Ipi volume 5 issue 3 2013

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Volume 5 Issue 3

Proactive Pharmacovigilance A New Model for the 21st Century Supplementary Protection for Medicines –Functioning or Failing?

Water purificationThat Stays Ahead of Legislation

Medicines OnlineThe Control of A New Channel

International Pharmaceutical Industry Supporting the industry through communication

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2013 PHARMA PUBLICATIONS

Volume 5 issue 3 - (Summer / Autumn 2013) September 2013

International Pharmaceutical Industry Supporting the industry through communication

Contents06 PUbLISHER’S LETTER

REGULATORY & MARKETPLACE

08 Big Pharma vs. Small Pharma: Current Trends in the Pharmaceutical and Biotech Industries The pharmaceutical and biotech jobs market has seen many significant changes in the past few years and some of these changes have been fairly dramatic. Dominic Graham at Kelly Scientific Resources looks into the impact of the global recession on the UK’s pharma industry, resulting in job cuts, redundancies and site closures for big pharma companies and how this has had a massive effect on the industry.

12 The New Landscape for Patent Protection in Europe Vicki Salmon at IP Asset LLP last wrote about the proposals for a new patent landscape in Europe last year. The idea of a single patent covering nearly all countries in the European Union seems ideal. However, industrial patent departments are not yet convinced that this is the right answer for their companies’ patent portfolios. So will it be right for you? This article will identify some of the complexities which lie beneath the surface.

16 Happenings in Pharma bPE has left London’s QEII Centre to explore new ventures in Europe’s capital cities, and UbIFRANCE has moved on to promoting the leading life sciences conference organised by GENESIS 2013. Katie Docwra at UbIFRANCE explains why despite the economic crisis in the Eurozone, it is clear that the French biosciences sector has pushed on through these tough times.

20 Life Science Austria: Advancing Life Science at the Heart of Europe Over the past decade, Austria has established itself as a well-respected hub of the life science industry. Region by region, the life science industry has spread across Austria, from the capital, Vienna, to the powerhouses of Styria, Tyrol and Upper and Lower Austria. Sonja Polan at Life Science Austria looks into a region and how it has its own special culture and particular strengths that are reflected in the local companies who are organised through regional life science sclusters.

24 Compounding Success: Patenting Known Molecules in Europe and the UK Once an inventor has identified a candidate pharmaceutical molecule, the prime objective should be to secure patent protection for the molecule itself, together with the largest group of similar compounds that the patent examiner will allow. However, how should the inventor proceed if the molecule is already published in the prior art or indeed already covered by an existing patent? Dr Matt barton at Forresters looks at some other types of patent claims that the inventor can use to obtain patent protection for the candidate molecule.

28 Supplementary Protection for Medicines – Functioning or Failing? The legislation governing Supplementary Protection Certificates for medicinal products, EU Regulation No. 469/2009, ‘the Regulation’, scores well on brevity but it falls down badly when it comes to clarity. David Rose at SJ berwin LLP considers whether the “dysfunctional” label is merited and if so why. In doing so, three specific aspects of the SPC system will be considered: combination therapies, new indications and active ingredients.

32 Partnering to Drive Innovation – A Supercritical Success Story Paul Titley at Aesica Pharmaceuticals and Peter York at Crystec Pharma discuss how the design, development and manufacture of modern medicines pose numerous scientific and technical challenges to drug delivery and pharmaceutical companies. Increasingly,

companies are finding that approaches which have traditionally been used to overcome these problems and in-house experience/ expertise available are no longer appropriate or sufficiently versatile to solve many of the emerging issues.

DRUG DISCOVERY, DEVELOPMENT & DELIVERY

38 Biocatalysis is a Key Technology for Successful Chiral Synthesis It is now well-recognised that the need for green, economic, robust and scaleable processes is at the forefront of customer research plans for the synthesis of chiral APIs and intermediates. Tom Moody and Stefan Mix at Almac provide an overview of how the chemical industry is under severe pressure to make their chemical processes greener, lower costs, minimise waste and shorten existing syntheses.

42 Engineering Enhancements in Drug Delivery The accelerating pace of technological development is offering new possibilities for manufacturers across the industry, and the need for all sectors to share both knowledge and best practice is crucial. To illustrate just how far some technologies have extended their reach, Mark Jennings at Dawson Shanahan describes how a process once used to forge simple fasteners has recently provided a sophisticated solution for needle-free drug delivery.

48 Disruptive Change by Linked Data and Semantic Technologies in Healthcare and Life Sciences The pharmaceutical industry is undergoing an enormous shift in structure and strategy to reinvent how to bring new drugs to market efficiently. Hans Constandt at Ontoforce explains global drug development strategies - consolidation and partnerships, functional outsourcing relationships, innovation networks, expansion into emerging markets, orphan drugs, translational science, academic alliances and use of public private partnerships (PPP) - all reflect new thinking aimed at achieving higher R&D efficiency and greater return on investment.

52 Innovative Injectable Drug Delivery Systems Innovative and complex ideas in the field of polymer injectable drug delivery systems need a capable partner to succeed in realisation. Customised products such as new and innovative injectable drug delivery systems need a wide range of polymer technologies, including injection moulding, extrusion and assembly. Thomas Jakob at Raumedic AG provides examples of innovative injectable drug delivery systems, together with a broad range of know-how and experience of polymer technologies.

CLINICAL RESEARCH

58 Ancillary Materials for Manufacture of Stem Cell-based Products In the present healthcare industry, cell culture has increasingly become a cornerstone of biopharmaceutical development, bio-processing and the manufacturing of expanded or differentiated cell populations. Pawanbir Singh at Stemcell explains that this requires complex manufacturing protocols, specialised media prepared with carefully screened raw materials, and an array of analytical techniques for their characterisation.

62 Proactive Pharmacovigilance – A New Model for the 21st Century The discipline of pharmacovigilance (PV) largely originated in reaction to public health disasters caused by medications. Sidney Kahn at Sciformix Corporation looks into the approaches for detecting significant, previously unrecognised hazards of medications after their introduction into clinical use, and how this has been principally based on collecting anecdotal reports of suspected adverse drug reactions.

68 Cardiovascular Therapeutics Watch Column Rick Turner at Quintiles provides an overview of how one of the hottest areas in the treatment of hypertension concerns drug- resistant hypertension. Drug-resistant hypertension is commonly defined

as blood pressure (BP) levels above a specified target despite a patient’s adherence to at least three optimally-dosed antihypertensive medications of different classes, including a diuretic. In addition to these requirements, Turner and O’brien have recently argued that a patient should be on such a regimen for a minimum of three months before the classification is made. The methodology by which bP measurements are made also needs to be given careful consideration in this context.

LAbS & LOGISTICS

70 Dual Usage of LEAN as a Logistics Service Provider Within Pharma Even though many industrial sectors have experienced severe economic pressure, the pharma sector still offers some of the greatest opportunities in terms of growth potential and return on investment. Ian Kendrick and Sebastien Guenegan of TNT Express explain that the trends in the last decade in the pharmaceutical industry have turned into real and concrete daily challenges.

72 A New Generation of Pallets The complexity of pharmaceutical supply chains is growing exponentially, putting greater pressure on suppliers to deliver superior service and more cost-effective products. Jim Hardisty at Go Plastic Pallets explains that in Europe, a new generation of pallets is helping pharmaceutical companies streamline production and lower their operating budgets.

76 Partnerships Herald the Future for Pharma and Biopharma Industries In the multifaceted interconnected world in which we work, timeworn models of competition are becoming increasingly outmoded. Today, we take for granted how the internet and intranet have developed into an integral part of the way we go about our daily lives. Patrick Jackson at Vindon explains that with the advent of new technology, offices have become virtual, the workforce is not confined to one location, and exchange of information is possible on a scale never before imagined.

Summer / Autunm 2013 Volume 5 Issue 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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MANUFACTURING

82 Smart Synthesis, Membrane Filtration and Chromatography For Time-efficient and Cost-effective Production, at the Required Purity Molecules reaching the market in recent years present an ever-growing complexity. In the meantime, purity criteria are more important than ever to ensure patient safety. Aline Devoille at Novasep looks into how the combination of these two facts represents a big challenge for the manufacturing industry, where the right combination of state-of-the-art synthesis and advanced purification is necessary to meet the demand in a cost-effective and time-efficient manner.

90 Water Purification that Stays Ahead of Legislation Last year, the World Health Organization revised its guidelines regarding the manufacture and distribution of water for pharmaceutical use, emphasising the appropriate specification and design of water purification systems. By utilising the latest purification technology and techniques, pharmaceutical companies can meet such requirements and make considerable improvements in water quality and delivery, explains Steve Mines at Purite.

96 Choosing an Automated Rapid Microbial Method Pharmaceutical manufacturers are under continuing pressure to bring product to market faster and at a high level of quality. This pressure has driven pharma manufacturers to look to lean principles and automation as a means to streamline operations and enhance efficiency. David Jones at Rapid Micro Biosystems Inc explains one area where these principles are starting to find traction is microbial quality control testing.

Formulation for Improved Liquid Biotherapeutics Many biotherapeutic drug products are prepared as lyophilised powders, but there is a growth in the number being formulated as liquid presentations for prefilled syringes. Nicholas Darton at Arecor Ltd explains how this move towards prefilled syringes is driven by the user-friendly and cost-effective attributes of these devices.

PACKAGING

Turning Your Smartphone into an Authentication Device Counterfeit drug incidents continue to increase, predominantly in developing countries, but also in developed ones, as the recent counterfeit cancer drug cases attest. Fred Jordan and Jennifer Yribar at AlpVision look into a new forecast from the International Data Corporation Worldwide Quarterly Mobile Phone Tracker that expects “…2013 will mark the first year that smartphone shipments surpass those of feature phones”.

Packed with Innovation Pharmaceutical packaging has many functions to perform, including information conveyance, aiding patient compliance, and product protection. Increasingly, however, the value of packaging in brand identification and protection via anti-counterfeiting technologies is being realised. The application of new techniques and technologies could aid this functionality and also enhance the consumer experience and empathy with a brand. Carol Hammond at Chesapeake looks into how the consumer will interact with packaging in the near future.

Medicines Online: The Control of a New Channel Internet pharmacies provide consumers with the ability to purchase prescription drugs online. There are thousands of internet pharmacies, yet only 16 have been accredited by the National Association of boards of Pharmacy (NAbP). Marga Romo at Nekicesa looks into how many unaccredited internet pharmacies entice unsuspecting consumers with deep discounts on medications.

126 Analytical Laboratories Analytical laboratories, whether on-site or off-site, perform qualitative and quantitative analysis on samples, testing and packaging each drug. These labs are required to meet high levels of governmental approvals and copious amounts of testing, as the determination of the safety of a drug lies with the company. Tim Roberts at Packaging Coordinators Inc explains alongside this challenge, the financial and time constraints facing these companies has created a strong need for a solution that can eradicate all of these issues at once.

CONFERENCES & REVIEWS

128 Polska Bio and Pharma129 The Success of the Anglonordic Biotech Conference Continues130 CPhI Worldwide Event Preview (22-24 October 2013):133 Investor optimism at the 10th anniversary EPIC (European Partnering and Investment Conference) 134 Genesis Conference 2013: Where scientific, economic and healthcare success converge

Summer / Autunm 2013 Volume 5 Issue 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A pickup in new drug approvals, the promise of faster regulatory decisions and more targeted medicines have quickened the pulse of the pharmaceutical

industry as a big wave of patent expiries recedes.Manufacturers are producing more targeted medicines, designed to treat very specific groups of patients, thanks to a new understanding of the genetic basis of many diseases - most notably cancer.This is reflected in products that are really targeted to the underlying mechanism of disease and really make a difference. That also means the development time and review time is getting shortened because “when a drug works, our job is easy.”After approvals last year from the FDA for 39 novel medicines - a record only beaten in 1996 - the healthy pace has continued into 2013.And drug-makers are getting further help from a new FDA programme to accelerate life-saving therapies designated as a “breakthrough”, opening the door to earlier approval based on quicker studies, where clinical data is compelling.

The EMA also has a scheme to allow conditional approval based on good interim clinical trial results. This year’s haul of new drugs includes several

that analysts see as major sellers, like biogen Idec Inc’s multiple sclerosis pill Tecfidera; the first of a new class of diabetes drugs called Invokana from Johnson & Johnson; and a new type of “armed antibody” from Roche Holding AG that delivers a toxin directly to breast cancer cells.Still, more than a quarter of 2012’s new drugs were niche products for rare diseases - a far cry from the one-size-fits-all blockbusters that drug-makers traditionally banked on.

The shift means the value added to companies’ portfolios is not as great as the headline numbers might suggest.Credit ratings agency Moody’s said last month that drugs in late-stage tests or just launched represented, on average, 18.5 per cent of big drug firms’ existing sales, up from 14.9 per cent two years ago, but still down from the 20.8 per cent seen in 2005.Within this issue of IPI, we have a fantastic selection of features reflecting the growing strength and achievements of the drug industry.

Within the Regulatory & Market Report section, we start with Dominic Graham at Kelly Scientific Resources discussing the current trends in the pharmaceutical and biotechnology industries. In our Intellectual Property series, Vicki Salmon of IP Asset looks into the new landscape

for patent protection in Europe, and Matt barton of Forresters looks at some other types of patent claims that the inventor can use to obtain patent protection for the candidate molecule.

In the Drug Discovery & Delivery Section, Mark Jennings at Dawson Shanahan describes how a process once used to forge simple fasteners has recently provided a sophisticated solution for needle-free drug delivery. Thomas Jakob at Raumedic AG provides examples of innovative injectable drug delivery systems, together with a broad range of know-how and experience of polymer technologies.

In the Clinical Research Section, Sidney Kahn at Sciformix Corporation discusses proactive pharmacovigilance and why this is a new model for the 21st century. Dive into this issue of IPI to read all the very informative articles. At this time of the year, I am sure you are all preparing for the multiple exhibitions and conferences that are upcoming. IPI will be exhibiting at CPHI/ICSE in Frankfurt from the 24th of October. Out booth Number is 42N24. We hope to meet all of you at the event.

I wish you all a very successful business moving forward.

Mark A. barkerPublisher

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

Catherine Lund, Vice Chairman, OnQ Consulting

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

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

Franz buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

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

Georg Mathis Founder and Managing Director, Appletree AG

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

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

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

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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

Sanjiv Kanwar, Managing Director, Polaris bioPharma Consulting

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

Stefan Astrom, Founder and CEO of Astrom Research International Hb

Steve Heath, Head of EMEA - Medidata Solutions, Inc

T S Jaishankar, Managing Director, QUEST Life Sciences

Editorial Advisory Board

Publisher’s letter

Page 7 – ADVERT 3 – 1 BARC

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Big Pharma vs. Small Pharma: Current Trends in the Pharmaceutical and Biotech Industries

To counterbalance this, some large global biotechs are buying IP and pipeline research, as well as consolidating some SMEs into their businesses.

Many of these larger corporations are now moving away from traditional chemical-based development in favour of work with a biologics leaning, as they give greater focus to R&D in their quest to pioneer the ‘next big thing’ in biotech. Meanwhile outsourcing and managed service programmes are coming into their own, as companies demand certain skilled workers for a short period of time, and don’t want or need to take them on permanently. The flexibility of the pharma industry is fast improving.

What Does This Mean for Biotech / Biopharma Workers?The growth of start-ups has two clear consequences for candidates working in this sector.Firstly, scientists who can take a small-scale idea or solution and transfer it into large-scale manufacturing are strongly in demand – candidates with experience of both development and scale-up are highly sought after. These types of candidates tend to be found in small to medium companies, with most candidates from larger organisations specialising in a defined area. This means entrepreneurially-minded candidates are now valued highly, and these skills are often considered as significant as those gained by followers of one of the traditional graduate schemes.In the graduate market, companies are seeking innovative scientists that can offer solutions and are prepared to work hard to deliver their ideas on a large scale.Secondly, candidates increasingly need to show they have the ‘softer’ skills – such as communication, leadership and business sense – in order to demonstrate their innovative and creative side to the growing number of entrepreneurial start-ups. Start-ups are particularly looking for candidates that are able to work closely with their marketing or sales teams to ensure their ideas are well communicated – thereby helping them to compete with some of the bigger, more established biotech companies. They may also need to be involved in supporting funding applications so, again, communication becomes imperative.

We are therefore seeing a distinct rise in

demand for candidates who can offer ‘the full package’. Workers need to be dedicated, skilled at what they do – but also they need to be able to communicate well and have a strong sense of business acumen.

In terms of the specific areas that are in demand, we are experiencing multiple requests for protein scientists, as well as bioprocess sector specialists with both downstream and upstream experience. Candidates with cell culture and assay development are also an area of demand in the UK. These are all quite specific skill sets and we increasingly have to become more creative to find and secure the right people with the right skills for each job.

Where is it Happening?There are clusters of these smaller, start-up companies in Cambridge and Oxford. However, the north of England still remains a strong area for biotech, as both the North East and West grow into the biotech sector.

Of course, large companies’ consolidation is also leaving space for smaller companies to form and fill the gaps, with many large scientific site closures leading to these bases becoming incubators for start-ups, resulting in increased innovation. One such site is the former site in Sandwich, with another two sites in Stevenage. Previously dominated by these big pharma businesses, these sites are now being used by small start-up companies as an incubation area.

Advancing Science Careers in the Virtual WorkplaceAmidst this changing backdrop for the pharma and biotech industry, the increasingly socially connected world is fundamentally changing the way pharma and biotech employees work.

The growth of online is creating a more global competitive market in the pharmaceutical sector, and this is something that employees need to embrace. Whether it’s working across time zones, using social media in a professional capacity – such as LinkedIn or sharing knowledge online to boost productivity, it is no longer acceptable or advisable to not be online. Virtual workplaces are becoming the norm, facilitated through the adoption of collaborative platforms, and will play a significant role in the sharing of scientific best practice in the not too distant future.

Individuals therefore need to enhance their IT and technical skills, to ensure they are able


8 INTERNATIONAL PHARMACEUTICAL INDUSTRY Summer / Autmn 2013 Volume 5 Issue 3

As the director of a UK company, I have been close to the pharmaceutical and biotech jobs market throughout the many significant changes of the past few years.

Some of these changes have been fairly dramatic. The impact of the global recession on the UK’s pharma industry, resulting in job cuts, redundancies and site closures for big pharma companies, had a massive effect on the industry. A flood of candidates to market led many to believe skills shortage issues should be resolved – however the skills required did not necessarily meet the specific skills that were in demand. Meanwhile, a separate story was emerging through the growth of smaller, more nimble start-up pharma companies – providing both greater competition for the big boys, and also opportunities for a better, more collaborative approach in the industry.

Current Areas of Focus for the UK Pharma IndustryTo set the scene for the UK pharma industry at present, one of the key areas of focus for biotech, specifically in the UK, is the development of vaccines, such as the manufacture of the flu vaccine which is then exported throughout the world. The market for development of the vaccine is continuous as the flu virus mutates on a persistent global round-trip, meaning it is set to remain a strong area of focus for us in the UK.

Another key focus is that of innovation and vaccine improvement, both of which are driven by market dynamics. Hepatitis b and C vaccines, for instance, are very effective in some countries but are often needed in regions where the climate is quite hot. If there is no access to the correct refrigeration, the vaccine becomes ineffective, and so there is a real demand to make them more stable in warmer temperatures. Start-ups and Market ConsolidationSo what type of companies are currently working on these developments that have global reach?

As previously mentioned, the biotech and biopharma industries have seen a reduction in the dominance of ‘big pharma’ companies as the number of smaller start-up companies is increasing. I firmly believe that biotech and biopharma entrepreneurs will be a defining segment for the sector, and for biotech investment long into the future.

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10 INTERNATIONAL PHARMACEUTICAL INDUSTRY Summer / Autumn 2013 Volume 5 Issue 3

to stay abreast of the latest technology and emerging methods – to help their business remain competitive and to compete with other candidates in the market.

As already outlined, changes in the pharma market, such as the growth of the smaller, more entrepreneurial companies, mean that the bigger organisations have to be smarter about the way they conduct their business. Having previously focused on the macro level, they are now managing projects in micro-detail – meaning the individual employee with the specific required skill set has even greater influence on each project. A pharma business’s success is now, more than ever, down to a handful of employees. Finding the right employee for the job is arguably more important than ever before.

This is why many smaller organisations are collaborating with each other, to match skill sets and work together to deliver key aspects of certain projects for larger pharma corporates. This provides a faster response, and it is more efficient and saves costs for the larger company – while utilising the smaller start-up’s skills. At the same time, there is a demand for temporary and contract workers with the all-important STEM skill sets to fill certain short-term and project demands. For the individual employee there are two ways that they can take advantage of these changing trends, developing the right skills to become invaluable into the future.Firstly, they can improve their networking – both in terms of social networking, to extend their contacts and open up more opportunities, and also so that they can use scientific networks to help them complete their work. by showing prospective employers that they are confident at using these networking skills, they will be very attractive to prospective employers. Secondly, they could work closely with a specialist recruitment agency, particularly if they are seeking work on a project basis. Many agencies will assemble teams for the world’s largest scientific organisations, providing people


with the opportunity to work for different companies ‘full time’ – but without having to work for one company all the time.

