDominique is an active supporter of new ventures and founder director of several spin-out companies from the London cluster. She brings experience of both research and commercialisation in industry and academia, and is an expert in navigating the interface between the two. She joined London Genetics as CEO in 2009.Email: [email protected]

Figure 1: Above Figure 2: Below

Data and enablement

Patentbudget and

timelines

Portfolioand track

record

Publicationsand disclosures

Techologypush and

needs driven

Issues in IP management

Drivers for a less collaborative approach

Approaches on a sliding scale

Defining the scope

Measuring success

Involving key players

Managing change

Drivers for a more collaborative approach

Focus on input

Hard outcomes

Manager-led

Inflexibility

Focus on output

Soft outcomes

Champion-led

Flexibility

Key issues in constructing contracts for collaborations



people: the Missing Dimension?

countless informatics projects are competently specified, acquired and delivered to an expectant user base – only to flounder in the hands of those very same users. How can we ensure that the solutions we deliver will get used and deliver the return promised?

We can all think of at least one IT project where the resulting software ultimately had all the functionality that the end users felt was vital, and yet when faced with the prospect of using it on a daily basis they turn away. Sometimes those users say that it wasn’t what they asked for, but more often that it is too hard to use, or adds too much time and complexity to the existing process.

What is it that separates the successes from, not perhaps the failures, but the uninspired solutions? What makes you take to some devices or software straight away, feeling you would not want to go back to the “old way”, whilst others leave you feeling that somehow things always seem harder than they need to be?

a Focus on the Whole ExperienceThe meteoric rise of Apple on the back of the iPod, iPhone and iPad has been greeted with a great deal of cynicism from the vast majority of “techies” and expert commentators, who point out the technical shortcomings of Apple’s offerings compared to the competition. Yet Apple continue to ship impressive numbers of devices to an apparently insatiable demand, and their financial success, even in a tough economic climate, is undeniably impressive.

How can it be that a company can ship technically inferior products, yet achieve an apparently unassailable position in a market? By rights, the incumbents in any of those segments, and especially the multi-sector giant that is Microsoft, should have condemned Apple to be a bit-player. Yet we see Apple’s market value eclipse Microsoft’s, phone vendors desperately scramble to play catch-up in a market

that is now defined by Apple’s iPhone, and everyone is completely blindsided by the iPad’s success and implications.

Whenever something doesn’t make sense, there’s often a clear lesson hidden in all the frothy commentary, and often one that has wider applicability outside any particular circumstance.

Apple are undeniably geniuses at marketing, backed up by impressive engineering and manufacturing skills. Despite minor hiccups like “Antennagate”, the ramp-up on the iPad and iPhone 4 should inspire awe in anyone familiar with the complexities involved in getting electronic devices from the drawing board out into the market in bulk.

Despite these impressive operations skills, the defining aspect of Apple today is their relentless focus on every aspect of the user experience (“UX”). Not only have they thought about how the product works, but they also pay attention to the entire purchasing experience, from the Apple Store to “unboxing” and turning the device on for the first time. Purchasing, opening and owning an Apple device should be mandatory for anyone seeking to specify technology that other people use.

Apple’s focus on user experience has been the foundation of their success in the past few years. Their dominance is not only a reflection of how good they are, but also how much the rest of the industry has lost their way in this regard.

The problem and OpportunityThis perhaps is the lesson that Apple have for scientific information systems. Project teams tend to focus on the system – what it does, how it does it, what it is built on – rather than on the user, and how our new initiative will help them do their job. Unfortunately, despite our focus on these albeit worthy technical aspects, the success or failure of our project is determined by how we effectively support the human beings involved. It is at that point, and only that point, that value is

delivered. In the words of Douglas Adams, “We are stuck with technology when what we really want is just stuff that works.”

Have you noticed that in IT we call the humans we are trying to help “users”, which by the time it gets to the help desk becomes an almost derogatory term, in the worst cases becoming “lusers”, because the humans have become the problem?

Projects which deliver technically but fail once in the hands of the users are rewarded for following the project management process and meeting their technical goals, and “the business” is viewed to have failed to get the users to use the system.

Yet our whole purpose in scientific informatics is to enable scientists to do better science – quicker, more effectively to be sure – but it is still all about supporting the scientist.

It Starts with the projectApple’s take on product design starts with the requirements; they are defined as much by what they don’t do as by their specific features. The iPad is particularly extreme in this regard, culling so many sacred cows of “computer” functionality that many dismiss it out of hand.

Contrast this with the current accepted best practice for informatics projects:

Survey all the users to find out their requirements

Add all these requirements together, attempting to please as many people as possible

Add in a series of technical requirements, often unrelated to anything other than internal standards

Remember that of course people are important, so make a note at the bottom of the Request for Proposal that the system “must be easy to use”

More systems mean more cost, so attempt to do as much in any one system as possible

Try and get the “best” system for as cheap as possible, where “best” means

Summer 2010


the one that ticks as many boxes, and “cheap” means up-front cost

Measure success by timescales, seats deployed, and of course purchase cost

Following this process will of course insulate the project leadership from any “blame” in the event of a failure. Although of course the judgement of success is made on purely technical grounds – few projects are measured on people-centric outcomes. Perhaps this is because our scientific culture feels that humans should be rational beings, and will naturally use something that is “better” according to our technical measures.

An honest look at the desk and benchtop implications of this methodology often leads to a view that we could do better; however we don’t know how, and projects are seldom chartered in a way which allows a fresh approach.

Better Measures?Every project manager wants their project to be a success, and as a result the definition of “success” is crucial. Our preference is for measures which encompass not only the financial technical issues, but also the user-centric ones which ultimately determine success or failure. So we encourage clients to base their go/no-go decision after a pilot on a simple survey of users as follows:

• Would you use the system?• Would you recommend the system

to your colleagues?We believe these questions give the

project sponsor a much clearer indication of what’s likely to happen when the system is rolled out, rather than relying on a checklist of functionality delivered.

Requirements ManagementEvery project starts with a requirements gathering phase, when typically the project team gather together and each make their contribution from their own perspective. The resulting consolidated

list is often long and inconsistent, but with strong project management can often be wrestled into something that is more tractable, without upsetting too many people.

Through the requirements process, it is important that project teams always keep one truth in mind: they are designing for the people who aren’t on the team! By definition the team members are most invested in the solution to be delivered, yet the success of the system will be determined by the masses who aren’t participating.

A complete solution delivered on time and on budget is a necessary condition for a successful project; but it is not sufficient. The return on investment (ROI) only comes when users start to use it, which brings an interesting trade-off in terms of functionality vs usability. Clearly a piece of functionality present in the solution but not used is a potential waste of money, but there’s a more important cost – complexity.

Every additional function in a system adds to the cognitive load imposed on the user, which increases the barrier to use, and hence reduces the potential returns. Effective project teams carefully audit their requirements list, removing any “nice to have” functionality which might get in the users’ way.

This attention to cognitive load also applies to system configuration; for example, experience has shown that asking users for too many metadata items before submitting an experiment causes them to make up answers just to make the dialog box go away, which makes asking for metadata at all rather pointless. It is better to restrict yourself to asking for up to three pieces of critical information, and then using full text search capabilities for other searches. A somewhat related point is to ensure that users are only prompted for information they can answer, and can’t be gathered or inferred elsewhere.

Although it is hard to quantify the cost imposed on users, a good practice is to assign a cost (e.g. $10,000) for every field which needs to be entered by the user; this tends to focus the mind on the reality that whilst it might be “free” in a financial sense, there is a cost imposed on the users.

As Antoine de Saint-Exupery said, “A designer knows he has achieved perfection not when there is nothing left to add, but when there is nothing left to take away.” One downside of a project team approach to electronic lab notebook

(ELN) design is the lack of a clear design focus, and one of the frustrations vendors often face when dealing with supposedly

non-negotiable requirements lists is the mismatch between a “designed” product which has a sense of cohesion and a requirements list which is the result of a committee. If RFPs contained a question “Based on your experience of companies like us, which of our requirements should be dropped and why?” there would certainly be a a great deal of fruitful feedback!

use the Familiar, in a Familiar WayAside from good design, there are two

clear ways to make something “easy to use”.

• Use ideas and concepts that users are exposed to every day.

• Do less - less functionality, less to learn how to use.

People today in their working lives have countless computer systems they interact with; everything from the ever-present Microsoft Windows and Office suite, to specific solutions tailored for their particular job role. Home life brings a whole series of additional systems and metaphors; systems like Facebook, LinkedIn, and the Google applications might not be directly applicable to the working environment, but they are in the user’s head and can be reused to great effect.

General searching can be patterned on Google; more complex searches from sites like Amazon and eBay. Facebook has a whole series of intriguing possibilities – Farmville can get millions of supposedly sane adults to collaborate to the level of addiction helping each other with virtual gardens – why can’t the same techniques be used in science?

“Do less” is not just a matter of paring back the requirements; it is also a matter of co-opting existing systems generally through integration. Whilst this is often a matter of routine integration (“Must integrate with Microsoft Office”) the devil is in the details. The tools that you choose to integrate with must still act in a predictable manner, which is a particular problem with applications such as Excel where usability seriously degrades when embedded in another container application. One often wonders if purchases of “fully functional” ELNs really know they are spending $1,000 per head just to make Excel harder to use!

26 INTERNATIONAL PHARMACEUTICAL INDUSTRY


The peril of Horizontal SolutionsMany larger companies have invested in horizontal frameworks such as document management systems, Sharepoint etc., and there is often heavy pressure from IT to re-use such tools for any new application.

Often this works well for problems which are well suited to these tools; however this introduces three risks:

• The project loses focus on end-user usability and instead becomes an initiative to use the particular tool; if once a system has been designed it becomes apparent that a generic platform is the best approach, then so be it, but often the tool selection is made very early on before requirements have been fully developed.

• The general capabilities of these tools make it very tempting to add features just because they are “easy” and come bundled with the tool. This just takes a simple system and makes it much more complex, for no business benefit.

• General tools such as document

management force a vocabulary, way of working and organisation which is often not sympathetic to the problem being solved.

Improving ROI Starts with peopleWe deploy information systems to help people do their work; the extent to which the system is used effectively determines the return on investment achieved.

Apple’s success shows the power of a clear focus on user experience, and with a shift in mindset these benefits can be available to in-house teams as well. However before this can happen, the framework within which projects are chartered and measured needs to change from being purely procedural and technical, to one which focuses on the end-user experience n

Simon Coles MEng - CTO & Co-founder, Amphora Research SystemsSimon Coles has been working with ELNs since 1996, and was responsible for one of the earliest and largest ELN implementations in the world. He blogs on all things ELN related at http://elnblog.comAmphora Research Systems was formed to continue this work, and the company now supplies ELNs to a wide variety of companies worldwide. With some of the largest and some of the smallest installations, Amphora’s solutions are the most popular and trusted alternative to the traditional bound laboratory notebook. As one of the world’s leading authorities on ELNs, Simon has a wide range of experience in all aspects of the field, from design and implementation to the legal and regulatory considerations which form an essential part of any ELN project. A regular contributor to industry conferences, Simon holds a Masters in Information Systems Engineering as well as various technical qualifications. Email: [email protected]



Dr patricia Lobo – Editor of IpI & Managing Director of LifeSciences Business consulting speaks with Jean-claude Marcourt, Vice-president and Minister of Walloon Economy

Q: How can you explain the success of BioWin?A: Success rests in the fact that BioWin offers strong support to its members in all fields relevant to their activities. It has also attracted envy by going international.

Success is especially noteworthy in the specialisation of the operational team and in its field vision, allowing active and customised support to BioWin members (innovative firms in the field of medical biotechnology, academic laboratories and research centres). Support is based on three axes: development of scientific excellence through collaborative research projects, international radiance via European partners, and a specific training offer responding to market needs.

The development of scientific excellence translates into accompaniment of R&D project-holders during calls launched by the Walloon region. These R&D projects bring together at least two operators from the industrial sector (including one SME) and two partners from the academic world. BioWin support comes at an early stage (offering assistance in seeking industrial or academic partners), during the writing of the project (organisation of informative sessions about intellectual property and industrial valuation), but also when the projects are already certified by the Walloon Government (regular meetings with project-holders, mid-term evaluation by an international jury). Afterwards, the supplied support will focus on the industrial valuation, in order to optimise positive economic impacts for the beneficiaries.

BioWin benefits from international visibility and from international credibility. As a matter of fact, BioWin is solicited by other European poles or clusters which would like to conclude partnerships. The goal of these international partnerships is the setting up of clustering events, the conclusion of trade agreements between firms from different clusters, and the formation of European projects. These collaboration agreements, which bring

positive economic impacts for the SME, will be widened in the next few years.

In the context of its strategy training, BioWin members are allowed to follow training modules. These modules cover several fields for which weaknesses in terms of competencies have been identified. Ranging from Quality – Clinical Studies, to Innovation, Entrepreneurship and Transversal Competencies, these modules have to help to ensure an adequacy between the courses that are taught in university and the market expectation, without forgetting the continuous training of pole members.

BioWin has already concluded several partnerships with health poles, such as an agreement with EuroBiomed (France), and has the ambition of creating an interregional collaboration agreement with the Flemish Association on Biotechnologies (FlandersBio).

Thanks to its active participation within the Council of Euro BioRegions (CEBR) (European network of health poles), BioWin has been participating since last year in its first European Project: ABC Europe (Europe INNOVA). This project seeks to trade the best practices of 13 health poles, whose European leaders are Medicen (Paris), Alsace BioValey (Strasbourg), BioM (Munich), Medicon Valley Alliance (Suède-Danemark) and ERBI (Cambridge), concerning the international development of SMEs.

BioWin has also recently won the second European project in the context of the call Régions de la Connaissance (Regions of the Knowledge) made by the DG Recherche (General Director of Research). This project, called “TERM”, which also involves the leader of the project Atlanpôle Biothérapies (France) and BioMadrid (Spain), aims to establish and to implement a timesheet on mutual research on cellular therapy and on regenerative medicines. The regions from which the poles come, such as the Walloon region, are also included in the consortium in order to bear out

an interregional call for projects on the research fields previously mentioned.

Outside Europe, BioWin can rely on an agreement concluded by AWEX, the agency dedicated to exports and investments abroad, with Texas A&M, a group of technological Universities from Texas (US), to facilitate the penetration of Walloon firms into America. Moreover, at the end of June, in the context of the Walloon week organised in the Belgian “space” during the Universal Expo in Shanghaï, BioWin signed a collaboration agreement with SBIA, the association of the biopharmaceutics industry in the region of Shanghaï, which is the place to be in China with regard to the field of biotechnology development. Q: How is the BioWin pole financed?A: BioWin receives public subsidies from the Walloon region and from AWEX. These subsidies do not cover all BioWin operating costs, which is why the pole receives additional revenues from the subscriptions of its members and from sponsorship.In the context of its brand new and ambitious strategy (and from new financial needs which will result from it), BioWin has established a finance-oriented task force which will try to find new sources of financing. Q: What can be done to further improve the BioWin pole? How do you see the BioWin pole in the future?A: The BioWin pole has reoriented its strategy for the 2010-2014 period in order to improve its support in favor of SMEs in the health sector by defining four guidelines: 1. In the context of its activities supporting

innovation, sustained scientific excellence should be pursued while developing partnerships between academic institutions and industry, as



well as ensuring that the technologies or products developed fulfil market needs and can be commercialised as soon as possible. The strategic matrix concerning R&D projects likely to be adopted by the Walloon region has been redefined. This matrix will henceforth have one technological dimension (the vertical axis) and a time to market dimension (horizontal axis). BioWin wishes also to amplify its market valuation strategy with the help of new internationally recognised actors. The appearance of the time to market dimension is testament to the fact that BioWin has the ability to create short, mid and long term socio-economic value.

2. BioWin’s training strategy is highly ambitious. The training calls for projects (based on the model of the collaborative research calls for projects) which reflect ideas coming directly from BioWin members (bottom-up strategy). BioWin will have to better structure the competences offered according to the needs of SMEs from the health sector, but also to work further upstream through the integration of training modules in academic programmes (in colleges and universities).

3. Pursue the BioWin internationalisation politics to benefit the industry and particularly SMEs. The pole has defined a new international strategy which is structured around three main axes. BioWin will create an international unit in its operational organisation, which will contribute to the international development of SMEs from the pole in close collaboration with AWEX. For example, this may happen through missions to allow commercial prospecting and development of partnerships. It will reinforce clustering, and will actively participate in inter-pole European projects (focusing on SMEs) and to the implementation and development of partnerships for the projects which are under construction and those which already exist.

4. Promote the establishment of technological platforms and facilities encouraging the development of the biomedical sector in the Walloon region. BioWin has decided to encourage the creation of infrastructure projects and technological platforms. The goal of the pole is to seek to identify any common project idea aiming for the creation of a technological platform, and/or to fulfill a critical weakness in infrastructure for

the development of the biomedical sector in the Walloon region. Various projects concerning platforms are being assembled (industrial production of cellular therapy, exchange and provision of human material through a biobank, preclinical trial platform).

Q: What are the results of calls for projects?A: We have the results for the first five calls; the last one was not taken into account because the decision about the labelling has not yet been made.

The results encompass: 16 labelled projects related to three therapeutic axes (cancer, inflammation, central nervous system diseases) 27 industrial partners (of which 23 are SMEs) 57 academic laboratories (of which three are international) Five research centres (of which three are international)

Budget 52,406,984 € (including private components from companies)

Labelled projects• Regular contact with the project leader;

participation in scientific meetings (at least two per year)

• Mid-term evaluation (usually after two years) by an international jury with a special focus on the deliverables to be achieved and the valuation

• Regular reporting and close collaboration with the Walloon Administration

New call for proposals (6th and following)• Guidance and follow-up provided by

BioWin and the Walloon Administration to the consortia for building their dossier

• Dedicated training organised by BioWin for their members on intellectual property, market analysis, guidance for defence

• Strong support of BioWin to negotiate the consortium agreement between the partners and to valorise the products and technologies developed

Q: When will the next call for projects take place?A: The seventh call for projects will be launched during a kick-off meeting that will take place on the 7th of September.The completed records will have to be returned for the 31st of January 2011.All useful information will be communicated

during the kick-off session. The objectives of this session will be to present in further detail the chosen themes, the conditions of eligibility, the selection criteria and the main steps and the key dates for the assembly of the projects. The competent administrations (representative of the Walloon Government, DGO6, and FOREM) will also be present to answer eventual questions n

Jean-Claude Marcourt. Minister for Economy, SME’s, Foreign Trade and New Technologies in the Walloon regional Government and Minister for Higher Education in the French-speaking community Government.Jean – Claude holds a Doctor of Law (University of Li7ge). He is a Barrister at the Liege Bar (on leave since 1992)Several Positions held by Mr. Marcourt are as follows: 1992-1994 : Principal private secretary to the Walloon regional Minister for Internal Affairs1994-1995 : Principal private secretary to the Walloon regional Minister for Internal Affairs, Civil Service and Budget 1995-1997 : Principal private secretary to the Walloon regional Minister for Budget, Finance, Employment and Vocational Training and to the French-speaking community Minister for Budget, Finance and Civil Service 1998-1999 : Principal private secretary to the Deputy Prime Minister and Minister for Economy and Telecommunications1999-2003 : Principal private secretary to the Deputy Prime Minister and Minister for Employment2003-2004 : Principal private secretary to the Deputy Prime Minister and Minister of Justice2004-2009 : Minister for Economy, Employment, Foreign Trade and Heritage in the Walloon regional Government.Email: [email protected]


DRUG DISCOVERY / DEVELOPMENT & DELIVERY

a generic approach to the Validation of Small Molecule Lc-MS/MS Biomarker assays

In recent years, there has been a large increase in the use of both exploratory and validated biomarkers1, as they have been formally incorporated into the drug development process as indicators of the pharmacodynamic effect of drugs. a “biomarker” is a substance that is measured as an indicator of the normal biologic process, pathogenic process or pharmacologic response to a therapeutic intervention. However, while there is clear and comprehensive guidance on expectation of the approach and quality requirements for the generation of regulated pharmacokinetic or bioequivalence data2,3 this is not the case for biomarker data.

Recent studies have seen the development of an approach to the validation of laboratory biomarker assays in support of drug development (Lee et al.). However, the focus has been on the use of ligand binding assays for the measurement of biomarker concentrations in ex vivo body fluids and tissues. The fact that biomarkers come in all shapes and sizes, and many are small molecules that lend themselves to the use of liquid chromatography – mass spectrometry (LC-MS), has been neglected.

The traditional expectations for small molecule assays, in terms of performance, are significantly different from ligand binding assays for the generation of pharmacokinetic data5. Despite this, there is currently no published approach to validation of LC-MS/MS methods for endogenous small molecule biomarkers. Members of the pharmaceutical industry have struggled with endogenous assay validation for many years, and there is often confusion over which approach to take. The presence of endogenous analytes in a control matrix presents an added analytical challenge that must be overcome if small molecule biomarker assays are to be developed and characterised. There is

therefore a need for a generic approach to endogenous assay validation that can be successfully applied in most cases of small molecule biomarker analysis.

Some contract research organisations (CROs) are skilled in conducting this generic approach to small molecule biomarker validation of endogenous assays. As these CROs are extremely familiar with the method, they have the expertise to perform endogenous assay validation in the most effective way. Although there are no specific Food and Drug Administration (FDA) regulations for the validation of endogenous compounds, CROs performing endogenous assay validation are equipped to meet regulatory expectations and work with the scientific rigour required by such authorities.

In this article, a generic approach to the validation of LC-MS/MS endogenous small molecule biomarkers methods is presented for consideration as the optimal bioanalytical method for this type of assay. The recommendation is to use a surrogate matrix over traditionally used controlled matrices. This generic approach is one that is likely to be successful in most cases, particularly when conducted by CROs who have the confidence and familiarity needed to perform it efficiently and correctly.

Issues Specific to Endogenous assaysThe majority of small molecule bioanalysis performed today uses LC-MS, but the technique is frequently subject to matrix effects inherent in the ionisation mechanism. This is overcome where possible by matrix matching the calibration standards to the unknown samples, and the incorporation of stable isotope internal standards into the method to improve assay precision and accuracy.

Small molecule validation guidance documents, while referring to endogenous analytes, are written more specifically for xenobiotic drugs. The presence of the analyte in a control matrix presents an extra challenge, especially when

evaluating the validation parameters of selectivity, recovery, matrix effects and limit of detection. The approach taken in constructing the calibration curve is key to the success of this type of assay. It may be possible to select a control matrix that has a low concentration of endogenous analyte e.g. sex differences or disease states, in which case a conventional matrix calibration is applicable. Another approach demonstrated by Jemal et al.6 is the use of a stable isotope analogue of the analyte for construction of the calibration line in a control matrix. However, a second and different stable isotope was also required for use as the internal standard. If none of the above is possible, other approaches such as standard addition calibration or surrogate matrix calibration may be used.

The Benefits of Surrogate Matrix calibrationThe most conventional method employed with LC-MS where an analyte-free matrix is not available is standard addition calibration. The advantage of this approach is that differences in analyte response caused by matrix effects or differential recovery between calibration standards and samples are minimised due to matrix matching. However, it is also more difficult to estimate the lower limit of quantification LLOQ of the method, as there is no direct estimation of precision and accuracy of measurement below the calibration range. Furthermore, where endogenous analyte concentrations are relatively high in a control matrix, the measurement of relatively small additional amounts of analyte and the extrapolation of calibration lines below the measured range have the potential to introduce significant error in measurement. The FDA Guidance for Industry: Bioanalytical Method Validation document3 actively discourages the extrapolation of calibration curves beyond their range. This puts the regulatory acceptance of this approach into question as it relies on



the assumption that the relation between response and concentration remains linear, with a gradient equal to that observed for concentrations above the endogenous concentration.

An alternative to standard addition is the use of surrogate matrix calibration, which is defined as a calibration curve constructed using a matrix significantly different from the sample matrix. Previous surrogate matrix calibration methods were time-consuming and difficult to reproduce, resulting in a matrix containing low concentrations of residual analyte, and exhibited matrix effects when using LC-MS. This is because the method involves the preparation of a ‘stripped’ matrix using procedures such as charcoal stripping or some form of sample extraction process. However, a more sophisticated ‘synthetic’ matrix has been developed; where ‘synthetic’ refers to a matrix made up of multiple components representative of a real matrix made in the laboratory. The advantage of a ‘synthetic’ surrogate matrix over a ‘stripped’ biological matrix is that it contains no residual analyte, is well characterised and can be made up more consistently.

The generic approach developed for the validation of small molecule LC-MS/MS biomarker assays is based on the use of a ‘synthetic’ surrogate matrix calibration line. Its use can be successfully applied to endogenous analyte quantification and has advantages over other approaches. For example, this generic approach has been shown to overcome matrix effects between calibrators and samples by selecting suitable SIL internal standards. Table 1 shows examples of small molecule biomarker assays developed and validated using surrogate matrix calibration and LC-MS/MS analysis. The performance of methods, as measured by precision (%CV) and accuracy (%RE), indicates that matrix effects were acceptably controlled and the use of a surrogate matrix calibration was valid.

As this generic approach can be successfully applied in most cases and delivers the right answers first time, significant cost and time savings are generated. These are further enhanced by outsourcing to a CRO, who is equipped to apply the approach in the most efficient way.

conclusionA generic approach to endogenous assay validation has been developed which will allow method performance to be evaluated, and is closely aligned to the exogenous analyte regulatory validation guidelines. The surrogate matrix calibration protocol has been successfully applied to the measurement of a number of small molecule exploratory biomarkers used to evaluate drug treatments. The application of an analyte-free synthetic surrogate matrix by CROs enables conventional calibration curves to be constructed across the anticipated range of analyte concentrations. Matrix effects are minimised during development of the extraction method, and the recommended use of SIL internal standards has been

shown to correct for any ion suppression or enhancement observed in the sample matrix. The use of a matrix experiment, similar to the parallelism experiment used in ligand binding assays, can be used during validation to evaluate the extent of any measurement bias introduced due to differences between the sample matrix and surrogate matrix used for calibration.

The generic nature of this method development and validation approach lends itself to adoption as best practice for small molecule biomarker methods. Outsourcing to expert CROs to perform endogenous assay validation is beneficial, as they have the expertise and familiarity with the types of methods needed for it to be performed in an efficient and cost-effective way n

To learn more about Quotient Bioresearch and how the company can perform endogenous assay validation of small molecule biomarkers, please call +44 (0)1638 720 500, email [email protected] or visit www.quotientbioresearch.com

Analyte Matrix Range (ng/mL) %RE/%CV at LLOQ

5alpha-Tetrahydrocortisol (5a-THF) Urine 80 - 6,000 <1%/<4%

6beta-hydroxycortisol Urine 1 - 1,000 <-1%/<9%

aldosterone Plasma 0.2 - 10 <6%/<10%

alpha-Cortol Urine 16 - 3,000 <-4%/<8%

alpha-Cortolone Urine 100 - 10,000 <-4%/<8%

androstenedione Urine 0.2 - 175 <4%/<14%

androsterone Urine 50 - 10,000 <1%/<11%

beta-Cortol Urine 16 - 3,000 <-9%/<10%

beta-Cortolone Urine 100 - 10,000 <4%/<7%

cortisol Saliva 0.2 - 20 <8%/<8%

cortisol Plasma 0.6 - 300 <4%/<4%

cortisol Urine 0.6 - 300 <1%/<7%

cortisone Urine 2 - 500 <1%/<6%

cortisone Plasma 2 - 500 <-4%/<2%

DHEA Sulphate Urine 50 - 5,000 <6%/<7%

DHEA Sulphate Plasma 50 - 5,000 <5%/<4%

etiocholanolone Urine 50 - 10,000 <-3%/<14%

glycine1 Plasma 1000 - 200,000 <4%/<9%

glycine1 cerebrospinal fluid 20 - 4,000 <1%/<7%

hydroxyproline2 Urine 650 - 150,000 <-8%/<9%

hydroxyvitamin D23 Plasma 1 - 150 <8%/<10%

hydroxyvitamin D23 Plasma 3 - 150 <6%/<8%

tetrahydrocortisol (THF) Urine 50 - 5,000 <-5%/<4%

tetrahydrocortisone (THE) Urine 400 - 20,000 <-3%/<4%

Table 1: Parallelism experiment for etiocholanolone assay

DRUG DISCOVERY / DEVELOPMENT & DELIVER

References:1. Goodsaid F, Frueh F: Biomarker

Qualification Pilot Process at the US Food and Drug Administration. The AAPS Journal 9(1), Article 10 (2007).

2. Viswanathan CT, Bansal S, Booth B et al.: Workshop/Conference Report – Quantitative bioanalyitcal methods validation and implementation: Best practices for chromatographic and ligand binding assays. The AAPS Journal 9(1), Article 4 (2007).

3. Food and Drug Administration: Guidance for Industry: Bioanalytical Method Validation. Rockville, MD: US Department of Health and Human Services, FDA, Centre for Drug Evaluation and Research (2001).

4. Lee JW, Devanarayan V, Barrett YC et al.: Fit-for-purpose method development and validation for successful biomarker measurement. Pharm. Res. 23(2), 312-328 (2006).

5. DeSilva B, Smith W, Weiner R et al.: Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm. Res. 20, 1885-1900 (2003).

6. Jemal M, Schuster A, Whigan D: Liquid chromatography/tandem mass spectrometry methods for quantitation of mevalonic acid in human plasma and urine: method validation, demonstration of using a surrogate analyte, and demonstration of unacceptable matrix effect in spite of use of a stable isotope analog internal standard. Rapid Commun. Mass Spectrom. 17, 1723-1734 (2003).

About Quotient Bioresearch Quotient is a leading provider of early stage and specialist drug development services to pharmaceutical, biotechnology and medical device clients worldwide. The company offers a unique range of drug development services through its three key focus areas – Chemistry & Metabolism, Bioanalytical Sciences and Clinical Services. Quotient has grown rapidly in the past three years, through a combination of both acquisition-led and organic growth. Quotient Bioresearch is part of Quotient Bioresearch Group, which comprises Quotient Bioresearch and HFL Sport Science.

For further information: www.quotientbioresearch.com

For further press information please contact: Sarah Evans - The Scott Partnership, 1 Whiteside, Station Road, Holmes Chapel, Cheshire, CW4 8AA, United Kingdom. Tel: + 44 1477 539 539 Fax: +44 1477 539 540 E-mail: [email protected]

Richard Houghton, Principal Scientist, Bioanalytical Sciences, Quotient Bioresearch. Richard is a Principle Scientist in the department of Bioanalytical Sciences at Quotient Bioresearch Ltd. He has been in analytical chemistry for over 20 years, with the last 12 years in the pharmaceutical CRO industry. His particular area of expertise lies in the development and validation of LC-MS/MS methods for the measurement of drugs and biomarkers in clinical and pre-clinical samples.Email: [email protected]



Maximising protein yields with pichia pastorist

The yeast pichia pastoris is widely used as host for heterologous protein expression for hundreds of different proteins. Recently, the organism has received attention in the biologics industry when the first pichia-derived biopharmaceutical protein received market approval by the FDa. pichia expression cells can furnish yields of more than 10 g/L of secreted recombinant target protein. However, there are many aspects and factors influencing expression levels which have to be tuned properly in order to obtain a high performance expression strain.

The yeast Pichia pastoris is widely used as host for heterologous protein expression for hundreds of different proteins. Recently, the organism has received attention in the biologics industry when the first Pichia-derived biopharmaceutical protein received market approval by the FDA. Pichia expression cells can furnish yields of more than 10 g/L of secreted recombinant target protein. However, there are many aspects and factors influencing expression levels which have to be tuned properly in order to obtain a high performance expression strain.

The market launch of insulin approximately 30 years ago is generally regarded as the commercial advent of recombinant DNA technology. Since then the biotechnology drugs market has been growing at remarkable rates and the biologics industry is now generating annual revenues of more than $100bn, corresponding to over 15% of the total pharmaceutical market. Today, monoclonal antibodies (mAbs) are the dominating class of proteins on the biologics market. Besides mAbs, other proteins, such as for example cytokines, hormones, blood factors, fusion proteins or therapeutic enzymes, have found pharmaceutical application. As a matter of fact, the diversity of protein

molecules developed or marketed by the pharmaceutical industry also reflects certain varieties of molecular architectures and properties. Given the fact that so far the one universal expression host meeting all scientific and commercial requirements for manufacturig of recombinant proteins has not been established, one would conclude that the demand for a considerable variety of protein molecules has to be met by numerous different expression hosts. Nevertheless, from the group of mammalian expression systems Chinese hamster ovary (CHO) cells are the dominating technology, and on the microbial side, this role is occupied by Escherichia coli. These two expression systems have truly become the main workhorses of the industry, and are much appreciated by their well established performance and safety profiles. Roughly 30 to 40% of all biologics are produced in microbial organisms, and besides E. coli, yeasts such as Saccharomyces cerevisiae, Hansenula polymorpha and Pichia pastoris have found some application.

pichia in the Biologics MarketBiopharmaceuticals manufactured in Pichia pastoris which have been approved in different markets are human serum albumin (Mitsubishi Tanabe Pharma Corporation; product was withdrawn recently), hepatitis-B surface antigen, interferon alpha 2b (Shantha Biotechnics, now part of Sanofi-aventis Group) and Insulin (Biocon Ltd). Notably, in late 2009 ecallantide (marketed as KalbitorTM, Dyax Corp.), a plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema, has been granted market approval by the US Food and Drug Administration, and is currently undergoing approval process in the European Union. Judging from its current status and the recent approval of a Pichia-derived product in a major market, Pichia pastoris is gaining ground as a validated expression system for

biopharmaceutical manufacturing.Pichia pastoris is one of the few yeast

species classified as methylotrophic, due to its capability of metabolising methanol as the sole source of carbon and energy. In this context, the AOX1 promoter regulating the expression of the first enzyme involved in the yeast´s methanol catabolism – namely alcohol oxidase 1 – is one of the strongest promoters from the microbial kingdom known to date, and its application has proven a very good means to achieve high expression levels of recombinant proteins. From this perspective, it is not surprising that this regulatory element is the focus in one of the strategies to maximise protein yields with Pichia pastoris as discussed below.

A wealth of reports has been published describing the production of hundreds of different proteins in Pichia pastoris, and in many cases product titers of several g/L - sometimes even exceeding the 10 g/L margin – have been achieved. In addition, it is generally appreciated that this organism is also very effective in secreting a protein of interest into the culture medium, obviating tedious raw product recovery. For example, human serum albumin was obtained in the >15 g/L range by secretion into the culture medium (VTU Technology GmbH) and intracellular expression of a hydroxynitrilase enzyme furnished >20 g/L of product (Graz University of Technology).

Historically, Phillips Petroleum Company used Pichia pastoris in an industrial setting in the 1970s for the generation of single cell protein for production of high-protein animal feed. The company took advantage of the organism´s methylotrophic nature and fed the cultures with (at that time) cheap methanol. However, with the breakout of the oil crisis and rising methanol prices, the process never became competitive. In the 1980s researchers at SIBIA (Salk Institute Biotechnology/Industrial Associates Inc.) developed Pichia as a



system for foreign protein expression, and in the 1990s Research Corporation Technologies Inc. aquired the rights from Phillips Petroleum, and the components of the system became commercially available through Invitrogen (now Life Technologies) fuelling worldwide research and development with Pichia.

Nowadays, more and more companies are entering the biopharmaceuticals arena, and as a consequence an increasing number of players will be competing for market share in the different therapeutic areas. From that point of view, the economics of biopharmaceutical manufacturing are very likely to become more challenging. Secondly, with several biologics coming off patent soon, a price competition will be brought about by the launch of follow-on biologics. Today these products account for roughly 1% of revenues in the biopharmaceutical industry, but annual growth rates are projected to be approximately 50% over the next five years, and 30% over the next ten years. In light of that situation, biologics developers and manufacturers may have to devote increased effort to cost of goods reduction. Of course,

there can be no doubt that apart from manufacturing costs there are many more significant cost factors and drivers to biologics pricing, but manufacturing costs become increasingly detrimental, and increasing cell line titers will at least lay the foundation for a healthy cost structure.

Maximising yieldsFor the purpose of introducing a generalised view on different options to maximise protein yields with Pichia pastoris, it may be useful to discuss aspects concerning gene design, generation of expression cell line and genetic manipulation of the organism, as well as cultivation. Codon optimisation of the gene encoding a protein of interest should be taken into consideration in order to avoid transcriptional and/or translational bottlenecks. Many of the commercial suppliers of synthetic DNA have elaborated effective procedures to design and optimise genes for Pichia expression. As stated above, efficient secretion of recombinant proteins controlled by signal sequences is a very useful feature of Pichia pastoris, and a

number of different signal sequences having different effects on expression efficiency have been tested, among them Saccharomyces cervisiae €MF (alpha-mating factor prepro leader sequence), PHO1 (signal sequence of Pichia acid phosphatase 1) or human serum albumin signal sequence, to name a few. In some cases, the native signal sequence of a target protein also turned out to be beneficial. In general, €MF has been shown to be most useful in terms of efficiency and versatile applicability, making it the number one choice for this purpose.

The proper choice of promoters is a very important success factor in recombinant protein expression. Several different promoters have been applied with Pichia, of which GAP (Pichia glyceraldehyde dehydrogenase promoter) and AOX1 (Pichia alcohol oxidase 1 promoter) are the most important ones. GAP is a relatively strong constitutive promoter, and in some rare cases expression yields above 1 g/L range can be achieved. In addition, it is a useful alternative if the use of methanol which needs to be present for AOX1 induction needs to be avoided.



In terms of expression strength and protein yield the AOX1 promoter is much more powerful, allowing for titers of more than 10 g/L of secreted target protein. The gene product of AOX1 is alcohol oxidase 1, one of two alcohol oxidases – the other one being alcohol oxidase 2 – catalysing the initial step of the yeast´s methanol metabolisation. Although alcohol oxidase 1 accounts for more than 90% of the activity in this catabolic step, it is a relatively weak enzyme due to its poor affinity to molecular oxygen (the co-substrate in this reaction). As a consequence, huge amounts of alcohol oxidase 1 have to be produced by the cell once methanol is present, which explains the exceptional strength of this promoter. The AOX1 promoter is tightly controlled depending on the carbon source, and works by a repression/de-repression – induction mechanism. It is strongly repressed in the presence of conventional carbon sources such as glucose or glycerol, displays some activity at low concentrations of these substrates (de-repression), and unfolds its entire potential upon induction with methanol. In connection with recombinant protein manufacturing this tight control regime allows for a rapid accumulation of biomass - which is important for high protein yields - during the initial cultivation phase, without overburdening the organism´s metabolism prior to methanol addition.

Recently, researchers at VTU Technology GmbH (in collaboration with Graz University of Technology) have developed a panel of genetically modified AOX1 variants, and it was found that some of these variants exhibit even greater expression strength than the native promoter, resulting in higher protein yields.

A gene encoding a certain target protein, or to be more precise an entire expression cassette, is usually integrated into the genome of Pichia pastoris upon transformation of the cells, thereby allowing for a different frequency of integration events, resulting in clones with different numbers of gene copies. It is well accepted that copy number variations influence expression levels, and it has been shown several times that higher copy numbers lead to higher expression levels although the yield increase with copy number is not linear. In this context, James M. Cregg (Keck Graduate Institute of Applied Life Sciences, Claremont, CA) has developed

a method termed posttransformational vector amplification (PTVA) by which high copy number clones can be generated after the transformation event by exposing the cells to high concentration of selection marker. However, this interconnection of copy numbers and product yield is not as universal as it may seem, and one should keep in mind that for some proteins – for example toxic proteins or proteins requiring demanding posttranslational modifications – low copy numbers in the genome lead to better results. In other words, in some cases milder gene dosage will ultimately lead to higher space-time yields.

The process of protein synthesis inside a cell from gene to functional polypeptide comprises multiple steps and mechanisms, and a plethora of different proteins are involved. Recombinant overexpression of a foreign protein at high levels may face bottlenecks, as the cellular machinery may not be able to cope with this overflow. This problem has been successfully addressed by co-expression of several proteins, mainly those involved in protein folding, disulfide bridge formation, proteolytic processing as e.g. signal sequence cleavage, stress response or transport across organelles. Numerous protein factors influencing protein maturation and secretion have been identified e.g. by applying transcriptomics, and beneficial effects on target protein yields by co-overexpression have been demonstrated. In VTU´s labs this principle has been applied along with AOX1 promoter variants. These AOX1 variants not only show different expression strengths, but also exhibit different regulatory patterns during cultivation, mostly with respect to their de-repression behaviour. More specifically, in the phase of carbon source change from glycerol to methanol – i.e the change of promoter status from de-repression to induction - selected members of that protein library show elevated activity in the de-repression phase compared to native AOX1, and therefore allow for a pre-formation of one or more yield enhancing (helper) factors. This operation principle ensures that elevated amounts of crucial factors are already present at the time when methanol induces the strong expression of the target protein. This can help to alleviate the metabolic burden of the cells during heterologous protein production. By selecting the most efficient combination of promoter variants and helper factors aligned with the specific requirement of a

given target protein, a tremendous boost of expression levels and multiplication of protein yields can be achieved.

Screening is keyThe quest for the optimal clone for the production of a desired protein will only be successful if as many as possible of the aspects described above are tuned properly. However, a priori there is no patent remedy as different target proteins with different sequences and properties will require different combinations of the described aspects. As a consequence, there is a huge diversity caused by different copy numbers and the choice of tools such as promoters, signal sequences and helper factors, and this diversity has to be addressed in the course of expression strain generation. Since it is not possible to control all important aspects influencing transcription, translation, maturation and potentially secretion of a foreign protein of interest in a rational fashion, the screening of clones resulting from transformation is attributed a pivotal role. Firstly, this implicates that it might not be sufficient to analyse just a handful of transformants. Usually, when variable components such as genetic elements or different strains are included in the expression strategy, the number of clones to be screened for identifying high expressors should be several thousand, and methods for including multiple selection markers should be available. This is of great importance, especially for the expression of hetero-multimeric proteins and/or with concomitant co-expression of yield enhancing factors in order to minimise the appearance of false positives. Secondly, for strain selection purposes, efficient and reliable protocols for cultivation of the transformants in micro scale are indispensable. This is to make sure that out of thousands, the best expressers will be identified with very high fidelity in a high throughput screening fashion. Indeed, the stage of expression strain generation and clone selection – when performed properly – holds great potential to create a firm base for further development in a time-saving manner. A well balanced interplay of yield enhancing aspects identified in high throughput screening is a key to success, and paired with rapid and reliable scale-up can substantially increase speed-to-clinic.

cultivation of pichiaAfter having generated a productive cell line, its potential will need to be exploited by



cultivation on a larger scale in bioreactors, and there are several parameters to be considered. In general, the optimal cultivation procedure very much depends on the individual production strain and the target protein to be expressed, and therefore only the most important yield enhancing aspects will be discussed.

Pichia pastoris has the ability to grow to very high cell densities, amounting to more than 150 g/L of cell dry weight, and large amounts of cells will produce large amounts of recombinant protein. On the other hand maximum yields can only be achieved if the cells are kept vital throughout the entire cultivation process, not only to maintain maximum productivity, but also to prevent cell lysis accompanied by the release of endogenous proteases, resulting in sometimes rapid product degradation. For maintaining high productivity it may on some occasions be beneficial to perform the production phase at lower temperatures (20°C or below) in cases where expression is controlled by the AOX1 promoter and cultivation is divided into initial biomass generation followed by induction/production.

It has been shown several times that production controlled by the AOX1 promoter can also be performed efficiently by using methanol/gylcerol or methanol/sorbitol mixtures in the induction phase, fully maintaining productivity as long as the levels of repressing carbon source such as glycerol are carefully controlled and kept low. This strategy will help to reduce the amount of hazardous methanol to be used in the process (although industrial Pichia cultivations applying methanol as the sole carbon source have been performed at a several 10,000 L scale).

Of course an alternative which completely avoids the necessity for methanol is to apply GAP-controlled expression, feeding the culture with glycerol or glucose alone. In this context, a subset of VTU´s AOX1 promoter library shows highly appealing features. Some of the variants have been found to elicit high productivities already during the de-repression phase before the initiation of methanol dosing (in this phase wild type AOX1 is relatively weak). Maintainig these culture conditions, expression titers of several g/L of secreted proteins have been obtained. This means that these AOX1 variants are the strongest and most effective promoters known to date for recombinant protein production in Pichia pastoris for both methanol induction and methanol-free expression.

Furthermore, Pichia pastoris is distinguished by several additional advantageous features for the production of recombinant proteins. The stable integration of foreign DNA into the yeast´s genome leads to high mitotic stability of expression cell lines, which is a very important factor for batch-to-batch reproducibility. Besides, the application of strong promoter variants (e.g. AOX1 variants) can furnish highly expressing low copy integrants, and mitotic stability will be enhanced with a decreasing number of copies of expression cassettes. Pichia is able to perform posttranslational modifications such as proteolytic/signal sequence cleavage, folding or disulfide bond formation. Interestingly, despite the apparently well-functioning secretory pathway, Pichia releases only few endogenous proteins into the culture medium, and therefore foreign proteins can be obtained with purities of up to 80% post-fermentation. This tremendously simplifies downstream processing – yet another means of COG reduction. Cultivations are performed in chemically-defined minimal media, devoid of any antibiotic selection markers. Pichia is also very convenient in terms of product safety, since viral or endotoxin contamination will not be an issue.

Apart from yield enhancing efforts, Pichia-related research has seen fascinating developments in the field of genetic engineering. Protease deficient strains have been available for quite some time now, and recently glyco-engineered strains conferring mammalian-like glycosylation patterns on recombinant glycoproteins have been developed by Research Corporation Technologies Inc. (in collaboration with Ghent University) and GlycoFi Inc. (a subsidiary of Merck & Co. Inc.).

In summary, Pichia pastoris is a good choice to be selected as host for protein manufacturing – including biologics – as with this organism high yields of quality products can be obtained, and with the recent approval of a Pichia-derived biopharmaceutical product by the FDA the system has gained validation in the biologics industry. The availability of the entire Pichia genome will further fuel research and improvements to the system, and will very likely act as a catalyst for the discovery of many more yield enhancing aspects n

Dr. Roland Weis - Head of Research & DevelopmentRoland Weis is Head of Research & Development at the Protein Technologies Unit of VTU Technology GmbH, a technology company providing services for protein expression in yeast for the biopharmaceutical and other protein industries. He is responsible for technical supervision of customer projects and advancement of VTU´s proprietary Pichia pastoris technologies. Roland received his Ph.D. in molecular biotechnology from Graz University of Technology. He has been working at the forefront of industrial yeast protein expression research over the last decade and is co-author of several peer-reviewed publications.Email: [email protected]

Dr. Thomas Purkarthofer - Head Business DevelopmentThomas Purkarthofer is Head of Business Development at the Protein Technologies Unit of VTU Technology GmbH, a technology company providing services for protein expression in yeast for the biopharmaceutical and other protein industries. He is responsible for the commercialization of VTU´s proprietary Pichia pastoris technologies and global customer relations. Thomas received his Ph.D. in chemistry from Graz University of Technology. He has been coordinating and participating in several international protein related research projects and is co-author of several peer-reviewed publications.Email: [email protected]



clinical perspectives of Stem and progenitor cells for Liver Regenerative Medicine

Because the liver is the site of many vital functions, impairment of only one protein within a complex metabolic pathway is usually highly deleterious. Such a condition is called inborn error of metabolism, and concerns many genetic diseases linked to a non-functional enzyme in the liver. Treatments, and long-term management, are currently not efficient enough, and patients would greatly benefit from an innovative therapy that meets this medical need. Orthotopic liver transplantation is the only radical treatment of severe defects, and/or end stage diseases. cell therapy has been identified as the best alternative tool to overcome scarcity of organ donation. Several cell types are under investigation, and adult liver stem/progenitor cells represent an attractive cell source for liver regenerative medicine.

Medical context for Inborn Errors of MetabolismThe liver is a key organ in regulation of body homeostasis, and performs many vital functions such as blood glucose homeostasis, plasma protein synthesis such as albumin or coagulation factors, endogenous and xenobiotic detoxification. Hence, impairment of any one of the multiple liver functions leads to a dramatic impact on health. The total worldwide incidence of both acute and chronic liver diseases sets these pathologies within the first 15 causes of death, according to the World Health Organization.

There are many important enzymes in the liver, and so a number of them can be deficient, each deficiency being associated to a specific disease. Each of these diseases is rare, and incidences can be as low as 1 in 1,000,000 births. However, altogether liver-based inborn errors of metabolism affect one child in 2,500 live births. This means that, within the European Community only, 2000 new cases every year are diagnosed.

Beside congenital liver diseases due to a gene-metabolic defect, acquired disease may also affect the liver, due to infectious, toxic or immune mechanisms. Acute liver diseases may lead rapidly to severe functional impairment, such as in fulminant hepatitis, whilst more chronic damage will cause progressive fibrosis and cirrhosis.

Within the panel of these genetic diseases, some are very severe and life-threatening, while others are milder in their clinical expression. Nonetheless, they all impede the general quality of life of both the patient and his or her family. For instance, patients suffering from urea cycle diseases cannot detoxify free ammonium resulting from protein catabolism. Free ammonium is highly toxic to the central nervous system, and these patients are at high risk of metabolic decompensation leading to irreversible neurological damage. Long-term management of patients suffering from urea cycle diseases is mainly based on low-protein diet and the use of ammonium scavengers. Patients often develop anorexia and naso-gastric feeding is required, and the risks of sudden hyperammonemia persist. Many patients still develop intellectual impairment due to the chronic ammonium intoxication.

This example is representative not only of the poor quality of life, but also the life-threatening nature of these conditions. For instance, a retrospective study performed in Italy showed that for the 1935 cases diagnosed with an inborn error of metabolism, only 118 reached adulthood.

Currently, the only radical treatment of end stage diseases is orthotopic liver transplantation (OLT) but this procedure is serious, irreversible and limited by organ shortage. Medical treatments and long-term management are not efficient enough, and patients would greatly benefit from an innovative therapy that meets this medical need.

current Status of Liver cell TransplantationLiver cell transplantation (LCT) is the one of these emerging procedures. It consists of single or repeated infusions in the patient’s liver circulation of allogenic mature hepatocytes isolated from healthy adult donors. The procedure has been well described, and >30 clinical attempts have been reported in the literature, although probably many more have been effectively performed.

The proof of concept has been established that is feasible to bring a missing function within a diseased liver by infusing a suspension of mature hepatocytes. The best results have been obtained in miscellaneous inborn errors of metabolism, such as Crigler Najjar syndrome (1), urea cycle defects, glycogen storage disease, clotting factor deficiencies and Refsum disease.

These clinical reports have demonstrated that LCT is safe and can restore metabolic liver function for up to 18 months post-infusion, or more. For instance, repeated doses of mature hepatocyte infusions in a child with urea cycle disorder and important secondary psychomotor retardation led to the presence of donor cells in liver biopsies up to eight months after the last infusion, restoring de novo activity of arginosuccinate lyase (2). In this clinical report, infused cells have contributed to restoring liver metabolism, as well as improving psychomotor development (2).

LCT is a fully reversible procedure, and is much less invasive than OLT because it avoids the risks related to native liver explantation, non-function of the graft or even long-term graft loss. In addition, LCT maintains the possibility of performing later OLT, which have been performed without complications in children having undergone previous LCT.

For genetic disease treatment, LCT is based on allogeneic cells, and patients receive immunosuppressive treatment following the infusion.


However, several limitations in the use of mature hepatocytes prevent its wide application:1. Organ shortage as for classical OLT, as

only one or two patients can be treated by mature hepatocytes isolated from one donor.

2. Weak tolerance to cryopreservation. Cryopreservation of mature hepatocytes induces a severe impairment of cell adhesion, morphological changes of the mitochondria, loss of ATP production, alteration of mitochondrial respiratory chain enzymes, increased mitochondrial permeability and loss of membrane potential. Although some success has been reported with cryopreserved cells, these are clearly less efficient in the clinical experience, unless perhaps by selecting high quality cells from young donors, which is rarely achievable in routine transplantation.

3. Possible bacterial contamination of fresh hepatocyte preparation, unknown at the time of infusion, as it is also observed for whole organs, partially addressed by the use of prophylactic antibiotherapy covering gram negative strains during the infusion procedure.

These storage limitations, adding to the organ shortage issue, lead to the consideration of other cell sources such as stem cells, as an alternative for liver cell therapy. Stem/progenitor cells are undifferentiated cells that demonstrate a high ability for self-renewal and importantly, potential for expansion in vitro. Adult tissue-derived stem cells are safer than embryonic, fetal or induced pluripotent cells, are closer to clinical applications, and do not raise any ethical issues. Stem cells have also a good resistance to cryopreservation. The prospect is that these cells can soon be used for cell therapy of the liver, after induced or spontaneous differentiation into functional hepatocytes.

Extrahepatic Sources of Stem/progenitor cells

Bone Marrow and Hematopoietic Tissues

Adult bone marrow contains different cell populations, including mesenchymal stromal cells, endothelial cells, fibroblastic cells and hematopoietic cells. In different

studies, it has been postulated that these cells were able to improve hepatic function. In a mouse model of tyrosinemia, infusion of bone marrow from wild type mice was able to restore fumaryl aceto acetase activity in hepatocytes from the deficient mouse.

Beside direct functional activity of the transplanted cells, stem cells may also act through the release of cytokines or growth factors (“secretosomes”) that modify the microenvironment and contribute to hepatocytes proliferation/function. This mechanism, suggested in other tissue repair mechanisms, has been suggested in a mouse model of toxic-induced fulminant hepatitis, but cannot explain de novo acquired metabolic function in models of inborn errors of liver metabolism.

Mesenchymal Stem Cells (MSCs)MSCs were first described by Freidenstein and colleagues as plastic adherent fibroblastic cells with a high capacity for proliferation and differentiation into osteogenic lineage. MSCs have since then been isolated from various tissues such as skin, Wharton’s Jelly (3), adipose tissues, amniotic membrane of the placenta, and also fetal tissues. In vitro studies have demonstrated the ability of MSCs from different origins to differentiate into hepatocyte-like cells when specific growth/differentiation factors are added in

the culture medium. The adipose tissue is an easily

accessible source of MSCs, and can be obtained from plastic chirurgic waste material (liposuctions and abdominal resections). These cells share similar phenotypic and immunological features with bone marrow-derived MSC, making them an attractive source for allogeneic transplantation. Their hepatic differentiation potential has been confirmed with acquisition of functional activities such as albumin production, glycogen storage, and drug-metabolising activities. Transplantation into nude mice with acute liver injury can restore liver functions. Predifferentiation before transplantation may improve engraftment and the cells subsequently display in these animals human proteins such as albumin and HepPar. Besides their high potential for differentiation, MSCs have been demonstrated to have immunosuppressive properties, being also able to reduce inflammation.

Intrahepatic Sources of Stem/progenitor cellsIt seems logical to look for a candidate liver progenitor that would be already resident in the adult liver. Mature human hepatocytes play themselves an important role in liver tissue regeneration, and start to proliferate and repopulate the liver following an acute injury, under




Eric Haliouais CEO of the Belgium cell therapy company Promethera Biosciences. [email protected]; Eric holds two master degrees in Pharmacology and Molecular Biology and a Graduate from ESSEC business school, with an advanced degree from the Health Care ESSEC chair. Eric Halioua is co-founder of two biotechnology companies called Myosix and Murigenetics. He was as well principal of the international life sciences practice of Arthur D. Little based in Paris and Boston during 11 years. Email: [email protected]

stimulus from cytokines secreted by non-parenchymal cells. Besides regeneration from mature hepatocytes, different populations of stem/progenitor cells participate in the replacement of liver cell loss, including oval cells, small hepatocytes, liver epithelial cells and mesenchymal-like cells.

Oval cells are resident progenitor cells located in the bile ductules (canals of Hering), which are able to generate both hepatocytes and bile duct cells. They constitute the progenitor “niche” or “reservoir” of the liver. In response to injury, these cells proliferate and migrate to the liver parenchyma. However, these cells cannot be isolated and are not deliverable as cell suspensions, and are not therefore used in liver regenerative medicine.

Liver epithelial cells are derived from primary culture of human adult hepatic tissue. In vitro, they can be expanded and differentiated into both liver cell types including hepatocytes and biliary cells, and express mesenchymal and hematopoietic markers. They differ from oval cells by the absent expression of CD34 antigen and their polygonal shape morphology.

Small hepatocytes are isolated from the non-parenchymal fraction after a long culture period, and display a high potential for proliferation, but with a limited in vitro differentiation into mature hepatocytes.

ADHLSCs. The presence of mesenchymal cells, also named adult human hepatocytes stem/progenitor cells (ADHLSCs), was also identified in hepatocyte suspensions obtained after collagenase perfusion of the normal adult liver (4). These cells are isolated from a primary culture of hepatocytes, and demonstrate an important potential for proliferation, and a more advanced and complete morphological and functional differentiation into hepatocytes. In contrast with other MSCs, the cells have a preferential differentiation capacity into hepatocytes, and not into mature osteogenic and adipogenic cells, suggesting that these cells are already engaged in the hepatocytic lineage, being more progenitor than stem cells. Khuu and colleagues have demonstrated advanced liver metabolic activity of differentiated ADHLSC. Indeed, following in vitro differentiation, ADHLSC are able to metabolise ammonium, to conjugate bilirubin, and to express Phase I and Phase II enzymes responsible for metabolisation of both exogen (i.e. drug) and endogen

(i.e. bilirubin) compounds. The cells are also more specifically hepatocytic, and not hepatobiliary precursors.