In our experience, pharma companies, both big and small, are interested in connected, flexible workers, who are willing to think creatively and have all the necessary skills to see them through any project. These skills need to be both technical – in terms of IT/ STEM skill sets, to equip them for the online world, but equally they need to be softer skills, such as communication, necessary for creating a successful business proposition.

Impacting the Individual Businesses: A Case StudyWe’ve talked about the impact of these changing trends on the individual employee, but what exactly does it mean for the pharma businesses – particularly the big pharma giants? We were approached by a world-leading pharmaceutical company who needed top talent within its contingent workforce to stay at the forefront of its marketplace, and remain competitive amidst the growing start-up environment. We were brought in to create a service that sourced candidates, reducing time-to-hire and therefore helping the business to save money.

The ChallengeThe company in question has consistently been voted as one of the top workplaces and therefore has high standards, frequently looking to attract the best possible talent. Contingent workers, such as non-permanent temps and contractors are a key part of the workforce, providing support and resource during peak times, helping to deliver one-off projects and offering rare skill sets that are not necessarily required on a permanent basis. The company is very focused on the medical and scientific research spectrum, requiring workers with key skills in the scientific, professional and engineering disciplines. Many of these workers are only required for a short amount of time –

hence the company had relationships with many suppliers to source workers at a moment’s notice. As such, in 2011, they found themselves in the situation of having a supply system that was confusing for its managers, had duplication of processes, was inefficient, and ultimately was not delivering the quality of staff at the speed required.

It was therefore necessary to create a fully-integrated supply service for all contingent labour throughout the UK, improving the quality of workers, simplifying processes and improving compliance – thereby satisfying line managers and reducing direct and indirect costs.’

The OutcomeTo meet these challenges, we implemented a

full managed service programme – something that is fast becoming popular for these larger complex businesses. Within this, we introduced some strict criteria – all prospective employees were interviewed and shortlisted by us, and we ensured only specialist recruiters were used to find the rare skill sets required for certain projects.

Dedicated on-site representatives who could oversee the programme and ensure a consistently high standard were implemented in every location.As a result, the contingent workforce grew from 280 to 500 people, indicating a serious demand for temporary workers to best fulfil their staffing requirements. The company experienced cost savings of over £0.5 million, and line managers were able to focus on project delivery – rather than focusing on hiring staff and finding the right people with specialist skill sets.

Dominic GrahamDirector, Kelly ScientificResources UK and Ireland.

Dominic Graham, Having worked in the recruitment industry for over 15 years, specialising in engineering and scientific recruitment, Dominic Graham heads up the Professional and Technical division of Kelly Services, where he oversees the Kelly Scientific, Kelly Engineering and Toner Graham brands across the UK, ensuring they are positioned as the global recruitment supplier of choice. Email: [email protected]

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The New Landscape for Patent Protection in Europe

international application route, and delay the national patent filings for another 18 months. but at the end of the day, the patent application will need to be examined in each country of interest, and in an official language of that country. This is one of the reasons that patents are expensive.

Examination may lead to granted patents, for which renewal fees are usually payable annually1, until the patent expires, 20 years after filing.

The European PatentThe European Patent Office started operating in 1978. This was a route to obtain a granted patent for all of the member states and so avoid the previous expense of filing in each European country. The handful of original members has grown. Now patents for over 38 European countries can be obtained by filing a single patent application with the EPO. This means that the applicant can use a single patent attorney to handle the application and does not need to pay local fees and local attorney costs in each country.

Other savings come from the fact that the EPO operates in English, French and German only. So patents can be processed in only one of these languages. This means that there are no translation costs until nearer to grant and there is no need to translate communications with the EPO (unless you prefer to work in a different language). Originally, the patent application had to be translated before being filed and prosecution took place in each country in the local language. Now, it is only just before grant that the patent claims have to be translated into the other two languages. So if your application is in English, then translations of the claims into French and German is required, but it is not necessary to translate the rest of the text at this stage.

This map shows the countries for which the EPO gives coverage. This extends beyond the European Union.

However, when the EPO grants a patent, it promptly falls apart into 38 separate patents and has to be validated in each country of interest. In some countries there is little to do.

For example, validation happens automatically in the UK, France, Germany, Luxembourg, Monaco and Switzerland/Lichtenstein, although it is recommended to ensure that there is someone appointed to receive communications from the relevant patent offices.

Validation requirements in other countries vary. Some may require just the claims to be translated, (e.g. Denmark where the patent is in English). Others will require the entire patent specification to be translated (e.g. Spain, Italy and Poland). So often, a patent owner will pick and choose the most important markets and allow the patent coverage to drop in the remaining countries.

Patents have to be renewed every year. The cost goes up as the patent gets older, which encourages companies to drop cases for which they do not have a commercial need and so put the invention into the public domain. The advantage of the present system is that a company can review each country, as well as each patent family, and drop those which do not pay their way. The disadvantage is that all other activity in relation to the patent family has to be taken on a country-by-country basis. So if the company sells the patents, then the assignments need to be recorded in each country. If there is infringement of the patent, then enforcement must happen on a country-by-country basis.

The Unitary Patent


SummaryI last wrote about the proposals for a new patent landscape in Europe last year. The treaties have been signed and work on implementation is underway. The new system is expected to be implemented in 2015. For the novice, the idea of a single patent covering nearly all countries in the European Union seems ideal. However, industrial patent departments are not yet convinced that this is the right answer for their companies’ patent portfolios. So will it be right for you? This article will identify some of the complexities which lie beneath the surface.

Introduction to the Patenting Process For those of you not familiar with how to obtain patent protection, then the following will provide a brief guide.

before any publication of the invention has taken place, a patent attorney should be instructed to prepare a patent application. That may include reviewing competitors’ patent portfolios (if your own scientists are not already doing this). It will require a full understanding of the key ingredient of the invention and identifying the supporting experimental evidence you already have or will need to have to support the monopoly claim you wish to make.

It is helpful to identify the inventors at this stage. If you are using external research organisations, then it is also a good time to make sure that you know who owns the intellectual property rights. There needs to be a written statement to transfer this in the contract. Otherwise it will belong to the research organisation.

Patents take several years to grant and cost a significant amount of money. The first stage for most of our clients is to file a UK application and ask the UK patent office to examine it. The UK IPO fees are low, and a reasonable examination at this stage gives a better picture as to whether the patent will be granted later.

Within 12 months of the initial filing, patent filings in all other countries of interest must take place. Depending on the extent of the list, it may be more efficient to use the

Summer / Autunm 2013 Volume 5 Issue 3


The new system will introduce a Unitary Patent. This means that, when the EPO grants a patent, the owner will be able to opt for a single patent across a number of European Union countries. Individual validation is still required in the other countries of interest.


INTERNATIONAL PHARMACEUTICAL INDUSTRY 13www.ipimedia.com

renew the full Unitary Patent or let it drop. So the viability of this system will be heavily dependent on the size of renewal fees and the rate at which they increase year on year.Language regime. In due course it is hoped that machine translation will be of a sufficient quality to translate a patent into any language of interest. The EPO has been working on this and offers machine translations of documents found during a search. However, these are of variable quality and sometimes produce translations which just don’t make sense. So there is still a role for the qualified translator of legal documents. Until the machine translations reach the required level, there will be a requirement to translate all Unitary Patents. As happens now, the claims will continue to be published in English, French and German. but instead of then translating claims in some jurisdictions and full text in others, there will be a new requirement to translate the entire text once. If the patent is in French or German, it will have to be translated into English. If it is in English, then it has to be translated into one other European Union official language.

If your previous validation strategy had been for countries with no further translation requirement, then the cost of the Unitary Patent will increase your costs. However if you previously validated in each EU country, then this should lead to a cost saving.

Unified Patents CourtThe new system will also introduce a new court. Without having followed the negotiations over the last 40 years and the last-minute political wranglings over location, it will seem unnecessarily complex.

The Unified Patents Court will have

jurisdiction over all patents granted by the EPO for those European Union states who sign up. In due course we expect to see all those countries which were coloured blue on the map above, together with Italy.This means that the Unified Patents Court will have jurisdiction both over the new Unitary Patents, and also over the European patents which the EPO has granted until now and will continue to grant in the future.

There will be a Central Division and a Court of Appeal. The Central Division has been split between London, Paris and Munich. The split is along the lines of subject matter. biopharma and chemical cases will come to London. Mechanical engineering cases will go to Munich. The rest will go to Paris, which will also host the Court Registry. There are bound to be difficulties along the boundaries of which case goes where.

The Court of Appeal is to be based in Luxembourg. There is also the possibility of sending particularly tricky European cases to the Court of Justice of the European Union. It is to be hoped that this does not happen often, if at all, as the CJEU does not have any true patent expertise, is slow, and can produce opaque judgments which mess up the law.

In addition there are two arbitration and mediation centres in Lisbon and Ljubljana, with judge training taking place in Hungary.

However, it will also be possible to start cases in member states who set up their own local courts. Either a country may have its own Local Division. Or it may arrange with neighbouring countries to set up a Regional Division. Countries which have traditionally had many patent cases may have more than one Local Division. Much of this is still at the planning stage. There is likely to be a Local Division in the United Kingdom (possibly more than one, particularly if Scotland votes for independence) and there are likely to be several Local Divisions in Germany. Some Scandinavian states may get together for a Regional Division.

The aim is to staff these courts with trained patent judges and to mix up the nationalities. The long-term aim is to harmonise the law, particularly though the decisions of the Court of Appeal. However, this will take time and in the meantime there will be uncertainty for litigants.

Where you may be sued. The risk for companies trading in Europe is that they may find themselves on the receiving end of litigation started in a remote part of Europe. Although that risk exists at the moment, final injunctions are not usually European-wide,

The countries coloured blue on this map are the countries which are expected to agree to the Unitary Patent. We are still waiting to see who will ratify this arrangement and it is possible that not all countries will be ready when the system first starts, but may join later. The countries coloured yellow (including Turkey and Switzerland) are not part of the EU, and the EPO-granted patents will still need validation there as before – a full translation for Turkey, automatic validation in Switzerland. Spain, Italy and Poland are also planning to stay out of the Unitary Patent. So validation in those countries will be as before. Croatia joined the EU after the agreements were signed, but can sign up in due course if it wishes.

The advantage of the Unitary Patent will be that there will be one single patent to enforce and one single patent to renew. So that brings in similarities to the US, where there is a single patent granted to cover all states. However, the significant differences with the US are the language regime and the cost and frequency of patent renewal. So before opting for a Unitary Patent, as opposed to picking and choosing countries as now, it will be necessary to calculate whether there are likely to be any savings. As the fees are yet to be agreed, I can make no predictions about this and it remains to be seen whether it will make financial sense to opt for the Unitary Patent.

Renewal fees. Above I discussed how patent owners can review their patent portfolio and prune European territories each year to keep the renewal bill manageable. Once a patent owner has opted for a Unitary Patent, then it will remain that way until the end of its life and the patent owner will have to opt to




but just for the country in which that court is located. The Unified Patents Court can grant an injunction to stop patent infringement in ALL participating member states.So depending on where you sell and where the Local Divisions are set up, you might find a court in Estonia granting an injunction which stops manufacture in the United Kingdom.

There are rules as to where the litigation can start. but there are likely to be disputes over whether a case was properly started in the right court. Jurisdiction will generally depend on domicile. but it will also depend upon where sales occur – which can be tricky where sales are via the internet – or where another defendant is domiciled.

Where patents may be revoked. The risk for patent owners is that they may lose all (or nearly all) of their EU patent protection in one go, if a competitor applies to have the patent revoked.

For this reason, anyone wishing to start revocation proceedings must go to the Central Division. However, once infringement proceedings have started in a Local or Regional Division, then the defendant will be able to counterclaim for revocation in the same proceedings. That Local Division will be able to decide whether (a) to hear the revocation claim along with the infringement case, (b) keep the infringement proceedings and send

the revocation counterclaim to the Central Division or (c) send the whole case to the Central Division. The ability to split the case, or bifurcate, has been a hot issue. british lawyers see it as impossible not to consider the scope and validity of a patent at the same time as deciding infringement. but in those countries which currently separate infringement and validity proceedings (most notably, Germany) this is not something to be given up lightly.Opt-outs. Industry has lobbied not to be bounced into an untested system. So for seven years from the start of the Court, it will be possible for patent owners to opt out of this system. For a patent which has been opted out, patent enforcement and revocation will be in the national courts, as happens now. The way in which the opt-outs will be managed and the fees for doing this are still being discussed. If in doubt, it is likely to be sensible to opt out. It will be possible to opt back in later, if the court is seen to be doing a good job. before the opt-outs can be effected, the authorities must first compile a comprehensive list of the relevant patents. The EPO knows which patents it has granted. but renewals then take place in member states and patents may have been transferred on a state-by-state basis. As currently drafted, an opt-out will only take effect once it has been processed. If an opt-out has not been processed, then someone may apply for central revocation of

Vicki Salmonis a partner at IPAsset LLP. Sheis one of a handful of dual qualified patent attorneys and solicitors in the UK. With over twenty-five years’ experience, and a degree in biochemistry, she advises on a wide range of intellectual property issues and technologies, from obtaining patent, trade mark & design protection, through to commercialisation and enforcement.Email: [email protected]

the patent. This is likely to lead to a processing nightmare and we hope that there will be a “sunrise” period, whereby opt-outs for existing European patents can be processed before it is possible to start cases in the court.

Court procedure. At the time of going to print, there is a public consultation taking place on the court rules. It closes on 1 October 2013. The rules seek to fuse the different practices across Europe, trying to speed up and streamline cases, whilst not throwing out the ability for more forensic examination which has traditionally taken place in the UK. How this turns out is for a future article, as well as a review as to whether this will have the desired effect of making patent litigation less expensive.

ConclusionThe start of the new system is still a year or so away – currently expected in 2015. Patent lawyers are generally cautious and find change difficult. There is still time to help shape the system which is coming. We hope that this will be a change for the better, but, with our cautious nature, fear that this will be a change for the worse.

Reference

1. The US is an exception to this, with only three renewal fees required at irregular intervals after grant.

This map shows the EU with the locations of the various elements of the court.

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16 INTERNATIONAL PHARMACEUTICAL INDUSTRY Summer / Autunm 2013 Volume 5 Issue 3


As part of my role at UbIFRANCE, I spend a large portion of my time explaining the british healthcare system to French manufacturers, as many find it difficult to understand the way in which the NHS functions in terms of reimbursement and funding. Whilst I take the time to explain the mechanical workings of our much-debated healthcare system, I also spend a lot of time defending its importance and relevance in today’s society, where good healthcare for our population is becoming an ever-important issue, a growing concern on the collective consciousness both in and out of the NHS. Yet our system, certainly from an outsider’s point of view, appears complex, under-funded and struggling in the face of austerity. The French healthcare system, however, is considered to be one of the best in the world, officially ranked third in Europe for meeting the needs of its society. Internationally, France stands at number five, with the UK coming in at 25th position (source: IMD 2012). The NHS is, however, the UK’s biggest employer, an enormous machine serving the diverse needs of its population since the day of its conception in the immediate post-war britain. With all the changes it has undergone in the last few years, especially as of 1 April this year, the NHS still continues to be the nation’s dominant healthcare supplier, accounting for roughly 85% of total healthcare spending, and remains impregnated in our daily lives and cultures. I reiterate the importance of our system to French companies considering exporting to the United Kingdom, and this year has been very busy for me, with manufacturers of diverse healthcare products looking to gain their share in this rich and competitive market.

Regarding the life sciences industry, the UK is mature, well-established and dominated by both SMEs and large, multinational corporations. Of the world’s top 20 pharmaceutical companies, 17 have sites for development, manufacturing and marketing and sales based in the UK

(Strength and Development 2012). Our life sciences sector is vibrant, growing and sustainable. It employs over 167,000 people, hosts over 4500 companies, and has a combined turnover of £50bn. Medical biotechnology companies contribute 979 of these companies, accounting for £3.7bn of the turnover. The pharmaceutical market was calculated as being worth £30bn, with 24 companies out of 387 accounting for 80% of the turnover. Similarly, France is competitive, internationally renowned for innovation, with an emphasis on vaccine development. Last year the French biotechnology industry generated combined turnover of over €260m and raised over €178m in funding (a 77% increase on 2011 figures). Our Gallic neighbours are also ranked second in Europe for the number of patents filed each year (WIPO 2012). There is also strong collaboration between regional clusters, or “pôles de compétitivité”, centres of excellence and academic institutes, which support industry to develop nationally and internationally through funding and support. The life sciences clusters in France, established by the French government and regions to stimulate growth and development, promote excellence in a synergistic approach. There are 71 clusters and centres of excellence in France, covering

It has been two years since my first editorial for IPI, and with the new season beginning as the summer draws to a close, now seems like a good time to reflect on the last two years. My previous article focused on the work of UbIFRANCE, on the delegation we were assisting at the time in preparation for bioPartnering Europe, as well as our trade mission, which introduced French manufacturers of medical devices to the many curious ways of NHS procurement.

Turning the clock forward to today, bPE has left London’s QEII Centre to explore new ventures in Europe’s capital cities, and UbIFRANCE has moved on to promoting the leading life sciences conference organised by GENESIS 2013. We continue to mobilise French SMEs in the biotech and pharma arena, to assist in exporting their innovation and expertise in the research, development and marketing of new healthcare products and drugs. Despite the economic crisis in the Eurozone and fears of stagnated growth in both domestic and foreign markets, it is clear that the French biosciences sector has pushed on through these tough times. International exports are topping the list of priorities for companies looking to increase revenue and identify new business leads. In 2012, the UK ranked seventh in France’s top destinations for exports (all sectors), with over 13,000 companies exporting their goods and services to the UK, 70% of which were SMEs. This year, the French Minister of Foreign Trade, Nicole bricq, has declared that international export will become the French government’s first priority in a new plan to significantly reduce the trade balance, with healthcare being one of the four main areas taking precedence. The UK has been selected as one of a few targeted destinations, and over the next few years we should hopefully see a higher uptake of innovative French products into our primary care and hospital environments.

UBI France - Happenings in Pharma

It has been two years since my first editorial for IPI, and with the new season beginning as the summer draws to a close, now seems like a good time to reflect on the last two years. My previous article focused on the work of UbIFRANCE, on the delegation we were assisting at the time in preparation for bioPartnering Europe, as well as our trade mission, which introduced French manufacturers of medical devices to the many curious ways of NHS procurement. Turning the clock forward to today, bPE has left London’s QEII Centre to explore new ventures in Europe’s capital cities, and UbIFRANCE has moved on to promoting the leading life sciences conference organised by GENESIS 2013. We continue


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Katie Docwra, TradeDevelopmentAdviser. Katie is in charge of Healthcare andbiotechnology at UbIFRANCE, The French Trade Commission. Her role is to assist French SMEs in the life sciences sector with their move towards exporting, helping them to identify potential new business partners in the UK. Prior to this position, Katie worked as an in-house translator at a French publisher specialising in science and new technologies.Email: [email protected]

various sectors from life sciences to agriculture. The French bioscience clusters are an excellent point of entry for identifying partners with coverage from Lille to Montpellier, Nantes to Strasbourg. These clusters assemble businesses and research laboratories – both public and private – to work on world-class, leading research. Moreover, there are over 500 foreign companies contributing as research partners in these networks. These help small businesses grow and welcome foreign investment, enabling the regions to enrich knowledge, spur innovation and create leading new technologies for the world’s healthcare industries. Such networks, much like our own in the United Kingdom, make France an appealing destination for trade, investment and collaboration. Moreover, the French government offers particularly attractive R&D tax credits in the form of exemption from corporation tax calculated on profits within R&D activity. Covering 30% of R&D costs up to €100m or 5% above this threshold, which is one of the most competitive schemes in Europe, this incentivises businesses to conduct research in the country. Such fiscal incentives could benefit any company working in the life sciences sector. Moreover, working with clusters is an optimal way of ensuring that your company obtains the support it needs on a day-to-day basis. Inversely, at UbIFRANCE we frequently promote

the UK biosciences networks to French companies looking for british partners. The collaborative atmosphere and spirit of co-operation within these networks is certainly an asset for any company looking to develop their business in the UK. Moreover, the facilities provided by our networks offer excellent hubs for housing companies, and the training offered is diverse and of excellent quality. Whereas UbIFRANCE is focused on bringing French trade into the UK, our sister company, Invest in France (IFA) serves to take foreign investment into France, with offices in 22 countries across the world. IFA, like UbIFRANCE, is a French government agency providing a free-of-charge service to companies looking to set up in France. The team of Project Managers in our London office assist with information on the fiscal incentives such as the R&D tax credits, for example, and staffing and legal issues, as well as helping companies to decide on a location and choose a site for investment. They can also facilitate contact with regional and national governments, as well as any other bodies which may be useful to a foreign company looking to invest in France.