The ADHLSC ability to engraft, proliferate and differentiate into hepatocytes has been evaluated in animal models, and the results have confirmed their potential to be used as a liver cell-based therapy for the treatment of many liver diseases. Transplantation of undifferentiated ADHLSCs into rodents was followed by in vivo differentiation and synthesis of human albumin six weeks later, whilst the cells show a long-term engraftment potential.

Safety preclinical experiments also demonstrated the absence of tumorogenicity in vitro and in vivo (Scheers et al, unpublished data) in comparison with HepG2, a human liver carcinoma cell line.

Taken together, differentiated or not, ADHLSC could represent an excellent candidate for liver cell therapy.

conclusionStem cell technology allows to the current consideration of regenerative medicine of the liver, targeting inborn errors of metabolism – a so far major unmet medical need – as well as some acquired diseases of the liver. The proof of concept that cell therapy is able to restore liver function has been obtained with mature hepatocyte transplantation, but efficacy is partial and suitable alternative sources of cells are needed to replace hepatocytes. Adult liver-derived progenitor cells have shown promising results. The optimal combination of in vitro expansion and hepatic engraftment ability makes this adult progenitor cell a truly competitive tool for liver regenerative medicine. Moreover, the progenitor cell commitment to the hepatic lineage, associated with their ability to be cultured in vitro, can offer the biopharmaceutical industry an interesting tool for pharmaco-toxicology screening of new drugs and lead compound optimisation n

References:1. Lysy PA, Najimi M, Stephenne X,

Bourgois A, Smets F, Sokal EM. Liver cell transplantation for Crigler-Najjar syndrome type I: Update and perspectives. World J Gastroenterol (2008);14:3464-3470.

2. Stéphenne X, Najimi M, Sibille C, Nassogne MC, Smets F, Sokal EM. Sustained engraftment and tissue enzyme activity after liver cell

transplantation for argininosuccinate lyase deficiency. Gastroenterology (2006);130:1317-1323.3.

3. Campard D, Lysy PA, Najimi M, Sokal EM. Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology (2008);134:833-848.

4. Najimi M, Khuu DN, Lysy PA, Jazouli N, Abarca J, Sempoux C, Sokal EM. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes? Cell Transplant (2007);16:717-728.

Etienne Marc Sokal, MD,PhD, is founder and CSO of Promethera Biosciences. He is full professor and head of the paediatric research unit at Université Catholique de Louvain and head of the paediatric liver unit at St Luc Hospital, in Brussels. Paediatric Hepatology at UCL is world reknown, for clinical, fundamental and translational research in congenital and acquired liver diseases, liver transplantation and liver regenerative medicine. Email: [email protected]



In Vivo Measurement of Human Skin penetration: alternatives for Measurement of cutaneous BioavailabilityIn the case of systemically delivered drugs, plasma or serum drug concentrations are traditionally used for assessment of pharmacokinetic (pk) parameters, and to establish bioavailability (Ba). However, for topically administered drugs designed to exert a local effect in diseased skin, only a fraction of the administered drug usually reaches the systemic blood circulation, and active drug concentrations in the skin will be many times higher. Therefore, the evaluation of Ba of these drugs must be done in the target tissue itself. The development and validation of appropriate methodologies to determine the rate and extent to which a topically applied drug reaches its site of action within the skin is one of the biggest challenges in dermatological research today.

percutaneous penetration in Diseased versus Healthy Skin Whereas for systemically delivered drugs, in most cases the factors determining the rate and extent of absorption are not affected by the diseased state, this is rarely true for dermatological conditions. It is well known that drug absorption and distribution can be very different in healthy versus diseased skin, particularly in inflammatory skin diseases such as atopic eczema which are associated with impaired skin barrier function. Further, in inflammatory skin diseases there is increased blood flow to the skin and increased permeability of the vascular epithelium, which leads to an enhanced uptake and elimination from the skin1. Conversely, vasoconstriction or decreased blood flow to the skin will lead to an increase in skin bioavailability1. Therefore, the relevance of measurements of drug penetration in healthy skin may not be indicative of diseased skin, necessitating inclusion of measurements in patients with dermatological diseases to obtain relevant data of cutaneous BA.

MethodologiesMethods such as punch biopsies, suction blisters and shave biopsies can be used for the determination of in vivo percutaneous penetration, however these methods are invasive and not practical for obtaining kinetic data with drug concentration versus time profile. This article focuses on alternatives for determination of quanititative PK data in the skin, their usefulness and their limitations.

Dermatopharmacokinetics (Dpk)The DPK, or tape stripping, methodology allows determination of drug concentration, drug uptake and drug elimination in and from the stratum corneum (SC). The SC, the outermost 10-20µm of the epidermis, is not only the ultimate barrier to penetration of molecules through the skin, but also

serves as a reservoir for substances applied to the skin2. The SC is the rate-determining barrier to percutaneous absorption, and it is assumed that the SC concentration of the drug is directly related to the amount which diffuses into the underlying viable epidermis. Therefore, determination of a drug concentration versus time profile in this barrier layer may be a relevant strategy for determination of percutaneous penetration.

The method calls for standardised product application to test fields located on the volar aspect of the forearm. Residual product is removed after a defined treatment time, e.g. 30 minutes – 2 hours after application. Microscopic layers of the SC are then harvested by sequentially pressing adhesive tape strips or discs onto the skin and removing them by a sharp upward movement. Ten or more

Figure 1: Schematic of experimental set-up for MD and OFM. Courtesy of Dr. Frank Sinner, Institute of Medical Technologies and Health Management, Joanneum Research Forschungsgesellschaft mbH, Graz, Austria, [email protected] Figure 2: MD membrane has small micro-pores versus 100 µm open exchange areas in the OFM probe. Images courtesy of Dr. Frank Sinner, Institute of Medical Technologies and Health Management, Joanneum Research Forschungsgesellschaft mbH, Graz, Austria, [email protected]



adhesive film samples can be collected per test field. Following removal, the drug content is measured quantitatively in the individual or pooled tape strips. Since only the dead cells (corneocytes) in the outermost layers in the skin are removed, the procedure is only minimally invasive and relatively painless3.

In 1998 the FDA issued a draft guidance which included DPK methodology as a primary means to document BA and bioequivalence (BE) of topically applied products4. The guidance was subsequently withdrawn in the midst of controversy. The main reason for withdrawal was flaws in the recommended procedures for tape stripping, with contradictory results in inter-laboratory studies on the same products5.

Despite difficulties encountered with the original procedure, a number of researchers are working to optimise this methodogy, especially with regards to optimised analysis and presentation of results5,6,7. There is a large inherent variability in the data collected due to differences in the number of corneocytes collected per adhesive tape, a factor which is particularly dependent on sampling depth in the SC, and the large variability of SC thickness, not only between subjects, but also between test sites within a subject8,9. Ideally, results should be presented in a manner correlating to the depth profile of the SC and not simply to the number of strips collected5,9.

A consensus on the usefulness and limitations of the DPK methodology for topical drug BA and BE will hopefully crystallise as more studies with a broader range of formulations and active substances are investigated. At present the method appears particularly promising for determining the local BA

of drugs whose target site is in the SC, e.g. antifungal agents, UVA/UVB filters or antiseptics11.

Microdialysis / Open-flow MicroperfusionMicrodialysis (MD) and open-flow microperfusion (OFM) are methods for assessing penetration kinetics of drugs in the dermis and subcutaneous tissue. A feature of both is the ability to continuously monitor the extracellular concentration of a drug in real time. To do this a catheter is implanted into the dermis or subcutaneous tisssue which allows for microperfusion with continuous sample collection.

In 1991 Anderson et al10 first described the use of MD sampling in the dermis to measure percutaneous penetration of ethanol. This is the only method that allows free, unbound drug in the skin to be sampled, a very important distinction as the level of unbound drug generally determines the pharmacodynamic response1,11. For MD, a thin dialysis catheter with a semi-permeable membrane is implanted into the dermis or sub-dermis with the help of a guide needle. This catheter imitates the function of a small blood vessel: the catheter is attached to an inlet and outlet tube and is perfused with a physiological solution which equilibrates with the extracellular fluid, allowing substances to be exchanged by passive diffusion. The dialysis membrane is porous and is defined according to its molecular weight cut-off (e.g. 20kDa or 100 kDa). Only molecules smaller than the cut-off value can cross the membrane.

The insertion of the guide needle and catheter is a minimally invasive procedure and provokes minor tissue trauma with

increased local blood flow, increased skin thickness and hyperemia. Sufficient tissue recovery to near baseline levels generally occurs after 60-90 minutes1,11. After this time the values observed in the dialysate should reflect the concentration of the drug and its metabolites in the interstitial fluid. As an inflammatory response will occur after longer intervals, the length of a typical MD experiment is generally eight hours or shorter1.

While MD and OFM are similar in many ways, there are several key differences. These are related to the nature of the dialysis catheter. The OFM probe is a mesh design catheter with openings of 100µm rather than a porous membrane12. Because there is no limit in the size of molecules which can pass through the catheter, even middle and large sized molecules can be investigated. Further, both lipophilic and hydrophilic substances can be measured by OFM. MD is best for the detection of small, hydrophilic molecules and is not suited for very lipophilic substances. The other major difference between the methods is that whereas MD allows measurements of free, unbound drug, OFM only allows measurement of the total drug concentration including the protein-bound fraction. This can present a greater analytical challenge.

Further validation work is necessary for MD and OFM to be recognised by regulatory agencies as an option for BA and BE assessment. Standardised protocols must still be developed. A key issue is the reproducible insertion of the catheter to a consistent depth in the skin11, a procedure which requires extensive training and practice. In addition, the extremely small dialysate volumes and low drug concentrations in the dialysate

Figure 4: Raman Spectroscopy for determination of penetration into the upper skin.

Figure 3: OFM catheters inserted under skin. The OFM catheter is CE certified for clinical use up to 72 hours. Image courtesy of Dr. Frank Sinner, Joanneum Research Forschungsgesellschaft mbH, Graz, Austria, [email protected]



require highly sensitive analytical assays which can be very challenging.

confocal Raman SpectroscopyConfocal Raman spectroscopy is a more recent technological development which is currently under investigation to determine profiles of substances in the upper skin11. The method is particularly attractive as it is non-invasive. A major drawback is that the molecule of interest must be present at a sufficient concentration and possess a unique Raman signature that permits its differentiation from the spectrum of other skin components. Further, at present it is only possible to measure relative rather than absolute concentrations using this method. It is too soon to predict whether this approach will be a real alternative for measurement of skin penetration.

FazitFor dermatological product development it must be kept in mind that effectiveness and safety of a topical product is a composite of the active ingredient(s) and the vehicle. Therefore, the effectiveness of a product cannot be assessed solely on the ability of the active ingredient to penetrate into the skin. On the other hand, penetration into the SC and further distribution to the site of action in the skin is essential for pharmacological effects. The availability of standardised, routine methods to determine BA in the skin would be a huge boon to the development and optimisation of new topical formulations.

Determination of BA of topically applied drugs or BE between a new formulation and a marketed comparator usually require comparative clinical efficacy trials which are time-consuming and expensive. Currently the vasoconstriction or skin blanching assay for topical steroid formulations is the only acceptable BE method approved by the FDA and a number of other regulatory authorities. This situation will only change if alternative pharmacokinetic and pharmacodynamic models can be sufficiently validated, keeping in mind that whichever method is chosen, for regulatory acceptance it must correlate with the clinical outcome. n

References:1. Holmgaard R, Nielsen JB, Benfeldt E.

Microdialysis sampling for investigations of bioavailability and bioequivalence of topically administered drugs: Current state and future perspectives. Skin Pharmacology and Physiology 2010; 23:225-243

2. Vickers CFH. Existence of reservoir in the stratum corneum: Experimental proof. Arch Dermatol 1963; 88:20-23

3. Al-Otaibi F, Tucker AT, Johnston A, Perrett D. Rapid analysis of tetracaine for a tape stripping pharmacokinetic study using short-end capillary electrophoresis. Biomed Chromatogr 2009; 23:488-491

4. Guidance for Industry. Topical Dermatological Drug Product NDAs and ANDAs – In Vivo Bioavailability, Bioequivalence, In Vitro Release, and Associated Studies (Draft). Food and Drug Administration. Center for Drug Evaluation and Research (CDER). June 1998.

5. Au WL, Skinner M, Kanfer I. Comparison of tape stripping with the human skin blanching assay for the bioequivalence assessment of topical clobetasol propionate formulations. J Pharm Pharmaceut Sci 2010; 13:11-20

6. Nicoli S, Bunge AL, Delgado-Charro MBD, Guy RH. Dermatopharmacokinetics: Factors influencing drug clearance from the stratum corneum. Pharm Res 2008; 26: 865-871

7. Herkenne C, Naik A, Kalia YN, Hadgraft J, Guy RH. Dermatopharmacokinetic prediction of topical drug bioavailability in vivo. J Invest Dermatol 2007; 127:887-894

8. Pershing L. Dermatopharmacokinetics for assessing bioequivalence of topically applied products in human skin. 2000; 115:43-51

9. Weigmann H-J, Lademann J, Meffert H, Schaefer H, Sterry W. Determination of the horny layer profile by tape stripping in combination with optical spectroscopy in the visible range as a

prerequisite to quantify percutaneous absorption. Skin Pharmacol Appl Skin Physiol 1999; 12:34-45

10. Anderson C, Andersson T, Molander M. Ethanol absorption across human skin measured by in-vivo microdialysis technique. Acta Derm Venereol 1991; 71:389-393

11. Herkenne C, Alberti I, Naik A, Kalia YN, Mathy F-X, Préat V, Guy RH. In vivo methods for the assessment of topical drug bioavailability. Pharm Res 2008; 25:87-103

12. Holmgaard R, Nielsen JB, Bodenlenz M, Gatschelhofer C, Mautner A, Sinner F, Sorensen JA, Benfeldt E. Searching for the optimal methodology for dermal in vivo sampling. Poster, Perspectives Percutaneous Penetration, 2010; 12:85

Betsy Hughes-Formella PhD, - Betsy Hughes-Formella is Director of Business Development and Consulting at bioskin GmbH. She received her MS and PhD in Physiology from the University of Georgia in Athens before moving to Germany to join a research team at the University Medical Center in Hamburg. In 1993 Dr. Hughes-Formella joined bioskin where she is responsible for the coordination of business development activities and is a consultant and advisor for dermatological product development. Email: [email protected]

Figure 5: Depth profiles of ethanol penetration into the skin using Raman spectroscopy. Increas-ing penetration depth with increasing time of exposure can be seen. Curves measured at bioskin GmbH

Baseline 1min 5min 15min

Depth [um]

Eth

anol

(P

eak3

) [a

.u]

Ethanol penetration

-5 0 5 10 15 20 25 30 35 40

0.2

0.0


DRUg DISCOvERY / DEvELOPMENT & DELIvERY

Injectable Hydrogel Drug Depots are Coming of Age for Controlled Delivery

Injectable hydrogels form drug depots in situ after injection and they enable localized and controlled drug delivery for a wide variety of active pharmaceutical ingredients (APIs). This overview article describes the coming of age of a specific class of hydrogels, Physically Cross-linked Injectable hydroGels (PCIGs), and the benefits in commercialization that the PCIG’s offer over other injectable drug depots, both for marketed and novel APIs.

Executive Summary Physically Cross-linked Injectable hydroGels (PCIGs) are polymer-based liquid formulations that self-assemble into drug depots upon injection, and they are now entering clinics. Unlike chemical cross-linked systems, these water-based hydrogels offer benign storage and delivery conditions both for the Active Pharmaceutical Ingredients (APIs) and for the surrounding tissue. The PCIG-formulations can contain a wide variety of APIs, including biologics, and can be injected through thin needles of up to 31G in different locations for a variety of therapies. Upon injection, PCIGs rapidly transform in situ from a free-flowing liquid (0.1-2.0ml) into a discrete, sphere-like drug depot with good biocompatible properties. The formation of the PCIG-drug depot is driven by temperature increase, enantiomer interactions, or electrostatic attractions. The depot formation takes place within seconds upon injection, and the formation of the network leads to the physical entrapment of the APIs. The APIs can be loaded with up to 10 times higher quantities than comparable injectable depot systems such as microspheres and liposomes, and the APIs are released at kinetics tailored by the composition of the polymers. The pharmaceutical development route of PCIG-dosage forms from lab-scale via clinical supplies to commercial manufacturing is straightforward, cost-effective and avoids

complex up-scaling bottlenecks and regulatory hurdles typical for many drug depot systems.

Current Injectable Depot Systems for Controlled Drug Delivery and their LimitationsIn the last two decades, the development and clinical application of new drug delivery technologies based on biodegradable polymers has been expanding steadily. In particular, the quest for minimal invasive therapies and the management of chronic diseases drive the development of injectable solutions that do not require frequent administration. Moreover, many new APIs are poorly aqueous soluble and/or they have a short elimination half-life. Finally, the rapid market growth of biologicals and highly potent APIs has created a whole new set of criteria for sustained drug delivery (see Figure 2).

To date the most advanced injectable depot solutions are based on PLGA microspheres with marketed products such as Lupron®, Sandostatin®, Somatuline® and Trelstar® (1). Because of the hydrophobic nature of PLGA, these technologies are very suitable for hydrophobic APIs. However, the following limitations to their use have become clear, and they help define the unmet needs

for the new generations of drug delivery systems we discuss below:Delivery of hydrophilic APIs, and in particular biologics, is difficult. The encapsulation efficiency of these molecules is limited and aggregation/denaturation of these APIs often reduces bioavailability from such systems to well below commercially acceptable levels;Acidic build-up during polymer degradation is likely to happen when using PLGA as a main polymer matrix; Pharmaceutical product development has proved to be expensive and highly complex; the reproducibility of a defined microsphere population as well as incorporation of the API-payload and the subsequent release characteristics are scale-dependent steps, causing supply limitations and unexpected regulatory hurdles for late-stage clinical trial sourcing and market launches;Injectability: the spheres require the inner diameter of the injection needle to be a minimum of 10 times greater than the average sphere diameter. This limits both the retention properties for the APIs and applications where thin needles are required.

Migration of the micron-sized particles (100-20um) from the administration site has been shown in many cases, limiting

Figure 1: Physically

Cross-linked Injectable

Hydrogels (PCIGs)

rapidly form drug

depots in situ, then

slowly releasing their

API-payload via

degradation and

diffusion

the applications to systemic delivery.Liposomes are also in use as injectable

drug delivery systems. Liposomal dosage forms have been proven to be suitable for short term targeted delivery of several APIs. In particular, products are commercially available or in clinical trials for intravenous dosing, to control early peak release of APIs, or for targeting to difficult-to-access tissues such as the brain. Since the circulation time of the current liposomal carriers is limited to a few hours, the most challenging aspect of liposome research is to develop new platforms with significantly better API loading and retention possibilities (2).

Injectable in situ Forming Drug Depots, an Emerging Technology with Pioneer Products in the Market In order to develop new technologies that address the limitations described above, drug delivery research has been focusing on the development of novel polymer-based drug delivery systems over the last 20 years. This has led to three generations of injectable formulations with common features: injectable, physical cross-linking, in situ formation of the depot and biodegradation of the depot. An excellent state-of-the-art overview was written in 2009 by one of the pioneers in the field, the late Dr Jorge Heller (3).

The first generation products in the in situ drug depot field are the so-called solveogels; marketed examples thereof are Atrigel® and Saber®. A commercially available product with Atrigel® is Eligard®, offering up to six-month delivery for leuprolide in prostate cancer treatment. Posidur® or Optesiar®, both based on Saber®, entered late-stage clinical development. The principle of solveogels is the precipitation of hydrophobic polymers such as PLGA upon injection. The depot formation is achieved by the rapid diffusion of the solvent from the formulation upon injection, leaving the hydrophobic polymers to precipitate into a dense network capable of entrapping hydrophobic small molecule drugs. Clearly, one of the main drawbacks of solveogels is the use of organic solvents to achieve injectability. Organic solvents such as NMP, even though FDA approved, can induce local toxicity effects and pain during injection. Also, organic solvents and dense, hydrophobic polymer networks are typically not compatible with sensitive APIs such as biologics.

The second generation of injectable in situ forming drug depots has been pioneered by Macromed Inc. with ReGel®,

the first Physically Cross-linked Injectable hydroGel (PCIG). It is a biodegradable thermo-sensitive platform based on PEG and PLGA, yet does not use any solvents to form the depot. ReGel® has a tri-block copolymer architecture that possesses different solubility depending on composition and temperature, hence its thermo-sensitive character. Due to the polymer amphiphilic nature, hydrophobic APIs can be dissolved and released over periods of up to several weeks. ReGel® formulations are liquid at refrigerated temperatures, and upon injection in the body, solidify within seconds to minutes. OncoGel® (ReGel® loaded with paclitaxel) is in advanced clinical trial testing for treating esophageal cancer and brain tumors. Other examples of advanced thermo-sensitive hydrogels are poly(ortho) esters/PEG block copolymers that offer

the possibility to tailor release profiles for up to three months. The refrigerated, liquid formulations of these thermo-sensitive hydrogels can be injected using 25G needles, offering improved patient-friendly administration.

The main characteristic and advantage of PCIGs is that they form drug depots by physical interactions of the polymers after injection. This type of cross-linking does not require any chemical reactions to form the macroscopic drug depots, avoiding any chemical associations with, or denaturation of, the APIs. The formation of the depots can be completed within seconds to minutes upon injection, and the APIs are physically entrapped in the networks formed by the polymer chains. Physical cross-links come in three main varieties: (i) hydrophobic interactions e.g. triggered by increasing temperatures;



System Compounds Applications Therapy duration

InGell® Gamma

Thermo-sensitive micelles

PEGPCLLAAliphatic-chains

Small molecule drugs peptides, proteinsnano-particles

Days to months

InGell® Delta-1t

Stereo complex

DextranOligolactate

Peptides, proteinsnano-particles

Days to weeks

InGell® Delta-2

Electrostatic complex

DextranPoly(HE)MAAs

Peptides, proteins, cell fragmentsnano-particles

Days to months

Medusa® Hydrophobic/hydrophilic inter-actions

Poly-amino acids Small proteins Days to weeks

Figure 2: Controlled release not only benefits patient compli-ance, but also enables the use of highly potent APIs or sensitive biolog-ics while limiting side-effects and pro-longing half-life times.

Figure 3: InGell® Gamma: schematic representation of the micelles structure and API entrapment mechanism

(ii) enantiomeric complex formation of two components; and (iii) electrostatic association of polymers with opposite charges.

The amphiphilic nature of PCIGs allows a high water content, up to 90%. This leads to the formation of soft and ‘tissue friendly’ hydrogel depots. Developers of PCIGs have access to a large variety of hydrophilic and hydrophobic building blocks, allowing them to compose the optimum gel-networks. Different classes of APIs, including sensitive biologics, can be formulated and released effectively. Most of the polymer blocks used today in PCIGs are available as Pharma grades, and they are in use within multiple marketed products in both medical device and pharmaceutical markets.

These features, combined with the avoidance of undesired high drug

concentrations, make PCIGs very attractive platform technologies for controlled systemic and local drug delivery. Moreover, these innovative technologies offer new and promising openings for intellectual property positions.

The above-mentioned potentials of PCIGs have stimulated academic research in the last decade (4). Novel concepts use different types of cross-link triggers such as pH, inclusion complexes and so forth. So-called ‘Smart Gels’ feature release triggers such as pH switches or ultrasound, further enhancing the degree of control on the release of the entrapped APIs. At present, these novel concepts are still in an early stage and they are not yet evaluated for scale-up and commercialization.

Third Generation of injectable in situ forming drug depots: PCIGs are coming of age The third generation of injectable in-situ forming drug depots are represented by recent industrial entrants to the market such as the novel product platforms InGell® Gamma, InGell® Delta and Medusa®.

Medusa® a poly-amino acid nanogel system was developed by Flamel in the late 90’s. Medusa® is made of glutamic acid, a naturally occurring aminoacid, and Vitamin E, forming the hydrophobic domains. The design of the Medusa® “polypeptide-like” aminoacid polymers allows a non-covalent capture and subsequent delivery of native peptide or protein drugs as well as small molecules. Formulations are stable over a wide range of pH values and can be stored as either stable liquid or stable dry forms that can be easily reconstituted in water. Flamel’s most advanced products are in clinical phase: (i) FT-105, a next-generation formulation of long-acting native insulin, (ii) IFN alpha-2b XL, a second-generation long-acting native interferon alpha-2b, and (iii) IL-2 XL, a second-generation long-acting interleukin-2. Also, preclinical data with human growth hormone for the treatment of growth disorders, and, interferon beta for the treatment of multiple sclerosis are available. With initial delivery times limited to days, Flamel is working on improving the retention ability of Medusa® and on the possibility to increase the maximal injected dose by adding an additional processing step leading to the formation of dense microspheres by the aggregation of the nanogel.

InGell® Gamma has many similarities in its thermo-gelling nature with ReGel®, and it was originally invented as a follow-on technology by the same pioneering team from the University of Utah who invented ReGel®. Upon mixing of the polymers with the APIs, nano-sized micelles are formed containing the API. At lower temperatures, these micelles are dispersed in aqueous solution and they can be homogeneously injected. At body temperature the hydrophobic character of the polymer dominates and consequently the micelles rapidly aggregate to form the macroscopic gel as depicted in Figure 3.

Whereas ReGel® is based on lactic and glycolic acids, InGell® Gamma is based on less acid units and on caprolactone. The use of caprolactone enables longer degradation and longer



Figure 5: IL2 loaded InGell Delta-1: controlled release demonstrates 100% survival over 60% for freely injected IL-2 at 60 days (6)

Figure 6: Comparison of the three generations inject-able in-situ forming drug depots

Figure 4: Different polymer compositions can tailor the release of APIs from days to weeks

release profiles. InGell® Gamma also features aliphatic end-groups to tailor the hydrophobicity of the co-polymer and its affinity for the APIs. Both differences in polymer structure allow the extension of the retention properties. Preliminary in vivo studies showed that InGell® Gamma was well tolerated and stable in vivo for at least two weeks after subcutaneous injection (5). Recent product development routes by InGell Labs focus on localized and contained tissue applications, for instance for orthopedic and ophthalmic therapies addressing chronic diseases. The company has also managed to increase the injection temperature from the refrigerated state of ReGel® to ambient room temperature for InGell® Gamma, and has reduced the time of depot-formation to several seconds.

In vitro data with lysozyme and a low Mw ‘block-buster’ API show that InGell® Gamma can be tailored to release these compounds from one week up to four weeks by shifting the balance in hydrophobic and hydrophilic polymer units. The release profile in Figure 5 shows a combination of degradation-driven and diffusion-driven release mechanisms, leading to a range of release profiles for the same API-payload and release conditions.

InGell® Delta is a very different type of PCIG, comprising a series of breakthrough inventions performed at the University of Utrecht at the turn of the millennium. Specifically addressing the challenges that biologics pose, InGell® Delta has been taken into product development by InGell Labs. In contrast to the previous PCIGs, InGell Delta is driven by enantiomeric or electrostatic interactions to form the drug depot in situ, offering a very benign environment for biologics with good release characteristics. An example of that is the complete release and the full bioavailability of loaded model enzymes in in-vitro experiments, and the excellent efficacy of rhIL-2 in tumor suppression models as reported below. This type of PCIG is also independent of temperature-increase to form the gel. InGell® Delta products are based on hydrophilic polymers derived from dextran. Different versions of this technology exist based on different physical interactions: enantiomeric

(Delta-1) or electrostatic (Delta-2). InGell® Delta-1 is composed of a

dextran backbone grafted with either D- or L-oligo-lactate chains (5 to 15 lactic acid units). Upon mixing, both oligo-lactate enantiomers interact and form a strong yet flexible D/L-helix. Depending on the length of the oligo-lactates and the density of grafting, the mesh size of the network is tailored for fast/slow release of large/small proteins. The encapsulated APIs (biologics and complex HAPIs) are released depending on their size and their ability to diffuse out of the network. The degradation rate of the oligo-lactates controls the opening of the network and thereby the diffusion of the APIs. The release can be controlled from a few days up to several weeks in vivo. Successful preclinical proofs of concept were performed with IL-2, a 15.5-kDa protein used in human oncology treatment (6). In a laboratory metastasized tumor model, survival of the animals was ultimately improved with IL-2 loaded into InGell® Delta-1, compared to the repeated administration of IL-2 solutions. Animal survival of 100% after 60 days was obtained with InGell® Delta-1, whereas multiple IL-2 solutions gave only 60% survival in the same trial. InGell® Delta-2 is based on the OctoDex™ microsphere platform, and is particularly suitable for large and complex APIs

such as antigens, antibodies, receptors and cell-fragments; i.e. of interest for vaccination. The microspheres are composed of hydrated chemically cross-linked dextran chains. For InGell®

Delta-2, the OctoDex™ microspheres are derivatized with negative or positive charged moieties. The final product consists of a mixture of positive charged microspheres and negative charged microspheres. These oppositely charged microspheres attract each other to form a depot. By applying shear stress onto the formulation, i.e. by pressing on the plunger of the syringe, the electrostatic interactions loosen and the API-loaded hydrogel flows through the needle; when the force is released, the electrostatic interactions immediately form again, yielding a mechanically stable hydrogel. This technology has the advantage that very large APIs can be loaded between the microspheres, and smaller APIs within either microsphere type depending on their nature and charge, yet limiting the needle diameter to 23G injection needles. InGell® Delta-2 was successfully used in vitro with various model proteins (7) and in a very successful preliminary preclinical study with a large antigen showing release, activity and biocompatibility in an in vivo vaccine animal model (unpublished data).