The immediate future at the Healthcare & biotechnology department here at UbIFRANCE London is focused on various different projects with the aim of promoting the French industry. In November we will be hosting an extensive French pavilion in Dusseldorf, with 150 different manufacturers of healthcare products, including orthopaedic and dental implants, kits and MAb service companies. The Pavilion is a showcase of French excellence, and british companies planning on visiting MEDICA will undoubtedly be impressed by the quality of the products and services displayed. On a smaller scale, UbIFRANCE London will be hosting a French delegation at GENESIS 2013 organised by the UK’s largest life sciences network based on the outskirts of Cambridge, One Nucleus. As members of One Nucleus, UbIFRANCE London takes part every year in the GENESIS conference, promoting the French life sciences industry through promotion and customised visits the day prior to the event. This year we will have an exciting selection of French

companies at the convention, all looking to establish partnerships with UK companies, both smaller biotechs and bigger pharmaceutical companies alike. With France and the UK being homes to world-class research, development and production, it only seems natural that the two should come together at a conference such as GENESIS to explore the potential for collaboration. A special catalogue with details of the French delegation will be sent out to british partners and companies prior to the event, giving information on each company’s specialisation and activity. Any british companies wishing to know more about the specially-selected French delegation can contact UbIFRANCE London by using the contact details printed in this article.

As for the future, 2014 is already looking like it will be a busy and exciting period with many projects underway for next year as 2013 enters its final trimester. We will be assisting companies working in the healthcare and life sciences sectors throughout 2014 via representation at trade shows and individual, customised trade missions. For further details about any of the information in this article, please contact UbIFRANCE London, or Invest in France, www.invest-in-france.org.

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Life Science Austria: Advancing Life Science at the Heart of Europe

Over the past decade, Austria has established itself as a well-respected hub of the life science industry.Region by region, the life science industry has spread across Austria, from the capital, Vienna, to the powerhouses of Styria, Tyrol and Upper and Lower Austria. Each region has its own special culture and particular strengths that are reflected in the local companies who are organised through regional life science clusters.

All Eyes on Vienna!The growing life science sector is reflected in the increasing interest shown by international businesses in doing deals with companies in Austria. And it is not just the rise in corporate deals that shows Austria in a good light: the country is also proving to be an attractive location for operations and significant inward investment for a number of multinational companies. These investments come on top of a whole series of international venture capital investments in Austrian life science.

Another highlight showcasing Austria’s strength in the life sciences is this year’s hosting of bIO-Europe. Vienna will be the proud host of bIO-Europe 2013, the world’s largest stand-alone partnering event, for the second time since 2009. It’s only the second time this event will take place outside Germany, and in both cases the choice was Vienna. The 19th annual edition of bIO-Europe will gather leaders of the life science industry at the Wiener Messe to take biotech dealmaking to a new level.

Austria prides itself on a long tradition of revolutionary discoveries in the life sciences, with such famous names as Theodor billroth, Karl Landsteiner and Max Perutz. but today too, or perhaps especially today, Austria has a wealth of innovative potential to offer.

A thriving environment of successful and innovative companies has put Austria firmly on the European life

science map. The combination of global players, research facilities and young, dynamic start-ups in close cooperation with excellent universities creates an ideal environment for the development, growth and prosperity of the Austrian life science industry.

Biotechnology, Pharma and Medical Technology – Leaders in InnovationWith 723 companies active in the biotechnology, pharma or medical technology business, life sciences are an important part of Austria’s economy. Together, these companies were responsible for a turnover exceeding 17.5 billion euros in 2012 – about 5.4 per cent of the gross domestic product. More than 50,000 people earn a living working for an Austrian life science company.

A combination of innovation and tradition forms the basis for Austria’s success in life sciences. Young, well-trained entrepreneurs with fresh ideas benefit from a close network of excellent academic institutions and some of the world’s leading companies in their line of business. This might explain why the corporate landscape is ever-changing: a typical biotechnology company is only eight years old, and the average medical technology company has been in business for just about 17 years.

A short time in a country that takes pride in its long tradition of revolutionary discoveries in the life sciences. Overcoming Societal ChallengesThe ageing of society, increasing cost pressures in healthcare systems, climate change – challenges to society are legion nowadays. Life sciences are considered to be among the key technologies for providing solutions to these challenges.

Austria’s life science industry has already achieved an excellent worldwide reputation as a source of high-quality drugs, smart devices and creative new therapeutic concepts. First-class clinics and excellent research facilities, along with cutting-edge technologies and well-trained staff have laid the foundation for this development. It goes without saying that Austria’s life sciences industry is in a unique position to deliver on its promise due to its scientific excellence, its commitment to the life sciences industry, and continuous political support. An Attractive Business Environment Spurs the Development of the SectorWith R&D investment in 2012 at an all-time high of 2.81% of GDP,

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the government aims even higher: to make Austria an innovation leader within the European Union, and to raise the share of R&D investment to 3.76% of GDP by 2020. Furthermore, the Austrian Federal Ministry of Economy, Family and Youth presented its “Action Plan biotechnology” in June 2013. This plan aims to increase the size of the sector significantly within the next five years, in particular through new financial support programmes. There is also a very supportive and attractive tax regime, an R&D cash premium of 10%, and a maximum corporate income tax of 25%. Furthermore, the wide array of funding schemes available to life science start-ups contributes to this thriving environment.

Austria wirtschaftsservice (aws), the Austrian national promotional bank, provides financial support for start-up ideas for life sciences through its funding programmes ‘LISA PreSeed’ and ‘LISA Seedfinancing’. Other austria wirtschaftsservice initiatives include guarantees and loans. Furthermore austria wirtschaftsservices recently launched two new funds to close the financing gap for young companies. aws business Angel fund provides equity to business angels and other non-institutional investors for the financing of innovative companies in the form of co-investments. aws ‘gründerfonds’ provides risk capital to companies with high growth potential in the early stage as well as in the growth phase.

These powerful finance streams are complemented by financing vehicles

from other Austrian agencies, including the Austrian Science Fund (FWF) which supports basic research, and the Austrian Research Promotion Agency (FFG) which manages applied research funding with an annual budget of € 430 billion, of which about € 70 billion is spent on life sciences projects. As part of this remit, the FFG is also responsible for organising the Centre‘s programmes, which are among the most successful technology policy initiatives in Austria. These programmes are internationally recognised as models of best practice, and provide support to over 1500 researchers from science and industry, working together on jointly-defined areas of research at more than 40 centres.

What also makes Austria an interesting place for the life sciences are the close links between solid academic research and outstanding medical practice, access to highly-skilled and dedicated scientists and managers, paired with an active start-up community, and last, but certainly not least, an extremely effective government support system for innovative companies. The Austrian government is committed to this burgeoning sector and is helping to foster a business environment that allows such young spin-off companies to thrive.

All these measures are now bearing fruit, creating new and exciting jobs while securing Austria’s future as a hot spot for innovation.

Biotechnology, Pharma and Medical Technology – Leaders in InnovationAustria’s life science industry has already achieved an excellent worldwide reputation. A number of multinational companies are headquartered in or have facilities in the country, taking advantage of Austria’s ideal geographical location in the heart of Europe. However, small-to medium-sized companies dominate the scene.

In a field as widely diverse as life sciences, no company can do everything. This is why many Austrian companies have chosen to specialise in a certain line of business – and also why it is most natural to them to create close ties with other stakeholders. The degree of cooperation between producers, networks of suppliers and service providers, all within a

short distance of each other, is a truly remarkable factor in the Austrian life sciences scene. This is why many resulats are genuinely “Made Austria.”Austria’s life science industry basically consists of two equally important subsegments: biotechnology and pharma on the one hand, and medical technology on the other. In terms of size, both sectors are comparable with each other. To break it down further, Austrian life science companies mainly focus on innovative cancer cures, new vaccines and anti-infectives, advanced diagnostics and analytics, production and platform technologies, and in addition they serve the whole medical technology value chain.

InfrastructureGreat infrastructure is a key driver of the life science industry in Austria. Across different regions in Austria, a succession of science parks, incubators and tech transfer initiatives has ensured the growth of the indigenous industry as well as attracting a plethora of established multinational concerns. This is an ongoing process with a constant stream of new initiatives and investments being added to the existing ones.

Vienna has the longest-standing network of state-of-the-art technology hubs. both the city and the state of Austria are in the process of establishing a €52 million cutting-edge shared core facility located at the renowned Campus Vienna biocenter. Other recent developments include the establishment of a €10 million Vienna Institute of bioTechnology Equipment GmbH at LifeScience Vienna Muthgasse.

The city of Krems in Lower Austria is the location of the world-class Krems bio Science Park, a recent development with 48,000m2 of space for tailor-made facilities for biotech manufacturing and research.

Graz in Styria has also established an enviable series of state- and regionally-funded developments in support of the Styrian life science industries. In 2010, it constructed the Medical Science City which incorporates the ground-breaking ZWT Centre for Medical Technology Transfer.



Austria’s World-class Research BaseAustrian medical universities all over Austria focus on state-of-the-art R&D for new therapeutic substances, with more than 55,000 people involved in medical research. The Medical University of Graz is one of three Austrian medical universities with a significant research impact. The university focuses on four international research areas (cardiovascular research, cancer research, molecular bases of lipid associated diseases, neuroscience) and a cross-sectional topic “Sustainable Health Research”. The Innsbruck Medical University focuses on molecular biosciences, neurosciences, cancer research, molecular imaging and sports medicine. Innsbruck Medical University also hosts several internationally-renowned projects including the “Austrian Proteomic Platform” and “Oncotyrol” which both attract scientists from all over the world. The Medical University of Vienna is strong in interdisciplinary and translational research, as well as in clinical programmes covering multiple disciplines including allergology & immunology, oncology, neuroscience and vascular medicine.

besides the medical universities, there are also renowned academic bodies that significantly contribute to life sciences research in Austria, and that have generated many successful life science spin-offs. bOKU, for instance,

themes: life at the molecular and cellular level, information processing and storage in neural circuits, developmental mechanisms of organisms and diseases, and interdisciplinary approaches that combine ideas and methods from other fields to answer biological questions. The common goal in all of these areas is to elucidate the mechanisms and principles that underlie complex biological processes.

LISA’s Commitment Life Science Austria (LISA) promotes the life science sector in Austria on the international stage and is the first point of call for enquiries relating to it. LISA is committed to the development, growth and prosperity of the Austrian life science industries as a leading component of the Austrian economy. On the international front, LISA also works towards Austria itself being a country known worldwide for the excellence of its life science sector.

Organised through the regional life science clusters, LISA represents companies in the therapeutic, medical technology and diagnostic sectors, as well as providers of enabling technologies and related service companies located in the Austrian regions.

LISA is run by Austria Wirtschaftsservice GesmbH (aws) on behalf of the Federal Ministry of Economy, Family and Youth.

Sonja Polanis the International Marketing Managerof LISA - LifeScience Austriasince 2009.Previously she worked as Account Manager at the European Commission, mainly in chargecharge of marketing telecommunicationspolicies to the European public. The most important campaigns were for the newly established roaming regulation and telecom reform. before the European Commission, she worked for a major brussels-based European public affairs consultancy, and also had short stints with the European Parliament and with trade federations. She speaks German, English and French.Email: [email protected]

is the main university in the country for natural resources and life sciences, while the Graz and Vienna Universities of Technology play an important role in life science research and in the training of skilled engineers.

The University of Graz focuses on research and education in the molecular biosciences, specifically in the areas of enzymology and physiology, while the Veterinary University in Vienna deals mainly with the field of veterinary medicine and is also increasingly exploring avenues related to human medicine. Their main research objectives include the fast detection of epidemic diseases and of pre-emptive, direct measures to prevent epdidemics and provide healthy food.

The Universities of Applied Sciences (Fachhochschulen) located in every centre of population across Austria are further engines of research and a valuable source for life science recruiters looking for highly-skilled technicians, laboratory staff and future industry business professionals.

Alongside the universities, the Austrian Academy of Sciences (AAS) is the leading organisation promoting non-university-based academic research institutions in Austria. The AAS’s life science research portfolio is conducted in institutions including the Research Centre for Molecular Medicine (CeMM), the Gregor Mendel Institute of Molecular Plant biology (GMI), the Institute for biomedical Aging Research (IbA) and the Institute of Molecular biotechnology (IMbA). It is also worth noting the Institute of Science and Technology Austria (IST Austria), a PhD-granting institution located in the Vienna Woods and one of the principal locations of research in the natural sciences, including bioscience, and the Austrian Institute of Technology (AIT), Austria’s largest non-university research institute with a research focus on grand societal challenges.

The Max F. Perutz Laboratories (MFPL) are part of a joint research and training centre affiliated with the University and Medical University of Vienna, where 530 scientists pursue discovery research and offer education in the area of molecular biology.

Research at the Institute of Molecular Pathology (IMP) spans a wide range of topics, broadly organised into four



Compounding Success: PatentingKnown Molecules in Europe and the UKOnce an inventor has identified a candidate pharmaceutical molecule, the prime objective should be to secure patent protection for the molecule itself together with the largest group of similar compounds that the patent examiner will allow. However, how should the inventor proceed if the molecule is already published in the prior art or indeed already covered by an existing patent? This paper looks at some other types of patent claims that the inventor can use to obtain protection for the candidate molecule.

IntroductionSetting aside patent claims directed to the molecule itself, we take a look below at some other types of claim that could be drafted to cover the target molecule, at the European Patent Office (EPO) and UK Intellectual Property Office (UK IPO). Also we will consider which other structural analogues or variants of the target compound might be allowed by the patent examiner. Of course, in many instances, the allowability of such claims will be subjective and will come down to an argument with the examiner regarding the inventive merit of the proposed claims. The comments below therefore relate to which novel claims the inventor can theoretically pursue. Successful grant of a patent will also depend upon convincing the examiner that the claims are inventive.

Medical Use ClaimsEven if a chemical compound is already known and published, it is still possible to secure commercially vital patent protection for the compound in a particular medical application. Probably the most well-known and well-used form of second tier patent claim is a claim directed to the first or further medical use of a known compound.

In Europe and the UK, patent law prevents the patenting of methods of treatment of humans or animals, including methods of treatment by administering a chemical compound. So firstly, consider the situation that would arise if an inventor comes up with a target compound for treatment of eczema, but the compound is not novel over prior art cited by the patent examiner. For example, the same compound could be already published in a previous patent, but not in the medical field. The inventor cannot draft a patent claim to recite “a method of treating eczema by administering compound X” because this would go against the prohibition of claiming methods of treatment. However, the inventor can draft a claim in the so-called first medical use format. In other words, if the inventor is the first person to discover a medical use for a known compound then, at the EPO and UK IPO, the inventor can claim “compound X for use in the treatment eczema“ and this will be novel over the previous non-medical disclosure of the same chemical compound.

Indeed, if the inventor was the first person to realise that the compound had any medical use whatsoever, they would be well advised to draft a claim compound X for use in therapy” or “for use as a medicament” as well as a claim directed to treatment of the disease. This is because the relevant parts of the UK and European legislation provide that first medical use claims can be directed to a general method of therapy, surgery or diagnosis (European Patent Convention, Article 54(4) and UK Patents Act 1977, Section 4A(3). General first medical use claims provide the broadest possible patent protection for the first medical application of a known compound, and are commonplace and very important in pharma companies’ patent portfolios.

If a previous therapeutic use of the compound is already known in the

prior art and an inventor has discovered that the same compound can be used to treat a different disease, then this second (or further) medical use can also be claimed i.e. “compound X for use in the treatment of eczema”. Such “second medical use” claims are now enshrined in the European Patent Convention (Article 54(5) EPC) and in the UK Patents Act 1977 (Section 4A(4) PA 1977), which require that the compound is for a specific use, for example the treatment of a particular disease (though see below for further examples).

In the UK second medical use claims are understood to provide the patentee with patent protection for the particular compound when packaged for the claimed medical use, in particular when the drug is packaged with an indication of the intended treatment. In the example above, the patentee could claim a monopoly for the drug when packaged for the treatment of eczema. A third party would only infringe the patent if it attempted to (for example) sell the same known compound packaged with an indication of the same medical use. A person selling the drug packaged for a different treatment would not infringe the patent.

In addition to treatment of new dis-ease states by a known drug, second medical use claims can also be drafted to protect new kinds of treatment for the same illness, for example the treatment of a novel group of subjects, a new route or mode of administration or even a new dosage regimen.

In all cases, the patent description should contain at least basic data supporting the fact that the claimed molecule has the claimed therapeutic effect. Patent examiners understand that inventors need to file patent applications at an early stage, often well before any animal or human trials. However at least basic assays should be described in the patent on the filing date, in order to avoid

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objections of lack of support or inventive step.

Use ClaimsThe European Patent Office considers the use of a known compound for a particular purpose as being novel, if the technical effect (the achievement of the new use) was not made available to the public in the prior art. In the landmark decision of the Enlarged board of Appeal of the EPO G2/88 (“Mobil Oil”) the new technical effect of the patent application was the discovery that the claimed compound, which was previously known as a rust inhibitor in lubricant compositions, also had friction-reducing properties. The patentee claimed the use of that compound in a composition for reducing friction, and this was novel in the eyes of the EPO.

However, the UK IPO does not follow the same approach because it deems the new technical effect to be inherent to the compound and therefore not novel because it was always present in the art, even if not explicitly noticed by the public. The UK IPO only allows such “purpose limitation” in the special case of medical use claims.

FormulationsOne strategy which has received attention in recent months is the claiming of known compounds in new pharmaceutical formulations. That is to say, claiming a known drug but with a novel blend of excipients and attempting to convince the patent examiner or court that the new formulation is not obvious over what has gone before but rather provides an inventive technical effect.

Many well-known drugs, such as sildenafil, have been claimed in patents in formulations such as melting tablets, taste-masked oral compositions and sprays. However, such formulation claims are always open to argument from the patent examiner that the formulations areobvious. In addition, after grant of a patent, the claims may be attacked by a third party competitor and held invalid by the court.

For example, the anti-psychotic drug Seroquel™ (quetiapine fumarate) was patented by AstraZeneca, but

expiry of the “parent” Seroquel patent for the compund itself opened the market up for generics manufacturers to produce the drug. AstraZenecafiled and had granted a new European patent (European Patent No. 0, 907, 364) for a sustained-release version of the same active ingredient, marketed as Seroquel XR. However, despite having the patent successfully granted by the EPO, the validity of the sustained-release claims has been questioned in law-suits in variousjurisdictions. In Europe, in the UK and Germany the patent was invalidated by the courts. On the contrary, in Spain and the Netherlands, the patent was upheld. Meanwhile in the USA, the Federal Circuit upheld the equivalent AstraZeneca Seroquel XR patent and judged that the patent was being infringed. The question in all jurisdictions was whether the newformulation was inventive: would thethe skilled person obviously use the claimed excipients to produce a slow-release version of a known drug?

EnantiomersAt both the UK IPO and the European Patent Office, the description in the prior art of a racemic mixture will not deny novelty of a later patent claim directed to a single enantiomer. Both patent offices deem that the previous disclosure of the racemic mixture does not make available to the public the specific spatial configuration of the molecules contained within the mixture. Therefore, novelty can be easy to demonstrate for a specific enantiomer. However, the question of patentability again will come down to inventive step. For example, if the racemic mixture could easily be resolved by known methods, and if there was motivation to do so, then the examiner might argue that isomer was not inventive.

Crystalline or Polymorphic FormsA patentee can draft claims directed to a new polymorphic form of a compound that is already known. In the UK, in SmithKline Beecham plc’s (Paroxetine Methanesulfonate) Patent the court accepted that paroxetine methanesulfonate was monomorphic such that any method of producing crystals of the drug would always produce the same crystals. However, where polymorphism can

exist this would not be the case and in a situation where a polymorphic form of a known compound is claimed, this form of the compound would be accepted as novel.A patentee could attempt to convince the examiner that the new form was present using characterisation data such as X-ray diffraction, infra-red or other crystal structure determination.

In a recent EPO Technical board of Appeal decision (T777/08), the inventive step hurdle for claims directed to a specific polymorph was set relatively high. In the words of the board of Appeal, “in the absence of any technical prejudice and in the absence of any unexpected property, the mere provision of a crystalline form of a known pharmaceutically active compound cannot be regarded as involving an inventive step”. Therefore, if patent claims are directed to a specific polymorph, it is advisable to include some data showing how that polymorph overcomes a technical prejudice.

Chemical PurityOn the other hand, it can be much harder to convince an examiner that a higher grade of purity should be a novelty defining feature. Both the UK IPO and European Patent Office regard a prior art document disclosing a small molecule as disclosing that chemical compound in all grades of purity. A patent applicant will only succeed in claiming a higher grade of purity if there is an exceptional situation in effect which could justify the examiner reaching a different conclusion. For example, where all previous attempts in the art to produce a higher purity compound had failed, but the patent

Method ClaimsFinally, if an inventor has developed a novel method for preparing a known drug which is at least a non- obvious alternative to known methods, or provides an advantage (e.g. increased yield or fewer processing steps) then method claims should be included in the patent application. This provides patent protection for the method itself plus automatic protection extended to any product directly obtained by the process (Article 64(2) EPC and Section 60(1)(c) PA 1977). However in both the EPO and UKIPO examiners will object to “product-by-process” claims attempting to claim “known product X prepared according to method Y” where “product X” is indistinguishable from “product X” made by prior art methods. Such claims are deemed not novel.

ConclusionEven if a chemical compound is known, an inventor can still obtain extremely useful patent protection for the compound, if the compound is tied to another novel feature – be that a novel medical use, formulation or crystalline form. Whilst the gold standardis always a patent to the compound itself, pharmaceutical companies and others routinely use the claim formats described above to claim a monopoly for their research or to maintain their share of the market once their compound patent has expired. In fact we often include these types of patent claims in newly-filed patent applications, even when the molecule itself is believed to be novel, to provide commercially useful fall-back positions. Some of Europe’s best-known drugs are patented in this way.

applicant succeeded, a claim of “compound X having Y% purity” could be patentable. When an invention lies in forming a particularly pure compound, claims directed to the method steps which provide that purity level are more likely to be granted than claims to the compound itself at that purity level. Such method claims can be enforced against third parties who form the compound directly using the claimed method. Selections from Generic DisclosureVery often a prior art document cited in a search report generically covers a huge number of compounds whilst only focussing upon a few compounds or a sub-class. Typically, the prior art does not list each and every single chemical compound covered by the application, but rather presennts a a general structural formula with lists of alternatives for each substituent position. These are called “Markush groups”.

In general, the position of the European Patent Office and the UK IPO is that the generic disclosure of a large class of compounds is not to be taken as the disclosure of each and every member of the group. Therefore, a futurepatent applicant can attempt to secure patent protection for a sub-class of the compounds that were generically disclosed in a previous application, for example a single compound or narrower sub-range.

The approaches of the UK IPO and the EPO are largely the same. In short, the selection from the known group of compounds that the applicant makes must make a technical advance as compared to the larger group of compounds and cannot be merely an arbitrary selection. In other words “there must be something special about the later range” (UK court decision in Union Carbide Corp vs. BP Chemicals). So a “selection invention” can be novel, but to be inventive both the UKIPO and EPO apply the same set of criteria, from EPO board of Appeal decision T 939/93:1. The selection must not be arbitrary but should be justified by a previously not known technical effect;2. That technical effect must be produced by substantially all the selected members of the group; and 3. The technical effect must be identified in the specification as filed.So a selection from a previously disclosed pool of compounds can

be both novel and inventive, if the patent applicant can prove points (1) to (3). Nevertheless, the patent applicant needs to beware. If the previous generic disclosure is quite small, an examiner can allege that, in fact, all of the individual members of the group are disclosed. For example, in the UK court case Norton Healthcare LTD vs. Beecham Group PLC, the judge decided that a prior suggestion of a combination of sodium or potassium clavulanate with amoxicillin or amplicillin tryhydrate (four possible combinations) was a disclosure of each of the combinations.

AnaloguesClaims directed to analogous molecules may fail the inventive step test, because the examiner might well consider that it would have been obvious for a skilled person to investigate analogues of a known active agent. In the UK, in Pharmacia v Merck [2002] RPC 775 CA the Court of Appeal upheld an earlier ruling by the Patents Court that it would have been “obvious to try” structurally similar analogues of known Cox II inhibitors. In this case the analogue in question was simply a regioisomer of the known drug.

However, if the patentee makes different substitutions to a molecular backbone, and can argue that the new substituents would not be expected to have the same effect as those in the known molecule, then inventive step might be acknowledged. However, the patent applicant would probaly need technical reasons why the skilled person would have no resonable expectation of successfully solving the technical problem with the change of substituent.

Parameter RangesIt is sometimes possible to claim a known compound by including in the claim a characterising parameter range, for example a range of molecular weights for a known polymer, or other physical characteristics such as melting point or characterisation data. These claims will not be novel, however, if the prior art disclosure would inevitably lead to the same claimed parameters, for example if following the instructions in a prior art method automatically leads to a compound having the claimed melting point, even if that melting point is not explicitly disclosed.



Dr Matt Barton isa partner and memberof the Life Sciencesand Chemistry team atForresters patent andtrade mark attorneys.Based in Forresters’ Munich office, Dr Barton specialises in patent prosecution at the EPO and UKIPO and coordinates clients’ patent portfolios worldwide. He is a specialist in chemical and pharmaceutical patent applications and has considerable experience of EPO opposition and appeal matters, often defending his clients’ interests at oral proceedings. Email: [email protected]




delay in marketing their patent-protected medicines pending the grant of a marketing authorisation (MA).

In order to secure an SPC it is necessary to fulfil three positive requirements and a single negative requirement. The three positive requirements are:• The existence of a product protected by a basic patent. A “product” is defined as the active ingredient (including a combination of active ingredients) of a medicinal product. The Regulation includes a prolix definition of “medicinal product”. For present purposes, we can assume that the definition covers a medicine, i.e. a substance one gives to a human (or animal) for curative or diagnostic purposes.• An authorisation under the EU medicines code to place the product on the market as a medicinal product.• The aforementioned authorisation is the first authorisation to place the product on the market as a medicinal product.The negative condition is that the product has not already been the subject of an SPC.

Combination TherapiesApplying the SPC regime to combination therapies has presented an almighty challenge to Courts across member states, the fundamental conundrum being whether the scope of an SPC is equivalent to that of the underlying basic patent.The issue is best illustrated with an example.

Facts: Active X is used in combination with Active Y in Medicine A. Medicine A is the subject of a marketing authorisation. Active X is protected by a basic patent but Active Y is not (whether alone or in combination with Active X).

Protection under the basic patent: During the lifetime of the basic patent, an unauthorised third party selling

Medicine A infringes the patent: even though Medicine A is a combination of two active ingredients, the basic patent protects Active X howsoever used. Protection under the SPC: An SPC is not an extension of the basic patent per se; the scope of protection is framed by the Regulation. To secure SPC protection the product (i.e. the active ingredient or combination of active ingredients of the medicinal product) must be “protected by a basic patent in force”. This suggests that, because Medicine A consists of a combination of Active X and Active Y, to secure SPC protection the basic patent must likewise disclose and claim the two active ingredients in combination.

The notion that the basic patent must disclose the combination of active ingredients (“the disclosure test”) is one which found favour with the UKIPO and the UK Court in a triumvirate of cases in the 2000s - Takeda (2003), Gilead (2008), and Astellas (2009).In the Gilead case, Mr Justice Kitchin rejected the alternate “infringement test” theory favoured by patentees (i.e. that the product was protected by the basic patent if its sale etc. infringed the basic patent). His reasoning was that the

Supplementary Protection for Medicines – Functioning or Failing?

The legislation governing Supplementary Protection Certificates (“SPCs”) for medicinal products – EU Regulation No. 469/2009 (“the Regulation”) - is admirably short, running to a streamlined 11 recitals and 23 Articles. However, whilst the Regulation scores well on brevity, it falls down badly when it comes to clarity. This lack of clarity has recently boiled over into judicial frustration, most vividly articulated by Mr Justice Arnold in the recent decision of GlaxoSmithKline Biologicals (21 March 2013). In that case the learned Judge - avoiding any opportunity to fence-sit - had the following to say on the SPC regime:

“…I would observe that this is the third time in six months that I have had to refer questions of interpretation of the SPC Regulation to the CJEU. I do so with considerable regret. That this should be necessary demonstrates the dysfunctional state of the SPC system at present. This is primarily due to the poor drafting of the SPC Regulation and to the failure of the European Commission, Council and Parliament to revise it to address the problems which have emerged. Matters have not been assisted, however, by the fact that the Court of Justice’s recent case law interpreting the SPC Regulation has not provided the level of clarity and consistency that is required.”This article considers whether the

“dysfunctional” label is merited and if so why. In doing so, three specific aspects of the SPC system will be considered: combination therapies, new indications and active ingredients.

SPCs – The BasicsAn SPC gives up to five additional years of patent equivalent protection for a medicine following patent expiry, the underlying rationale being to compensate patentees who experience



infringement test could be considered contrary to the purpose of the Regulation “which is to provide an effective period of protection for the invention the subject of the patent and so encourage research, and not to provide an extension of protection based upon the adoption of another, possibly quite different, ingredient.”

In the Gilead decision, Mr Justice Kitchin recognised that the application of the disclosure test could produce harsh results, for example, where the patentee had chosen to market its product only in combination with another active ingredient.1 Such a situation arose in the Medeva case, where MAs had been secured for, inter alia, four vaccines, each of which featured two antigens protected by the basic patent in combination with additional actives (which were not claimed in the basic patent). Medeva’s application for SPC protection for these four vaccines was refused by the UKIPO as they were not protected by the basic patent - they contained active material undisclosed in the patent. The case went to the Court of Appeal which, in June 2010, sent six questions to the Court of Justice of the European Union (“CJEU”).

The CJEU rejected the infringement test in the Medeva reference (and in four further references decided at the same time)2 and held that an SPC should not be granted if it related to active ingredients which are not “specified in the wording of the claims of the basic patent”.

The decision of the CJEU has met with considerable criticism. In Novartis v MedImmune (2012), Mr Justice Arnold observed that:

“… not only has the Court not answered the question referred, but also the guidance it has provided is not sufficiently clear to enable future disputes to be resolved.”

He went onto observe that:“…it is unclear precisely what is meant by “specified (or identified) in the wording of the claims”. … For example, is it sufficient, say, for the claim to incorporate a Markush formula which covers a large number of compounds one of which is the product in respect of which an SPC is sought? Is it sufficient for the product to be defined in functional terms? Even in

combination cases, it is not clear to me how the test enunciated by the Court should be applied in a case like Gilead. Regrettably, therefore, it is inevitable that there will have to be further references to the CJEU to obtain clarification of the test.”

A little more diplomatically (albeit the underlying frustration is clear), the Court of Appeal had this to say in 2012 when it was tasked with applying the CJEU’s reasoning in the Medeva case:

“...the ambit of ‘specified’ may range from express naming, through description, necessary implication to reasonable interpretation. Where on that scale the dividing line is to be drawn will necessitate further references in due course in the light of the facts of the cases in which the issue arises.”In the way of any self-fulfilling

prophecy there has now been two further references to the CJEU on this question. In Actavis v. Sanofi (Sept 2012), Sanofi had secured an SPC for a combination of the antihypertensive drug irbesartan and the diuretic HCT. The basic patent relied upon by Sanofi claimed irbesartan in combination with a diuretic, but there was no specific claim to HCT. Actavis challenged the SPC on the basis, inter alia, that the combination was not protected by a basic patent. Again, Arnold J felt compelled to refer further questions to the CJEU because of the lack of clarity following the Medeva (and related) references. Specifically, he referred the following question: “What are the criteria for deciding whether ‘the product is protected by a basic patent in force’ in Article 3(a) of the Regulation?”In doing so Arnold J offered up his own thoughts in the hope that it would assist the CJEU. He said that “In my view, the answer is that the product must infringe because it contains an active ingredient, or a combination of active ingredients, which embodies the inventive advance (or technical contribution) of the basic patent. Where the product is a combination of active ingredients, the combination, as distinct from one of them, must embody the inventive advance of the basic patent.” On that basis the Judge considered that the Sanofi SPC was not valid because the

combination of irbesartan with either a diuretic in general or HCT in particular did not embody any inventive advance. Subsequently, the same question has been referred to the CJEU by Warren J. in Eli Lilly v. Human Genome Sciences (October 2012) (albeit the case concerned a claim to an antibody or class of antibodies).

New IndicationsArnold J has also had much to say in recent cases about the CJEU’s Neurimdecision, which endorses SPC protection for new applications for existing ‘old’ active ingredients. Neurim’s patent was for a medicinal treatment for insomnia based on use of the natural hormone melatonin (Circadin). The UKIPO had rejected Neurim’s SPC application because of Hoechst’s earlier MA for melatonin for use in regulating the seasonal breeding activity of sheep (Regulin) i.e. Neurim’s MA was not thefirst authorisation to place the product on the market as a medicinal product. On appeal to the Patents Court, Arnold J, following the CJEU’s line of decisions in Pharmacia (2004), MIT (2006) and Yissum (2007), agreed with the UKIPO and refused the SPC.

On appeal, Jacob LJ, whilst referring questions to the CJEU, rejected the approach taken by the UKIPO and Arnold J because it had the consequence that

“…the [SPC] Regulation will not have achieved its key objects for


cynics, “teleological” and “making it up as we go along” can be considered synonymous). Whilst the CJEU’s decision in Medeva at least confirmed that the infringement test is inconsistent with the Regulation, applicants for SPCs and their generic competitors are no closer to understanding what is meant by ‘specified or identified in the claims’. The concern now is that the CJEU will repeat what it said in Medeva, leaving it to national courts to determine the necessary scope of protection. Inevitably that will lead to inconsistency of protection between member states, the very opposite of what pan-EU legislation such as the Regulation is supposed to promote. Indeed, one already sees this with irbesartan. As noted, whilst he has made a reference to the CJEU, Arnold J is of the opinion that the combination is not protected by the basic patent and that SPC protection should be refused. However, in Germany, France and the Netherlands, Sanofi has secured injunctive relief against generic makers of the combination. In those actions, the Courts have taken a provisional view that HTC is sufficiently specified in the claims of the basic patent.

References1. This was not the case in Gilead where the patentee had enjoyed SPC protection for lansoprazole and was seeking to secure additional SPC protection for lansoprazole in combination with an antibiotic.

2. Georgetown University, Yeda, Daiichi and University of Queensland.

ASO3 and one for a vaccine comprising an antigen and ASO3 – in both cases, relying on an MA for a pre-pandemic influenza vaccine marketed under the trade mark Prepandrix. The Comptroller rejected both applications as ASO3 was not an ‘active ingredient’, whether in its own right, or in combination with the antigen contained in Prepandrix, as it did not have a therapeutic effect on its own. The fact that AS03 enhanced the therapeutic effect of the antigen when combined with it in the vaccine was not sufficient. In particular, the Comptroller relied on the CJEU’s decision in MIT which adopted a strict interpretation to the concept of ‘product’.

Again, Arnold J felt he had no choice but to make a reference to the CJEU. He acknowledged there was merit in the argument that the primary purpose of the Regulation was to reward the type of innovative research that led to GSK’s development of ASO3 and Prepandrix, but concluded that this should bow to legal certainty: “I consider that the SPC Regulation was intended to provide a simple and predictable system that could be operated … in a uniform manner. To achieve these objectives, it is necessary to have bright-line rules.”The German bundespatentgericht has recently made a reference to the CJEU (Bayer CropScience) concerning the similar provision in the Plant SPC Regulation (1610/96/EC). The question posed is whether a ‘safener’ (a substance added to herbicides to eliminate or reduce their phytotoxic effects on certain plants and which works in combination with the herbicide) can be an ‘active substance’. Like Arnold J, the German Court prefers a strict interpretation of ‘active substance’, limiting it to substances which have a direct therapeutic effect or plant protection action of their own; although the safener is an integral part of the plant protection product, it does not necessarily constitute an active substance.

Concluding RemarksThe frustration expressed by Arnold J in response to the CJEU decisions in Medeva and Neurim is entirely understandable. In Neurim, a whole line of case law was ignored by the CJEU in favour of a seemingly teleological approach to the Regulation (for

large areas of pharmaceutical research: it will not be fit for purpose”. He expressed a clear policy view that “it would be most unfortunate if second medical use patents could not get the benefit of an SPC”.

The CJEU’s decision supported Jacob LJ’s assessment (albeit, in doing so it failed to mention its earlier case law which had been relied upon by Arnold J at first instance). It decided that the existence of an earlier MA for a medicinal product would not preclude the grant of an SPC for a different application of the same product. In reaching this conclusion, it adopted a teleological approach to the interpretation of the Regulation, focussing in particular on its “fundamental objective”, i.e. “to ensure sufficient protection to encourage pharmaceutical research, which plays a decisive role in the continuing improvement in public health”. Further, it decided that it was apparent from paragraph 29 of the explanatory memorandum to the EU Council proposal for the earlier version of the Regulation that patents protecting a new application for a new or known product could lead to an SPC being granted.

As with the Medeva decision, Arnold J has been forthright in his views on Neurim. In two subsequent decisions (AstraZeneca v Comptroller (10 October 2012) and GlaxoSmithKline Biologicals (21 March 2013)), he expressed concern that the CJEU failed to mention (let alone follow) earlier case law which was inconsistent with its decision. In particular, in AstraZeneca he suggested that the CJEU had placed “undue emphasis” on the Regulation’s first objective, i.e. to ensure sufficient protection to encourage pharmaceutical research when there were two further objectives of the Regulation which should also be taken into account: namely the need to prevent the heterogeneous development of national laws which may create obstacles to the free movement of medicinal products in the Community and the need to take into account all of the interests at stake, including those of public health.

Active IngredientsIn the GlaxoSmithKline Biologicals case, GSK had filed two applications for SPCs - one for an adjuvant known as

David Roseis a Partner atSJ berwin LLP andHead of the IPDepartment. Hechairs the firm’sLife Sciences & Healthcare Group and has considerable experience in this sector, having acted in many of the major pharmaceutical patent actions in recent years. Email: [email protected]




masking are particularly important considerations). In addition, challenges of patient compliance or adherence and environmental factors also contribute to this recognition of the need for change in the industry.

Early consideration of the manufacturing flexibility that a technology offers is becoming increasingly important as companies are forced to think about their target populations in a more separate and segregated manner. Table 1 highlights a number of attributes which will increasingly be sought when formulating, processing and manufacturing medicines for clinical studies and targeted patient populations.

A number of innovative approaches in preparing and processing drug substances have emerged over recent years, and there has been a growing interest in drug particle design; especially given the fact that over 80% of medicines are preparations which contain solid drug particles. There are a number of very exciting new technologies that are arising which have the potential to address the urgent need for more efficacious therapies, and which overcome the

Partnering to Drive Innovation: A Supercritical Success Story

The design, development and manufacture of modern medicines pose numerous scientific and technical challenges to drug delivery and pharmaceutical companies. Increasingly, companies are finding that approaches which have traditionally been used to overcome these problems and in-house experience/expertise available are no longer appropriate or sufficiently versatile to solve many of the emerging issues.

The new chemical entities (NCEs) and biotechnology-based macromolecules being discovered, screened and selected to be transformed into efficacious and safe medicines, albeit with reduced frequency now compared with previous decades, often require alternative, innovative strategies in order to facilitate this journey and enable new therapies to enter the market.

Figure 1 highlights a number of the aforementioned ‘difficult’ properties of these small and large molecule drug substances (active pharmaceutical ingredients – APIs) together with examples of associated desirable

pharmaceutical attributes now required to generate medicinal products which meet the demands of the medicine regulatory agencies, for example the Medicines and Healthcare Products Regulatory Agency (MHRA) amongst others. These requirements are becoming more stringent, and so many companies are looking ‘further afield’ in order to find suitable solutions.

In parallel, the changes in the size of target population groups for specific APIs, as a result of increased knowledge in genomics and proteomics and successes with diagnostic agents, together with the awareness that the design and form of medicines for sub-population groups clearly impact on the changing nature of manufacturing processes. Thus, the future of pharmaceutical medicines is likely to focus on adaptable, versatile, scale-down technologies that can cater for these inherent physiology and biochemistry differences in sub-population groups. There is ever-increasing awareness of the need to design medicines suitable for sub-population groups, including paediatrics and geriatrics (where dose flexibility and efficient taste

Figure1: Challenging properties of emerging small molecules and biotech macromolecules with examples of drug delivery and dosage form administration requirements

Table 1: Attributes and requirements of processing operations for preparation of APIs, formulating and manufacture of modern medicines

employed is based on the use of supercritical carbon dioxide (scCO2) as an anti-solvent against a stream of drug solution (or drug with other functional additives in solution) under supercritical conditions. The scCO2 rapidly extracts the solvent and a uniform, dry powder (of API/API composite particles) is formed and retained in the particle formation vessel (see Figure 2). Due to the inherent design of the process, it is thermodynamically stable, which allows a high level of control over the particle size, particle size distribution and particle morphology.