Microspheres Liposomes Physically Cross-

linked Injectable

hydrogel (PCIg)

Formulation development and sourcing

API choice

Applicability

Development cycle time Slow Fast Fast

Formulation scale-up Difficult Difficult Straightforward

Processing conditions Harsh Harsh Mild

API range Limited Limited Broad

API loading capacity Limited Limited High

Release steering properties Harsh Limited Good

Protein denaturation High Low None/ low

Use in organ tissue Not preferred Possible Possible

Localized release Limited No retention Highly suitable

Needle size 20-23G 23-31G 23-31G

Depot imaging (CT, MRI, X-ray) Limited Difficult Good

Audrey Petit. Principle Scientist, InGell Labs. Before that she worked as formulation scientist at Q-chip, DSM Biomedical and Octoplus for parental drug delivery systems.

Mike de Leeuw – Mike is the co-founder of InGell Labs and Branching Tree. Mike started-up DSM Biomedical, and he was an international executive at DSM, Unilever and Shell in various business positions. Mike holds an MSc in molecular biology and business administration. Email: [email protected]

Leo g.J. de Leede – Leo has over 25 years experience in drug development, biophar-maceutics and controlled release dosage forms within the Pharmaceutical industry in various companies. He is active as resident consultant within the drug development team of InGell labs and he is managing director of Exelion Bio-Pharmaceutical Consultancy BV.

Wim E. Hennink – Professor Dept. Bio-pharmaceuticals, University of Utrecht, NL. Wim and his teams pioneered the polymer based stereo-complex technology and the electrostatic-gel technology, now licensed to InGell Labs. Wim is actively involved in several world class academic drug delivery forums.

From Lab Bench to Marketed Products: Development and Commercialization Benefits of Physically Cross-linked Injectable hydroGelsThere are clear commercialization benefits where PCIGs differ from other drug delivery systems: pragmatic pharmaceutical development strategies, straightforward manufacturing, high loading capacity, and a range of novel therapeutic applications.

From a development point of view, PCIGs have a substantial advantage over, for example, microspheres and liposomes. PCIG-formulations are prepared by simple dissolution of the polymer raw material and the API in an aqueous buffer. Poorly soluble APIs can be progressively incorporated within the hydrophobic micelles structure. Compared to microspheres and liposomes, where formulations are complex and difficult to scale-up emulsion processes, the injectable gel dissolution process is minimally influenced by batch size. In early feasibility and preclinical studies PCIG-formulations can easily be tuned and adapted to improve performance within short development cycles. During clinical trials, dosage forms of any scale can be produced and characterized in a very reliable and robust manner. Formulation and scaling-up will thus not be the rate-limiting step in the (pre-)clinical development and commercialization of the products, providing substantial cost and investment benefits, as well as significantly reduced project risk profiles. The chemistry behind the synthesis of the copolymers is well-established. Synthesis is mainly based on polyesters which are routinely produced in large scale and the PCIGs can be made available today at cGMP-levels. Moreover, the polymers used by most PCIGs are well-known within the regulatory approval boards and accepted in multiple long-term medical applications.

Another strong clinical and commercial benefit of PCIGs is total loading capacity for API-payload. Indeed, loading is intrinsically much higher compared to other drug delivery systems. The ’encapsulation efficiency’ approaches 100%, since all API used during formulation will be loaded in the final dosage forms. In parallel, the full injection volume is available for the API, which is not the case for microspheres, where only maximally 10-20% of the injection volume contains the polymer carrier in suspension. This makes controlled drug delivery for many APIs, as for instance

low potent APIs, more feasible. Clinical opportunities for PCIGs are

driven by unmet medical needs. In applications where a very thin needles and localization is required, PCIGs are very suitable, eg in ophthalmology, CNS and orthopedics. For applications where the size of the needle is less critical, thin needles provide a clear advantage in patient compliance and product distinction. Finally, the clearance of the polymer networks of the drug depot via normal in situ hydrolysis is complete and on time, meaning that it coincides with the release of the API. Long-term tracing or ‘drag-on’ effects of API still entrapped in residue-breakdown products are a thing of the past with well developed PCIGs as described above.

ConclusionIn the injectable drug delivery arena, Physically Cross-linked Injectable hydroGels (PCIGs) provide important commercial opportunities in:• Novel therapies for localized delivery

in difficult-to-dose tissues (e.g. intra-ocular and intra-articular applications, CNS)

• Less frequent injections with more patient-friendly administration procedures using small bore needles

• Sustained delivery forms for biologicals • Dosage forms with high load for (poorly

soluble) APIs• Ease in tuning of release profiles, short

development cycles• Straight-forward scale-up of

manufacturing from clinical to commercial product batches

• Valuable IP protection for the lifecycle management of marketed products.

In the area of local drug delivery, injectable hydrogels form essential technology platforms since there are no current alternatives which form defined and soft depots after injection with thin needles n



COMPANY PROFILE

Astra Biotech GmbH

Astra Biotech GmbH is an ambitious, young biotech start-up founded in 2009, and located due south of Berlin in Brandenburg, in the Biotechnological Park in Luckenwalde. The company specialises in CE-labelled in vitro diagnostics for use with human blood samples covering a wide range of medical indications. Materials available for sale are standard (96-well MTPs) lab test-kits in ELISA and in PCR formats, as well as semi-finished products such as antibodies, antigens, conjugates and calibrators, and varied production capacities for OEM manufacturing tailored to individual customer requirements.The indications covered are: • Hormonal diagnostics

Adrenal functions Fertility (SHBG, testosterone, progesterone etc) Prenatal Neonatal Endocrine

• Tumor markers CA125• Anaemia• Allergy (IgE), both total and specificand• Osteoporosis• Thrombosis• Sensitivity towards anticoagulation medication• Cystic fibrosis*• Tendency to psychological

diseases*(depression and others) • Infectious diseases* and • TORCH** Planned NPLs

Astra Biotech GmbH is a young company, whose team has skills and expertise extending to almost two decades of practical experience in various R & D fields and in the entire supply chain, thus allowing for a high degree of competency and professional handling.Astra Biotech’s primary guideline is that disease prevention or monitoring is better, easier and more cost-effective than curing the condition later. Accurate and prompt diagnostics constitute the first and indispensable element in the “therapy-to-health” link. We research, develop and create our products in order to make diagnostics available for everybody.


ADvERTISEMENT


Our target is to offer high-quality affordable diagnostic reagents, comparable to, and even exceeding, the products of the world leaders, to laboratories, clinics, hospitals and diagnostic centres all over the world. This philosophy, coupled with state-of-art research in the various medical fields, leads Astra Biotech to work continuously on the design of test-kits which contribute significantly to achieving this goal. Thus, the available test-kits were designed with the health considerations in mind, which allow doctors to make diagnoses to help their patients reach informed decisions based on their current state of health. Goal achievement translates into a further guideline in Astra Biotech’s philosophy towards their customers: a total product concept which takes into consideration both the fulfilment of all technical specifications, and the elements to guarantee complete customer satisfaction: product, sales conditions, scientific and marketing support and logistics all come together.

We offer our customers three distinct business lines: the ELISA test-kits are one, which mainly cover hormonal and immunological indications, as well as testing for ferritin, and for a tumour marker. High quality, very stable reagents are used to produce consistently reproducible results. A further business line is our group of PCR tests, which involves testing for genetic predispositions and which is being constantly expanded to include new areas. This area is a main pillar of Astra Biotech’s philosophy of determining pre-symptomatically the existence of diseases, and bringing these under control. Thirdly, Astra Biotech considers requests for OEM manufacturing and co-operation and strives to fulfil the customers’ requirements by affording products of high quality and the support necessary for them to keep and grow their own customer base.

Astra Biotech GmbH is dedicated to broadening the parameters of the development of PCR-based diagnostic tests. Genetic tests are based on the principle that testing a sample of genetic material will allow pre-symptomatically determination of whether the patient has an innate predisposition to certain diseases. This determination can occur at any stage of the individual’s life, and allows those who test as carriers

of certain previously identified polymorphisms to be identified and thus to (a) be aware of their predisposition towards the condition tested for, (b) initiate monitoring or preventive measures, or (c) start treatment.

The conditions currently covered are some which affect large portions of the population, e.g. osteoporosis or thrombosis, or testing an individual for sensitivity to certain drugs. In the first case, there are over 75 million people affected by the disease in the European Community, the USA and Japan, 12% of whom suffered disease-typical fractures. This is a prime example of a condition, the predisposition to which can be determined quite early on, allowing preventive measures to be taken. Today’s reality shows that most often these helpful measures to reduce the effect of the disease are not started in time. As a result, bone fractures can cause a substantial reduction in quality of life, if not a terminal outcome. In the latter case, thrombosis affects increasing numbers of the population and has multi-factorial causes. Any one of several gene polymorphisms affecting a stage in the coagulation cascade can cause predisposition to the condition. Patients at medium risk due to environmental factors may actually be at a higher risk due to – as yet – undetermined genetic factors. For them such testing is of great use as the risk of thrombosis can result in sudden death with very little or no warning. Likewise, testing a patient prior to deciding what drug or what dosage is much more effective in prescribing the appropriate treatment, rather than making use of a “trial-and-error” method which is neither cost-effective nor patient-friendly. This is what the Pharmaco Kit accomplishes, by identifying the degree to which an individual is susceptible to anticoagulants. Further kits are currently being designed and developed to continue contributing to the world of diagnostics.

We strive to continue expanding our portfolio while achieving our targets of maintaining the high and stable quality of all our products.

Contact:Alexandra ghicaPhone: +49 (0) 3371 / 681-450Fax: +49 (0) 3371 / 681-451E-Mail: [email protected]: www.astrabiotech.de


CLINICAL RESEARCH

CRO Leadership

We have all felt the commercial impact meted out by the economy in the CRO industry. In particular, the preclinical development market has experienced a significant drop in outsourced preclinical projects.

For small and large pharmaceutical companies alike, focus has been on clinical development, continuing their progress to NDA, new product launch and sustained revenue flow. Consequently, there has understandably been some reticence to commit funding for early development projects. This, and the longer lifecycle of a clinical development programme, has meant that CROs in the clinical development sector have not experienced such a steep decline.

Three key observations have emerged for the CRO industry. These are the opportunities to internally review and streamline operations and cost centres, to diversify service offerings, and to build strategic partnerships with clients.

There is an opportunity for companies to review and analyse their business strategies and operations in preparation for the new business environment that evolves as the economy regroups. A number of challenges face the CRO industry. Pricing in a commoditised market is more competitive, and cost-effective operations must be deployed to ensure growth expectations are met, ensuring profitability for shareholders and longevity for clients.

To minimise the ebb and flow of revenue streams in the future, recent experience has enforced the business need to diversify the range of services. This may play out as opportunities for investment, or mergers and acquisitions, as our market begins to recover.

The compensatory demands on CROs are motivating fundamental overhauls in structure for greater efficiency, which benefit both the client and CRO. Current outsourcing trends seek solid, effective partnerships with fewer providers than before, often selecting a single, full-service CRO to conduct studies. This partnership provides open dialogue and regular strategic and tactical meetings, offering business and cost advantages to both parties. For the CRO, it provides

a reliable and consistent revenue stream, which is important in reducing the amplitude of the peaks and troughs in income, and creating more financial stability and confidence for the CRO’s financial partners.

A planned and consistent schedule of programmes allows more cost-effective scheduling of staff and resources. Our clients, too, are rationalising their internal costs by looking to new strategies to be more cost-effective in their discovery and development of new medicines. The partnering approach helps our clients to better manage long-term cost and timelines for programmes, a more collaborative team process works to utilise expertise from both organisations in designing study programmes, problem solving, and integrating the project management process.

The element of diversity of services has another advantage in this model. For this to be an attractive proposition for their client, the CRO needs to offer the appropriate range of services that provide the expertise to meet the clients’ product development milestones. We recognise the importance of flexibility and responsiveness in accommodating the changing needs of our customers and their projects. For over 30 years, we have developed strong long-term working partnerships and relationships that have benefited both us and our clients.

The expectation for more competitive CRO pricing generates the use of greater internal efficiencies with available resources. Thus, companies must endeavour to streamline their workflow process through rigorous self-evaluation and appropriate application of new technologies.

Where strategic partnerships can help in controlling and managing costs, there are technologies that should be integrated into the operations that will help achieve the required cost efficiencies. This calls for a continual review and challenge of the CRO’s operations – from procedures outlined in SOPs, to how laboratory data is generated, processed, checked, reported and quality assured. For example, new technologies such as BASi’s LDTD (Laser Diode Thermal Desorption) analysis,

present a dual cost advantage over LC-MS/MS, by increasing the rate of analysis and decreasing consumption and disposal of solvents.

Other innovative techniques are also being explored and implemented. We are now working with clients to realise the mutual benefits of dried blood spots over the traditional blood draw techniques. The application of automated online sample analysis will likewise reduce overall analysis time, improve the cost efficiency, and retain the quality of the data. These factors will allow us to continue to develop and maintain valuable bioanalytical services.

Each organisation will address their needs as opportunity and investment allows. It is clear that the market is slowly recovering, but the window of opportunity for organisations to reset their strategies and realign operations to meet future needs is rapidly closing. We continue to have faith that the pharmaceutical industry will evolve and adapt through partnerships between CROs, and pharmaceutical companies will develop and create a stronger, leaner, more productive industry, to meet our mutual target of delivering effective medicines to patients n

Anthony S. Chilton, Ph.D. - President & Chief Executive Officer of BASiDr. Chilton brings to BASi more than 30 years of experience as a scientist and executive in leading life sciences companies in England, Canada and the United States. He has responsibility for the scientific services provided to the BASi’s customers from three locations in the U.S. and one in the U.K. Dr. Chilton received his Bachelors Degree in Chemistry from the University of East Anglia in 1981, and his Ph.D. in Analytical Chemistry from the University of Hertfordshire in 1993.Email: [email protected]


CLINICAL RESEARCH

Japanese Cardiac Safety Requirements – The Rising of a New Regulatory Landscape

Cardiac adverse drug reactions are typically serious and can be fatal, as was seen for various drugs that were removed from the market in the UK and the US in the 1980s and 1990s 1. These fatalities prompted regulatory attention that led to the development of the ICH Guidelines S7B2 and E143, released in 2005, which formalised non-clinical and clinical assessments of an investigative drug’s proarrhythmic liability, respectively. This paper focuses on clinical assessment and therefore on ICH E14, which was adopted several years ago by regulatory agencies in Canada, Europe, and the US1, and recently by Japan4. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) adopted the ICH E14 guideline in October 2009. The period of time between then and November 1st 2010 represents a ‘grace period’ during which sponsors are recommended to consult with the agency. On 1st November 2010 the guideline will be fully implemented, and Japanese New Drug Application (NDA) submissions will be subject to this document.

On 25th-26th May 2010 the DIA held its first Cardiac Safety Workshop in Japan, at the Tower Hall Funabori, Tokyo. Several regulators from the PMDA sat on the programme committee, along with representatives from Japanese pharmaceutical companies and individuals from academic medical centres. These and many other experts gave presentations, including regulators from Health Canada, the European Medicines Agency (EMA), and the US Food and Drug Administration (FDA). The programme chair was Dr Boaz Mendzelevski. The author acknowledges this meeting as the source of certain information presented in this paper.

Cardiac Safety Evaluation for Noncardiac Drugs: The ICH E14 GuidelineThe ICH E14 Thorough QT/QTc (TQT) study represents an initial step in a

two-fold strategy to identify potentially excessive risk of drug-induced proarrhythmia, with specific reference made to the polymorphic ventricular tachycardia Torsades de Pointes. While it is not a perfect indicator, the study employs the degree of drug-induced prolongation of the electrocardiogram’s QT interval, the length in the time domain from the onset of the QRS complex to the offset of the T-wave, as an index of the degree of prolongation in repolarisation, and hence of the drug’s proarrhythmic liability. If the study reveals that the degree of QT prolongation is below the ‘threshold of regulatory concern,’ ECG monitoring in later-phase studies will proceed as normal for a drug of that class. If it is greater than the threshold, more extensive monitoring to more accurately determine the actual degree of prolongation will likely be requested by regulators. While the study itself has been addressed previously in many paperseg

5,6, a brief overview is provided here to put the following discussions of the PMDA’s implementation of ICH E14 in context.

Brief Overview of the ICH E14 Thorough QT/QTc StudyThe parameter QTc represents the measured QT interval (the raw data) ‘corrected’ for heart rate. The QT interval is affected by heart rate, which can therefore be a confounding effect (especially if the test drug has a notable effect on heart rate). Various correction formulae have therefore been proposed to ‘correct’ for heart rate, i.e., attempting to remove its influence. These include the commonly used Fridericia and Bazett formulae. In both cases, the same formula is used for all subjects in a study – a process that generates QTc values designated as QTcF and QTcB, respectfully. Population-specific formulae also exist, notably the Framingham correction. The value QTcI represents a subject-specific correction methodology in which previously obtained data from each subject in a given study

are used on a subject-by-subject basis. While increasingly more sophisticated

designs are being proposed and implemented, the ‘traditional’ TQT study typically employs healthy adults and the following treatment arms:• A positive control that is known to

increase the QT/QTc interval and hence to demonstrate assay sensitivity. It is critical to demonstrate that the study’s methodology is capable of detecting drug-induced QT/QTc prolongation if the test drug does indeed have a true influence. (Absence of a positive control, which need not necessarily involve a pharmacological agent, needs justification.)

• The proposed therapeutic dose of the study drug.

• A supratherapeutic dose of the study drug that is several multiples of the proposed therapeutic dose. This is intended to mimic what may happen in the worst case scenario should the drug be approved and taken by patients who have compromised metabolism and/or excretion and patients taking other medications, each of which may lead to greater than intended concentrations of the drug in the body.

• A placebo.

A crossover or parallel study design can be employed, depending on which is considered more advantageous in a specific case. In the former, each subject serves as his or her own control, thereby reducing variability for estimates of the drug’s effect on QT/QTc, and permitting a smaller sample size. A parallel design is the better choice in various circumstances, including when a long period is needed for the drug to reach steady state, the drug has a long half-life, and active metabolites have a delayed appearance.

Regulatory guidances, including ICH E14, do not always provide precise and unequivocal formulaic instructions on the conduct of recommended studies.


CLINICAL RESEARCH

Since its release in 2005, assimilation and interpretation of existing knowledge and the acquisition of new information and related interpretations have proceeded at a quick pace, making the degrees of freedom within the guidance meaningful: not every TQT study should (or can) be conducted in precisely the same manner. As the guidance states, “The investigational approach used for a particular drug should be individualised, depending on the pharmacodynamic, pharmacokinetic, and safety characteristics of the product, as well as its proposed clinical use.” This approach allows sponsors to formulate sound scientific and clinical rationales for proposed studies, and allows regulators a certain degree of decision-making latitude when considering arguments submitted by a sponsor for a particular approach. Accordingly, it should be emphasised that starting a dialogue with the respective regulatory agency at an early stage in preparing to conduct a TQT is a sensible strategy for a sponsor, and one that is certainly encouraged by the PMDA.

Creation of the PMDA Cardiovascular Safety Evaluation TeamGiven the significant increase in the number of PMDA consultations related to ICH E14 since October 2009, and the desire to provide consistency on communication to sponsors regarding the assessment of QT prolongation (and other cardiovascular safety issues)

among drugs from all relevant therapeutic classes, the PMDA Cardiovascular Safety Evaluation Team was formed in April 2010. Its members comprise reviewers from each category of review office (the Office of New Drugs, I-V, and the Office of Biologics, I and II), as well as a representative from the Office of Safety. The team will also collect cardiovascular safety data in the post-marketing arena as well as during pre-approval development, and share this information throughout the PMDA.7

A Key Issue: Extrapolation of the Data from Non-Japanese TQT Studies to Japanese NDAsThe ICH E5(R1) Guideline addresses ethnic factors in the acceptability of foreign clinical data in all ICH regions. It provides guidance “with respect to regulatory and development strategies that will permit adequate evaluation of the influence of ethnic factors while minimizing duplication of clinical studies and supplying medicines expeditiously to patients for their benefit.”8

When focusing on one region, this region is referred to as the ‘new region’ and other regions as the foreign region. If a large set of data have been collected in the foreign region and a sponsor wishes to submit them for consideration by the regulatory agency in the new region, a bridging study conducted in the new region may prove helpful. Bridging studies

are studies “performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the population in the new region.” In this regard, the following section from ICH E5(R1) is pertinent:To assess a medicine’s sensitivity to ethnic factors it is important that there be knowledge of its pharmacokinetic and pharmacodynamic properties and the translation of those properties to clinical effectiveness and safety…Characterization of a medicine as “ethnically insensitive”, i.e., unlikely to behave differently in different populations, would usually make it easier to extrapolate data from one region to another and need less bridging data. Factors that make a medicine ethnically sensitive or insensitive will become better understood and documented as effects in different regions are compared. It is clear at present, however, that such characteristics as clearance by an enzyme showing genetic polymorphism and a steep dose-response curve will make ethnic differences more likely.

While this text refers to the ethnic sensitivity of a specific medicine, this paper addresses the topic of potential ethnic sensitivity of one particular response, QT interval prolongation, to many drugs. The fundamental questions here, therefore, are the following: For a given drug, can compelling evidence be provided by a bridging study (or studies) to assure Japanese regulators that the proarrhythmic liability information provided for a drug by the foreign data set will be equally applicable to the Japanese population? Or, must that data be collected in Japanese study participants?

The ICH E14 guideline commented in 2005 as follows with regard to ethnicity: “Although data are limited, it is not expected that the results of the ‘thorough QT/QTc study’ would be affected by ethnic factors.”3 It is still true that data are limited in general, and specifically with regard to Caucasian and Japanese data: as of the time of writing, the PMDA does not have adequate data with which to address this question. Accordingly, it is of considerable interest to the PMDA, and indeed the scientific community, to obtain empirical verification or otherwise of this expressed expectation with regard to Caucasian and Japanese data.

The ICH E14 guidance will be applied by the PMDA to all NDAs from November 1st 2010. From that date, a submission lacking Japanese TQT data will need


CLINICAL RESEARCH

to present the proper reasons why it was impossible to conduct a Japanese TQT study. During the intervening grace period, the PMDA strongly recommends that sponsors consult with them. The suitability of foreign data will be assessed on a case-by-case basis. It is possible that foreign TQT data, or, if no foreign TQT data are available, foreign concentration-QT data, may be informative if a sponsor is able to demonstrate to a scientifically satisfactory degree that such foreign data can provide compelling evidence concerning Japanese risk.

Threshold of Regulatory Concern for QT Prolongation by the Test DrugFollowing appropriate concentration-QT evaluations, the PMDA expects that a TQT study will be performed using the four arms described earlier (if a supratherapeutic dose is not precluded by safety/tolerability issues), and that, for the drug treatment arms, QT assessments will be made around Cmax, i.e., at the time of and shortly before and after Tmax, as well as at other meaningful timepoints. The degree of prolongation will be deemed not to be of regulatory concern if the largest time-matched mean difference in the QT interval is less than 10 msec (the value of 10 msec appears in ICH E14 and has been used in Caucasian studies to date). It will be deemed to be of regulatory concern if the largest such difference is 10 msec or greater. In the former case, baseline and periodic on-drug ECG assessments as conducted following usual practices in a given therapeutic area in late-phase studies will be acceptable. In the latter case, expanded ECG monitoring may be required. Data in the NDA should address the following:• The effects of the drug on QT intervals

in the target patient population;• The effects of the drug in participants

with additional risk factors for Torsades de Pointes;

• Dose- and concentration-related effects, including participants exposed to the full range of potential doses and ECGs taken at the anticipated peak drug concentrations.

Additionally, a range of adverse event (AE) data must be presented. This includes the following:• Information on participants who develop

marked QT prolongation (values greater than 500 msec) or experience a serious

cardiovascular AE that suggests the occurrence of arrhythmia;

• Analysis of ECG and AE data from certain groups of participants:

• Those with electrolyte abnormalities (e.g., hypokalemia), heart failure, or impaired drug metabolism;

• Female participants;• Participants aged 65 and older.

It is important to emphasise here that the PMDA holds the same view as the FDA with regard to the 10 msec threshold: a value of 10.1 msec does not automatically mean that, no matter how good the drug’s overall safety and efficacy profile, it will definitely not be given marketing approval. The author strongly encourages sponsors not to take an automatic decision to terminate an investigational drug’s development programme if the threshold of 10 msec is exceeded, without first consulting with regulators.

Technical Issues in Conducting a TQT StudyHaving considered the key question of ethnic generalisation of proarrhythmic liability information, useful information was provided at the DIA meeting regarding other issues of conducting TQT studies in Japan.

Choice of the Positive Control used in the TQT StudyIf assay sensitivity is not established, data from the therapeutic and supratherapeutic dose treatment arms cannot be meaningfully analysed. The choice of moxifloxacin as the positive control drug is acceptable to PMDA. However, various attendees at the conference discussed and debated the notion that, at this time, the dose to be used in studies involving Japanese participants is not clear, and is one of several issues directly related to the question of whether or not noteworthy ethnic differences in drug responses will be seen.

In Caucasian populations studied to date, a 400 mg dose of the antibacterial agent moxifloxacin has commonly been used, since its administration leads to a predictable increase in QT/QTc of around 5-8 msec at Cmax. This degree of prolongation is not considered harmful, but it is sufficient to provide compelling evidence of assay sensitivity, evidence operationalised by the FDA as demonstration of a drug-induced increase of 5 msec or more at one or more timepoints of assessment 9. A question of interest becomes: if moxifloxacin is to be

used for Japanese participants, what dose should be chosen? Given the extensive knowledge of the pharmacokinetics of this dose in Caucasians, it can reasonably be argued that it would be advantageous to make use of such experience and use the same dose. However, it can also be reasonably argued that a different dose might be more appropriate. Further, this different dose might potentially be lower (Japanese body mass is typically less) or higher (should it be found that Japanese individuals metabolise the drug to a notably greater extent). Determining the appropriate dose is particularly pertinent if one wishes to use the same value of 5 msec (used in Caucasian studies to date) in the operational definition used to provide assay sensitivity.

Placement of the TQT Study within a Clinical Development ProgrammeThere is no strict PMDA stance concerning the precise timing of the TQT study in a clinical development programme. However, since the TQT study is a key determinant of the extent of ECG monitoring in later-phase trials, an ideal time is once the expected therapeutic dose to be used in the later studies is known.

Choice of Heart Rate Correction FormulaOne particular heart rate correction formula is not favoured. Rather, the PMDA prefers to see a range of correction formulae applied to the raw QT data, a strategy that allows the overall consistency of individual correction strategies to be evaluated.

Concluding RemarksIn this author’s opinion, while the rising of a new regulatory landscape in Japan requires sponsors to pay additional attention to regulatory considerations, it also brings a powerful opportunity for us all to learn more about the degree (if any) to which ethnicity impacts drug-induced proarrhythmic liability. The mandate of regulatory agencies is to look after health at the public health level. In addition to protecting its citizens from unacceptable risk, agencies also wish to bring acceptably safe and efficacious drugs to their markets. The PMDA has made it very clear that it welcomes consultations from sponsors, and that it wishes to work with both sponsors and other ICH regions in advancing the ‘Science of Cardiac Safety’ and in licensing appropriate drugs in a judicious manner.

CLINICAL RESEARCH

References1. Turner JR, Durham TA, 2009,

Integrated Cardiac Safety: Assessment Methodologies for Noncardiac Drugs in Discovery, Development, and Postmarketing Surveillance. Hoboken, NJ: John Wiley & Sons.

2. ICH Guideline S7B. The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. May 2005. http://www.ich.org/LOB/media/MEDIA2192.pdf.

3. ICH Guideline E14. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. May 2005. http://www.ich.org/LOB/media/MEDIA1476.pdf.

4. Mendzelevski B, 2010, No Borders for Cardiac Safety: Japan to Implement the ICH-E14 Guidance. DIA Global Forum, April issue, 78-79.