Unlike conventional crystallisation processes, supersaturation in this scCO2

depends on pressure; therefore different solutes will precipitate at different stages of expansion. As a result, it is possible to manipulate crystallisation impurities which may affect solid state form1 and to allow different components in a multi-component system to precipitate in a single particle, which may be desirable for taste-masked formulations.

by changing the process conditions, directed changes in the physical, chemical, solid state and/or surface characteristics of the particles can be made offering clear versatility in the SCF approach. Typical average particle sizes of narrow-ranged distributions obtained are from hundreds of nanometers to tens of microns, a range which encompasses the sizes being found relevant in dealing with challenging APIs.

Many APIs formed by this process exhibit extremely smooth crystal surfaces, which help to explain a number of the advantageous secondary processing characteristics observed when handling powders formed using the supercritical anti-solvent (SAS) process. Typically SCF



challenging issues that can often lead to inefficient drug delivery (see Figure 1), faced by new and existing APIs in development, or where companies are looking to extend the life of product protection through innovation.

Such novel technologies include 3D printing, stem cells, regenerative medicines, cell scaffolds and targeted delivery systems which employ SiRNA as well as viral vectors and /or aptamers. All of these new, ‘unconventional’ technologies show great promise, but still need to gain approval from relevant regulatory authorities through approval of developed medicines being launched into the marketplace.

Of these ‘new’ technologies, supercritical fluid (SCF) based crystal and particle engineering has shown great promise, and the first SCF-engineered medicine, a suspension metered dose inhaler (MDI) product for treating migraine directly via drug delivery to thelungs, has completed Phase III studies and is currently awaiting approval by the US Food and Drug Administration (FDA). As a consequence, the manufacturing process itself, and equipment that has been used to produce the material, have been approved by the FDA, making it a commercially viable alternative to the more traditionally used techniques for producing micron-sized drug particles, for example jet-milling.

Pioneering studies and continuing research into SCF processing of APIs and API composite particles have been carried out in bradford, UK. This has been enabled through University of bradford spin-out small and medium enterprise (SME) companies for over 15 years, and the work is currently being progressed by CrystecPharma. Larger pharmaceutical companies are now beginning to value the flow of ideas, and new viable approaches that SMEs can offer in the design of medicines, for both new APIs and for improving the bio-performance of current medicines, as is often sought in life cycle management (LCM) strategies.

This particular application of the SCF technology is a ‘bottom-up’ technique offering the opportunity to design crystal and particle characteristics in from the outset with the end application in mind. As such, it is particularly attractive in terms of incorporation of quality by design (QbD) ambitions.The process

Figure 2: Crystec SCF process for the single-step formation of dry API particles from solution

processed APIs and / or API composites (in crystalline and semi-crystalline states) have few crystal defects (which can act to affect chemical purity and lead to both chemical and physical stability issues). The low surface energy mentioned above reduces cohesion between particles, improving the flowability of the powder, and overall enabling good secondary processing behaviour of the particles 2,3.

Additionally, the in-vitro and in-vivo performance that the powders demonstrate over similar sized particles prepared using ‘top-down’, high-energy milling processes is impressive. Benefits that contribute to this improvement in execution include facile aerosolisation to primary drug particles, good flow and mixing properties, and rapid dissolution of particles engineered and designed to have a high surface area. Figure 3 compares the morphology and particle size uniformity of a milled micronised sample and an SCF processed sample of an API. The regular, smooth surfaces and particle size uniformity of the SCF sample is clearly evident.

Figure 3 Micronised starting material

Figure 3 SCF processed powder

for example suspending agents and valve lubricants in MDI formulations that can have a detrimental impact on the final pharmaceutical product (e.g. encourage crystal growth etc.). This ease of aerosolisation can be seen in the data presented in Figure 5. Another area that is of interest, both in inhalation and for delivery of medicines via the oral route, is in taste-masking/encapsulation techniques which provide a uniform coating on core API particles without impeding in-vivo efficacy. Many drugs have an unacceptable, bitter and unpleasant taste, which can lead to poor compliance and consequent


34 INTERNATIONAL PHARMACEUTICAL INDUSTRY Spring / Summer 2013 Volume 5 Issue 3

In this article, examples are given of the many applications of SCF technology. Inhalation is increasingly being considered as an alternative route of delivery for some medicines that have challenges when delivered in other ways, such as by intravenous injection or oral delivery. As an example, the product mentioned previously, which will be the first SCF-engineered drug to be launched, is an inhaled formulation of an existing drug which was originally delivered intravenously. The product, LEVADEX®, will be used to treat migraine, taking away the need for hospitalisation for treatment and making it much easier for sufferers to manage their own condition in a convenient, socially acceptable inhaler devices, will be used to treat migraine, taking away the need for hospitalisation for treatment and making it much easier for sufferers to manage their own condition in a convenient, socially acceptable inhaler device.The impressive batch-to-batch reproducibility that SCF allows can be observed in Figure 4. The seven batches that are overlaid on this graph are daughter batches of an in-house pipeline product being developed at laboratory scale (600 ml vessel) in bradford. All measurements were made by a Sympatec laser diffraction analyser (4 bar) and show D10, D50 and D90 particle fractions of 0.5 µm, 1.3 µm and 2.9µm, respectively. Thus the thermodynamic, highly controlled process that SCF encompasses allows confidence in achieving excellent batch consistency, thus enabling daughter batches to be blended.The above-mentioned smooth crystal surfaces also allow the powders to be compatible with a wide range of inhaler delivery devices. There is far less device dependency than with powders that are produced using the more conventional micronising techniques. This is because all of the intrinsic powder properties that have been described lead to strong aerodynamic performance characteristics of the powder alone, without the need to add other agents to improve the inhalable functionality of the powders. This leaves open opportunities for simplified formulations as there is no need to add complicated and undesired excipients,

sub-optimal health outcomes in children and older people and other adults. It is a problem which is increasing in frequency and must be addressed. SCF processing can provide a solution in these circumstances. For example, successful taste-masking of diclofenac sodium was achieved using the technology, and Figure 6 shows the clinical in-vivo performance in human volunteers of two taste-masked formulations. Success in taste-masking efficiency of the formulated SCF preparations was confirmed from studies by using a taste panel. The final formulation was an orally dispersible tablet (ODT), requiring rapid dissolution and thus rapid achieivement of the

Figure 5: Typical aerosolisation behaviour of an SCF powdered product designed for an inhalation medicine (measured by Sympatec dry powder particle sizing equipment)

Figure 4: Particle size data for seven batches of an API for inhalation drug delivery



posed by new APIs, such as poor aqueous solubility and/or low absorption characteristics can be overcome. In addition, the flexibility of the process and facile scale-up/scale-down operation enable specific formulation and dose requirements of sub-population groups and ‘personalised’ medicines to be met.

Whilst in-house experience and know-how at bradford extend to the design, commissioning and operation of SCF process equipment at scale and under cGMP, the current focus is to build on existing strengths to provide innovative and pioneering solutions in particle design and crystal engineering

desired plasma levels. Figure 6 shows no loss in speed of uptake, or bioavailability (i.e. area under plasma level-time curve) compared with the marketed product. This was thus a demonstration of successful secondary processing into tablets of SCF-coated particles and maintenance of the taste-masking coating.

This flexible, single-step SCF process provides the range of attributes highlighted in Table 1. Through careful design of processing conditions, resulting API/API composite particles can be designed so that many of the physiological and formulation challenges

Figure 6: In-vivo performance of successfully taste-masked diclofenac sodium as assessed by a taste panel. SCF based rapid release test formulations meet bioequivalence criteria regarding extent of absorption and result in very rapid and complete absorption

of APIs for clients to allow therapies to progress through development that would otherwise have been disregarded as unmanageable from a chemical or manufacturing point of view.

The ‘journey’ from API to regulatory approved medicine is lengthy and costly, and also requires a wide range of additional expertise and facilities. The necessity to move from ‘blockbuster’ drug manufacturing to a more personalised approach is becoming increasingly necessary to allow treatment of patients in the most effective way. At Crystec, the in-house product development pipeline focuses on exploiting the inherent


Paul Titley isDirector of businessand Commercial Development at AesicaPharmaceuticals.He founded R5Pharmaceuticals in2006 to provide formulation development, analytical chemistry and GMP services to the global biotech and pharmaceutical industry. The company was acquired by Aesica in June 2010 to operate as the company’s Formulation Development business Unit; a leading provider of pharmaceutical dosage form development across Europe. Paul has been instrumental in the formation of partnerships between Aesica and companies like CrystecPharma. Prior to establishing R5 Pharmaceuticals and joining Aesica, Paul qualified as a chemist during his twenty-five years’ service with Wellcome, which he left in 1996 as Head of Worldwide Technical Support. He also worked in business development and senior management for Quintiles and Encap Drug Delivery, before becoming an independent consultant in 2005 working with clients in India and the Czech Republic. E-mail: [email protected]

Professor Peter York Emeritus Professor of Pharmaceutics at bradford UniversityProfessor Peter York was Professor of

Physical Pharmaceutics at bradford School of Pharmacy from 1991 to 2010. He is now Emeritus Professor of Pharmaceutics at bradford University and a world-leading expert in pharmaceutical materials science with specific expertise in supercritical fluid (SCF) processing. He is also currently Chief Scientist at CrystecPharma (a SCF company). Peter has published over 350 scientific articles, supervised over 60 successful PhD students, acted as External Examiner for over 100 PhD examinations in the UK and overseas, holds numerous patents and has received several research awards. Peter co-founded bradford Particle Design Ltd in the 90s, a spin-out venture from the University of bradford, which was acquired by Inhale Therapeutics in 2001. He holds Fellowships of the Royal Pharmaceutical Society of Great britain, the Royal Society of Chemistry, and the American Association of Pharmaceutical Scientists. He sits on regulatory review panels and is an Honorary Visiting Professor of the Shanghai Institute of MateriaMedica, Chinese Academy of Science. E-mail: [email protected].


most importantly – the patients!

References

1. Edwards, A.D., Shekunov, b.Y., Kordikowski, A., R.T., York, P. Crystallisation of pure anhydrous polymorphs of carbamazepine by solution enhanced dispersion with supercritical fluids (SEDS). J. Pharm Sci. 90, 1115-1124 (2001)2.Rehman, M., Shekunov, b.Y., York, P., Lechuga-ballesteros, D., Miller, D.P., Tan, T., Colthorpe, P. Optimisation of powders for pulmonary delivery using supercritical fluid technology. European J. Pharm Sci., 22, 1-17 (2004)3.Lobo, J.M., Schiavone, H., Palakodaty, S., York, P., Clark, A. SCF-engineered powders for delivery of budesonide from passive DPI devices. J. Pharm Sci., 94(10), 2276- 2288 (2005)

benefits that SCF processing can offer and the challenges that it can help to overcome in order to create products to surmount unmet clinical needs.

It is vital that SMEs, such as Crystec, continue to explore new approaches for drug delivery systems and design medicines which will provide benefits to patients whilst forwarding innovative technologies, such as SCF processing, for exploitation in the pharmaceutical industry, ultimately creating medicines with superior performance. Through partnering to drive innovation, we can ensure that promising drug candidates progress along the ‘journey’ to the clinical testing stages, and eventually to market, in an efficient and coordinated manner. What emerges is a ‘win-win-win’ strategy – with distinct benefits for the research organisation, contract manufacturer, and

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Dr Tom Moody, Head of Biocatalysis and Isotope Chemistry and Dr Stefan Mix, Biocatalysis Team Leader at Almac describe the latest biocatalytic technologies developed by the company and how they are assiting in API development. The technology is used to support its broader chemistry offerings for the synthesis of advanced chiral intermediates and APIs for pharmaceutical and biotech customers.

It is now well-recognised that the need for green, economic, robust and scaleable processes is at the forefront of customer research plans for the synthesis of chiral APIs and intermediates. The chemical industry is under severe pressure to make their chemical processes greener, lower costs, minimise waste and shorten existing syntheses.1-3 At Almac, the selectAZymetm platform provides a diverse, A-Z range of enzymes including reductases, transaminases, hydrolases, nitrilases and many others.

In collaboration with their customers, Almac selects the optimum enzyme to provide an efficient and cost-effective process for scale-up. These enzymes are finding uses in applications from A-Z in medicinal chemistry, metabolite synthesis and in the large-scale manufacture of speciality chemicals. “The power of enzymes is their unequalled selectivity for the chemical reactions they catalyze”.4 biocatalysis is becoming the workhorse of the chemist’s toolbox for chiral chemistry5 and is now at the epicentre of key drivers in process design and economics, including:

• Determination of key cost contributors• Route scouting• ID and prioritisation of routes to be investigated• Key reaction optimisation and DoE• Investigation into waste stream management

Discovery of new enzymes for a novel synthesis at Almac involves research scientists searching the chemical literature and carrying out bioinformatics to create a panel of enzymes that can be optimised through gene-informed diversity screening.

Biocatalysis is a Key Technology for Successful Chiral Synthesis

Following on from this, desired mutations are introduced into the genes, resulting in novel enzymes with the desired biocatalytic activity. Each ‘optimised’ enzyme is then screened against a range of standard drug- and intermediate-like compounds to determine its selectivity and activity and whether further optimisation is required.

Screening, upscaling and biocatalyst production takes place at Almac’s integrated facilities in Craigavon, UK, which includes molecular and microbiology, analytical, radiolabelling, process chemistry and pilot plant facilties. For any new molecule, the company can complete route invention, screening, enzyme production, process optimisation and manufacture to GMP standard. For production of biocatalysts beyond pilot plant capabilities, Almac uses its UK and European specialist fermentation partners for multi-thousand-litre-scale production.Why has there been a surge in the application of this green technology? The answer is simple, says Dr Tom Moody: “success breeds success; the key difference today with biocatalysis compared to 10 years ago is - we now have all the supporting technologies that can really make a difference in enzyme development such as bioinformatics, enzyme evolution, high-throughput screening, etc. The list goes on and on; we can now get processes running in weeks and can evolve enzymes in months”. The application of green selectAZymeTM technology is a first choice for Almac when looking at chiral synthesis, and enzymes now offer myriad chemical transformations, as shown in Figure 1.

Another key advantage of running these processes is the timeline required for implementation. From selection of a selectAZymeTM catalyst to actual manufacture of product, timelines are similar to those of conventional chemistry optimisation and scale-up. Typical timelines are shown in Figure 2.

Figure 1. Examples of selectAZymeTM platform transformations

Figure 2. Timelines for using the selectAZymeTM

platform

Biocatalysis and API Clinical Trials SupplyIn the timely delivery of batches of API to support clinical trials, options to simplify or shorten the synthetic route are always welcome. (S)-2-bromocyclohex-2-enol(1) is frequently encountered as the starting point in a number of natural product syntheses, including (+)-trans-195A (2), the name assigned to a decahydroquinoline alkaloid isolated from the skin of dendrobatid frogs.6

blechert and coworkers prepared 1 on a 0.5 g scale in 95% yield and 99% e.e. using a CbS reduction followed by chromatographic purification. Almac had a requirement to synthesise 100 g quantities of 1 for a novel therapeutic agent currently under development, and wanted to evaluate the use of a CRED enzyme for this. Screening of the selectAZymeTM CRED kit identified an enzyme that exhibited high conversion and high enantioselectivity, albeit using a glucose / glucose dehydrogenase coupled system.7 There are a number of reaction parameters to consider when developing a CRED reduction, including temperature, pH, cofactor regeneration and % substrate loading. Systematic evaluation of these parameters identified good reaction progress at 30oC (lower temperatures gave slower reaction progress; higher



to on-time delivery of API of the required purity.Another typical project at Almac includes, for example, a Phase IIb compound where nine steps of chemistry resulted in the formation of three chiral centres from a registered starting material with a global yield of 7.4%. Key to winning the project was the marriage of Almac’s synthetic, analytical and solid state chemistry and introduction of green selectAZymeTM

chemistry for induction of chirality. The project was initiated with clear objectives:1) Increase productivity of the process >50% kg/[L/day].2) >20% reduction in waste.3) Removal of expensive and toxic solvents.4) Removal of heavy metals and subsequent contamination.5) Removal of necessity for specialised equipment (currently high-pressure hydrogenation).6) Development of a process with consistent quality of product.7) Lower the cost per kg of product.

The original chemistry involved myriad steps including a late-stage classical resolution using an expensive amine resolving agent and high-pressure hydrogenation using metal catalysis. The late-stage resolution resulted in huge volumes having to be processed until step 7. Almac’s challenge was to make a scaleable lower-volume route that had green and cost incentives for change. Almac completed route invention, proof-of-concept demonstration followed by 100s of kgs scale-up prior to tonne manufacture. The revised route consisted of five steps using three different selectAZymeTM

enzymes with a global yield of 23.4%.Innovation was achieved by delivering

a green process that was scaleable,

temperatures also gave slower reaction progress, presumably due to denaturation of the enzyme), pH 6-6.5 (pH 8 gave significantly slower progress) and 20 volumes of solvent.

IPA (20% v/v wrt substrate) was shown to be effective at regenerating the cofactor. Lower (sub-stoichiometric) concentrations of IPA gave incomplete reaction, while higher concentrations also produced a detrimental effect. Convenient as IPA is to use for cofactor regeneration, it does lead to an equilibrium that doesn’t favour complete substrate reduction. This problem was overcome by applying a partial vacuum to the reaction mixture to remove acetone, while sparging in IPA to maintain a sufficient concentration in the reaction mixture. Application of these conditions on 100 g input substrate scale, using the CRED as a cell paste, generated the desired product as a colourless oil in 88% yield with an enantiomeric excess of 99.8%. Significantly, the product was of sufficiently high purity to use directly in the subsequent step without any further purification.

For many projects, biocatalysis can be purposely employed from the outset. However, biocatalysis is also a highly valuable technique when problems are encountered with a process. One example of this is shown in Figure 3.

Delivery of this project required access to a chiral amino alcohol of high enantiomeric purity. On lab scale, this had been readily achieved by a traditional diastereomeric resolution. However, as this chemistry was developed for scale-up it quickly became apparent that this resolution wasn’t working as required, with low yields and

challenging filtration issues being observed. To ensure that the committed delivery date for the API was met, work started on an enzymatic resolution approach, while continuing to work on improving the crystallisation. Following a selectAZymeTM

hydrolase enzyme screen, a lipase was identified that converted the undesired enantiomer to an acetate ester, simply by running the reaction in ethyl acetate (both as acyl donor and solvent). The two product components (desired enantiopure alcohol and undesired ester) were readily separated and, following some focussed development work, the lipase approach was successfully applied on scale, leading

derived from readily-available feed stocks, and used “off-the-shelf” selectAZymeTM

enzymes with no “strings” attached. From retrosynthetic analysis it was demonstrated that the registered starting material could be made from feed stocks that would not have any long-term supply issues and could be sourced readily from India and China. Having the proposed route on paper, the next step was to synthesise the key intermediates and begin enzyme screening. The project involved an early-stage bioresolution that resulted in a monoacid product with >96% ee. From this, a bioreduction step introduced another chiral centre. Key to this enzyme screening was to find a carbonyl reductase (CRED) enzyme that was able to stereospecifically reduce the ketone of the desired enantiomer feedstock and not the undesired (2%) enantiomer from the bioresolution step. The CRED identified resulted in a stereospecific reduction and subsequent biopolish of the diastereomeric mixture. The remaining undesired ketone was easily removed using conventional work-up at the next step. The process ran from start to finish using two solvent combinations. Having developed the process, all stereoisomers (seven different products) were synthesised readily from other key selectAZymeTM enzymes so that analytical development could be undertaken to determine the fate of these potential impurities. The summarised advantages of the green enzyme process are shown in the table below –

It is clear from the example described herein, that biocatalysis offers an attractive approach for synthesis resulting in greener processes with real benefits for both the environment and costs of your APIs.

The increased demand for oxidative metabolite synthesis has resulted in more and more research and published literature in the area of P450 enzymes. Their utilisation in practical synthesis of Phase I metabolites has led to a greater diversity of off-the-shelf catalysts that

Figure 3. Examples of selectAZymeTM platform transformations



manufacturing scale. The collaboration also enables Almac to offer its customers a preferred partner for large-scale production.

Moody states: “The success of the projects undertaken between Almac and DSM already demonstrates there is a market for scaleable green technologies to access difficult-to-make chiral chemicals.”

At the enzyme discovery stage, the collaboration between Almac and UCL in the area of metagenomics has boosted enzyme throughput into Almac’s growing collection of enzyme platforms. Metagenomics, a culture-independent technique used to extract the total DNA from environmental samples, can allow access to 99% of enzyme genes in these samples. Work previously carried out at UCL has allowed a series of metagenomes to be obtained from various unusual sources. The use of bioinformatic tools will allow the metagenomes concerned to be mined for enzymes usable in both

can be used by the synthetic chemist. The ease of access of P450 enzymes even from published gene sequences meant Almac was able to complete a carbon-13 project where the customer required the corresponding carbon-13 metabolite (Figure 4). Almac simply identified the P450 gene sequence from the literature and obtained the synthetic gene. The gene was cloned and expressed and the isolated enzyme obtained from fermentation was used in the isotope labs to easily access the customer metabolite incorporating the desired carbon-13 labelled sites.

Partnerships and CollaborationThe Almac/DSM agreement grants each company access to their respective enzyme platform technologies, services and expertise for the manufacturing of APIs. Almac’s expertise in rapid enzyme identification, scale-up and implementation into early-phase projects complements DSM’s experience of more than 30 commercial manufacturing bioprocesses run on a multi-ton scale, providing green processing from preclinical to commercial

synthetic chemistry and synthetic biology projects.

Moody further commented, “The need for more diverse enzymes has never been greater, and this research programme further emphasises Almac’s commitment to UK research and to biocatalysis development. Almac is working with Celbius (an ultrasound company) in the development of ultrasound-assisted biotransformations to increase throughput and ultimately drive down the cost of manufacturing. Having access to this technology is finding real benefits for our customers from bioremediation projects, through chemical synthesis to increased fermentation titres. Cost remains a prevalent issue within the industry, and the introduction of enzymes into processes earlier in the drug discovery pipeline helps to drive cost down as projects move forward. Our partnerships and collaborations are delivering real rewards to clients from both a technical and financial perspective.”

Future Directions“The growth of the biocatalysis business has been the direct result of increased acceptance and application of the new enzyme platforms used both in-house by Almac and by their customers for the identification of enzyme hits,” says Moody. “The biocatalyst is now being applied by Almac in the optimisation and delivery of both chiral and achiral intermediates, as well as in GMP manufacturing supporting their customers worldwide. “There are increasingly more and more chiral molecules in the drug development pipeline, and biocatalysis is increasingly the technology of choice for their synthesis,” he adds. “Almac started employing biocatalysis in its custom chemistry services five years ago, initially using biocatalysts supplied by external vendors, and has since been developing its own IP-free enzymes for chiral synthesis. At Almac, biocatalysis has been show to be a technology that can reduce costs due to the potential of minimising processing steps at production, as well as minimising waste and impurity removal costs.”

Mix comments: “As our customer demands changed, we rapidly recognised the best technology to access chiral compounds was through biocatalysis technology. Historically we did not have control of the technology and we subsequently realised that we needed to improve our knowledge in this area and to develop in-house biocatalysts. Critical to the biocatalysis business is to ensure to the

customer security of supply of the catalysts for repeat manufacture. Today, we are now in a position to implement a biocatalysis-based synthesis for a new compound right from medicinal chemistry through to GMP manufacture – biocatalysis is our ‘first point of call’ for any project involving chiral moieties because it’s as quick as or quicker than other processes to develop, and is predictable upon scale-up.”

Moody adds: “In the past, due to customer demands for rapid supply, we often had to employ an inferior technology to produce the compound of interest, resulting in a sub-optimum process that ‘we were stuck with’. This resulted in a process that was not easily changed and lacked the potential for futher cost reductions using the biocatalysitic option. Nowadays, biocatalytic methods can be developed and employed just as quickly as chemocatalytic methods. Therefore development timelines are now the same as in a chemocatalytic approach, and biocatalysis is the first method explored when developing a synthetic route to a new compound at Almac.”

SummaryThe existing pool of recombinant enzymes, both in the literature and available commercially, provides an ample resource from which to develop this technology further. In our opinion, the future focus for enzyme research needs to be on applying new technologies at the molecular level. However, this should also be integrated with methodologies aimed at improving biotransformations at the reaction level,

Figure 4: P450 mediated hydroxylation of a carbon-13 API.

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Protein Production Bacterial and mammalian production - from process development to purified product.

From Active Compound To Administration Drug characterization, analysis, and formulation development.

Immune Models In vitro models for prediction of immuneregulatory effects of compounds.

Biomarkers Identification, validation and documentation of disease relevantbiomarkers.

Molecular Histology Service In situ detection of microRNA. Image analysis - quantitative ISH. Combined IHC and ISH service.

Stem Cell Technology Adult – and pluripotent stem cell characterization. Stem cell models for regenerative medicine. Cell (stem) motility models.

Bioneer A/S Kogle Allé 2 DK- 2970 Hørsholm

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including both physical and chemical approaches.5 Future development of enzymic reaction systems could investigate and integrate the use of technologies that are known to speed up catalysis in other systems. Almac’s continued investment into evolution technologies and metagenomic programmes further confirm the company’s commitment to green technologies that offer solutions for their customers. This commitment is being driven by market needs and stresses, and the key to future success is flexibility and rapid response to change. biocatalysis is a maturing technology and is certainly aiding future success stories for the rapid supply and delivery of chiral intermediates, fine chemicals and APIs by Almac.

References

1. Moody, T. & Geffroy, D. Sp2 magazine, January, 27-29, 2011, “biocatalysis is the key to successful chiral synthesis”.2. Moody, T. and Mix, S. Pharma magazine, September issue, 2011, “Choosing biocatalysis to accelerate

chemical development, minimise cost for fine chemical and API manufacture and metabolite synthesis”.3. Mangan, D. & Moody, T. Speciality Chemicals Magazine, 2011, 31(11), 20, 22, “Spoilt for choice”.4. Sutton, P.W., Adams, J.P., Archer, I., Auriol, D., Avi, M., branneby, C., Collis, A.J., Dumas, b., Eckrich, T., Fotheringham, I.,Mangan, D. & Moody, T.S. “Biocatalysis in the fine chemical and pharmaceutical industries”; Practical Methods for biocatalysis and biotransformations 2, edited by John Whitall and Peter Sutton. Published by John Wiley and Sons Ltd., 2012, 1-59.5. Caswell, J.M., O’Neill, M., Moody, T.S. & Taylor, S.J.C. Curr. Opin. Chem. biol, Vol 17, Issue 2, 271-275, 2013, “Engineering and application of P450 monooxygenases in pharmaceutical and metabolite synthesis”.6. Holub, N., Neidhofer, J. & blechert, S., Org. Lett, 2005, 7, 12277. Calvin, S.J., Mangan, D., Miskelly, I., Moody, T.S. & Stevenson, P.J., OPRD, 2012, 16, 82-86.

Dr Tom Moody Head of biocatalysis& Isotope ChemistryAlmac Sciences.Tom Moody (Head of biocatalysis &Isotope Chemistry)

received his 1st Class bSc (Hons) (1998) in Chemistry and a PhD in Physical Organic Chemistry (2001) from The Queen’s University of belfast (QUb). He has completed a Masters Degree with Distinction in business, specializing in business strategy. He has earned numerous awards, including a Foundation Award, The AGB Scientific Award for best Oral Presentation at the 53rd Irish University Chemistry Research Colloquium, and the best PhD thesis at QUb. He also holds the position of honorary lecturer at Queen’s University, belfast and the recipient of the 2012 bMI technology award.Email: [email protected]




The accelerating pace of technologicaldevelopment is offering new possibilities for manufacturers acrossindustry, and the need for all sectors to share both knowledge and best practice is crucial. To illustrate just how far some technologies have extended their reach, Mark Jennings, Engineering Director at Dawson Shanahan, describes how a process once used to forge simple fasteners has recently provided a sophisticated solution for needle- free drug delivery.

Engineering Enhancements in Drug Delivery

A new report has raised concerns that medical device testing isn’t as far-reaching as perhaps it should be. The report, carried out by the Medicines and Healthcare products Regulatory Agency, and supported by the Academy of Medical Sciences, has called for the industry to take note of the engineering model for assessing safety, which has been built through dialogue between industry and regulators.

The medical device report makes a number of important points and raises several vital areas for discussion. In particular, the need for all sectors of industry to share both knowledge and best practice is crucial if we are to continue to exploit new technologies and practices safely and to best effect for medical device manufacturers, health professionals and patients alike.

Help may be at hand in the shape of new funding initiatives. The UK’s Technology Strategy board (TSb) and the Medical Research council have recently allocated investment of up to £47 million to UK businesses and universities. The investment will be of great benefit in assisting medical professionals in the UK to develop healthcare solutions that will aid the country’s ageing population. The move will also support innovation. The UK has long been famed for its innovative approach to solving technical problems, so it is good to hear that further support appears to

be on the way. In recent years, the accelerating pace of medical equipment development has wrought dramatic improvements in areas such as body scanning and drug delivery. Just last year, we supplied key components for an innovative, needle-free drug delivery system introduced by our partner Zogenix. by utilising precision cold-forming and engineering techniques we were able to produce a highly efficient system that helps reduce patient stress. This case study illustrates that when the know-how of an expert precision engineering firm and a collaborative partner come together, the results can be innovative and truly ground-breaking. And when funding which benefits medical equipment engineering is added into the mix, the results can significantly boost both patient wellbeing and the UK economy.

Zogenix was founded with the goal of enhancing and differentiating medicines using new technologies to relieve the suffering of people with CNS and pain disorders. The company’s leading product, SUMAVEL DosePro (sumatriptan injection) system, is a drug-device combination that enables needle-free delivery of subcutaneous sumatriptan for the acute treatment of migraines and cluster headaches.

bill Feinstein, Director, Operations Planning and Procurement at Zogenix, commented, “We knew that we would need to partner with a company who could offer a high level of knowledge and experience in this sophisticated technology, while also providing a superior degree of support during the development of SUMAVEL DosePro. With Dawson Shanahan being an important partner to our business, it was a natural step for us to approach them to help us create this new solution, which represents a truly ground-breaking approach to needle-free drug delivery.”

The company has been working with Dawson Shanahan on the development of this unique product since its inception.

Zogenix had heard of the benefits of cold-forming in terms of both quality and manufacturing cost savings, and approached Dawson Shanahan to produce one component of the DosePro device by cold-forming. They were so impressed with the innovative solution that they then asked us to make a second component, again to demanding tolerances.

Using our intricate cold-forming processes we were able to achieve a specially engineered part with a highly accurate pressure and finish that would enable the drug to be shot into the system without the need for a needle. A mirror surface on the inside of the piston and the angles in the design also played a crucial role in ensuring that the trigger mechanism works effectively.

CellGro® is a registered trade mark of CellGenix in several European countries and Japan.In the USA and Canada CellGro® products are distributed under the name of CellGenix™

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We began to work closely with Zogenix to enhance the design of the DosePro system and suggested that we could manufacture a number of integral elements of the system in-house and within their budget. With assistance from Simon West at E-Tech, we set to work creating the bespoke machining and tooling needed to manufacture one of the components, and together developed and tested the parts until an optimum solution was found.

The precision-made components produced by Dawson Shanahan, including an aluminium chamber and steel ram, have been specially engineered to administer the drug into the user’s body without the need for a needle. As a result, medication can be administered quickly, simply and without anxiety. The success of the design is partly due to the high-quality finish and intricate production of the cold-formed parts, which make it possible for the administration mechanism to work.

bill Feinstein believes that the partnership between the two companies has been key to the successful development of DosePro, stating, “Throughout the manufacture process, Dawson Shanahan have been extremely collaborative, throwing the necessary resources at challenges to help us find the best solutions. DosePro is a product based on physics and comprises many parts that all have to work exactly the way they are intended and in harmony together. Dawson Shanahan has played a vital role in making this possible. We’re extremely excited about launching

this truly revolutionary system, and look forward to continuing to work with Dawson Shanahan in the future”.

With solutions such as this already enhancing the manufacture of medical devices, it’s perhaps surprising that cold-forming is not more widely adopted in this and other industries. Cold-forming – the extrusion of a part from a blank – is a fast, economical way to produce robust, complex components in a wide range of materials, but is often ignored in favour of alternative methods. The reason for this may be simply that because cold-forming originated as a method for producing fasteners during the 19th century, it is still seen as a means of producing simple, high volume components. Today, however, the process is capable of delivering precision-engineered parts with up to 80% less scrap than machine processes, which, given the current economic climate, is a statistic that ought to attract the attention of any component manufacturer. Coupled with faster lead times, better surface finish and improved mechanical characteristics, cold-forming offers an opportunity for manufacturers across industry to take advantage of enhanced component quality while also reducing costs.

As it is performed at ambient temperatures, cold-forming is a far quicker process than more conventional options, allowing manufacturers to achieve much shorter production processes. This in turn means that components can be made to order extremely quickly, cutting lead times. Aside from tangible cost savings, cold-forming makes for superior quality products by plasticising metals along

their grain boundaries, rather than cutting across, thus producing parts with extremely low levels of stress deformation and high levels of mechanical integrity, resulting in far greater performance and reliability. Furthermore, cold-forming offers outstanding levels of definition, even on parts with complex contours. Typically, dimensional tolerances can be to within plus or minus two microns, with the added benefit of extremely fine surface finishes, which in many cases require no further machining or polishing.

Additionally, parts undergo work hardening during the cold-forming process, improving their machinability and durability still further. Work hardening dislocates the structure of the metal in a way that prevents further dislocations, resulting in a stronger component. As this increase in strength is comparable to that of heat-treating, it can be more cost-effective to cold work a less costly and weaker metal than to hot-work a more expensive metal, particularly where a precision finish is required.

The cold-forming process also makes it possible to produce component parts with a superior finish, both internally and on the surface. Accurate internal profiles and complex external profiles are possible, enabling precision parts to be manufactured that can have a significantimpact on the performance of the equipment in which they are used. Furthermore, there is almost no limit to the shape, size or complexity of the metal components that can be produced using cold-forming. Simple cold-headed parts or highly complex cold-formed and finished machined components can be produced for a diverse range of applications.Considerable work has been dedicated to developing a solution that allows stainless steel to be cold-formed. As a result, the Dawson Shanahan research and development department has been able to create and apply a unique coating and lubrication process that acts as a protective barrier, while minimising friction when each part is formed. The company has had finished parts independently tested by world-leading laboratories, which have confirmed that the physical and chemical properties of the stainless steel had been retained during the process. Furthermore, the specialist protective barrier prevents



Those who may not have given enough thought to cold-forming need to consider the fact that, while some configurations, tolerances and/or hybrid designs will always require additional operations, many second operation processes have been eliminated by the expanded capabilities of cold-forming equipment and tooling.

Finally, cold-forming also delivers as a necessarily separate process; it significant ecological benefits compared to processes such as hot-forging, where the high level of heat, and thus energy, required comes at a price to the environment. Consequently, cold-forming can contribute to a lower carbon footprint, as well as enhancing productivity and business performance. Dawson Shanahan specialises in the manufacture of precision-engineered components and assemblies for the medical and healthcare sectors. Our manufacturing operation includes custom-built cleanrooms and is supported by an extensive onsite QA laboratory, using the latest precision measuring systems and data analytical tools. With full accreditation to ISO 9001 and ISO 13485 we offer guaranteed levels of quality control and full traceability at every stage of our operation, from initial planning to final delivery anywhere in the world.

of years. Recently, Dawson Shanahan engineered a cold-formed aluminium tube for the purpose of holding nitrogen gas. Our customer specified that a minimum pressure must be maintained within the chamber for a period of two years. A rubber seal contacting the chamber inner surface was created to prevent gas loss. It was therefore critical that the chamber surface was free from scratches, eliminating gas leak paths and, in turn, loss of pressure. Although the drawing specification required a 0.2Ra radial surface requirement, the process produced results between 0.04 and 0.08Ra. This case is one of many that demonstrate that there is great potential for engineers to consider, and take advantage of, the various modern methods of processing manufactured aluminium to suit the needs of different applications.

The research and development of cold-forming continues; in recent years there has been an increasing shift from ‘experience-based’ development to computer-aided research, facilitating a deeper and more analytical approach to developing the process.Cold-forming continues to present new opportunities across industry, but it is important not to consider cold-forming as a necessarily separate process; it can be allied to other processes in the interest of economy and product quality.

Mark Jennings is the EngineeringDirector for Dawson Shanahan Ltd. Mark joined the company, basedin Potters bar, in

2000 and now has over 30 years of cold-forming experience making components for many industries, including automotive, aerospace and medical. Combining engineering with production management, Mark has extensive experience of modern production techniques and quality control systems, including cGMP.Email: [email protected]

galling, thus retaining the desirable surface characteristics of stainless steel. As cold-forming retains the integrity of the metal, while also producing parts with highly polished surfaces and no galling, the performance of a component can be improved dramatically. Historically, cold-forming in stainless steel has been problematic due to the hardness and unique mechanical properties of the metal, and the difficulty is that many of the punch and die sets used in cold-forming are also made from stainless steel, so they tended to collapse slightly when first used. However, Dawson Shanahan is developing a complex tooling design to allow for this controlled deformation. This latest innovation opens up a world of new opportunities for the manufacture of precision parts in the healthcare sectors, including surgical instruments and equipment.

To give a specific example of one of the ways in which cold-forming can affect the physical characteristics of aluminium, consider the potential of this process for achieving a unique surface finish. Cold-formed parts have surface finishes that mirror the smooth condition and dimensions of the dies. Not only does this somewhat ‘burnished’ condition often eliminate the need for secondary finishing, it can also invest parts with the capacity to preserve, for example, gases with zero leakage for a number

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IntroductionThe pharmaceutical industry is undergoing an enormous shift in structure and strategy to reinvent how to bring new drugs to market efficiently. Global drug development strategies - consolidation and partnerships, functional outsourcing relationships, innovation networks, expansion into emerging markets, orphan drugs, translational science, academic alliances and use of public private partnerships (PPP) - all reflect new thinking aimed at achieving higher R&D efficiency and greater return on investment.

Semantic technologies - based on advanced statistics, data mining, machine learning and knowledge management - have existed for years, but are gaining much more momentum dealing with the growing need for efficient information management (IM). Gartner recently named it in the “Top 10 Technology Trends Impacting Information Infrastructure, 2013”1 because of the renewed business requirement for monetising information as a strategic asset. Increasing volumes, variety and velocity - big data - requires semantic technology that makes sense out of data for humans, or automates decisions. better application of semantic technologies in linked data combined with the urgent need for better data-sharing may well be the next disruptive wave for efficient information handling in healthcare and life sciences.

Need for Disruptive Innovation in the Pharmaceutical SectorNew drugs grow slowly and the likelihood that they will skyrocket to blockbuster status soon after launch is no longer reality. It typically takes five years or longer to achieve such success, and many never do. Despite unprecedented investment in pharmaceutical research and development (R&D), the number of new drugs approved by the US Food and Drug Administration (FDA) remains low. Pharmaceutical companies introduced ~1200 new drugs that have been approved by the FDA since 1950, and new-drug output from pharmaceutical companies in this period has essentially been constant, and remains so despite the attempts to increase. This reflects the limitations of current R&D models. The crucial question is how to

Disruptive Change by Linked Data and Semantic Technologies in Healthcare and Life Sciences

concept proposed by Tim berners-Lee. Linked data applies the machine-readable formats that makes it easy for web applications to operate and communicate without human intervention or additional programming.

Linked data gets more and more adoption to discover and connect new and legacy data sources, private and public, to make big datasets useful, showing the unique information, uncovering new patterns to improve decision-making. It is clear in the next five years, semantic technologies will play key roles in modernising information management and in making the role of information governance increasingly important, closely tied to trends of big data and modern information infrastructure.“Semantic technologies extract meaning from data, ranging from quantitative data and text, to video, voice and images. Many of these techniques have existed for years and are based on advanced statistics, data mining, machine learning and knowledge management. One reason they are garnering more interest is the renewed business requirement for monetizing information as a strategic asset. Even more pressing is the technical need. Increasing volumes, variety and velocity — big data — in IM and business operations, requires semantic technology that makes sense out of data for humans, or automates decisions.”1

“The 5 Star Scheme” or the Rules Reusable Open Data Must Apply ToIt is essential that open data complies to the proposed 5 star scheme for assessing the degree to which datasets are re-usable by Tim berners-Lee, inventor of the WWW and

achieve sustainability for the pharmaceutical industry that needs to embrace more radical change and seize the opportunity to redesign its business model2.

Strangely enough, this innovation crisis in the pharmaceutical industry is occurring in the midst of a new golden age of scientific discovery. Large companies must innovate and reinvent their research model with lower costs and increased output as a result of harnessing the scientific diversity of biotechnology companies and academic institutions, and combine it with their own development expertise. Some experiments already bring radical and successful change and could be used as building blocks or for inspiration; for example, Innocentive3, Chorus4, the Open Malaria Product Pipeline5, public-private partnerships like IMI OpenPHACTS6 and IMI eTRIKS 7, open-source R&D8, FIPNet9, opening clinical trial data10, accelerated clinical discovery using self-reported patient data collected online and patient-matching algorithms11, and various combinations of these and other initiatives. Harnessing the ‘global brain’ to access the best science and ideas, wherever they may be, demonstrates the key advantages of open R&D architectures amplifying competition, reducing costs, increasing agility and enabling ‘disruptive innovation’ located outside the corporate walls and bottom-up approaches enabled by passionate entrepreneurs.