5. Turner JR, 2009, Interpreting the Interval: Design, Conduct, Analysis, and Interpretation of the ICH E14 Thorough QT/QTc Study. European Pharmaceutical Contractor, September

issue, 64-66.6. Beasley CM Jr, Dmitrienko A, Mitchell

MI, 2008, Design and analysis considerations for thorough QT studies employing conventional (10s, 12-lead) ECG recordings. Expert Reviews: Clinical Pharmacology, 1:815-839.

7. Shinagawa K, 2010, Overview of Final E14 Guideline: PMDA Perspective. Presentation given at the 1st Cardiac Safety Workshop in Japan at the Tower Hall Funabori, Tokyo, May 25th.

8. ICH Guideline E5(R1). Ethnic Factors in the Acceptability of Foreign Clinical Data. March 1998. http://www.ich.org/LOB/media/MEDIA481.pdf.

9. Zhang J, Machado SG, 2008, Statistical issues including design and sample size calculation in Thorough QT/QTc studies. Journal of Biopharmaceutical Statistics, 18:451-467.

Please note: The author notes that this paper has not been sanctioned by any representative from the Japanese regulatory agency. It reflects his best efforts to capture the PMDA’s position at this point in time concerning their adoption and implementation of ICH E14.

All sponsors are strongly encouraged to establish direct dialogue with the agency with regard to cardiac safety evaluations of their drugs under development n

Dr Rick Turner. is Senior Scientific Director, Cardiac Safety Services, Quintiles, and Affiliate Clinical Associate Professor, University of Florida College of Pharmacy. He specializes in the design and analysis of clinical trials, with a special interest in the cardiac and cardiovascular safety of non-cardiac drugs. He has published over 50 peer-reviewed papers and 10 books. Email: [email protected]


CLINICAL RESEARCH

Cutting Edge ECG Technology Reinforces the Continued Advancement of Centralised Cardiac SafetyAbstractContinual developments in technology are helping to provide solutions for the problematic issue of data inconsistency and inaccuracy in the analysis of Electrocardiograms (ECGs). Until recently the use of a decentralised model was the main method of collecting ECG data, however this is now being replaced by a centralised approach which is increasingly being utilised throughout the industry. A new study of investigative sites conducted by the Tufts Center for the Study of Drug Development (CSDD) revealed that over 50% of respondents predict that over the next five years the increased usage of the centralised method will be significant. An explanation for this adoption of centralisation can be linked to the multiple advantages it offers in comparison to the decentralised approach. In addition to being more economically viable for companies, a critical advantage of this approach is that it offers greater consistency for clinical trials, while significantly increasing data quality.

An essential factor in assuring the adoption of the centralised model is the need for extremely compact instrumentation that can remove the problems associated with larger, more heavyweight ECG equipment typically used in the pharmaceutical industry. To achieve this and therefore make the implementation process easier for companies, hand-held ECG collection devices are now appearing on the market, facilitating a seamless integration of the centralised system with customers’ central databases.

Cardiac SafetyResearch has shown that arrhythmias are just one of the many serious cardiac conditions that have an increased risk of occurrence as a result of certain drugs. The repercussive effect of this is that drug withdrawals from the market, labelling changes and the denial of regulatory

approval for marketing most often occur due to issues relating to cardiac safety. All new drugs entering the market must therefore be subjected to exhaustive clinical testing prior to their release, to confirm they do not have a negative impact on the cardiac health of patients. Precise analysis, accurate collection and consistent interpretation of data are therefore vital. Facilitating this process for biopharmaceutical organisations, contract research organisations (CROs) and medical device companies are newly emerging electronic data capture and transfer technologies. These new technologies offer essential tools which enable trial sponsors to reliably evaluate the effect of investigational drugs on the electrical functions of the heart.

The Regulatory PerspectiveDespite there being no current legislative mandate in place with regard to ECG assessment across clinical trials, the performance of a Thorough ECG Trial (TET) for new compounds has been stipulated as a key requirement by the US Food and Drug Administration (FDA) with a few limited exceptions. More specifically, the ICH E14 guideline was implemented with the intent of monitoring the QT/QTc prolongation in new drugs to ascertain their cardiac safety risks. The guideline also has an advisory function, specifying how best to conduct trials to determine the cardiac effects of a new drug.

A key requirement of the ICH E14 guideline is that a proof of concept, providing evidence that a centralised ECG system can be successfully used, must be done prior to the commencement of a TET trial. The guideline advises that if any cardiac safety concerns arise, a more thorough and intense ECG collection will be necessary for Phase III trials. A centralised method employs digital ECGs and a core laboratory, which deals with the majority of the work that would be handled by clinical trial sponsors, CROs and individual investigational sites. ECG

equipment will be supplied by the core lab to investigator sites, demonstrating one of the key benefits of centralised methods: consistency. The centralised method promotes consistency through its focus on standardised data and quality controlled equipment and staff. Another advantage to using digital ECG data collection methods at the core lab is increased speed of the analysis process. In addition, the use of high resolution digital methodology eradicates transcription and misinterpretation errors that are typical of the decentralised approach, therefore producing more focused and consistent data.

Benefits of Centralisation When a decentralised model is employed, ECG studies are conducted within a variety of investigator sites, using local ECG machines. Inconsistent results often occur as a consequence, due to different types of instruments using varying algorithms for calculations. In contrast, a centralised approach overcomes this issue of inconsistency by digitally collecting high quality data in a standardised format for assessment, with the use of consistent and validated systems. All interval duration measurements (IDMs) are assessed by a qualified individual, and every ECG is evaluated by a qualified cardiologist who is trained to follow standardised procedures which are continually validated through a quality control programme. As a consequence, time that participants previously would spend on site is significantly reduced. Additionally, centralisation facilitates proactive data monitoring and tracking, with demography and missing visits noted automatically, thereby enabling the collection of valuable data as studies progress.

With the adoption of a centralised method, clinical trial sponsors can utilise emergent technology, improving the quality and accuracy of data collated, lowering the time commitment of investigators and improving the general


CLINICAL RESEARCH

participant experience. As a result of employing these new technologies, investigator sites can collate immediate, consistent, accurate data, improving site operations for stakeholders and offering a better service and value to pharmaceutical companies. The centralised approach also eradicates issues such as data variability stemming from inconsistent ECG collection and evaluation methods, which are commonplace in paper-based decentralised studies.

Although the advantages of a centralised system are clear and well supported, it is still commonly believed that centralisation is not the most economical method. As a result, a decentralised ECG study model continues to be utilised throughout a large majority of clinical trials, with the use of multiple investigator sites employing local ECG machines.

Cost ImplicationsThe slower conversion from decentralised to centralised ECG collection is largely based on the concern over the true costs of a centralised model. Estimating an approximate figure of how many ECGs are required ahead of a study programme is difficult, therefore making the appraisal of an accurate cost of centralised versus decentralised ECGs problematic. Unknown variables include staffing costs, the number of investigator sites and the number of ECG machines required. Sponsors commonly still maintain the understanding that a centralised ECG provider is more costly than a localised or internal method, primarily as a consequence of the hardware distribution involved. Recent research conducted by Tufts indicated that sponsors perceive centralised ECG providers to be more expensive, although they reflected that increased accuracy and accessibility of central providers more than substantiates the extra cost.

When a decentralised model is employed, the majority of collection, transcription and interpretation of ECG data is conducted by the sponsor and the individual monitoring site. As a result, the majority of companies working with this method perceive the core laboratory in a centralised system as a non-essential added expense. Contrary to this belief, a centralised approach has been proven to save costs. When using a decentralised approach, sponsors must pay a sizeable ECG acquisition fee which includes charges for technician time and the use of ECG machines at the investigator site. In addition, the expense for labour

required for both the site and sponsor/CRO personnel to manually transcribe, double-data enter, monitor and quality control data from multiple sites is very high. These costly labour and associated fees are reduced when using a centralised approach. The Tufts report illustrates that sponsors are focused on this area and there has been a shift in the perception of a centralised approach, with 70% of respondents identifying the costs of using an ECG core laboratory as less than, or equal to, the costs of using paper.

The Importance of Innovative ECG TechnologyAlthough the study findings have confirmed that centralisation offers key benefits over the decentralised model, clinical trial sponsors still have a strong requirement for efficient and innovative instrumentation to ensure accuracy, consistency and cost-effectiveness. With reference to the ICH E14 guideline, the effectiveness of the ECG database is reliant on the employment of contemporary equipment with the facility for digital signal processing, which ensures an efficient safety assessment of ECGs. With the development of new

lightweight and compact ECG machines which have a significantly smaller footprint than existing systems, the challenges raised by previous heavy and expensive instrumentation are removed. The key advantages of the new ECG devices are that they are much easier to maneouvre and less costly to ship and store, resulting in companies being more inclined to adopt the centralised system. In addition to their newly compact size, the cutting edge instruments are improved on a technical level, offering more consistency and improved accuracy while effortlessly integrating with computer systems through a web application.

Increasingly studies are required to provide digital ECG data to a central digital system for the purpose of regulatory inspections. This data can then be stored on a central system and analysed by regulators to assess data quality. While this is not presently a compulsory requirement within the pharmaceutical industry, the majority of clinical studies will submit their data. According to the Tufts research, only a third of investigative sites assessed are obtaining ECG data in electronic form. The arrival of new ECG machines will


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 15 years of clinical research experience, specialising in regulatory compliance and computer system validation.Email: [email protected]

facilitate the data submission process, with all data being stored centrally and information easily transferable to the database when needed.

ConclusionHeightened awareness regarding the cardiac safety of drugs has sparked closer examination of all new compounds, with intense pressure being placed on the biopharmaceutical industry to supervise the potential influence of new drugs on the electrical functions of the heart. Despite a decentralised approach to ECG data collection being used at length within the industry, it is currently afflicted with multiple restrictions, including low accuracy, consistency and efficiency of ECG data. The application of the centralised model benefits the industry in a number of important areas, including data quality and data capture, the reduction of workload for sponsors and the ECG site, leading on to significantly lower overall costs. As made evident in the Tufts report, 97% of respondents rate the central labs as more accurate and 90% view them as more efficient.

The Tufts study provides evidence to suggest that the advantages of

centralisation are increasingly more recognised, with respondents identifying core labs as an effective and preferable method for conducting ECGs. A correlation between the adoption of centralised cardiac safety assessment and that of blood work, lab work and electronic data in clinical trails is highlighted within the Tufts study. After an initially slow period of adoption, recognition of centralised solutions and their benefits has dramatically increased since the implementation of regulations and increased knowledge of the advantages by industry professionals. The implementation of the ICH E14 guidance indicates that despite there being no plans for ECG to be mandatory within the pharmaceutical industry, recognition of the value and advantages of ECG centralisation is continually increasing n

References1. International Conference on

Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, The Clinical Evaluation of QT/QTC Interval

Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, E14, Current Step 4 Version, Dated 12 May 2005, http://www.ich.org/LOB/media/MEDIA1476.pdf

COMPANY PROFILE ADvERTISEMENT

Glycotope & Glycotope-BiotechnologyGlycotope (Berlin, Germany) is a leading biopharmaceutical company in the fields of glycomics and immunotherapeutics that has developed a unique and regulatory approved platform technology for the development and production of NBEs and improved second generation biopharmaceuticals / BioBetters and that offers its know-how also for development of BioSimilars. Glycotope-Biotechnology GmbH, a full subsidiary based in Heidelberg / Germany, produces biopharmaceuticals in mammalian production systems under GMP conditions including the fill & finish of the final drug for clinical trials.

GlycoProfiling, GlycoEngineering and the GlycoExpress™ toolbox of novel glycoengineered human cell lines comprise the world’s broadest glycosylation technology, suitable for both antibodies and non-antibody proteins such as growth factors, glycoprotein hormones, cytokines, certain enzymes, blood factors and thrombolytica. The targeted alteration of glycosylation constituents (e. g. sialylation, fucosylation, galactosylation) and conformation (branching, antennarity) leads to a significant improvement of the clinical characteristics of biopharmaceuticals such as manifold higher bioactivity, prolonged half life and reduced immunogenicity. As a consequence, the optimized and fully human glycosylation permits a new patent protection and yields enormous therapeutic and economic advantages. Also due to its excellent production features, GlycoExpress™ serves as the base of Glycotope´s product pipeline of currently 4 glycooptimized therapeutic antibodies for the treatment in various cancer indications – the first two of which have entered the clinic in 2009 and in Q2/2010 – and a glycooptimized protein-hormone for the treatment of infertility. In addition, multiple case-studies and customer projects have underlined GlycoExpress’ suitability to strongly improve a biotherapeutic’s therapeutical potential.

Since more than 25 years in operation, Glycotope-Biotechnology GmbH is one of the most-experienced and fully GMP-compliant contract manufacturing organisations in Germany. The rapid approvals of the two currently ongoing clinical trials for Glycotope’s

pipeline further confirmed Glycotope-Biotechnology’s capability to develop, produce and finish products at the highest and GMP-compliant quality within short time.

With 4 independent GMP-production suits for fed-batch and perfusion fermentation of mammalian cell-lines, Glycotope-Biotechnology GmbH offers the entire process of biopharmaceutical manufacturing from the clone to the drug ready to be administered in clinical trials. From cell-line development, design and implementation of USP- and DSP-processes, quality-control & analytics down to aseptic Fill & Finish and release of the drug substance, Glycotope-Biotechnology GmbH has a long-lasting track-record as a reliable and innovative partner of the pharmaceutical industry.

The main service spectrum focuses on the development of biotherapeutics (BioBetters or BioSimilars) from the gene to the drug for clinical trials:

Development of NBEs / BioBetters / BioSimilars with optional GlycoOptimization• Clone / Cell-Line Development • Generation & identification of high-

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• Full spectrum of GlycoAnalytics and other biochemical methods for product characterization

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With together more than 130 employees, Glycotope and Glycotope-Biotechnology represent one of the largest biotechnology organisations in Germany.


LABS & LOgISTICS

Challenges of the Clinical Trial Supply Chain for Stem Cell Products

A high percentage of new therapies being announced and discussed in the news currently are based on stem cell products. Products derived from embryonic stem cells and adult cells are now beginning to enter the clinical trial phase of development. As research has developed in this field, so too have the regulations to control not only the use and production of the cells, but also the products derived from these cells.

The clinical trial supplies for these products needs to be conducted under similar regulations to conventional pharmaceuticals, which can be a challenge when many of the products are unconventional, and are stored at temperatures as low as -196ºC. Within this article I will assess some of the present challenges and consider some possible solutions.

The Current RegulationsIn the US, the National Institute for Health (NIH) is the central governing body for stem cell research, but each state is entitled to determine its own legislation. Similarly, in the European Union, the European Medicines Agency (EMA) is the central body but each member state maintains its own national legislation.

In the US, regulation of the cell therapy products derived from stem cells comes under the responsibility of the FDA, under their Center for Biological Evaluation and Research (CBER). In Europe, EMA has the overall authority for the products, but their quality, safety and efficacy is assessed by the Committee for Advanced Therapies (CAT), a Europe-wide committee of experts, whose opinion is submitted to EMA’s Committee for Medicinal Products for Human Use (CHMP) for final approval. Due to the very specific nature of the products, the expertise required to assess the material goes beyond the traditional pharmaceutical field, covering biotechnology and often medical devices. To locate such expertise within each

European member state is not currently possible, therefore unlike standard investigational medicinal products (IMP), which can be submitted to the EU country authority in which the trial will be conducted, Advanced Therapy Medicinal Products (ATMPs) must be submitted centrally to EMA.

Challenges of TrialsHaving successfully developed an advanced therapy medicinal product that has clinical potential, identified a method for production, and met the initial regulatory criteria for efficacy and safety required by authorities, the product is ready for clinical trial.

Phase I trials are generally conducted at a single site with one investigator and a close relationship between the investigator and the sponsor. The investigator in trials of this type of material is often a pioneer in his or her field, and closely involved with the development of the product. The products may have been developed using the patients’ own cells (autologous) as well as products from a donor source other than the recipient. There are difficulties in the clinical supply chain with both types of material.

Trials involving autologous products require collection of cells, treatment of the cells, and delivery back to the same patient; this whole operation may be conducted on a single site, or alternatively it may require transport to a separate site for cell processing, and then the return of the material to the same patient. Although the manipulation of the material and the technology to process the cells is extremely complex, the logistics of the trial are relatively simple. It requires secure traceability of the sample, obtained by following good manufacturing practice (GMP) guidelines and a nitrogen shipper, which transports the material at -196°C between the patient and the processing site. Following production and labelling, the material will require confirmation that it is GMP compliant. In the EU this is a

Qualified Person (QP) certification and this can be the first of the obstacles to be overcome.

Often, the tests which must be satisfied to confirm that the cells have been manufactured correctly and are suitable for use (for example are free from infection), take longer than the shelf life of the product, which may only be a few days. In the EU this has been overcome by applying a similar release process to that of radioactive treatments which have a half-life shorter than the testing time. Great emphasis is placed on prevention, ensuring good GMP in the manufacturing facility. Key tests are carried out before use; the product is then certified for use in the trial and the full testing results are completed after the patient has received treatment. It is important that the Qualified Person releasing this product is experienced in the release requirements for the cells, as well as being comfortable with the principles for releasing radioactive pharmaceuticals. This experience is very different to releasing traditional pharmaceuticals or even biopharmaceuticals, and until these trials become more common, it may be difficult to find a Qualified Person able to release these products.

The requirement to have the manufacturing site, the patient and the QP all available at the same time adds considerable complexity to the process. For small numbers of patients this can be achieved, but it becomes increasingly difficult to co-ordinate as more patients are treated, and as the product progresses from Phase I to Phase II testing.

Following the successful completion of the Phase I trial, the product may proceed into Phase II. At this phase, treatment is likely to take place at more than one investigator site. For autologous treatments this has the added complication of more than one patient’s treatment being processed at the same time. Traceability of samples is critical, and the synchronisation of patients, the


LABS & LOgISTICS

manufacturing site and QP availability becomes even more complex. However, competent project management and good planning should overcome these difficulties.

Another issue may arise when initiating recruitment of patients at more than one site. Some treatments require devices to deliver the cells to the appropriate site within the patient. Where these devices are ‘off the shelf’ marketed equipment in that country, being used in the standard way, there is no issue. However, if a device has been used by an investigator in the US very successfully, the sponsor may prefer to use the same device in Europe, but find that it is not CE marked. Alternatively there could be a device available, but it needs to be used in a different way to its current licensed use. In the EU the use of these devices should be included in the Clinical Trial Application (CTA). Where it is a new device, and the device is determined to be a combination medicinal product, the application will be considered under the Advanced Therapy Products Directive1, rather than requiring a separate device application. Conversely, in the US a separate device application would need to be made.

For the drug developer, considering all the other hurdles and complexities they face, this issue may appear minor. However it is important to give consideration to the equipment being used to deliver the treatment, not just for its medical capability but also for its licensing status, as it could prevent the need to submit a device application which adds cost and could delay the IMP trial process.

The other type of product is allogeneic products. These are products derived from stem cells which are used to treat people other than the donor. These cells are generally manufactured in batches and then delivered to the patient for treatment. Generally these cells have a longer shelf life and the QP certificate process for manufacture of the product can be more like that of biopharmaceuticals, with full test results available before the product is used.

Unlike autologous products which are made to order and labelled for the known patient as they are manufactured, these cells are typically manufactured on a larger scale, and may be intended for use in trials in a number of countries. The regulatory labelling requirements for ATMPs are very similar to those of other materials, but in addition they must identify the source of the cells.

Possible SolutionsThere have been trials conducted in the EU where the material was produced and identified with a unique number and basic information on the primary container, but was not designated for use in a trial until after manufacture, therefore the primary label did not meet the regulatory requirements. The cells were frozen to -196ºC following manufacture and had to be maintained at this temperature until they were thawed at the trial site and injected into the patient. Applying a new label at -196ºC was impossible, as glue will not adhere at this temperature.

The solution used for this material was to import the material into the EU, QP release the manufacturing stage of production, and store the material at -196ºC. Prior to dispatch to site, the

required tubes of cells for the patient were selected and transferred into a nitrogen shipper which was then labelled with fully compliant labelling, in effect making the shipper the secondary packaging. The cells then stayed in the shipper at site until the patients had been treated, before returning the shipper ready for the next patient delivery.

The drawback to this method was the requirement to secure specific permission from the regulatory authority to use this method of labelling, as the primary label was not compliant. In addition, using the shipper as the secondary packaging meant that the cell transfer to the shipper and the shipper labelling had to be treated as an assembly operation, which was effectively equivalent to packing a drug kit, and therefore this required batch

US EU

Regulated as Biologics under Public Health Act, section 351.

EC Regulation 1394/2007 on Ad-vanced Therapy Products.

21CFR 210 - cGMP regulations for manufacturing, processing, packaging or holding of drugs

EU 2003/94/EC GMP for medicinal products.

EU2001/20/EC Clinical Trial Directive.

21 CFR 211 - cGMP for finished pharmaceuticals.

EU 2001/83/EC Medicinal products for human use (including Advanced Therapy Regulation).

21 CFR 314.126 - Clinical Trials

Figure 1: Summary of the US and EU regulations for stem cell-derived products.

Table of EU labelling requirements for ATMP primary and secondary containers.

Secondary container Primary container

• Unique donation and product codes• For ATMPs for autologous use, the

patient ID and ‘for autologous use only’ statement

• The name of the medicinal product followed by its strength and pharma-ceutical form

• A list of excipients • The method and route of administra-

tion • A warning that the medicinal product

must be stored out of the reach and sight of children

• The expiry date • Batch number• Storage instructions• The name and address of the holder

of the authorisation for the clinical trial• The number of the authorisation

for placing the medicinal product (EUDRACT/Protocol)

• instructions for use

• The name of the medicinal product • The name of the holder of the

authorisation for the clinical trial• The expiry date• The batch number

Summary of the EU clinical trial labelling requirements 2


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documents to be completed and a final QP release to be performed before the cells could be shipped. This method was possible for a small Phase I trial to a single site, but would not be practical for larger trials.

From experience to date with clinical trials of ATMPs, the sponsor defines the product as a single tube containing cells, with patients requiring a varying number of tubes to supply the clinical dose. Orders for the product are made requesting tube numbers XXX to YYY of a particular batch to be sent to the site. These are selected, put into tube carriers and sent to the site. On arrival the investigator removes the tubes from the tube holders, identifies those designated to the patient, calculates how many tubes are required to deliver the determined dose of cells and proceeds with treatment.

The process is very similar, in logistical terms, to dosing oncology patients who require titration to determine their dose, and can be translated for stem cell studies. Successful packaging and clinical supply for these trials has been performed for many years. Although many of these products are cold (2-8ºC) rather than -196ºC, the same general principles of supply chain can still be applied.

For example, kits of tubes could be prepared containing fully compliant primary labelled tubes placed into a cryostorage box. The box would be labelled with the secondary label at ambient temperature prior to the tubes being added, eliminating the issue of labels not adhering at very cold temperatures. The tubes would then be transferred to the labelled boxes as part of an assembly operation which would then be QP certified. This style of kit could be prepared in advance of an order and allows for a number of kits to be prepared and QP released at the same time, reducing QP time and therefore keeping costs low also. Furthermore, material is available for shipping as soon as an order is received.

There could be difficulties with cell wastage if there is a set number of tubes per kit, but this could be handled with a ‘just in time’ packing method, which has proved successful in more conventional drug trials where the drug is either very scarce or very expensive. This method does not save the QP costs, as QP certification would be required for each dispatch, but does mean the product is compliant with the labelling regulations.

Placing the materials into kits makes the logistics of the trial far simpler. However

it does not address the issue of primary labelling. An option could be to print the primary labels for the trial in advance of the cells being dispensed. The tubes would be labelled at ambient temperature prior to being filled and then frozen to -196ºC. This method overcomes the issues of labels not adhering at -196ºC but would require the label text to be agreed very early in the trial phase, before manufacture has taken place.

Receipt at the investigational site would be simpler using the kit model, allowing receipt of a kit containing tubes in the range of XXX to YYY rather than having to check each individual tube into inventory. In addition the secondary container could be tamper-proof, giving added protection to the primary tubes. This can be particularly important if the cells are to be stored at the investigator site’s own cryostorage facilities rather than in the nitrogen shipper, as cross-contamination could be a risk. Although long-term on-site storage is not common at the moment, as stem cell products enter Phase II and Phase III trials, storage at site will need to be addressed. It will not be realistic to send the material to site on a patient by patient basis. If the shippers are sent with a number of kits and then remain at the site acting as the storage vessel until all the material is used, they will need to be properly maintained and monitored under GMP compliant conditions. Also the company performing the distribution of the products in the trials would have to have enough nitrogen shippers and monitors available to meet the shipment demands. These are not as readily available as polystyrene-based shippers used for most other low temperature shipments, and they are considerably more expensive, and will need to be returned and cleaned before re-use. Therefore last minute changes to shipping forecasts and site initiation ahead of schedule will be more difficult to accommodate.

None of the issues in the clinical trial supply chain of stem cell products is impossible to overcome, as long as there is consideration given very early in the trial process to the method of labelling, distribution and on-site storage of the product. Unlike the more conventional trials, products cannot be over-labelled at a later date to meet regulations, although to date the regulatory authorities have been understanding and open to alternative solutions. However sponsors will be expected to comply fully with the

legislation as trial procedures develop.Even for conventional products, it is

a challenge to persuade sponsors to carefully consider the clinical supply chain at a sufficiently early stage. For stem cell products this is perhaps even more essential, but because of the academic nature of much of the research, seems likely to be one of the last considerations for the sponsor. It will be a continuing challenge over the coming years for the supply chain companies capable of supporting ATMPs to convince the sponsors to engage with them at an early enough stage to ensure the provision of a service that can meet patient recruitment needs and is affordable for the sponsors n

References.1. ATMP as defined in Directive /83/EC,

medical device defined in 93/42/EEC and active implantable medical device defined in Directive 90/385/EEC.

2. Articles 54 and 55 of Directive 2001/83/EC

Rachel griffiths, is the director of operations at Biotec Services International. After joining Biotec in 2004, Rachel has maintained responsibility for the UK-based pharmaceutical company’s production and warehouse. With a degree in microbiology and virology, Rachel has previous experience as a development scientist, a technical support scientist and a product support specialist. Now operations director at Biotec, Rachel assists the team which specialises in the import, QP certification, labelling, assembly, storage and world-wide distribution of clinical supplies for Phase I to IV trials, through to commercial supplies. Email: [email protected]


LABS & LOgISTICS: TEMPERATURE CONTROLLED LOgISTICS

In the quest for cost-effective, sustainable transportation, temperature control logistics professionals are exploring shipping high-value pharmaceuticals by ocean. With the annual Cool Chain Europe conference in Rotterdam for 2011, participants will engage in discussions on best practice operational procedures, qualification of equipment and risks of shipping by sea.

In addition to examining ocean freight, the 10th anniversary CCE event will examine the current state of the airline industry and their abilities to service temperature sensitive pharmaceuticals. Plus, true qualification of trailers and reefer trucks will also be discussed.

CCE 2011 themes include:• Regulatory Readiness: ‘Open

Microphone’ Discussions • Quality Systems for Cool Chain GDP • Evaluating Cost-Effective Multi-

Modal Transportation • Airline, Airport and Air Transport

Processes, Compliance and Security Shipping by Ocean: Case Studies and Developing PCCIG Guidance • New Markets Focus on Middle East • CRT or Ambient Temperature

Strategy: Profiles, Qualification, Risk Profiles, Transportation Available and Quality Agreements

• Cool Chain Packaging: Green, “Last Mile” and Alternatives to Active ULDs

• Integration of Temperature and Supply Chain Data: Product Visibility and Flow

Transportation Partner Perspectives: Airlines, Couriers and LSPs The only European event of its kind!If you only have time to go to one conference in the year, hands down, ask anybody - Cool Chain Europe is the place to be. Over the past 10 years, CCE has become the stomping

ground for temperature control logistics and QA professionals in Europe to shape ideas for the future.

Today, the annual event exceeds 400 participants, making it the largest event of its kind. People have come to rely on the annual event to discuss best practices and hash out problems to distributing efficacious drugs to the patient.

Networking is at its best! CCE is the biggest cool chain exhibition in Europe featuring major airlines, freight forwarders, packaging/container and data monitoring companies - an ideal place for partnering!

Plus, CCE is the only cold chain event to feature a Gala Dinner and Excellence Awards recognizing successful projects in temperature control logistics and quality initiatives. Visit www.coolchaineurope.com/IPI to read about the 2010 winners.