Linked Data, Open Data & Semantic TechnologiesTo understand linked data requires an understanding of the world wide web (WWW) itself. Most data published on the WWW exists as raw dumps in comma-separated values (CSV), XML or marked-up HTML table formats. These formats make it very difficult for people to mix and match different content to make use of this growing wealth of information. The terms “linked data” and “open data” are not the same, because when data is accessible on the WWW, it is “open” but it doesn’t mean this data is linkable to other sources. “Open data” is simply data on the WWW, whereas “linked data” is data “in” the web. The term “linked data” is often associated with the concept known as the “Web of Data” or the “Semantic Web”, a

PRODUCT FOCUS

Sartopore® PlatinumSartorius has introduced a new generation of sterilizing-grade filters• Modified membrane increases product yield and improves manufacturing workflows• TwinPleat® geometry increases filtration performance and reduces filtration costs

Sartorius Stedim biotech (SSb), a leading international pharma and biotech supplier, presents a new generation of sterilizing-grade filters: Sartopore® Platinum. This product family sets new standards in sterile filtration and expands the comprehensive Sartorius filter portfolio.

Higher product yields and more efficient manufacturing workflows The surface of the Sartopore® Platinum polyethersulfone filter membrane has been modified using a hydrophilic and highly thermostable polymer. This surface modification gives the membrane excellent wetting properties and minimizes its protein binding. Fewer than five liters of WFI (Water for Injection) are needed to wet a 10” Sartopore® Platinum cartridge fast and reliably for subsequent integrity testing that provides dependably accurate results. The membrane’s minimized protein binding considerably increases product yield, thus augmenting the efficiency of manufacturing processes. Sartopore® Platinum filter cartridges can be dry-steam sterilized in the forward or the reverse direction, without altering the properties of their membrane. These sterilizing-grade filters can be used in the entire pH range from 1 to 14 and thus for nearly any filtration application in biopharmaceutical manufacturing.

Better filtration performance and lower filtration costs The membrane of the Sartopore® Platinum filter cartridges has been pleated using SSb’s newly developed, proprietary TwinPleat® process. The alternating long and short pleats of the membrane increase the filter area of a 10“ cartridge by more than 60 percent. At the same time, this geometry ensures that liquids flow through the entire filter area so that the filtration capacity of the cartridge is used to the fullest extent. As a result, Sartopore® Platinum filter cartridges substantially boost filtration performance and lower filtration costs.

The new sterilizing-grade filter cartridges are available in a choice of different sizes and constructions ranging from lab to production scale. In all sizes, identical materials of construction with consistent performance characteristics are used. Therefore, Sartopore® Platinum enables linear scale-up for a large number of applications in the biopharmaceutical industry.

A Profile of Sartorius Stedim Biotech Sartorius Stedim biotech is a leading provider of cutting-edge equipment and services for the development, quality assurance and production processes of the biopharmaceutical industry. Its integrated solutions covering fermentation, cell cultivation, filtration, purification, fluid management and lab technologies are supporting the biopharmaceutical industry around the world to develop and produce drugs safely, timely and economically. Sartorius Stedim biotech focuses on single-use technologies and value-added services to meet the rapidly changing technology requirements of the industry it serves. Strongly rooted in the scientific community and closely allied with customers and technology partners, the company is dedicated to its philosophy of “turning science into solutions.” Headquartered in Aubagne, France, Sartorius Stedim biotech is listed on the Eurolist of Euronext Paris. With its own manufacturing and R&D sites in Europe, North America and Asia and a global network of sales companies, Sartorius Stedim biotech enjoys a worldwide presence. Its key manufacturing and R&D site is in Germany. The company employs approx. 3,000 people, and in 2012 earned sales revenue of 544 million euros.

Contact for Sartorius Stedim Biotech

Dominic GroneGroup Corporate CommunicationsT: +49 (0)551 308 3324E: [email protected]: www.sartorius.com

Company Profile

director of the World Wide Web Consortium (W3C).12

• Available on the web but with an open licence

• As machine-readable structured data (e.g. electornic data formats and not image table scans)

• Using non-proprietary formats (e.g. CSV instead of Excel)

• All the above plus use of open standards from W3C (RDF query-able with SPARQL) to identify things, so that people can point at your stuff• All the above, plus: link your data to

other people’s data to provide context.



All data should have metadata about the data itself, and that metadata should be available from a major catalogue. Any open dataset (or even datasets which are not but should be open) should be registered. And then linked data is essential to actually connect the semantic web. It is quite easy to do and should become second nature taking into account various common-sense considerations to determine when to make a link and when not to. If healthcare data supports and applies these conventions in a scalable architecture, linked data could very quickly disrupt data-driven R&D, significantly shortening drug discovery cycles empowering information management strategies.

Democratising Technologies Make Disruptive Innovation HappenClayton Christinson explains disruptive innovation in a way that applies to semantic technologies, that must be transformed from an expensive and complicated product to which only a few people have access, to a more affordable and accessible solution that a much larger public gets access to.13 There is a very urgent need for democratised

semantic technology that everybody has access to, so linked data becomes reality not only for R&D experts but for all scientists, healthcare professionals, policy-makers and patientsA team of MIT and Max Planck researchers released EyeWire14,15 and demonstrate it as an online game for any user as citizen scientist. by “playing” Eyewire, a game of colouring brain images, citizen scientists can help map the connections of a neural network without prior specialised knowledge of neuroscience. Improvements in the underlying computational technology will eventually make it powerful enough to detect “miswirings” of the brain that are hypothesised to underlie disorders like autism and schizophrenia. This is an example of new ways of science harnessing the power of now up to 50,000 people online for free, instead of paid experts, and has many years to go. This approach shows that democratised tools with easy-to-understand interfaces and a layer of gamification lower thresholds to engage users quickly and on a large scale. This approach will also be applied in the linked data field with success in the coming years to assist the semantic technologies break through sharing and integrating information. Often these approaches are called killer apps, but in reality are agile, quick and bottom-up, fast-growing, startup business models taking on new markets.

Semantic Technologies and Linked Data to Reinforce the Call for Sharing in Healthcare and Life SciencesFrom the dawn of time, the sharing of knowledge has been one of the main forces driving science and innovation. Yet in recent decades, a proprietary culture, which wrongly posits that all intellectual property must be restricted, has spread across the pharmaceutical industry and threatens to stall the engine that has given us so many

valuable outcomes. Pharmaceutical companies, together with universities and government agencies, will gain much from reversing that trend and engaging in widespread collaboration early in the research process to expand foundational knowledge and create a shared infrastructure to tap, making everyone better informed with increased success as a result. The new internet, the semantic web, offers unprecedented potential, holding the hope of repowering a new golden age of drug discovery, eliminating duplication and redundancy so pharmaceutical companies compete in areas that offer a viable return on investment where pre-competitive collaboration helps all of us discover new therapies more effectively and efficiently, as patients and society demand it.

In summary, we want to reinforce and re-issue the call to action stated by bernard Munos and William Chinn together with many colleagues in the pharmaceutical industry, universities, and government agencies, to join hands and intensify sharing in order to help repower pharmaceutical innovation.16 And we believe semantic technologies, if applied appropriately and in an agile democratised way, could catalyse and make this change happen at an incredible and continuously growing speed.

References

1. Gartner Names Semantic Technologies To Its Top Technology Trends Impacting Information Infrastructure in 2013 by Jennifer Zaino on March 7, 2013 SemanticWeb.com (http://semanticweb. com/gartner-names-semantic- technologies-to-its-top-technology-trends- impacting-information-infrastructure-in- 2013_b35767).

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2. Munos, b. Lessons from 60 years of pharmaceutical innovation. Nat. Rev. Drug Discov. 8, 959–968 (2009).3. Wilan, K. Profile: Alpheus Bingham. Nature biotech. 25, 1072 (2007).4. bonabeau, E., bodick, N. & Armstrong R. A more rational approach to new product development. Harvard bus. Rev. (March 2008).5. Moran, M. et al. The malaria product pipeline (The George Institute for International Health, Sydney, 2007).6. OpenPHACTS IMI JU funded project - http://www.openphacts.org/7. eTRIKS IMI JU funded project - http:// www.etriks.org/8. Munos, b. Can open-source R&D reinvigorate drug research? Nature Rev. Drug Discov. 5, 723–729 (2006).9. Maurer, S. Choosing the right incentive strategy for research and development in neglected diseases. bull. World Health Organ. 84, 376-381 (2006).10. Rabesandratana, T. Drug Watchdog Ponders How to Open Clinical Trial Data Vault, Science 22 March 2013: Vol. 339 no. 6126 pp. 1369-1370.

11. Wicks, P., Vaughan, T.E., Massagli, M.P. & Heywood, J. Accelerated clinical discovery using self-reported patient data collected online and a patient- matching algorithm. Nature biotechnology 29, 411–414 (2011) 24 April 2011.12. Tim berners-Lee proposed 5 star scheme by Tim berners-Lee-June 2009 – (http://www.w3.org/DesignIssues/ LinkedData.html)13. Disruptive Innovation Explained - HbR blog Network – March 6 2012 (http:// blogs.hbr.org video/2012/03/ disruptive-innovation-explaine.html) 14. Eyewire, play a game to map the brain - http://eyewire.org/15. Neural ‘connectomics’ game unveiled - Nature News blog 11 Dec 2012 - http: //blogs.nature.com/news/2012/12/ neural-connectomics-game-unveiled .html16. Munos, b.H. and Chin, W.W. A Call for Sharing: Adapting Pharmaceutical Research to New Realities. Drug Discovery - 2 December 2009; Volume 1 Issue 9 9cm8

HansConstandt, CEO of OntoforceHans has abackground in medicine, biotechnology, businessmodeling, bioinformatics,portfoliomanagement, knowledgemanagement and business liaison in the pharmaceutical industry. His expertise in drug discovery, ICT, sustainable business models and fundraising serves to bring innovative solutions like DISQOVER to reality in healthcare and life sciences.

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Technologies for Innovative Drug Delivery SystemsIn order to bring the first idea to reality in almost every customised development, after a brainstorming and idea matrix assessment, prototyping is used in order to create the first sample. Therefore you can use different technologies, where you have prototypes simply for clarifying the design, or with original polymer material used later in the process in order to clarify the design and the functionality in clinical trials.

For injectable systems, except needle-free systems, a special needle in a broad range of dimensions is embedded in a polymer injection moulding part. Therefore in principle, three technologies can be used for the connection: gluing, overmoulding and welding.The best process technology depends on the one hand on the needle size and surface, and on the other hand on the polymer type, size and geometry of the injection moulding part. Furthermore,

Innovative and complex ideas in the field of polymer injectable drug delivery systems need a capable partner to succeed in realisation. Customised products such as new and innovative injectable drug delivery systems need a wide range of polymer technologies, including injection moulding, extrusion and assembly. Starting with a first idea through prototyping, design studies, risk analysis, research and development up to mass serial production under clean-room conditions, packaging and sterilisation, the complete supply chain is more than just complex. In the following article examples of innovative injectable drug delivery systems are described, together with a broad range of know-how and experience of polymer technologies. The most common starting point of all innovative injectable drug delivery systems is a customer idea.

Innovative Injectable Drug Delivery SystemsWith a share of approximately 25%, injectables were the number two in the global pharmaceuticals market in 2010, preceded only by oral medication. In particular, double-digit growth rates, for example in the areas of biotech products and injectable generics, show the importance of this market segment. Besides prefilled commonly known syringes, vials and containers, more and more customised and innovative injectable drug delivery devices, such as safety syringes, customised pen systems, needle-free or intradermal injectors are required from the market. Currently in the injectable drug market, an estimated 2.7 billion prefilled syringes are used annually1. In particular, the polymer systems in comparison to the glass systems are estimated to achieve double-digit growth rates in the next years especially those custom- developed for new drugs.

Innovative Injectable Drug Delivery Systems

Figure 1: Fully automatic needle gluing, using UV glue and LED lamps for the curing process.

Figure 2: 100% visual control of the needle glue process as well as of the quality of the needle tip.

facts needed later, like the holding forces, determined use in practice, and of course the economic targets, are relevant for the right choice of the connection technology between the needle and the injection moulding part.

In Figure1 an example of a fully automatic needle glue process is shown by curing a UV glue with LED lamps. Afterwards a 100% visual control of the result and an addi-tional 100% needle force control according to standard norms are realised, as illustrated in Figure2.

Page 53 – ADVERT 17 – FEF CHEMICALS

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The fully automatic needle handling itself needs absolutely precision in the fully automatic assembly lines, as well as narrow tolerances for the injection moulding parts. One example of such a high-precision injection moulding part where later on a needle is glued fully automatically.

The second highlight in the development is the injection tool concept, where a 64-cavity tool was built with a highly innovative melt disc hot runner system.

Figure 3: 100% visual control of a needle glue process with a fluorescent UV glue, cured by UV or LED lamps.

Figure 4: High-precision injection moulding parts from the polymer material polycarbonate, produced from a 64-cavity tool with hot runner system


Figure 5: Example of one possible fully automatic needle handling, where needles can be fully automatic assembled, glued or overmoulded under clean -room conditionsISO-class 7

For a very good 100% visual control, a special fluorescent UV glue system is used. The fluorescent glue is visualised with a fluorescent light as shown in Figure 3.

technologies are possible, starting frommanual needle handling to fully automatic handling (Figure 5) with linear or 6-axis robot systems, where needles can be directly overmoulded with a polymer injection moulding part.

With the multi-component injection moulding technology, hard and soft thermoplastic polymers can be combined in one product without post-assembly. In particular, for applications such as sealing and connecting combinations of different thermoplastics, this technology can perfectly be applied.

The soft component reacts chemically with the hard component and can only be separated through destructive force. This makes the product perfectly safe - an important factor in the pharmaceutical industry. Furthermore, the reduction of individual parts contributes to reduced costs.

The multi-component technologies can even be enriched by combining them with metal insert technology.

The benefits for the customer are accurate holding forces of the subsequently embedded and glued needle for a customised prefilled syringe system.For the handling systems, different

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demand for new customised technologies in the field of overmoulding and fully automatic needle handling systems. One reason for this is the growing system complexity in combination with new polymer materials. The third trend is the growing demand for innovative safety-needle systems. There are approximately 385,000 needlestick injuries per year among US hospital workers, despite laws requiring innovative safety mechanisms on needle systems.3

References

1. Greystone Associates, Prefilled Syringes, 2009.

2. www.getinge-lacalhene.com

3. CDC, 2004: Panlilio A. et al. “Estimate


Dr. Thomas Jakob, Director business Unit Moulding / Pharma SolutionsDr. Thomas has been part of the RAUMEDIC AG since 2004. Since 2009, he has been Director of the Moulding/Pharma Solutions business unit.Email: [email protected]

Additionally in the field of injectables, there is a broad range of established processes and special testing equipment, for example the evaluation of the penetration and gliding forces of the needles, as well as the necessary needle treatments like tip or spray siliconisation in order to improve the gliding forces, which help to streamline the production processes.

Trends in the Field of Innovative Injectables

Regarding current developments in the pharmaceutical market and technology developments there are significant trends. The first trend is a growing discussion for new devices for directly overmoulded needles. In particular, regarding extractables and leachables, the advantage is that the drug is only in direct contact with the polymer and the needle, but not with any glue. A second trend is the growing

Figure 6 shows a metal needle directly moulded with a two-component injection moulding technology, first with a soft, and subsequently with a hard, polymer. In the two-component luer cannula, the soft component has an additional sealing function. besides that fact, the adhesion between the metal insert and the polymer is comparable with gluing processes. Applications can be found in all kinds of injection systems.

A systematic project and quality planning regarding product and process are the key factors of success. Last but not least, the packaging plays an important role. This can be special customised packaging solutions, but also standardised packaging solutions well-known in aseptic filling lines, like tub and nest packaging or bags with ports from Getinge-La Calhène2. The subsequent sterilisation processes with all commonly-used sterilisation technologies must be done with certified partners.

Figure 6: Metal cannula directly moulded with a two-component injection moulding technology first with a soft, and second with a hard, polymer.


of the annual number of percutaneous injuries among hospital-based healthcare workers in the United States, 1997- 1998.” Infect Control Hosp. Epidemiol, 2004, 25(7), 556-562.

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IntroductionBackgroundIn the present healthcare industry, cell culture has increasingly become a cornerstone of biopharmaceutical development, bioprocessing and the manufacturing of expanded or differentiated cell populations. This requires complex manufacturing protocols, specialised media prepared with carefully screened raw materials, and an array of analytical techniques for their characterisation. because producing cells for downstream applications is expensive and complicated, optimising cell culture bioprocesses is of paramount concern to organisations engaged in these activities.

The complex nature of manufacturing and delivering cell populations typically necessitates long development time-frames, especially for cells intended for transplantation. Screening and predictive toxicology of small molecules and protein therapeutics is another application in which the use of stem cells or their differentiated progeny can reduce drug attrition rates, significantly reduce costs and improve the success of subsequent clinical trials1.

A cardinal way to accelerate the commercialisation of such cell-based products without increasing risk can be through supplier-manufacturer collaborations to resolve common manufacturing challenges in pre- and early clinical stages. However, a significant challenge for suppliers in such collaborations is the relative lack of industry standards regulating the use of ancillary materials (AMs) present in stem cell-based products. Due to the safety issues associated with the manufacture of these products, regulatory authorities expect that all AMs (synthetic or animal-derived) must be appropriately qualified and tested before use in clinical manufacturing2. Product developers may, however, have difficulty determining what, for instance, designations such as “animal-free”, “GMP compliant” or “GMP grade” actually mean from a regulatory perspective while they are dealing with their suppliers. Moreover, due to short shelf-life and limited quantities of material available for testing, there may often be constraints

on conducting extensive in-process and release tests on stem cell-based products. Some of these hurdles can be overcome by early engagement with suppliers to understand these issues and to ensure that they are able to provide consistently high-performing AMs that have undergone rigorous material qualification together with application of manufacturing process controls. Access to requisite information, for instance, sourcing, safety and purity profiles, and quality management systems for ancillary and relevant raw materials, should be provided by the suppliers, whilst the developers engage the relevant regulatory authorities to demonstrate consistent product manufacture to a

predefined quality and specification. Such early interaction between developers and suppliers, and exchange of information, will help in consolidating supply-chain reliability between suppliers and clients, and facilitate any required adjustments to AMs and/or their components to address regulatory requirements.

Another fundamental concern is the use of animal-sourced AMs, such as fetal bovine serum (FbS) in cell bioprocessing. Components derived from animals are not fully-defined and involve labour-intensive production, typically with high batch-to-batch variation, due to inherent biological variability. With serum, autologous human material can be used for the maintenance and expansion of cells intended for autologous use. This application may be considered low-risk3. However, use of human serum poses various challenges, including risk of transmission of infectious agents, variation due to donor age, varying levels of growth factors and/or the presence of inhibitory substances that may

alter biological processes in vivo. Further, from a commercial standpoint autologous cell therapy model is not considered economically feasible in terms of scalability, manufacturing, and cell harvesting together with cost and time required to manipulate the cells 4.

This article is focused on the implications of standard and qualified AMs on the production process, primarily focusing on the manufacture of cell populations, as they can have a significant impact on the overall quality, function and potency of the final cell-based product.

Ancillary MaterialsMost applications that utilise stem cells or

their progeny require maintenance of cells for some period of time ex vivo. This employs various components critical to the manufacturing process, such as specialised culture media, plasma- or serum-derived products, and additives including cytokines and growth factors. Such components assist expansion of cells and/or induce them to differentiate and acquire characteristics that impart the desired effect. These components are typically referred to as ancillary materials (AMs) or reagents (Table 1) because they are critical during manufacturing but are not intended to be present in the final product. However, AMs can have a significant impact on the safety, stability, potency and purity of the end product, and as such should conform to various requirements (Table 2). These materials come in direct contact with cells that are subsequently used for different applications, including cell therapy and drug screening. Due to the biological nature of the finished cell-based product, they cannot be entirely

Ancillary Materials for Manufacture of Stem Cell-based Products

Table 1: Typical ancillary materials used in cell bioprocessing

suitability, traceability and consistency of AMs. The degree of qualification may be more limited for AMs that are approved for clinical, as compared to materials proposed for research purposes. Such qualification programmes become vital when the AM is being used beyond its intended scope to determine its suitability in an altered manufacturing process or in a novel application.

Regulatory OversightRisk frameworkAs a risk framework, guidelines established for AMs used in drug manufacturing have been modified to encompass production of biologics (i.e. peptides, antibodies, and vaccines) which now also apply to the manufacturing of stem cell-based products7. In production of biologics, the final product is ultimately separated from the cells in which they are expressed. On the contrary, in cell-based products, the cells themselves comprise the ultimate product and therefore, might impose further regulatory and qualification hurdles.The United States Pharmacopeia Convention establishes standards for drugs and biologics, together with AMs used in their manufacture. Specifically, United States Pharmacopeia (USP) 29 Chapter <1043> Ancillary Materials for Cell, Gene, and Tissue Engineered Products highlights the risk assessment and improvement strategies, and the qualification

characterised, and there is limited ability to carry out extensive in-process and release tests for AMs. Therefore, AMs must be rigorously qualified for safety beforehand with established toxicological and adventitious profiles suitable for use in stem cell bioprocessing. A significant challenge is that few of these materials are previously approved or manufactured in a GMP-compliant process 2.