2011 Speaker Preview• Rafik H. Bishara, PhD,

Technical Advisor and Chair PCCIG USA Branch, PDA

• Dr. Mary Foster, Chair, Packaging and Storage Expert Committee, US Pharmacopeia (USP)

• Ian Holloway, Manager, Defective Medicines Reporting Centre, MHRA

• Cornelia Nopitsch-Mai, Scientist, Federal Institute for Drugs and Medical Devices Germany, BFARM

• Umit Kartoglu, Technical Officer and Scientist, World Health Organisation

• David A Ulrich, QA Director - Distribution, Global Pharmaceutical Operations, Strategic Quality Initiative, Distribution QA, Abbott Laboratories

• Lisa Mazzoni, Project Lead, Temperature Controlled Supply Chain, F. Hoffmann-La Roche

• Anna Hallgren, Senior Logistics Specialist, Vitrolife Sweden AB

For more information about the speakers and 2011 agenda, please visit www.coolchaineurope.com/IPI

To register as a delegate call +44 (0) 207 368 9300 email: [email protected] or visit the website at www.coolchaineurope.com/IPI

For more information about sponsoring or exhibiting contact Gal Cohen on +44 (0) 207 368 9300, or email: [email protected]

What others are saying about Cool Chain Europe:“Good opportunity to meet peers and gain understanding of new regulations – very valuable” - Senior Quality Manager, International Distribution, Amgen Europe BV “Very practical and lots of new knowledge. Excellent interaction with Exhibitors” - Galapagos NV “Great event to understand temperature control industry concerns and need – definitely valuable” - Area Sales Manager, Continental Airlines Cargo “Great ‘state of the art’ update on temperature sensitive clinical trial suppliers!” - Actogenix Belgium

Cost-Effective, Quality-Driven Temperature-Controlled Transportation & Logistics24th - 26th January - The World Trade Centre, Rotterdam, The Netherlands

IQPC’s 10th Annual Cool Chain Europe conference moves to Europe’s ocean freight epicenter - Rotterdam


LABS & LOgISTICS


LABS & LOgISTICS: TEMPERATURE CONTROLLED LOgISTICS

Opticooler: Optimal safety for temperature-sensitive airfreight shipments

A key to the success of Lufthansa Cargo’s Competence Center Temperature Control are the Cooling- and heating shipping containers. They help when transporting temperature-sensitive airfreight consignments- regardless of weather conditions and at a predetermined temperature. With the “Opticooler”, Lufthansa Cargo has extended its portfolio, with a newly developed container, with which Lufthansa Cargo once again justifies its reputation as perhaps the world’s most innovative airline. How the procedure at Frankfurt airport works, becomes clear with the example of a shipment of vaccines destined for Washington DC.

Frankfurt airport, 1 p.m. on a warm sunny day, LH 418 has taken off on time: destination is Washington DC. Aboard the Boeing 747 are more the 400 passengers and four very special cargo containers- completely loaded with urgently needed, extremely temperature-sensitive medicines.

Flashback: 6 a.m, Lufthansa Cargo Center, on the same day. Cargo, which is scheduled to take off shortly, must first be unloaded on the street. Every day, several hundred trucks pass through the security gate of Lufthansa Cargo. With their loads of freight, they will fill the bellies of the passenger aircraft and the loading bays of the freighters.

Some of the trucks have sensitive goods on board- for example pharmaceutical products. They are shipped with the Cool/td-Active-Product of Lufthansa Cargo for controlled-temperature transport. Truck driver Ali Konak delivers medicinal products regularly, on behalf of a large airfreight forwarding agent. He gets them directly from the production location of a Marburger pharmaceutical company and brings them directly to Frankfurt in the Perishables Center of Lufthansa Cargo. There the team of Karin Krestan, Senior

Handling Manager in the Competence Center Temperature Control with Lufthansa Cargo, takes over the valuable cargo. “We see to it, that the consignments, in accordance with the temperature-control guidelines, are handled up to the takeoff, as carefully and as quickly as possible”, Krestan tells us. “Moreover, we keep our

eye on every single shipment-from the booking to the delivery”.

The diligence of the handling team is supported by a special container which is capable of cooling, as well as heating. Lufthansa makes available to its customers approximately 300 of these high-tech boxes. Because of high market


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LABS & LOgISTICS

demand for this product, this number increases regularly from month to month. These “intelligent” containers come in two sizes and with different technologies: in the RAP there is room for five Euro pallets, in the RKN there is only one. Usually, the customer stows his goods in the container himself and then brings it to the airport in a truck. Forwarding agents also bring the consignment and the container to the receiving point for the customer, so that the controled temperature remains uninterrupted. It is possible to precisely adjust the temperature within the container to temperatures between -20 and+30°C. Due to the built-in cooling- and heating systems, the shipping boxes are able to maintain a constant temperature, no matter if the outside temperature is blazing hot or icy cold. Lufthansa Cargo always tries to maintain a deviation within the box of no more than +/- 3°C. Generally, however, the temperature varies less than half a degree Centigrade – the cooling and the heating are so finely tuned. The containers on a given trip must sometimes work very hard. “For example, when the aircraft takes off in the winter from Chicago where it’s -20°C, and then arrives in Dubai where it’s +40°C”, relates Hans-Peter Justus, Senior Product Manager in charge of Cool/td in Lufthansa Cargo’s Competence Center Temperature Control. “Such extreme spans of temperature in the outside world pose really no problems for our cooling/ heating containers- as long as the batteries are filled and the wished-for temperature is carefully set.” Specialists from Lufthansa Cargo doublecheck before takeoff the correct programming of the container.

Deutsche Lufthansa is known traditionally to be one of the most innovative airlines in the world. Thus, it is not surprising, that the further development of the refrigerated containers, for the most part, was driven forward by this airline. After all, already in 2004 the company, together with a container manufacturer, for the first time developed a container of its own- at that time an unknown procedure in the industry. “We wanted a solution which would bring advantages to all our customers”, explains Justus. “For this reason, we decided upon a product of our own development and which was precisely adapted to our handling processes.”

During the subsequent years the team from the Competence Center Temperature Control has used its comprehensive know-how to continuously optimise the containers. As the first cargo airline, Lufthansa Cargo could offer numerous

advantages to its customers with it, like the active temperature control, a complete data recording and intuitive operation.

The latest coup of the temperature experts, mutually developed with the container manufacturer Dokasch, is the “Opticooler”. Without using dry ice, the Opticooler only needs electricity to reach and maintain the desired temperature. The Opticooler is therefore the perfect supplement in the chill container portfolio of the cargo airline. Justus sees the operational area everywhere where a cooling with dry ice is not possible: “There are certain goods, for example insulin, which may not get into contact with carbon dioxide.“ Particularly pharmaceuticals are subject to strict, governmental constraints and demanding in-house standards of quality. These strict directives are not surprising.

Raw materials for medicine, serums or sophisticated preparations for the fight against cancer tolerate as a rule only very low temperature variations. Otherwise their molecular structure is distorted and they go bad. In the case of the shipments to Washington it concerns vaccines. They must be transported at between two and eight degrees Centigrade to maintain their effectiveness. This is a big responsibility, to which all partners are aware. “We not only have a professional obligation to do our job as optimally as possible, but also a moral one“, says Christopher Dehio, Senior Key Account Manager in the Competence Centre of Temperature Control with Lufthansa Cargo. “Every person who goes to the doctor and is given a medication, should be able to count on the fact that the quality is first class.“


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The shipments are watched-over with the necessary strictness: Beside the manufacturer, who continuously records the temperature of his product, Lufthansa Cargo’s

cooling- and heating container notates the temperature on the inside: for the makers of pharmaceuticals, an important proof of quality that state authorities in consignee markets increasingly demand. With this, the regulations of the health authorities after the complete supervision have clearly increased. “We at Lufthansa Cargo can fulfil these requirements completely“, says Hans-Peter Justus. “Besides, a team of experts is available to our customers, round-the-clock, that supervises all temperature-sensitive transports worldwide.”

With respect to the general increase of requirements, Lufthansa Cargo responded in 2006 with the foundation of a Competence Center Temperature Control . The service team is available to our customers there 24-hours-a-day and seven days a week. The product management is responsible for providing the containers, as well as for the continuous improvement of the Cool/td-Services. The Key Account Managers maintain contact with forwarding agents and the pharmaceutical industry. They were also the ones, who sat down at the table with the forwarding agent and the manufacturer before the first transport of vaccines to Washington and talked through all the requirements of the transport, Christopher Dehio tells us. In order to safely and reliably execute the complex transport of the almost always valuable goods, it is necessary, that all people involved, i.e. the consignor, the forwarding agent and the airline, plan the shipment together as early as possible.

Temperature is the one thing, speed is the other. The colleagues from Fraport also know this and lose no time in taking- over the transport of the cooling-/heating containers to the waiting aircraft. The very valuable airfreight must pass through one last security gate and then the freight is on its way to the airplane. About one third of all the cooling-/heating containers are sent with Lufthansa Cargo freighters, two thirds fly with the wide-bodies of Lufthansa. These are the large passenger aircraft like the Airbus A340, the Boeing 747 or also the largest passenger airplane in the world, the A380, which take off in Frankfurt and Munich and then flies to the four corners of the world. Lufthansa Cargo has equipped 90 stations to handle the cooling-/heating containers and the

tendency is rising. Very recently the long-haul destinations of Austrian Airlines can be offered through Vienna Cool/td Services. This is made possible through the integration of the freighter business of Austrian Airlines AG into Lufthansa Cargo. But it doesn’t matter if it’s Wien, Dubai or Moscow: well-schooled employees must stand at both ends of the transport chain. They are responsible for dry ice for the cooling, electric sockets to charge the container and for accelerated processes. No other carrier offers such a competent and world-wide network. Even the pilot finds out precisely where and what goods are stowed in the cargo holds, so that not only the passengers, but also the cargo shipment will arrive intact.

It is for this reason, that “Cool/td-Active” is not only interesting to the pharmaceutical industry, but also to other economic sectors. In the meantime, temperature-sensitive high-tech equipment is sent on its journey in the cooling-/heating containers, as well as valuable chemicals, paints and resins. All of these could not be transported with simple cooling alone. Many adhesives which are used in the aviation industry, can only be shipped with temperatures between 20° and 28°C, or else they begin to set.

Refrigerated transport in airfreight has been around as long as DC3s which had been taken out of service after the Second World War flew in ice-cold tuna to California out of the South Pacific. Since then, the possibilities have greatly increased. Flying airfreight shipments for highly-sophisticated industry customers within narrow temperature parameters belongs to Lufthansa Cargo’s core competences.

Only one thing has not changed over the years: the goal to develop new and innovative products, which promise the customer a real added-value and which guarantee, that the temperature-sensitive freight reaches its destination safe and sound n

Michael Breul is the Director Competence Center Temperature Control of Lufthansa Cargo AG. Michael holds a Master degree in economic/sport from the University of Mainz. He started at LCAG Import/Export Lufthansa Cargo Center Frankfurt, and then held several positions as the regional management Iberien, located in Madrid, Manager in routemanagement Europa/ located in headquarter Frankfurt, LCAG Director in Brasil/ located in Sao Paulo, Director Produktmanagement Standard and Express/ Frankfurt and since the 1st of Feb 2010 as Director Competence Center Temperature Control, Frankfurt. His in depth experience in pharmaceutical logistics & temperature controlled shipment management has proved invaluable to customers over the years. Email: [email protected]


MANUFACTURINg

Bridging the Gap between Early Phase Development and Commercialisation

The challenge of taking a drug candidate from discovery through to market should not be underestimated, as there can be many hurdles to face along the path. Some of these barriers will be unforeseen, but many can be anticipated and, through careful planning and consideration, they can be avoided, or at the very least, minimised. Careful use of external contractors during development can alleviate some of these challenges. Getting the selection wrong, on the other hand, can create additional complications for the development programme.

The aim of this article is to look at some of the challenges that need to be considered when outsourcing activities from early phase through to late phase development, then scale-up, and ultimately commercialisation. By considering the challenges at each stage of development, it should be possible to minimise both the time taken and money spent when progressing an entity from molecule to market.

What are the Early Phase Challenges?Early phase development challenges will inevitably vary from those encountered during the later phases and commercialisation. Nonetheless a consistent need arising throughout development will always be to minimise the amount of money spent, whilst at the same time reducing the length of time taken to get to the next project milestone. The first point to consider, and one that is very often overlooked, is for the company to think about its business model and the entity that it is developing. It may be that the company’s approach is to complete the proof of concept activities itself, and then look for a partner to take the entity through late phase development and commercialisation. Alternatively, the company may want to take the entity into

the marketplace by itself. Understanding the business model fully will allow it to use its time and effort more effectively, enabling it to add value to the process where it really counts.

The second consideration is intimately linked to the first, and relates to the level and structure of the funding available to get the entity initially into first time in man studies. By fully understanding the funding available, an appropriate strategy can be planned accordingly. For example, it may be appropriate to progress the first time in man studies with a simple “fit for purpose” formulation. This will bring the benefits of reducing the initial development outlay, and should also reduce the length of time taken to get into the clinic in the first place. The counter-argument to this approach is that the formulation may not be appropriate for scale-up in later phases, and will almost certainly be unsuitable for the final marketed product.

Availability and cost of the active pharmaceutical ingredient (API) or drug

substance will also play an important part in defining the development strategy. The API or drug substance is often scarce and difficult to obtain during early phase development. It is therefore important to consider not only the formulation development requirements at this stage, but also the processing equipment to be used to supply the clinical trials material. By choosing the approach and equipment carefully, significant reductions in API usage can be obtained, thereby ensuring the availability of sufficient drug product for use in clinical trials. A miscalculation in material requirements at this stage can jeopardise getting into clinical trials, leading to extensive and costly delays.

Speed to clinic is the next point to consider. There will always be pressure from key stakeholders (senior management, board members, shareholders, etc.) to get into clinic as quickly as possible, especially where milestone payments may be triggered. It is therefore important to identify the


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right strategy that will allow challenging, but hopefully realistic, timeframes to be successfully set and achieved. It is perhaps worth reminding stakeholders and senior management occasionally that a rushed but unsuccessful clinical trial is of no use to anyone.

This neatly leads into the next point for consideration: the chances of success, or indeed failure, during clinical trials. Everyone hopes to develop the next blockbuster, but the reality is that the attrition rates through clinical development are high. It is of no surprise to anyone that some of these failures are due to poorly conceived and executed development strategies, especially during the formulation development activities, which do not give the entity the best chances of success.

Different Approaches to Outsourcing Early Phase Development Activities

There are many different approaches to tackling the development of a drug product, and the approach taken will define the strategy for outsourcing. The advantages and disadvantages of just four approaches are listed in the table below. The four approaches considered are as follows:1. Minimise the initial development costs

by choosing to work with a small, local contract development and manufacturing organisation, with a simple formulation that is fit for purpose for first time in man studies.

2. Invest additional API and time in the early phase development in order to design an optimal formulation, right from the start. This approach may be beneficial if a company knows that it is going to commercialise the product itself.

3. Carry out the formulation development activities with a specialised company in advance of sourcing the clinical trials material manufacture.

4. Identify a partner that has the right skills and expertise to carry out your early and late phase development and scale-up to commercial supply ... is this ever possible?

Planning for Success: What are the Later Phase Challenges?Planning the development programme must also consider the approach to be taken after the success of first time in man studies. This again will be shaped by the particular business model employed by the company. It will also differ depending on the approach taken for earlier development. Decisions taken

during the early phase development will have consequences throughout the development and commercialisation pathway. These should therefore be considered right from the start, even if ultimately, the company will not itself be carrying out the next stages of development.

Scaling up any process that has been developed in the early stages now needs to be addressed. Points to consider will, of course, depend on the particular dosage form that the company is targeting. This may be the same as one used previously, although it may now need to be changed. For example, a simple powder blend in a capsule may have been selected initially, but the development of a tablet formulation is required for the next phase of development. Was the powder blend formulated in such a way that it has the right excipients and characteristics to potentially be compressed into a tablet? What studies will be required to confirm this? If the dosage form remains unchanged and the formulation can be carried through to the next stage, the robustness of the process and the type of equipment to be used need to be taken into account. Consistency in the type of equipment and the performance can be critical.

The most important consideration however, is the expertise and knowledge of the people involved. The partner selected for early phase development does not have the capability to scale up to the batch sizes required for later phase, requiring selection of another contractor. In such a situation, the effective transfer of information becomes a very important factor: loss of accumulated knowledge and experience can be a very real concern. Success may depend on the team having a thorough understanding of the challenges inherent to the entity (for example, light sensitivity, susceptibility to oxidation, powder characteristics etc) as this may in turn significantly impact other processes.

As seamless a transfer as possible from one clinical phase to the next is desirable. This is facilitated by a consistency of approach, which may inevitably be compromised if switching from one contractor to another. The potential benefits of avoiding switching include minimising regulatory risks and avoiding the expense of additional API use, through the need to reproduce experiments, perform bridging studies etc. Of course this is not always possible, especially if the approach taken during the

early phase was to use a fit for purpose formulation. Use of a fit for purpose formulation is a perfectly acceptable, and in many cases a more viable, option, but its potential limitations should be borne in mind and built into the plan accordingly.

Scale-Up Activities – A Case StudyIn order to minimise scale-up issues it

is important to consider various aspects of both the process and the equipment. A number of factors can affect the outcome of a scale-up process, and all must be considered right from its beginning.

A recent case study from Patheon’s Lyophilisation Development Centre of Excellence, in Ferentino, Italy, highlights the points to consider when scaling up from early phase activities. The initial activities had been successfully performed by a small, university-based CMO that did not have the capability to take the batch size to the next level required by the client. The process was therefore transferred to Patheon, with no issues being considered by the client. However the diligence of the Italian team identified a number of potential causes for concern, and the team undertook a series of investigations in order to eliminate them.

The first was to consider the ratio of the condenser surface area to the shelf surface area, and the ratio of the shelf surface area to the condenser opening area. Through lyophilisation cycle optimisation, it was possible to obtain a similar level of efficiency, in the removal of water vapour, between the original lyophilisation chamber and that within the Patheon facility. Mapping of the temperature across the chamber shelves ensured uniformity, and the same diathermic fluid was utilised to get a similar heat transfer coefficient from the shelf to the vial for both chambers.

A machine trial was also undertaken on the filling equipment, as the early phase clinical trials material had been produced using semi-automated equipment. It was therefore important to see how the fully automated equipment performed in relation to the defined process parameters. During this trial it was observed that the stoppers did not form a proper seal with the vial. Review of the components showed that this was due to a mismatch between the stopper and the vial, caused by the lack of a “blow back” feature on the vial. This mismatch had not been identified at the very small scale but would have become a major problem in manufacture if it had not been identified by the team.


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Technology TransferIn the case study above, potential issues were encountered, even though the client did not anticipate these. This highlights the importance of a methodical and rigorous technology transfer approach. Loss of information can be a real challenge when transferring products and processes from one service provider to another. It is therefore vital that the technology transfer team plan the transfer in detail, leave nothing to chance, and involve all of the relevant parties. The team should be made up of members from all of the relevant functions, and may include the following:

Process and formulation development scientists• Manufacturing experts• Analytical development scientists• Quality assurance• Project management• Engineering

Ultimately there is no substitute for an experienced and expert technology transfer team that have devised and used a robust technology transfer process on multiple occasions.

SummaryDevelopment is an untrodden path

which can guarantee that challenges and obstacles will be encountered during

progress from early phase development. There is no one solution that will fit all of the different scenarios, as there are many different approaches to development activities.

It is possible to divide development activities between multiple partners, to best suit the immediate clinical phase needs of the project. However, such an approach, while offering apparent benefits in the short-term, is likely to increase the overall cost of the project, add additional risk to the process and inevitably add more time to the overall process through technology transfer activities.

In general, a reduction in the overall timeline will yield an overall financial benefit in the marketplace, far in excess of any cost savings during the development. Minimising the number of service providers throughout the process will offer the best chance of success by retaining product and process knowledge, reducing overall timelines, avoiding duplication of activities, and reducing risk. It will also minimise the number of contractor relationships which need to be managed, which in itself can be a drain on a company’s resources.

Whatever development approach is taken, it is vital to map out the whole of the process in advance, taking the points listed above into consideration, in order to avoid many of the common development pitfalls, by keeping in mind the overall strategic objective and thereby ensuring

the greatest chance of success n

Neil Jones - Associate Director, Market Research and Business Development Strategy of PatheonNeil started working for Patheon, at their Swindon facility, in 1999 and has held various roles within the company, including positions within Quality Control, Production Management and Business Services. Neil progressed to his current role as Associate Director, Market Research and Business Development Strategy in 2009. Prior to working for Patheon Neil worked for Hoechst Marion Roussel (now Sanofi Aventis) and Sigma-Aldrich. Neil holds a BSc. In Chemistry from the University of Bristol. Email: [email protected]

Development Approach Potential Advantages Potential Disadvantages

Small, local CDMO, tsimplified formulation

Early phase develop-ment costs may be reduced Greater flexibility “In the neighbour-hood” when things go wrong

Potential lack of scientific expertise No eye on commercialisa-tion Scalability issues

Additional TT costs

Optimal formulation at early phase

Confidence that scale-up will not be an issue

Bridging studies not required

Easier regulatory path

De-coupling from process development – which is inter-related with formulation development

Tech transfer can be costly and problematic

May need to re-formulate as a consequence of the above

Standalone formulation development

High level of scientific expertise

May be perceived as the only option for difficult to formulate entities

Stents, tissue grafts

“One stop shop” Scientific expertise retained throughout the process

Risk of tech transfer issues reduced

Building of a solid relationship

Time and overall cost to market reduced

Initial costs may appear higher Selection process can take longer

Does such a company exist?

Table 1


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Carbon Neutral Solvents in a Carbon Neutral Future Part 2: Practical Applications

This is the second part of an article proposing a carbon neutral vision for the future of the chemical industry. This vision prompts for practical steps en route to a zero carbon footprint desiderate by encouraging the strategic adoption of solvents from renewable resources.

In the first part of this article, we showed that the Kyoto Protocol provides for a globally accepted legal mechanism to reduce the carbon footprint of the chemical industry by switching from petroleum-based solvents to solvents from renewable resources1. Petroleum-based solvents generate by incineration anthropogenic CO2. Under the provisions of the Kyoto Protocol, anthropogenic CO2 contributes to the national greenhouse gas (GHG) inventories. Solvents from renewable resources are carbon neutral because they generate through incineration biogenic CO2. Biogenic CO2 does not contribute to the national GHG inventories under the Kyoto Protocol. Carbon neutral solvents provide therefore an excellent legal and regulatory hedging strategy for the chemical industry.

These ideas are not mere legal abstract concepts. They find practical support in existing carbon neutral solvents.

In the second part of this article several examples are given of carbon neutral solvents that are competing successfully with fossil-based solvents.

All these solvents are currently available from Pennakem, the leader in furan-based chemicals.

Furfural-based carbon neutral solventsThe chemical community realised a long time ago the potential to derive chemicals from vegetal feedstock as an alternative to oil, gas and coal. One of the pioneering efforts was financed by the US government as part of the WWII effort, and resulted in the industrial development of furfural-based chemicals. Pennakem is the direct descendant of this initiative, and

continues to successfully manufacture and distribute chemicals from renewable resources.

All furfural-based products have their origin in naturally occurring pentoses, as shown in Figure 1. The non-edible corncobs are transported, ground and boiled in acidic aqueous solution to generate furfural. From furfural, through reductive and oxidative processes, Pennakem obtains a full range of C5 chemicals that are used in a wide spectrum of industries around the world.

Starting from furfural one can obtain carbon neutral, protic and aprotic solvents such as 2-tetrahydrofurfuryl alcohol (THFA), tetrahydrofuran (THF)

and 2-methyltetrahydrofuran (2-MeTHF) (Figure 2). THFA is used in a variety of formulations ranging from agchem, to surface treatment in electronics manufacturing and graffiti removal.

THFA is an excellent replacement for NMP, acetone, glycol ethers and other solvents that carry risk phrases under EU legislation. THFA is easily biodegradable and can be used in water-based formulations.

MeTHF, another solvent available from Pennakem, has risen quickly from the status of an academic curiosity to one of the fastest emerging solvents in the pharmaceutical industry. Today it is poised to become one of the top 10 solvents

Corn cobs

Sugar cane

Pentoses Furfural

Food & cosmetics

FineChem

AdChem

Rubber

Figure 1: Furfural as feedstock chemical

Figure 2: Commercially available carbon neutral solvents from furfural

FurfuralCHOo

Tetrahydrofuran ecoTHF

CH3o

2-MethyltetrahydrofuranCH3o

2-tetrahydrofurfuyl alcohol

CH2OHo

Furfuyl alcoholCH2OHo

Furano


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sometime during the next decade (Figure 3)1. The global market demand proves that there is intrinsic technical and economic value in the solvent. The fact that MeTHF is also carbon neutral is simply an added benefit.

MeTHF has something to offer to all stakeholders involved in the buying decision process. To R&D it gives the opportunity to create intellectual property while improving processes. From a work safety perspective it is comparable to or better than THF, the industry-accepted norm today. From an environmental perspective MeTHF is a green solvent because it is a carbon neutral solvent and generates biogenic CO2. Moreover, it also allows a dramatic improvement in the process material intensity (less raw materials per kg of product) as well as improvement of the process energy intensity in the recycling step of the solvent. From a purchaser’s perspective, introduction of MeTHF contributes to a reduction of the solvent variable cost compared to THF. Last, but not least, due to the fact that MeTHF supply chain is disconnected from the oil feedstock, MeTHF provides a hedging strategy to wild fluctuations in the price of petroleum-based solvents.

Figure 4 shows a head to head comparison of a Grignard reaction step in THF versus 2-MeTHF. The initiation of the reaction is very smooth and reproducible, excluding the potential of having a runaway reaction. Since no excess of Mg turnings is necessary in MeTHF when making allylic and benzylic Grignards, the problem of dealing with the excess pyrophoric Mg dust is eliminated.

Much higher concentration of organometallic reagent is often possible; e.g. in the case of phenylmagnesium bromide the maximum concentration in THF is around 15%, while in 2-MeTHF one can work at around 40% w/w concentration. The dimerisation side-reaction of benzylhalides to dibenzyl is suppressed. As a result, the reaction yield is improved on average by 15% to 20% 1. MeTHF is more stable to highly acidic solutions than THF. It is also more stable to very basic reagents like alkyllithiums than THF. This gives the solvent an extraordinary versatility in a wide range of chemistries. For example, MeLi reactions can be run without decomposition of MeTHF. This stability to acids and bases provides for a better and more reproducible impurity

profile when MeTHF is used compared to THF.

MeTHF has a higher boiling point and therefore generates less VOC than THF. It also allows shortening reaction time by 50% in certain applications. Telescopic reactions in MeTHF (that is running several reaction-aqueous work-up cycles without isolating the intermediate from its solution) are common. After every aqueous work-up, the organic phase can be dried easily through azeotropic distillation of a small quantity of MeTHF. This is not possible when using THF.

In the work-up phase, MeTHF phase separates like any other organic solvent. In the THF normal work-up, one needs to add a hydrophobic co-solvent such as toluene in order to obtain phase separation. Moreover, the aqueous phase, which is a mixture of water and THF, needs to be extracted several more times with toluene in order to recover the product.

Last, but not least, MeTHF can be recycled and dried very easily by using simple distillation at atmospheric pressure.

This makes recovery of MeTHF possible even for smaller campaigns. By contrast, THF is generally not recoverable for small campaigns and is simply incinerated as a mixture with toluene.

For large volume products, such as blockbuster drugs, THF is recovered in specialised distillation plants, and the product is dried through a process called “swing distillation”. This is an energy-intensive process. The simple distillation process used in MeTHF recovery is much more energy efficient. The energy savings when we compare simple distillation for MeTHF with swing distillation for THF are around 60 to 70%.

In conclusion, MeTHF renders the process greener through vast improvements in the process material intensity (PMI) as well as process energy intensity (PEI). This ultimately leads to important cost savings.

Last but not least MeTHF is an extraordinary versatile solvent.

After Pennakem brought MeTHF to the attention of the pharmaceutical R&D community in 2004, there was a flurry of

10

20

0

25

05

15

35

30

2005

34

28

22

13

20072006 2008 Beyond 2009?Figure 3: 2-MeTHF use as carbon neutral solvent

Figure 4: 2-MeTHF versus THF comparison

Petroleum Corncobs

THF 2-MeTHF

grignard generation

grignard generation

Reaction ReactionReagent ReagentRecycled THF

Recycled 2-MeTHF

Toluene THF

C02

Toluene Water

Concentration

Filtration Filtration

Extraction Extraction

Product Product

From renewable resources

Smooth grignard initiatiaon No excess Mg turning needed No filtration of excess Mg Pyrophooric dustHigher grignard concentrations possible Higher reaction yields

Less impurities from solvents (more stable to basic and acidic pH)Faster reaction (50% cycle time) Telescopic reactions

Easy phase separation No need for co-solvent Fewer extraction steps

Easy recycling by distillation at atmospheric pressureEnergy savings (no pressure needed) Easy drying due to azeotrope with water


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publications and patents highlighting applications in nearly every conceivable field of chemistry.

Discussing the diverse chemistry recently developed in MeTHF is beyond the scope of this article, however Table 1 provides a general feel for the breadth of technical applications along with entry points in the literature.

Pennakem is also producing carbon neutral THF from furfural. Our ecoTHF (to differentiate it from the THF produced from petroleum) is perfectly interchangeable with ordinary THF. Pennakem’s ecoTHF has already been qualified and is being used or is about to be introduced as a solvent in a range of industries, such

as the pharmaceutical, cosmetics and fragrances industries.

In conclusion, ecoTHF could replace ordinary THF in any existing pharmaceutical process without facing regulatory hurdles. This ecoTHF will bring a considerable reduction in the reported GHG from solvent incineration due to its vegetal origin.

ConclusionsIntroducing strategic programs for carbon neutral solvents in the pharmaceutical industry is critical for the rapid reduction of the chemical industry carbon footprint.

CN solvents from renewable resources can reduce GHG emissions because

they generate through incineration biogenic CO2; biogenic CO2 is no CO2 for environmental reporting purposes.

For multinational companies active around the world, CN solvents represent a long-term global regulatory risk hedge

This article shows the advantages related to the use of THFA, 2-MeTHF and THF obtained from renewable resources.

In particular, 2-MeTHF is increasingly becoming a universal, carbon neutral solvent; its versatility creates an opportunity to reduce cost and carbon footprint at the same time n

Dave Aycock is s a senior research chemist at Pennakem, LLC. He has over 30 years experience in industrial product and process development of fine chemicals and polymers. He is the principal contributor that developed the technical data in support of Pennakem’s marketing of MeTHF. He holds an undergraduate degree in chemistry from the U. of Florida and a PhD from the U. of S. Florida.Email: [email protected]

Dr. Bogdan Comanita has a broad chemical industry experience spanning chemical engineering, organic synthesis and business development. He is drawing on this vast technical experience in steering the strategic and tactical marketing for various chemical and biotech companies he is involved with. Bogdan is the author of more than 40 publications, including a number of patents in Canada, US and Europe. He holds a MBA from Richard Ivey School of Business at the University of Western Ontario, a PhD degree in Chemistry from University of Ottawa and a degree in Chemical Engineering from Iasi Technical University.Email: [email protected]

Application Literature entry point

Mg/Cu• Regioselective from 1,2 &1,4

additions •Enantio, diastereoselective reactions

• B. Comanita; D. Aycock, Industrie Pharma Magazine, No.17, 2005, p 54;

W. Zhong*, Y. Wu, X. Zhang, J. Chem. Res, 2009, p 370.

Lithiation • B. Comanita, R. Aul, 2-MeTHF A Green Alternative to THF, Manufactur-ing Chemist, May 2007, p 34

Hydride based reduction • U. Lischka, A. Murso, U. Wietelmann, Chemetall, US Patent 2009/0140201

Organopalladium coupling • E. J. Milton and M. L. Clarke*, Green Chem., 2010, 12, p 381

Organonickel coupling • C. Werner, F. Platz, A. Kanschick-Conradsen, Honeywell, US 7.205,414 B2, April 2007

Organozinc chemistry • D. Aycock, Org. Process Res. Dev. 2007,11,156-159

Biphasic reactions; DCM replacement/PTC

• D. H. Brown Ripin, M. Vetelino, SYN-LETT 2003, No. 15, p 2353

Enzymatic acylation of nucleosides • Y. Simeóa, J. V. Sinisterra, and Andrés R. Alcántara*, Green Chem., 2009, 11, p 383

Haloform reaction • Minakem internal communication

Addition to nitrile • Minakem internal communication

Peptide coupling • Allessa Chemie

Table 1: 2-MeTHF applications and literature entry points


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Product Lifecycle Management: Create Value for your Product and a Future for your Company

The iPod. Compact fluorescent bulbs. Cell phones. The razor blade. What do these items have in common? All are examples of products that have been re-engineered through a manufacturing concept known as product lifecycle management, or PLM.

PLM is not new. In fact, companies have been incorporating this principle into their manufacturing and marketing efforts for decades. Simply viewed, PLM’s purpose is to better serve the current and future needs of an existing manufacturer’s customer base by improving the quality of life of the end user, adapting the product to meet the changing needs of the market and helping to achieve better outcomes. Properly executed, PLM can increase the shareholder value of a company

For pharmaceutical and biotechnology manufacturers, PLM is critical, considering the enormity of the expense, time and effort it takes to bring a drug to fruition.

Making the Most of Each ProductAlthough PLM always played a role in the modern pharmaceutical and biotechnology industry, its importance has grown over time. In years past, companies concentrated most heavily on reaping the returns on their investment and developing the next products in their pipelines as earlier patents neared expiration. Today, however, pipelines have dwindled and the patent cliff looms for many best-selling drugs. The ever-increasing expenses of development and marketing mean that companies need to get the most benefit out of already-licensed agents for as long as possible.

Market TrajectoryA new drug will typically enter one of two types of markets – non-competitive or competitive – each requiring a different strategic approach. In a non-competitive market, a drug that is first in its class requires a quick launch, to

meet patient/physician demand for a newer or better treatment and to beat potential competitors to the marketplace. However, once a drug’s patent expires, the introduction of low-cost generics turns the market fiercely competitive.

The importance of generic competition cannot be underestimated. Generics manufacturers – whether standalone firms or divisions of innovator companies – are in business to anticipate patent expirations. They have submitted their data to regulators well in advance and are ready to launch as soon as possible after the starting gun fires. Typically, by owning a period of exclusivity, the company first out of the box captures the market and collects the rewards. That is why manufacturers of branded pharmaceuticals and biotechnology drugs need to start PLM planning early – so they can anticipate the anticipators and devise a counter-strategy.

Staying Flexible to Meet Changing Market NeedsWhen to start PLM planning depends on factors like the company’s culture, therapeutic area, and the projected competitive landscape. In prior years, companies’ pipelines were robust with new and lucrative compounds that were quickly introduced to the market with very little thought given to PLM. Today, with many pipelines drying up, ever-increasing costs associated with research and development, and a far more competitive market for new products, many companies have changed their business models to focus on PLM planning as early as the clinical phase. Regardless of timing, flexibility is important. Changes in the marketplace or regulatory environment may prompt companies to reconsider a drug’s design.

As an illustration, approximately 10 years ago, US policy-makers suggested that one way to help lower Medicare costs would be for doctors to prescribe higher doses of a medication than a

patient actually needed, and then instruct the patient to split the tablets in two. But there were concerns about whether the tablets could be split precisely enough to yield two identical doses. Careful research found that some medications could indeed be split with less-than-exact precision, yet still yield two comparably effective doses. This meant that some medications theoretically could be made available in a larger, scored tablet.

This case study demonstrates that a carefully crafted PLM plan might enable a company to anticipate changing market needs and be prepared to quickly meet them – conferring an earlier advantage to the innovator.

Industry Attitudes PLM is quickly gaining increased importance in the pharmaceutical and biotechnology industry, as it can play a significant role in the success of a product. Most pharmaceutical executives agree that PLM, particularly when incorporated early in the planning process, can not only boost a product’s chances of success, but can also help save costs.

Components of an Optimal PLM StrategyPharmaceutical and biotechnology firms can use various combinations of the following PLM tactics, depending on the product and its market.

New Geographical MarketsSeeking product approvals across appropriate international markets may be the most straightforward way to extend a product’s lifecycle. To be successful, the company must incorporate a carefully honed regulatory strategy into its development process, based on in-depth knowledge of different markets’ regulatory requirements, and keep abreast of changing standards. New IndicationsUsing the same drug to treat different


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conditions allows the drug to reach entirely new markets. Recently, it was announced that a well-known wrinkle reducer is being considered for approval in the United Kingdom for the prevention of chronic migraine headaches, with a likely US approval this year.1

Product RedesignReformulating a drug can be another way to extend a product’s patent protection, as well as potentially making it more appealing or user-friendly. Take oral medications, for example, which averaged nearly 65 percent of the pharmaceuticals market (value in US dollars) from 2001– 2009, according to IMS Health. Different doses of the same tablet or capsule can be colour-coded, making it easier for both patient and pharmacist to distinguish dose strength, and potentially prevent medication errors. For tablets that some patients find taste bad or are difficult to swallow, a coated formulation can be developed, or the drug can be redesigned as a capsule. Developing extended-release formulations reduces the frequency of dosing, which not only enhances convenience but may help some patients maintain compliance with their medication schedule. For some patients, a well-scored, easily split tablet with evenly distributed active ingredient provides cost savings while not compromising effectiveness.

Features like coatings, colours and robust scoring offer an additional benefit: they are relatively expensive for the drug manufacturer to provide. That means generics firms, which compete almost exclusively on price, offer such luxuries less frequently. Coatings are rare, and scored tablets may crumble when cut without using top-of-the-line capabilities. Should the innovator company decide to take its drug generic – at generic prices

– after patent expiration, it offers value to patients that competitors would find hard to beat. The incremental costs of providing such benefits would be built into the product’s price over the lifetime of the drug.

When an innovator introduces an improved version of its drug, it does so for one of two reasons:1. To offset inevitable generic competition

with a version generics firms couldn’t afford to manufacture themselves, or

2. To offset competition by another innovator company that has a new but similar compound. The sleep aid market offers a fine example. In 2005, a new controlled release version of a popular sleep aid was launched in the US by the drug originator. Although the original version of the drug was successful and continues to be marketed, its patent was due to expire. The new version of the sleep aid is being marketed as “the first and only extended-release prescription sleep medication”. This new version has a long patent life due to the extended-release technology, and is more expensive to manufacture.

User ComfortHow a drug is administered – that is, its delivery system – is a key part of PLM. To make good choices means really understanding the current state of the market and emerging trends. Knowing a drug’s intended patient population is an important first step. Today, conditions that require long-term or chronic care are being managed more and more through homecare programmes. This suggests that pharmaceutical and biotechnology manufacturers should use the most patient-friendly formulations and drug-delivery systems possible.

Injectable drugs – which comprised

almost 25 percent of the pharmaceuticals market (value in US dollars) between 2001 and 20092 – present distinct PLM challenges. If a company first introduces a drug using a vial/diluent system, because it is the quickest way to bring a much-needed drug to the market, it may decide that switching later on to a system like a prefilled syringe or cartridge/pen will provide added benefits. For example, managing conditions such as rheumatoid arthritis and diabetes increasingly requires that patients self-administer their medications.

Another example of patient-friendly packaging is the dual-chamber syringe, which allows lyophilised drug to be packaged along with its diluent. Such a system allows the end user, whether patient or caregiver, to reconstitute and administer the drug with one push of the plunger, rather than needing a clinic-based nurse to mix and inject it. The system may also help prevent medication errors by providing an accurate prepackaged dose.

Other enhancements to injection systems, such as anti-needle-stick features and anti-counterfeiting measures, also benefit the patient.

Following Technical and Marketplace DevelopmentsTo manage a product’s lifecycle as effectively as possible, a company needs to apply technological and marketplace insights, which requires following key trends, including:

The demographics and characteristics of the target patient population, along with their needs and preferences

Whether a drug is likely to be administered in the home by the patient or family member, or in a clinical setting by a healthcare professional.

Adapting a PLM strategy quickly

Market situation at time of launch

Options

Non-competitive market

• Significant need for medication

• No competitive drug on the market

Launch first-in class product as quickly as possible• Introduce simple

administration form first• Develop alternative versions

in parallelProduct lifecycle management Competitive

marketEstablish unique selling point(s)• Cost • User-friendliness, e.g.,

• Coatings • Colors • Extended release • Auto-injection/pen • Dual-chamber syringe

• Improved molecule

• No urgent need perceived for this version of medication

• Competitive drugs already on the market

Figure 1: Introducing a new drug will require one of two approaches, depending on whether the therapeutic market-place is non-competitive or competitive. In either situation, early product lifecycle management is important to long-term success.


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in response to new marketplace developments is one key to long-term product success.

Pricing StrategyRegulation and price are tightly interwoven. Governments are continually looking for ways to increase quality of care while reducing costs. Staying on top of pricing trends and concerns among regulatory bodies is critical. Even in countries such as the United States that have no formal cost controls in the private market, they exist nevertheless. Whether governments or insurance companies impose controls, pharmaceutical and biotechnology firms must prove their product worthy to be put on formulary for reimbursement.

Pricing strategy is key to any PLM plan. Points to consider:• Is the product novel?• Does it improve management of the

disease it’s meant to treat?• Does it offer advantages over existing

products? • How urgent is the need for the product,

and for how many people?• Is it best to seek a premium price, due

to the need and utility of the product, or to price it competitively with other, lesser products, to make quick inroads into the market?

Robust scientific and carefully designed pharmacoeconomic studies will help

convince regulators and purchasers that the product is priced appropriately. An auto-injector, for example, may cost more per unit than less sophisticated systems. But if a patient can inject herself at home, rather than racking up expensive office visits, or can avoid a hospitalisation because prefilled dosing prevents medication errors, the more advanced technology may demonstrate cost savings (this argument is particularly challenging when publicly traded insurance companies feel pressure to show quarterly rather than long-term results to justify their financial decisions to shareholders).

Maintaining Both a Short and a Long View for Successful PLMTo maintain a drug’s clinical value – and marketplace profitability – pharmaceutical and biotechnology companies should incorporate PLM into their products’ development from the earliest point possible. Waiting until competing products have reached the market will be too late and will shorten a drug’s viable commercial life. Easier, safer, more patient-friendly dosing, packaging and administration can be achieved only by carefully planning. These advantages position the company to continue to market a beneficial product while developing its portfolio and pipeline.

Finally, don’t underestimate the power of a trusted brand name. Patients who do

well on their drugs don’t want to switch to a no-name generic. Securing customer loyalty will serve companies well that decide to take their branded drug generic post-patent. Marketing strategy is an

integral part of an effective PLM plan n

References1. “U.K. Approves Botox for Migraines,”

The Wall Street Journal, July 9, 2010, http://online.wsj.com/article/SB10001424052748704075604575356900330525706.html?mod=djemHL_t

2. IMS Health

Max Horn has been a Managing Director of Vetter Pharma-Fertigung GmbH & Co. KG since November 2002. He joined the company in 1981 after graduating from the German Academy of Business and Administration in Ravensburg, taking a position in the finance department. Four years later, he became head of the department and in 1993 assumed the position Director of Controlling. Max Horn was named Vice President of Controlling in 2000.Email: [email protected]

Making products more user-friendly can be part of an effective PLM strat-egy. Pictured below, the dual-chamber syringe holds the lyophilised active drug in one of its chambers, the other the diluent. The contents of the two chambers are combined directly before administration. This all-in-one concept increases dosage accuracy and ease of administration for the end user, whether patient or caregiver.

COMPANY PROFILE Dr.C.SOLDAN® GmbH

We develop, produce and market high-quality products for health and well-being. By using natural raw materials and ensuring our products live up to the highest standards of quality, we satisfy people’s need for a sense of well-being and security, and for healthy treats.

History1899 Medizinal-Drogerie (medicinal drugstore) established on

Hefnersplatz in Nuremberg by pharmacist Dr Carl Soldan1923 Em-eukal® cough drops first available as

Eucalyptus Cough Drops ‘with the flag’.1928 Official market launch of Em-eukal®

1960 Opening of production site in Adelsdorf1972 Innovation: First cough drop for children!

Mild vitamin sweet called Kinder Em-eukal®

1989 Development of sugar-free sweets using the sugar substitute ISOMALT

2004 First sweet manufacturer to offer: Sugar-free sweets with the sweetener SUCRALOSE

2005 Change of generation: Company management assumed by Perry Soldan; family-owned company in fourth generation

The all-round feel-good sweets specialist• More than a century’s worth of experience and a pool of

over 1000 in-house recipes built up over the years• In-house laboratory staffed by pharmacists and food chemists• Pharmaceutical manufacturing licence for GMP-

compliant production of medicines• Manufacturing according to GMP guidelines (Good

Manufacturing Practice ~ DIN ISO 9000 ff.)• Manufacturer of Organic products• Premium brands with 100% taste made from natural raw

materials and ingredients of the highest quality

Diverse product portfolioBoiled sweets • With and without sugar• Unfilled or filledCough drops • With and without sugar• Gelatine, pectin or gum arabic-basedgenuine Bavarian malted sweets• Traditionally boiled over an open fire • Broken up into pieces Many years of experience in manufacturing speciality sweets and pharmaceutical preparations. Particular strengths:• Manufacturing cough drops and herbal sweets• producing sugar-free products• Enriching products with vitamins and minerals

Own famous brandsEm-eukal® – “The all-round feel-good sweet”These soothing sweets with the traditional Em-eukal® formula have an unmistakable taste and are available in flavours such as lemon and wild cherry• Natural protection against coughs and sore throats• Natural balsam for throat and voice• Naturally refreshing• For naturally fresh breath

Kinder Em-eukal® range • Kinder Em-eukal® – Helps and protects naturally for kids of all ages • the popular wild cherry Kinder Em-eukal® vitamin cough drops, • as great tasting sugar reduced multivitamin jelly sweets • as compressed dextrose multivitamin tablets• always with 5 carefully selected vitamins

Contract Manufacturing:Dr. C. SOLDAN® has been producing goods in partnership with major players in the pharmaceutical industry and on the retail market for many years. We have a wide experience in the production of speciality sweets and pharmaceutical preparations.

We use high-quality ingredients to produce sweets in a variety of product categories.

Talk to us about your needs and requirements. We would be delighted to advise you in respect of the wide and varied production options we can offer. Production • Pharmaceutical manufacturing licence in

accordance with the German Medicines Act • Production in accordance with GMP standards • Highest standards in terms of quality and laboratory services

thanks to permanent quality assurance and control • Process and product validation • Creation of manufacturing documentation

Service • Recipe development and application engineering advice • Flexible production of manual and automated samples • Cost-effective procurement of raw materials • Logistics optimised in terms of cost • Analytical studies • Experience marketing and agency services

for the ideal packaging design

Packaging • Bulk (wrapped and unwrapped) • Bag filling • Folding boxes – with or without inner bags • Boxes • Flip-top boxes • Other types of packaging on request

ContactDr.C.SOLDAN® gmbHPharmazeutische Präparate + Bonbonspezialitäten Em-eukal Werk Eric MaurerContract Manufacturing and Export DirectorHerderstraße 5-990427 Nürnberg, Germany

Phone: +49 (0) 91 95-8 08-643PC-Fax: +49 (0) 91 95-8 08-36 43 Mobile: +49 (0) 1 75-2 91 63 58E-Mail: [email protected]

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Safe Products and Technologies for the Pharmaceutical Industry – Optimising your Manufacturing Process, Drug Formulation and Drug DeliveryToday’s pharmaceutical industry is witnessing a shift towards biopharmaceuticals, as innovative biological therapies become an increasingly important branch of the healthcare sector. Between 1990 and 2006 the compound annual growth rate (CAGR) of the pharmaceutical industry was 12%, with biophama 20%, and small molecules 11%. From 2006 to 2015 CAGR will have reduced to 3% for the industry overall, with biopharma 12%, and small molecules only 1% of growth. With an estimated 30% of all drugs under development in the biopharmaceutical sector, and a market size of $203 billion USD by 2015, this industry is becoming an increasingly important player in the global economy.

Nevertheless, there are economic challenges facing the biopharma industry. An increasingly ageing population creates pressure to provide improved healthcare in a timely manner and at reduced costs. This demographic shift has potential to create new markets, but also encourages the introduction of new lower-cost competition such as biogenerics. With a new therapeutic typically taking eight to 12 years, at an average cost of $1.2 billion USD, many small to medium biotech companies struggle to bring these molecules to market due to cost pressures. Companies are being forced to re-examine their product pipeline with the increasing cost of development, demanding regulatory requirements across the product lifecycle, and uncertainty of global market share.

Current requirements of the biopharmaceutical industry are to provide affordable and accessible healthcare at reduced timelines, through investment in innovative and accessible technologies. Many companies are investigating single platform technologies to produce multiple drug products, thereby reducing process development

and commercial manufacturing costs, while reducing product timelines and regulatory requirements. Due to these enhanced regulatory requirements, the development of animal-free recombinant products and technologies to ensure process consistency and drug purity, and to enhance safety profiles, has also emerged as a crucial inclusion in the biomanufacturing process.

Addressing Biomanufacturing ChallengesNovozymes, a world leader in microbial protein expression, with over 700 key products across 40 industries, and a patent portfolio numbering greater than 6000, has applied its recombinant know-how to the needs of the biopharmaceutical industry in the biomanufacturing, process development, drug delivery and medical device sectors for over 25 years. Through innovative animal-free products and technologies that ensure consistency, security of supply and regulatory compliance, these technologies provide the biopharmaceutical industry the opportunity for faster product development and cost reductions across the product lifecycle.

Products Designed for the ProcessMammalian-based expression systems continue to dominate as the production platform of choice for biotherapeutics manufacture. Over the last decade there has been a shift away from the use of serum and other animal-derived media components, to chemically-defined serum-free media in the upstream manufacturing process. The key driver for this shift was primarily regulatory concerns of contamination of the final drug product with animal-derived adventitious agents. However, lot-to-lot variability and security of supply, resulting in lack of process consistency, also played a role.

Development of animal-free recombinant protein supplements such as albumin, transferrin and growth factors

are an example of Novozymes’ response to industry needs. Scientifically proven and manufactured exclusively for the cell culture industry, these recombinant products are manufactured to the highest quality standards, ensuring upstream manufacturers’ process consistency with optimal performance.

The supply of growth factors to serum-free media (SFM) is essential for the growth of many cells in culture. Traditionally, recombinant insulin has been the universal supplement supplied to SFM to enhance cell growth and productivity. However, due to its activity being directed primarily through the activation of the IGF-I receptor (IGF-IR) rather than its own insulin receptor (IR), insulin is generally required at supraphysiological concentrations to support cell growth. Development of the insulin-like growth factor analogue, LONG R3IGF-1, that acts directly and at a much higher potency on the IGF-IR, has been shown to be equivalent to, or to outperform, insulin and IGF-I in supporting CHO cell growth and productivity.

Iron is another factor required by industrial cell lines such as CHO and NSO to attain optimal cell growth and productivity, and is essential for cell growth in the regulation of key metabolic processes such as DNA synthesis and oxygen transport. Transferrin has historically been one of the most effective methods for delivery of iron into the cells, and has most commonly been available in the form of serum-derived purified human transferrin (hTf) or bovine transferrin (bTf). Novozymes’ rTransferrin, expressed in Saccharomyces cerevisiae, is a recombinant analogue of human transferrin and has shown equivalence to hTf and superiority to bTf in stimulating cell growth and productivity across a number of cell lines. Supplied as human holo-transferrin, rTransferrin binds specifically to the transferrin receptor, facilitating iron uptake into the cell for maximal cell culture performance.

Requirements for albumin in cell


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culture vary depending on the cell line; for example, the myeloma cell line, NSO, lacks the functional pathway for cholesterol synthesis and, therefore, requires cholesterol. Albumin has been used as a carrier of cholesterol, although cyclodextrins have been used as alternative carriers of cholesterol and other lipids in culture media. Recently, recombinant animal-free forms of albumin developed by Novozymes have become commercially available for both industrial and specialised cell culture applications. Recombinant albumin (rAlbumin) potentially delivers many benefits in cell culture, including the maintenance of osmotic balance and interaction with lipids or other bioactive factors which can influence the growth and performance of cells in culture.

Post-Production Improvements DeliveredBiomanufacturing challenges can also be encountered following manufacture of the drug product, where protein stability and reduced efficacy due to poor drug half-life and bioavailalbity of the drug substance can be major concerns. These factors can lead to unstable drug concentrations in the patient, which may result in unwanted side-effects or increased dosage regimes. Albumin is a natural carrier protein with a typical half-life of 20 days. Novozymes’ albumin fusion technology allows the coupling of the drug product to albumin for improved half-life and increased efficacy. Expressed in yeast to cGMP/Q7 quality guidelines, this proprietary technology allows for single-step expression of the fusion molecule, requiring no external coupling procedure. The technology has been shown to improve drug stability and ease associated downstream purification procedures to provide significant cost savings to the manufacturer. Enhanced stability of the drug substance with increased half-life also ensures more cost-effective treatments and reduced dose size, thereby limiting the likelihood of drug toxicity and improving patient compliance. Importantly, this yeast-based albumin fusion technology is free of animal-derived products, therefore also addressing the increasing regulatory requirements within the industry.

The occurrence of protein instability and degradation is not limited to the time after the drug is administered, but can occur during manufacturing, transport, and storage, where the protein therapeutic can also be exposed to a variety of stresses. Protein instability can be the result of either

physical or chemical degradation, and with the potential to increase the immunogenicity and decrease efficacy and shelf-life of the protein drug product, protein stability is a key issue in the final product.

To protect against degradation, protein therapeutics are commonly formulated with excipients, providing the product with an acceptable shelf-life for storage and shipping. Human serum albumin (HSA) has been used as an excipient in a number of therapeutic protein formulations such as erythropoietin, antihemophilic factor (FVIII), and interferon beta-1a. As the most abundant protein in human blood, the potential for HSA to elicit an immunogenic response is minimal. However, due to regulatory concerns over risk of blood-borne contaminants such as prions or viruses contaminating these animal-derived products, biopharmaceutical manufacturers have moved away from its use in drug formulation.

Recombinant human albumin (rAlbumin), expressed in Saccharomyces cerevisiae and manufactured to cGMP, has demonstrated its ability as an excipient to prevent or minimise physical and chemical degradation of drug substances in

various test formulations, including small molecule and vaccine formulations. Used in the manufacture of an FDA- and EMEA-approved childhood vaccine (M-M-RTM II form Merck and Co) rAlbumin is a proven excipient in drug formulation. rAlbumin also has proven applications in numerous biomedical fields, including use as a bulk drug or device manufacturing ingredient, advanced cell therapy products, IVF medium and medical device coatings.

Unique Technologies Provide Biomanufacturing SolutionsHyaluronic acid (HA), one of the most-used human biomaterials, has a wide range of practical applications from cosmetics to pharmaceuticals. Despite this, HA currently on the market is generally derived from animal-derived sources, such as rooster comb, or expressed in Streptococcus, which is naturally pathogenic. Novozymes Biopharma has developed a new hyaluronic acid, produced by fermentation of the safe bacterial strain Bacillus subtilis. The fermentation process is environmentally friendly and safe, not requiring any organic solvents in the recovery of HA during production, and is free of animal-derived


MANUFACTURINg

components. Moreover, Novozymes HA is characterised by a well-controlled and reproducible molecular weight, and exhibits advantageous formulation properties. Effective across a wide range of administration routes and providing unique advantages in topical, intra-articular, intraocular and intravenous drug delivery, HA is an important drug delivery tool.

Due to its native intrinsic biocompatibility, resorbability, diverse biological functions, and the possibility for an easy chemical functionalisation, HA constitutes an excellent starting material for the design of advanced biomaterials. As an example, Novozymes has developed a proprietary technology to chemically cross-link HA to form a hydrogel. The cross-linked material exhibits strong mechanical properties and is resistant to the degradation by hyaluronidases, making it potentially advantageous for subcutaneous and intra-articular drug delivery. Drug release can be controlled by controlling the cross-linking degree. This cross-linking technology could also be used for topical dermal delivery of drugs.

In addition to its application as a broad spectrum biomaterial, Novozymes HA

also delivers a unique range of production benefits, including improved heat stability, faster dissolution time, longer shelf-life, and smaller particle size, with consistent and stable molecular weight. These optimal product properties give the manufacturer confidence to address their formulation requirements.

Innovations for Future GrowthThe biopharmaceutical industry has become an increasingly important player in the global economy, with continued success dependant on the development and implementation of cost-effective, robust and scalable production processes. To meet these requirements, the industry must address regulatory concerns in addition to process and product efficiencies, which have the potential to translate to cost reductions in the manufacturing process. Through developing industry partnerships, continued dialogue, and awareness of our customer’s challenges, Novozymes has developed recombinant technologies and products across the biomanufacturing product lifecycle that will drive these efficiencies and deliver optimum process

performance n

Sally grosvenor is the Scientific Communications Manager for Novozymes Biopharma Australia. Sally graduated from The University of Adelaide, 1989(B.Sc Hns) where she majored in Biochemistry. She was Senior Scientist at Gropep Ltd in Australia for 10 years where she specialized in the area of gene expression and fermentation technology. As scientific communications manager at Novozymes Biopharma Sally has published numerous articles relating to upstream media development for cell culture applications, particularly at industrial scale. Currently, Sally is studying Scientific Communications at the University of Queensland.Email: [email protected]

COMPANY PROFILE

RoviCM & Rovi Alcala offers contract manufacturing services in a wide range of pharmaceutical forms, including prefillable syringes and vials, suppositories and tablets.

Prefillable syringes and vialsWith more than 15 years of experience, RoviCM specialises in filling and packaging parenterals in prefilled syringes and vials. All syringe formats are available from 0.5ml to 20ml.

Syringes and vials are filled under aseptic conditions in sterile areas. If needed, terminal sterilisation can be performed in our brand new counter-pressure autoclave.

The quality of pharmaceutical products manufactured is guaranteed by compliance to the strictest international guidelines.

Safety device assembly equipmentIn many countries, safety legislations are making the use of integrated protection systems mandatory in order to minimise the risk of accidental needle contact.RoviCM offers to assemble safety devices on prefilled syringes with new fully-automatic assembly equipment, operating at 21,000 units per hour.

Water for Injection in prefilled syringes (WFI)RoviCM also provides water for injection (WFI) syringes in different sizes and volumes. A common technical dossier (CTD) module 3 and a Drug Master File (DMF) can be offered to our WFI customers at no extra cost, in order to facilitate the registration process.WFI is produced following European Pharmacopoeia and US Pharmacopoeia requirements.Syringes types and volumes:• 1ml filled at 0,5ml• 1,25ml filled at 1ml• 3ml filled at 2ml• 10ml filled at 5 and 10ml• 20ml filled at 15 and 20ml

SuppositoriesRoviCM also have facilities for producing and packaging suppositories in aluminium blister.

ADvERTISEMENT

One of the largest FDA approved plant for solid forms in Europe Rovi Alcala also provides contract manufacturing services with a new production site specialising in the manufacturing, testing and packaging of solid oral pharmaceutical dosage forms

This plant has been manufacturing and packaging pharmaceutical products since 1969 as a Merck Sharp and Dohme site, with high compliance and a history of productivity and performance

ComplianceTo provide access to all markets our plant is GMP and FDA approved. We also hold Japanese, Mexican, Brazilian and Gulf Countries approval

TechnologyIn an 83,000m2 terrain, facilities include:

Formulation Areas• Lowest production costs with our

large capacity Roller Compactor process train (dry granulation).

• The highest quality solid forms through our High Shear and Low Shear granulation systems (wet granulation), including fluid bed drying, milling and ribbon blending.

• Planetary mixers• Different compression bays

for direct compression and granulation compression

• Film coating is also available.

Packaging Areas:• Different high speed blistering lines,

flexible blister lines and flexible semiautomatic lines providing capability for Alu-Alu, PVC-Alu, PVDC-Alu and blistering.

• Cartoning, labelling, marking, overwrapping and casepacking capability for every packaging line. Every line is equipped with high tech vision system capability.

• Sacheting, casing, cartoning, labelling, marking, overwrapping and casepacking lines.

Oral Solid Dosage and Raw Materials Testing Area:• Brand new quality lab constructed

in 2005 in a separate building (4.600 m2) which include Microbiology lab, Chemistry lab and Quality Assurance offices.

A complete service: production - testing - packaging and storage• Huge total and free capacity available

to comply with medium to very large production (global capacity 3.000 Million tablets/year).

• From batches of 100 kg up to batches of 1.000 kg

• Flexible and/or large volume packaging available Datamatrix.

• A top class laboratory to provide quick and reliable results.

• Simplified storage management through our large size warehouse (6000 pallets) which includes a cold room (2 to 8 C°) of 400 pallets.

• Integrated management system including:6 sigma, Lean manufacturing, 5S, Visual management, Lean management and QMS (Quality Management System).

Rovi Contract Manufacturing & Rovi Alcala ContactsC/Julian Camarillo, 3528037 Madrid, SpainTel: + 34 91 151 99 11Fax: +34 91 754 17 [email protected]


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HCPC Europe’s 5th Annual Conference on Patients’ Adherence/Compliance AbstractHCPC Europe, a not-for-profit organisation whose mission is to assist and educate the healthcare sector in the improvement of patient compliance through the use of packaging solutions, invites participants to its annual conference, which this year will take place at the Millennium Hotel in London on November 3 and 4. The conference focuses on the return on investment of innovative compliance/adherence-enhancing medicinal packaging, as well as the benefits for patients, the healthcare system and the pharma industry. Heneghan, Glasziou and Perera found in their study about the role of packaging with regard to long term medicinal treatment that: “People often miss taking prescribed medication, because of forgetfulness, changing medication schedules or busy lifestyles. It is estimated that between 40% and 60% of people do not take medication as prescribed, which can lead to worse health outcomes. Packaging of medications with reminder systems for the day and/or time of the week is an attempt to help people take long-term medications.”1

While it will be difficult to influence some of the causes for non-compliance/adherence, the main factor – forgetfulness – can rather easily be dealt with. Calendar drug packages, or innovative packs incorporating a chip with reminder functions, capable of communicating with a central database, are commercially available and designed to help patients to adhere to their therapies.

An essential element of the conference is an award for novel pack design for supporting patients’ adherence to medicinal therapy. The jury consists of members of HCPC Europe’s advisory board, and the board will have to decide between a large number of entries encompassing creative low-cost solutions as well as most sophisticated high tech drug delivery systems/packaging.

HCPC-Europe’s 5th Annual Conference on Patients’

Adherence/ComplianceEveryone involved in patient care, including the patient himself, loses when a prescribed medicinal therapy is discontinued early, instead of continuing with the medicine for the intended period of time, which is often meant to be lifelong. The patient who stops taking the medicine is deprived of its therapeutic benefits. The third party payer may save some money on drug costs, but incurs whatever added costs arise from the absence of the drug’s therapeutic effects, plus costs that may arise if the discontinuation escapes clinical recognition.

The European HCPC a not-for-profit organisation whose mission is to assist and educate the healthcare sector in the improvement of patient compliance through the use of packaging solutions, was set up between the pharmaceutical, the packaging and the machinery industries with the assistance of patient organisations, driven by the awareness that healthcare systems are losing enormous sums of money through medication that is taken improperly or not at all. Thoughtful packaging of medicines, the founders and members of HCPC Europe argue, can in itself play a significant part in patient compliance and, by organising as a body, HCPC Europe can be effective in promoting packaging-related initiatives which will help improve patient compliance.

New models for cost coverage of medicines underline the importance of HCPC Europe’s initiatives. Last year’s conference, which took place at the Basel City facilities of the Institute of Pharma Technology at the FHNW School of Life Sciences in Basel, Switzerland, concentrated on a Voice of the Patient survey carried out by HCPC Europe and the European Patients’ Forum (umbrella organisation of European patients’ organisations representing 150 million patients). This year’s conference,

scheduled to take place on November 3 and 4 at the Millennium Knightsbridge Hotel in London, will focus on the implementation and commercial use by the pharmaceutical industry of the many clever ideas presented for the Columbus Award, ranging from low-cost solutions using conventional technology combined with clever design, to highly sophisticated electronically-assisted drug delivery systems. And as in previous years, HCPC are again expecting many exciting and innovative entries for the Columbus Award 2010.

Top experts in the matter of healthcare will discuss the benefits of improved patient compliance and how it can contribute to more effective use of medicines and to better outcomes. At the Conference in Basel last year, Steve Richmond, head of global packaging at AstraZeneca, addressed “The Value of Packaging to Patients” and underlined the importance of making drug packaging part of the treatment. “To be the industry leader in serving patients and delivering value, AstraZeneca is embracing change in a world that is changing faster than any time before. Improving patient compliance is at the same time a challenge and a huge opportunity, and the task is clear: assist patients to remember to take their medicine. A large number of aspects need to be considered like portability, sustainability, aesthetics, the way of presenting information etc.” He concluded: “solutions are available. They just need to be implemented.” Andrew Degnan, Process Development Manager at Chesapeake Pharmaceutical and Healthcare Packaging, stated that a market pull was needed to meet the technology push in order to get these innovations implemented.

This is where the conference in London is precisely aimed at. Patients have often expressed their concerns about pharmaceutical pack design, and that their needs and requirements were too often neglected. In particular, those


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whose non-adherence to their therapy could potentially be life-threatening wish to get more support, and complain that their requests regarding compliance-enhancing packaging are met insufficiently or not at all. The community of chronic myeloid leukemia patients has a great deal of experience in this. Jan Geissler, part of this community and Director of the ECPC - European Cancer Patient Coalition considers packaging “a very important topic [which] I have quite a strong opinion on. For example, some oral cancer drug manufacturers are currently switching to bottles, which is a nightmare in terms of compliance/adherence. Some do blisters of 10 pills which never divides well on a seven pills/week schedule. Cardboard blisters are troublesome to remove single pills, and often damage the whole blister when trying to remove one pill. So there are issues,” he argues.

HCPC Europe serves as a platform for patients to make themselves heard. At the same time it is a forum for packaging engineers and pack designers to learn about innovative solutions which are designed to help patients in their medicinal regimens, and a place for executives of the pharmaceutical industry to liaise with peers about their experiences and the benefits of enhanced adherence.

Simon Exell, Merck Serono International (CH), will speak about Adherence Monitoring in Chronic Injectable Therapy

Dr Kamal Mahtani BSc PhD MBBS, University of Oxford (UK), will tell the audience about the effectiveness of Reminder Packaging for Improving Adherence to Self-Administered Long-Term Medications

Søren Skovlund, Novo Nordisk (DK), will explain why the pharmaceutical industry has an interest in improving patients’ compliance

Dr Isabelle Moulon, Head of Medical Information, European Medicines Agency (UK), will give an insight as to how pharmaceutical packaging can benefit patients and the healthcare sector from an EMA perspective

Sandy Craine, CML Support Group, European Cancer Patient Coalition (UK), aims to influence and effect real change in healthcare policy at both a national and a European level. She will share her experience of why patients might not be compliant/adherent

Peter Behner, Vice President at Booz & Companies (DE), one of the leading consulting companies in the world specialising in healthcare matters describes ways to enhance Patient

Treatment Compliance with Product Specifications

The Conference will also include a declaration from the following Directors and members of the Board of HCPC-Europe about the future strategy how to encourage the industry to implement innovative solutions designed to assist patients in their therapies.

These include: • Phill Marley (Packaging Account

Manager, AstraZeneca, Global Operations (UK))

• Norman Niven (CEO, Protomed (UK))• Chris Johnson (VP Alliances and

Marketing, Cypak (SE)) Chair, 11073-104772 Medication Monitoring ISO/IEEE Vice Chair, Continua Marketing

At the end of day two the Columbus Award will be given to the company presenting the best and most effective new pharmaceutical pack.

We are all working together to set the agenda for change in managing patient compliance throughout Europe.

Tassilo Korab is Managing Director of TKM Handelsg .m.b.H., Vienna, Austria, a consulting company in the sector of Flexible Packaging for the pharmaceutical and healthcare industries. He was one of the co-founders of HCPC-Europe, the Healthcare Compliance Packaging Council, a not-for-profit organization uniting the pharmaceutical industry, packaging materials suppliers, packaging machine manufacturers and patient organisations in their common endeavour to improve drug packaging design in the interest of the patients. He has been representing the organization first as founding member and member of the board and, since September 2005, as Executive Director. Email: [email protected]


LABS & LOgISTICS


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Child-resistant packaging Offering safety, security and convenience

“Children are curious and are risk takers. They have lots of courage. They venture out into a world that is immense and dangerous. A child initially trusts life and the processes of life.” John Bradshaw, philosopher, counsel, theologian and teacher

Medicinal drugs are the leading cause of non-fatal poisoning in children in middle-income and high-income countries. Young children are particularly susceptible to the ingestion of poisons, because of the inquisitive nature of a young child. They are more likely to put items in their mouths and often are unaware of the consequences. Younger children are more susceptible to poisoning because of their smaller size and less well-developed physiology.

Further, children tend to associate the shapes and colours of medicines, such as tablets and capsules, with those of sweet-tasting candy and chewing gum. Sweets and chewing gum are often sold in blister packs similar to those of medicines, thus children may correlate blisters with something positive and edible.

Only at the age of three are many children able to understand rational reasons about the dangers involved with pharmaceutical products. At age three they are more willing to accept a “no” and follow educational advice and simple safety rules to avoid ingesting poisons. From this point on, educational measures become increasingly important. This is why around 90% of all accidents involving the swallowing of alien substances happen with small children at the ages between 10 months and 4 ½ years old, with a significant peak for children aged 1 to 2 ½.1

Among the most common agents involved in childhood poisoning are over-the-counter preparations such as paracetamol, cough/cold remedies, vitamins and iron tablets, antihistamines and anti-inflammatory drugs, and prescription medications such as antidepressants, narcotics, analgesics

and illicit drugs2. In England and Wales, during the period

1968–2000, medications accounted for 12.8% of unintentional poisoning deaths in children aged less than 10 years3. In the United States, in 2003, some 570,000 pharmaceutical exposures were reported in children less than six years old - 23.8% of all poisoning reports4. Additionally, more than 50,000 children under the age of five years were treated in emergency rooms for an unintentional exposure to medicinal drugs.

There are many tactics that can be employed to try and reduce the number of accidental consumption cases of pharmaceuticals by children. It takes a joint effort from parents and caregivers, governments, consumer groups, non-governmental organisations, and of course a special focus by the producers and retailers of the pharmaceutical products, including the engagement of the entire supply chain.

Legislation and enforcement of child-resistant packaging is one of the best-documented successes in preventing the unintentional poisoning of children5. The Pharmaceutical Association of Great Britain (PAGB) has been investigating accidents at home for many years, and has found that poisoning accidents of children during the period 1982 until 1998 have decreased by 33% for all children, and by more than 50% for children under five years of age. In this same period, the proportion of non-reclosable pharmaceutical packages has been increasing tremendously6.

The history of child-resistant packages started in the United States with the Code of Federal Regulations Part 1700 to 1750, subchapter E: “Poison Prevention Packaging Act (PPPA), 1970 regulation”. This legislation introduced the concept of having packages tested by children and adults. The effort by the US was soon followed by more countries which introduced standards and legislation with regard to child-resistant packages (both reclosable and non-reclosable).

United States 1970Canada 1975Germany 1979Italy 1984Australia 1985The Netherlands 1985United Kingdom, BS7236 CoP 1989United Kingdom, BS8404 2003EN 14375 2003Korea 2007

According to the EN 14375, child-resistant packaging is defined as a “package which complicates opening (respectively access to the content) for small children but facilitates appropriate usage by adults”.

The unregulated packaging and distribution of medicines in sachets and containers that are not child-resistant increases the ease with which children can gain access to them. Child-resistant packaging means safety, security and convenience to prevent children from gaining access to medications, all while considering the functionality for adults and senior citizens. The challenge is developing packaging that is difficult for children to access, but allows ease of use for senior citizens.

The development of a package is influenced by the age-specific abilities and difficulties of the user. The difficulties and abilities of children and adults are reciprocal (Table 1). The standard for the testing of child-resistant packaging adopted in most countries requires that at least 85% of children aged from 42 to 51 months must be unable to open the container within five minutes, and at least 80% must fail to open the container in the five minutes following a non-verbal demonstration. Standards for CR/SF packaging also considers process testing of senior adult user-friendliness.

Pharmaceutical companies have many requirements for their CR/SF packaging, beyond meeting the regulatory standards. CR/SF packaging must be cost-effective and should be feasible at high volumes

AMCOR: ABOUT USAmcor Flexibles Global Pharmaceutical offers customers an unmatched range of packaging solutions that respond to the unique needs of the global pharmaceutical marketplace for end uses such as tablets, powders, gels, liquids, granulates, creams and devices. We hold unmatched expertise in high barrier material and help customers succeed by providing a broad range of concept-to-market capabilities supported by extensive global resources.

As the new Amcor, we offer an expanded range of packaging solutions, new technologies and increased production capacity with a wider geographical presence and greater expertise. Our enhanced product offering includes the greatest selection of packaging options that span across multiple formats, dosage forms and user requirements with proven expertise in areas such as: • Unit dose • Child-resistant • Senior-friendly• Patient compliance • Anti-counterfeiting• Sustainability

FOCUS ON CHILD RESISTANT SOLUTIONSAmcor offers a wide variety of CR/SF packaging solutions including blister pack lidding (peelable, peel-push and tear-open varieties), pouches, sachets, SafeStick™ stick packs and blister cards. Amcor invented Guardlid® one of the first child-resistant blister lidding material, and as a result can offer knowledgeable application advice.

Working closely with customers, regulatory bodies and machine manufacturers, Amcor strives to continuously improve upon existing specifications and develop new ones. Standard specifications within each of Amcor’s packaging formats have been developed to meet American regulatory standards and the European EN 14375 and BS8404 standards. This includes the proper puncture-resistance testing and also barrier properties in relation to moisture vapour transmission rate (MVTR) and oxygen transmission rate (OTR).

FOCUS ON N’CRYPT® PHARMA SECURITY SOLUTIONSN’CRYPT® Pharma Security Solutions represents an innovative and proven approach in delivering patient safety, supply chain integrity and pharmaceutical brand protection. The program is built on 3 pillars of competence: 1. A security-enhancing process workflow that is aligned

across three dedicated supply sites 2. An industry-leading range of validated overt, covert and

forensic security solutions that have little or no impact on a customer’s packaging line performance

3. Proven excellence and expertise in integrating new security technologies for pharma applications

The proliferation of counterfeit medicine has indeed become a matter of global significance. The World Health Organisation and national governments alike are actively progressing legislative measures to enhance patient safety via supply chain and authentication technology.

Amcor can offer competent advice on how packaging can help address brand protection needs. The company began in the mid 1990’s developing the N’CRYPT® portfolio of anti-counterfeit products and services. Today, the N’CRYPT® brand has successfully established a premier security supply pedigree across our market leading range of pharmaceutical packaging materials.

FOCUS ON THERMOFORMABLE FILMSAmcor’s thermoformable film offering is a total packaging solution for the rigorous pharmaceutical and medical marketplace. Amcor is an approved healthcare converter of Honeywell’s Aclar® brand to create a material ideal

for products highly sensitive to moisture and can be combined with other substrates to provide oxygen protection. Polybar-Aclar films offer clarity, which allows for easy determination of the product for compliance packages, product identification and quality. Aclar is often laminated to a white opaque film to offer child resistance. Polybar-Aclar is non-yellowing and no special storage conditions are required. It can be used on existing PVdC tooling and is available with a variety of substrates (clear and opaque).

Also within the Polybar brand of thermoform films, Amcor offers COC (Cyclic Olefin Copolymer). This material is ideal for mid-range moisture sensitive products. Polybar-COC is halogen free and can be a solution for non PVC initiatives. COC is available in a wide variety of contact surfaces including PP, PETG and PET. The film offers excellent yield and has very good crush resistance. COC is non-yellowing and requires no special storage conditions.

Amcor has added PVdC to the Polybar family of films. PVdC coated films offer mid- to high-range moisture and oxygen protection. PVdC can often be used on existing PVC tooling and can be customized to meet the level of barrier protection needed.

OUR EXPERTSScott Denley, global Product Manager, N‘CRYPT® pharma security solutions

Scott Denley is the Global Product Manager responsible for Amcor Flexibles’ N’CRYPT® pharma security solutions, Steril-Up® sterilizable lidding materials and the growing range of patient compliance / track & trace solutions. He is located at the pharma center in Kreuzlingen, Switzerland.

Scott has been instrumental in progressing the development of Amcor’s product security portfolio, moving the organisation from a technology focus to its current market position as a packaging material supplier with a premier security pedigree. Further, he is in the process of validating a range of mass serialization solutions, driven by the recently enacted regulatory requirements for a drug pedigree contained in both the California e-Pedigree and FDA Revitalization Act legislation.

Scott has set the personal goal of establishing Amcor Flexibles at the forefront of the developing product security and pedigree markets.

Sandra Luciano, global Product Manager, Thermoformable Films

Sandra Luciano is the Global Product Manager responsible for the Amcor Flexibles high performance thermoformable flexible materials, using Polybar®, Aclar®, COC and PVdC. She is based at the pharma center Shelbyville, Kentucky USA. Sandra holds a bachelor’s degree in Business Administration with a minor in Marketing. She has been involved in pharmaceutical and medical device packaging for over twenty years.

In this role, Sandra manages Amcor’s line of “aluminum free” thermoformable products, which is a key line of products within the company’s core competencies of high barrier films. She works closely with customers and Amcor’s global technical team to facilitate product development and adoption of our thermoformable films, always working towards “the perfect match” of top and bottom web materials.

CONTACT US TODAYScott Denley can be contacted directly at +41 71 677 7244Sandra Luciano can be contacted directly at + [email protected]/pharmaceutical


PACKAgINg

and high production speeds as well. The pharmaceutical industry is also interested in considering new CR/SF packaging solutions. All this must be done in a way that does not significantly alter processability.

Global packaging suppliers like Amcor Flexibles have been providing CR/SF packaging that meet the balance between child-resistance and senior-friendliness, but that also consider the overall supply chain process and the marketing goals of the pharmaceutical companies. Most specifically, packaging suppliers have focused on developing a wide range of packaging formats that are suitable for the broad variety of medicines on the market including tablets, capsules, powders, granulates, creams, gels, liquids and oral dissolve strips.

Today’s CR/SF packaging formats go beyond the traditional child-resistant cap and closure. Packaging solutions like blister packs have been designed to meet CR standards and require complex opening features such as peel-open, peel-push and tear-open. For instance, to successfully open a peel-push blister one must first separate the individual blister cavity at the perforations, then peel off the top layers at the designated place and finally push the pharmaceutical product through the foil. Other novel solutions include pouches, sachets and stick packs with a hidden tear notch. Instructions must be followed in order to open the pack at

a tear initiation point. Finally, blister cards solutions are being used more and more with CR/SF features. In this format, the blisters are integrated in a cardboard package where access to the product is achieved by manipulation (pushing, turning) and subsequently the product is pushed through the lidding foil.

These unit-dose packaging formats noted above provide added benefits to the consumer and manufacturer beyond CR/SF. Unit-dose formats provide improved tamper evidence, increase shelf life, enhance portability for consumers, and can contribute to positive branding and marketing efforts. Further, unit-dose formats are known to facilitate patient adherence and compliance to the drug regimen. By partnering with packaging suppliers at early stages in the drug manufacturing process, pharma companies can ensure package design and functionality that fits with the drug regimen and therefore offer a complete solution to improve patient and consumer safety.

When it comes to the safety of our children, we cannot be too careful. Children are curious in nature. Children are risk-takers who do not have a full understanding of the consequences of their actions. Child-resistant packaging cannot be a substitute for other safety measures –parents and guardians have a duty to keep medicinal products out of the reach of children– but optimal CR/SF

packaging formats can play an important role in child safety. Ultimately, CR/SF packaging improves consumer trust of a pharmaceutical brand by helping to reduce the chance of a child gaining access to medications n

References: 1 EN 14375 standard was agreed upon

by the CEN (Comité Européen de Normalisation, Geneva) member states: Belgium, Denmark, Germany, Finland, France, Greece, Ireland, Iceland, Italy, Malta, Luxembourg, Austria, The Netherlands, Norway, Portugal, Sweden, Switzerland, Slovakia, Spain, Czech Republic, Hungary, UK.

2 Child-Resistant and Senior-Friendly Non-Reclosable Packages for Pharmaceutical Products – a Total Contradiction?, Dr. Erwin Pasbrig, 2005.

3 World Health Organization, World report on child injury prevention, 2008.

4 Flanagan R, Rooney C, Griffiths C. Fatal poisoning in childhood, England and Wales, 1968–2000. Forensic Science International, 2005, 148:121–129.

5 McCullough JE, Henderson AK, Kaufman JD. Occupational burns in Washington State, 1989–1993. Journal of Occupational and Environmental Medicine, 1998, 40:1083–1089.

6 Van Niekerk A, Rode H, Laflamme L. Incidence and patterns of childhood burn injuries in the Western Cape, South Africa. Burns, 2004,. 30:341–347.

7 Tassilo Korab, presentation TATAL Exhibition Birmingham, March 2004.

8 Medicines and Healthcare products9 Regulatory Agency, September 2003.

Sandra Luciano, Global Product Manager, Thermoformable Films, Sandra Luciano is responsible for the Amcor Flexibles high performance thermoformable flexible materials, using Polybar®, Aclar®, COC and PVdC. With over twenty years experience in the pharmaceutical and medical device packaging industry, Sandy works closely with customers, suppliers and industry stakeholders to develop customized CR/SF blister design and patient compliance packaging solutions.Email: [email protected]

Abilities Difficulties

Children clamping

pressing

biting

tearing

hitting

do it with perseverance

eager to learn

imitation

experimenting with pleasure

visual preferences

fundamental positive attitude

combining

executing simultaneous and complex motions

reading

writing

strong force

semantic

experience

ine-motor

motions

Adults combining

executing

simultaneous and complex motions

reading

writing

pressing

clamping

biting

tearing

pulling

hitting

semantic experience

understanding

taste prefer-ences

loss of force

weak vision

low contrast perception

low compre-hension of new technical subjects

uncontrollable fine-motor motions

loss of memory

mental block

typically negative approach to new things

Table 1: Abilities and Difficulties of Children and Adults


LABS & LOgISTICS


ExHIBITION PREvIEWS & REvIEWS

The Biobridge Foundation acts as a global platform on regenerative medicine. Its purpose is to encourage research and discussion in stem cell-related treatments, as well as forging working relationships between high-level scientists and physicians. Research and development in biotechnology requires the collaboration of its industry members, in a common effort to drive advancements in health through innovations, as well as building profit centers in this growing area. The Biobridge Event offers a platform through which scientific researchers, industry representatives, manufacturers and investors can forge and strengthen ties on a regional and international level, and thus make possible the development of new applications in regenerative medicine. The Biobridge Event 2010 will be held on the 11th of October 2010 in the Assembly Hall of the United Nations Office in Geneva (UNOG), Switzerland. A focal point for multilateral diplomacy, UNOG is one of the busiest conference centers in the world. For three years it has exceptionally opened its doors to a non-governmental organisation whose projects and missions have aroused the interest of the Director General, Sergei Ordzhonikidze.

The Biobridge Event is organised this year in collaboration with BioAlps, the Lake Geneva Life Science Cluster, one of the four bioclusters in Switzerland, together with the Basel Region, the Greater Zurich Area and Biopolo Ticino. The BioAlps cluster, with more than 500 research laboratories and more than 5000 researchers engaged in cutting-edge fundamental, clinical and applied research has been called by Science magazine “the most important life science research centre of excellence in mainland Europe”. The aim of BioAlps is to promote Western Switzerland as a world

class centre for the life sciences, and to foster the growth of this specific industrial sector. It promotes synergies between academia, entrepreneurs, investors, authorities and new businesses in order to translate ideas into new products, and bring new technologies to market.

The aim of the Biobridge Event is to present developments in research on stem cells and their promising clinical applications in regenerative medicine. The previous conferences were very successful and reunited attendees from the five continents and from 35 countries. For the 3rd “Generation Regeneration” Conference, we have gathered outstanding international experts in the field of cell therapies and their use in managing problems caused by aging. The highlight of the morning thematic plenary session will be the lecture by our special guest, Prof. Robert Marx. He is the leader in the use of platelet rich plasma (PRP) and bone marrow cells for bone healing. His results have found applications in many domains, like maxillofacial surgery, orthopedics, skin graft and plastic surgery, and his scientific contribution is now mentioned as a revolution in cell therapies.

In the afternoon there will be parallel workshops organised by BioAlps and Regen Lab. BioAlps will focus on the development of biotech in Western Switzerland and on the transfer of new technologies from the bench to the clinical level. Regen Lab, which aims to support progress in regenerative medicine, has acted as the main sponsor of Biobridge Event since its creation. A leader in autologous cell therapies, it works on developing new therapies. It manufactures and markets medical devices designed for the specific needs of physicians in the areas of wound care, aesthetics, surgery and sports medicine. The Regen Lab

workshops will focus on the use of stem cells in orthopedics, cell combination in plastic surgery and cell therapies in skincare.

At the end of the afternoon, Prof. Marc van Montagu, President of the European Federation of Biotechnology (EFB) will present his organisation and open the panel discussion. Established by European scientists in 1978, the EFB is Europe’s non-profit federation of national biotechnology associations, learned societies, universities, scientific institutes, biotech companies and individual biotechnologists working to promote biotechnology throughout Europe and beyond. The mission of EFB is to promote the safe, sustainable and beneficial use of the life sciences, to promote research and innovation at the cutting edge of biotechnology, to provide a forum for interdisciplinary and international cooperation, to improve scientific education, and to facilitate an informed dialogue between scientists and the public. The EFB wants to develop its activities in Switzerland, and therefore decided to collaborate with Biobridge to organise seminars and workshops for the next Biobridge Events.

For more information visit the websites:www.biobridge-event.comwww.bioalps.orgwww.regenlab.comwww.efb-central.orgOr contact directly:BioBridge EventRue de l’Eglise, 5CH-1146 MollensSwitzerlandTel +41 (0) 21 864 35 40Fax + 41 (0) 21 864 38 [email protected]

Monday the 11th Of October 2010 at the Palais de NationsUNOG (United Nations Office Geneva), Switzerland

“Generation Regeneration” Conference


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