As the manufacturing processes for stem cell-based products can evolve through the development phase and especially as a product approaches clinical use, manufacturers must respond to increasingly rigorous regulatory requirements and accordingly modify the qualification programme for the employed AMs. With patient safety as their guiding principle, regulatory authorities will require testing to determine the impact of AMs on the composition of the product at various stages during the manufacturing process as well as the final product, including end-stage product stability, if possible. In addressing these requirements it is important to recognise that the identity, source, manufacturing technique, composition and specifications of AMs used for generating a cell population are inherently unique and can have a profound effect on the final product attributes. This concept is central to the classic ‘process equals product’ paradigm5. Detailed qualification data for AMs can be invaluable to assess whether any process changes have a significant impact on the final product performance and safety. This data depends on the analytical methods used for qualification. Consequently, if it is likely that comparability data will be required, appropriately validated analytical methods should be used for AM qualification. This is important as clinical programmes have been delayed

Ideally, AMs that are approved for clinical use will be preferred over those qualified for “research use only”, as the former are manufactured in accordance with controlled and documented procedures, are well-characterised with established toxicological profiles, and thus should confer a favourable safety profile. Nevertheless, the product developer is still required to design a scientifically rational and comprehensive qualification programme to ascertain the safety,

The qualification programme includes acceptance criteria and specifications for reagents used in manufacturing to ensure the highest quality and safety of the final product. These USP standards for ancillary and process materials support the entire product life-cycle by providing quality specifications. However, certain evolving AMs such as proprietary customised defined media and recombinant materials present considerable challenges. Defining quality criteria and functionality tests for complex materials such as serum with undefined components is another impediment. Therefore, context-specific flexibility in accordance with the guidelines will be important when complex AMs are used in the production of cellular products and specifications for reagents used in manufacturing to ensure the highest quality and safety of the final product. These USP standards for ancillary and process materials support the entire product life-cycle by providing quality specifications. However, certain evolving AMs such as proprietary customised defined media and recombinant materials present considerable challenges. Defining quality criteria and functionality tests for complex materials such as serum with undefined components is another impediment. Therefore, context-specific flexibility in accordance with the guidelines will be important when complex AMs are used in the production of cellular products. Typical regulatory concerns regarding the use of AMs are safety and qualification, together with characterisation and control of their manufacturing. AMs must be qualified on the basis of a comprehensive and scientifically rational qualification programme that includes an identification

profile of the AM with source and processes employed in its manufacture. The qualification programme should also consider characterisation profile that includes quality control testing to assess elements such as identity, purity, functionality and freedom from adventitious agents. Further, as AMs can be a potential source of variability that may impact final product potency, lot-to-lot variability and material stability at applied concentration should also be investigated as part of the qualification plan.manufacturing. AMs must be qualified on the basis of a comprehensive and scientifically rational qualification

CLINICAL RESEARCH

Table 2: Requirements for ancillary materials used in cell bioprocessing


development could constitute a heavy financial burden, particularly on academic institutions and start-up firms. Therefore, product developers and trial sponsors need to discuss continuity of supply of AMs and long-term conformance to a predefined specification with the suppliers early in product development.

AM Qualification As more cell-based products enter the development pipeline, carefully controlled qualification programmes for AMs will become increasingly important for risk reduction throughout the manufacturing process (Figure 1).

AMs or critical components within them may become limited, and some may not be available with the required quality, traceability and documentation. For instance, animal-sourced serum carries a high risk for transmission of spongiform encephalopathy, prion contamination and of generating a host immune response10,11. Further, maintaining a serum-based process for generating large number of cells might outweigh the supply of a particular validated lot of serum. The FDA allows the use of existing human embryonic stem cell lines that have been exposed to animal products but classifies them as xeno-transplantation products, which must meet additional testing criteria and undergo extra clinical monitoring 12.

A key way to satisfy concerns about such AMs is through qualification, using a systematic and scientifically rational programme. AM suppliers work under established quality standards and use reference materials for manufacturing their products, which can be also used to validate assays and reference standards. As regulatory agencies tighten their oversight of cell-based products it may be reasonable to eliminate all animal-sourced materials from the production process in early stages of development, not only to develop a robust manufacturing process, but also for safety. As a major concern from a regulators’ standpoint is the risk of transmissible diseases and biological contaminants, they demand rigorous control of such materials. This consolidates the rationale for a significant need in the industry to eliminate the presence of animal-origin raw materials completely

from the supply chain/production process.Due to this increasing regulatory burden around AMs of animal origin and their

CLINICAL RESEARCH


Table 3: An example framework of aQC/QA bio-safety plan for ancillary productqualification/characterisationthatcould be used in cell-therapy manufacture

Figure 1: Typical workflow in an ancillary material qualification programme

programme, USP 29 Chap <1043> provides a tier-based framework of risk categories (box 1). As products move from tier I to tier IV, the associated risk increases. The products in tier I can have high upfront costs, however there are built-in cost savings as the products will require a less extensive qualification programme. On the other hand, products in higher tiers can be less expensive upfront but require an elaborate and stringent qualification programme that might result in increased overall costs.

Bio-safety and Qualification of AMsA cell-based product undergoes a variety of manufacturing steps involving various AMs to attain the desired characteristics. More often than not, AMs are utilised only transiently at different stages of cell production, and are not intended to be part of the final product. Nevertheless, evaluation of the bio-safety of these AMs is important as they come in contact with cells that will subsequently become part of a downstream clinical/non-clinical application. The extent of any bio-safety programme, while essential to comply with regulatory authorities, will primarily depend on the origin of the AMs (synthetic vs. animal- or human-derived) and whether the reagent was supplied for “in vitro research only” versus a product previously approved by a regulatory authority for human use.

Regulatory agencies undertake the risk assessment of suppliers and their materials during the IND/bLA (Investigational New Drug/biological License Application) process, which is covered under the Type II master files. For this reason, the product developer is ultimately responsible for devising procedures for risk evaluation and bio-safety. This requires additional qualification and testing regardless of the regulatory status of an AM. Thus, it becomes imperative for a developer to work in conjunction with the supplier to establish AM specifications and furnish qualification data together with supplychain details (Table 3).

It might also be important to establish either the removal or absence of AMs from the final product by appropriate additional testing, as residual reagents can have undesirable effects in vivo if they are functionally active or toxic. Adverse effects can range from direct toxicity of the AM to an immunological reaction. Analytical detection assays can be used to measure the levels of an AM during the manufacturing process and in the final product. It is important to note here that there is no equivalent master file process in Europe. However, the same principles are applicable and this is addressed in the quality portion of the product dossier.

A major difficulty in following the guidance presented in USP 29 Chapter <1043> for developing qualification programmes for AMs is to establish whether they are safe according to the final use of the product. For instance, TeSRTM2, a defined serum- and feeder-free formulation for the expansion and maintenance of human pluripotent cells (hESC and iPSC), can be used to manufacture cell populations which can be used in vitro, for example in predictive toxicology assays for small molecules, or for cell-based therapies. For both applications, cells are expanded using similar protocols but the end-product will be utilised entirely differently so both the medium and cells would need to be assessed by different end-product stability and safety tests.

Many reagents are only available as ‘research-grade’ or are manufactured by small companies with limited resources available for extensive quality testing. This is particularly challenging for product developers who, in pre-clinical and early clinical stages, may have used such research-grade reagents not approved for human use. by the time their product reaches Phase III, the regulatory agencies require reagents to be completely characterised and produced to GMP standards9. Working with GMP grade reagents in the initial stages of product

CLINICAL RESEARCH


consequent expensive qualification, certain product developers look to source xeno-free (and cGMP) reagents. To support such requirements, suppliers must provide complete documentation around sourced raw materials, with manufacturing process controls in place and proof of consistency of AMs that corresponds to the selection criteria. AMs of animal origin, if still being pursued, require additional documentation including country of origin, chain of custody, material traceability and grade certificates. Qualification of AMs should address the relevant acceptance criteria, which generally include attributes such as identity, purity and functionality to ensure consistency and performance of the manufacturing process. This is important, as the basic release criteria of the vendors for a particular AM may or may not match the acceptance criteria of product developers. Acceptance criteria are established on the basis of data obtained from lots used in preclinical and early process development studies, and from other relevant analytical procedures. Predefined acceptance criteria for an AM decrease their performance variability which, if not addressed, can unfavourably influence the potency and/or consistency of the final product.

Suppliers’ manufacturing facilities must be designed to reduce risks (for instance, cross-contamination) associated with the manufacture of different formulations for multiple cell-types. Appropriate cleaning and sterilisation controls must be implemented. In-house raw material qualification is essential to ensure that all ingredients, ingredient components and sub-components are safe and pure. This information can be summarised in the quality system documentation together with certificates of analysis, including safety testing and quality assessment. Such procedures will assist product developers to accelerate their vendor qualification, and reduce risk and regulatory uncertainty.

Adoption of Quality by Design (QbD) PrinciplesCommercial manufacturing of cell-based products involves high-throughput, scalableand cost-effective technologies that are deployed within a well-defined process. Ensuring cost-effective production demands an in-depth processs understanding and investment in AMs that complement the overall process. AM suppliers can increase their probability of successful integration within the manufacturing process by adopting ‘Quality by Design’ or QbD principles. QbD

strives to institute a more comprehensive understanding of the association between process parameters and the coveted quality attributes of the AM. It combines quality risk management with detailed scientific studies for increased process control and thereby, AM consistency. Further, it provides greater manufacturing flexibility, which is demonstrated by the ability to make process changes within the design space.

QbD requires more analysis to be focused on quality and formal risk assessments together with comprehensive evaluation of process parameters, raw materials and their effect on the final process and/or product. This is in contrast to traditional process development approaches that generally required less understanding of the overall process and, therefore, offered fewer opportunities for design/process modifications. By incorporating QbD in the AM development process, suppliers gain manufacturing flexibility and ensure product integrity and consistent performance for their clients. The QbD approach is complemented by high levels of process and environmental controls that enable production of high quality AMs, while minimising overall supply-chain risk for product developers.

ConclusionUSP 29 Chap <1043> is not a legally binding document and does not outline mandatory procedures. However, it can and should be used to define best practices for both AM suppliers and product developers, as it describes how AM safety can be achieved depending on the level of risk they conjure. AM risk can be minimised by proper identification of AM requirements, necessary qualification tests to measure purity and potency, and careful assessment of suppliers through vendor audits.A quality system based on appropriate regulations that is designed and implemented by taking into account the requirements of cell-based product developers is critical for manufacturing AMs by life science suppliers. AM quality and consistent performance is the key for careful selection and their further intended use. Another fundamental requirement is that AM manufacturing process validation complies with regulatory guidelines and can accommodate incoming material controls, inspections and change notifications by clients. To enhance manufacturers’ confidence in suppliers, established quality-controlled processes and technologies should be followed to mitigate and manage risk in this key part of the cell-based product development process. Application

of a robust AM qualification programme that includes AM risk assessment, the stage of product manufacturing where each AM is employed, and their corresponding quantities will improve the safety and efficacy of the ultimate product. Finally, full qualification of AMs will be essential to progress to cGMP quality for downstream applications.

References1. Ebert, A.D. and C.N. Svendsen, Human stem cells and drug screening: opportunities and challenges. Nature Reviews Drug Discovery. 9(5): p. 367-372.2. Louet, S., Reagent safety issues surface for cell/tissue therapies. Nat biotechnol, 2004. 22(3): p. 253-4.3. Aldahmash, A., et al., Human Serum is as Efficient as Fetal Bovine Serum in Supporting Proliferation and Differentiation of Human Multipotent Stromal (Mesenchymal) Stem Cells In vitro and In vivo. Stem Cell Rev: 2011 Nov; 7(4):860-84. Wilan, K.H., C.T. Scott, and S. Herrera, Chasing a cellular fountain of youth. Nat biotechnol, 2005. 23(7): p. 807-15.5. Archer, R. and D.J. Williams, Why tissue engineering needs process engineering. Nat biotechnol, 2005. 23(11): p. 1353-5.6. bethencourt, V., Virus stalls Genzyme plant. Nature biotechnology, 2009. 27(8): p. 681.7. United States Pharmacopoeia <1043> Ancillary Materials for Cell, Gene, and Tissue-engineered Therapy Products. USP 29-NF24. 2006.8. borellini, F., et al., 897. The development of standards for cell and gene therapy products: The activities of the United States pharmacopeia. Molecular Therapy, 2004. 9: p. S342.9. Lee, M.H., et al., Considerations for tissue-engineered and regenerative medicine product development prior to clinical trials in the United States. Tissue Eng Part b Rev. 16(1): p. 41-54.10. Selvaggi, T.A., R.E. Walker, and T.A. Fleisher, Development of antibodies to fetal calf serum with arthus-like reactions in human immuno deficiency virus-infected patients given syngeneic lymphocyte infusions. blood, 1997. 89(3): p. 776-9.11. Tuschong, L., et al., Immune response to fetal calf serum by two adenosine deaminase- deficient patients after T cell gene therapy. Hum Gene Ther, 2002. 13(13): p. 1605-10.12. Weber, D.J., Manufacturing considerations for clinical uses of therapies derived from stem cells. Methods in enzymology, 2006. 420: p. 410-430.

Pawanbir SinghDr. Singh is a ProductManager at STEM CELL Technologies. He isresponsible for strategic planning, tactical marketingactivities and business development. He holds a doctorate (PhD) in Regenerative Medicine from Loughborough University, a master’s (MS) in bioengineering from Indian Institute of Technology, Kanpur, India and a medical degree (MbChb).Email: [email protected]

CLINICAL RESEARCH


The discipline of pharmacovigilance (PV) largely originated in reaction to public health disasters caused by medications, e.g. tetanus toxoid (1912), sulfanilamide (1938), thalidomide (1962), etc. Approaches for detecting significant, previously unrecognised hazards of medications after their introduction into clinical use has been principally based on collecting anecdotalreports of suspected adverse drug reactions (ADRs). Further, communicating these new signals to regulators indivually and/or in the aggregate within the required time frames has been driven by categories defined by degrees of clinical concern. Similarly, regulatory oversight of pharmaceutical company safety activities for their approved products was, until very recently, largely limited to assessing the adequacy of and compliance with the procedures licence-holders established to meet their legal obligations, rather than on any identifiable public health outcome. This movement from reactive, procedural based safety oversight to a practical, health based approach has been met with greater public awareness of drug safety issues. In addition, emerging informatics-based methods for acquiring and analysing medical information have sparked multiple global initiatives to research ways by which the present reactive system can be transformed into one that is proactive, robust, and more useful clinically.

Pharmacovigilance in the second decade of the 21st century is therefore in significant transition. Improving both the quality of data sources and the tools that are used to analyse the data is key to unleashing this new model. Modern information technologies such as data mining tools have evolved significantly and allow for enhanced identification of rare, medically important, ADRs. However, detection of meaningful drug-event associations,

Proactive Pharmacovigilance: A New Model for the 21st Century

and drug interactions in particular, cannot be significantly improved simply by applying increasingly sophisticated analytical tools to data that is known to be inadequate and flawed. This becomes especially difficult, and may even be impossible, when a drug-related event is also relatively common in the untreated population, e.g. cardiovascular events in patients treated with NSAIDs, where an increased risk was eventually discovered in a large comparative clinical trial after going undetected by spontaneous reporting during decades of widespread global NSAID use. Since conducting such large trials is not feasible for more than a handful of drugs, post-approval PV will remain the mainstay for detecting new hazards of drugs after initial marketing approval based on the limited, essentially provisional, benefit-risk assessment obtained during clinical development. A major focus of new global PV initiatives is therefore the identification and/or creation of complete, clinically validated datasets to which more advanced analytical tools can be effectively applied.

Why do we Need a New PV Model? PV needs to change from being reactive to regulatory compliance concerns that are conducted by an often isolated “safety” function within pharma companies to one that is more closely aligned with actual public health promotion. For medicines to be valued as important public health interventions, all of their users (prescribers, patients, caregivers) require clear understanding of their attributable benefits and harms, without which individual prescribers and patients cannot make informed, rational decisions on what benefits and risks are acceptable. PV must become a means of evaluating, understanding, and effectively communicating both the real-world benefits and risks for each patient-drug combination, and not

merely a mechanism for identifying and quantifying overall population risks. During the next few decades, multiple avenues of research (e.g. genomics, epigenetics, metabolomics, microbiomics) will greatly increase our scientific understanding and identify many currently unknown factors that significantly affect individual patient responses, both positive and negative, to therapeutic agents. biological and technological advances will improve understanding of disease mechanisms and individual patientresponse factors, and provide tools for better clinical decision-making and therapeutic choices, particularly the comparative benefits and risks of different interventions. PV should be in the forefront of making this explosion of knowledge accessible and comprehensible to every stakeholder in the therapeutic chain.

What Might Effective PV Look Like in 2038?As stated above, scientific advances in biotherapeutics will create a shift away from our historical pharmaceutical model of “one size fits all”, with relatively minor modifications for relatively broad patient sub populations, e.g. the elderly, renally-impaired, etc., and towards individualisation of therapy. “Personalised medicine” will identify patients’ biological and disease characteristics and use them to tailor specific therapies for an individually optimised benefit-risk balance. Current PV methodology, which relies substantially on the analysis of large datasets of patients treated with palliative drugs for prolonged durations, does not support this model of therapeutic decision-making. New models will be needed for effective safety evaluation of novel therapies (stem cell transplants, gene therapy, live biotherapeutics, etc.), many of which may involve single or short-duration highly targeted treatments of small numbers of carefully selected

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patients in whom adverse effects may be delayed for very long periods. In this setting, effective therapeutic interventions will require highly accurate, reliable, and comprehensible information on benefits and risks. “When you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” (Lord Kelvin). One challenge for PV will lie in developing tools for accurate qualitative and quantitative assessment both benefits and risks from data that may differ greatly from that presently available.

Availability of New Data SourcesRegulatory agencies have been at the forefront of using electronic health record data and developing data-mining and analytical tools for active surveillance of real-world cllinical information to supplement or supplant today’s largely anecdotal safety data. The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) comprises over 170 research centres and healthcare data providers, with a comprehensive, searchable database and a registry of data sources for post-authorisation studies. In the USA, the FDA and the National Institutes of Health established the Observational Medical Outcomes Partnership to research analytical methods for systematic, proactive, and cost-effective

studies and might require significant changes to accommodate these new types of analyses.

Better Clinical Decision-makingMarketers and regulators of therapeutic products are obligated to ensure that reliable, actionable clinical information is effectively communicated to prescribers and users to allow informed therapeutic choices based on balancing benefits and risks. However, the ever-increasing flood of medical information far exceeds individual human capacity to assimilate and apply it. Today’s passive dissemination of information is already inadequate for patient protection – it lacks sophisticated decision support systems to match and evaluate patient- specific factors and drug characteristics to ensure appropriate medication choice and administration. It is also insufficient for this information to be available and comprehensible only to healthcare providers; patients and caregivers require access to the relevant information in an intelligible and actionable format.

Greater understanding of the drivers of prescriber and patient behaviour and factors that influ-ence them is necessary for successful interventions to improve the understanding of benefits and risks. This will require research into the sociological and psychological bases of such decision-making. In the USA today, healthcare activity is largely reactive and driven by financial incentives towards interventions, rather than prophylaxis.To change this paradigm, healthcare delivery requires incentives for data-driven risk prevention. Patients and caregivers will need to be active, health-literate participants in both regulatory and individual decisions regarding acceptable medication use.

Broad Accessibility of Appropriate InformationOpen access to benefit-risk information for both investigational and marketed drugs is steadily increasing. Spontaneously reported adverse event data from the FDA safety database has been publicly available for many years, although not in a readily accessible or usable format, while comparable data

use of electronic medical databases. The FDA also created the mini-Sentinel system for active surveillance, which links multiple healthcare data sources; this system contained >130 million individual patient records as of Dec 2012. Additional FDA safety initiatives include a pilot of pharmacological mechanism-based safety prediction and development of data-mining software for safety signal detection in literature reports that can “efficiently distinguish real signals from background noise in huge pharmacovigilance databases.” Finally, new safety signals may be identified or communicated via the web, social media, “cloud” storage etc. Early examples include analysis of web searches to identify epidemiological trends in influenza and data-mining of free-text clinical notes for hypothesis generation and analysis of suspected ADRs.

There are multiple commercial developers and providers of various types of software for analysis of clinical “big data”. However, these disparate data sources require new methods and analytical tools, including standardisation of benefit and risk characterisation, terminologies, data structures, outcome definitions, comparator selection, signal triage, privacy protection, etc., which are currently at a very preliminary, exploratory stage. Once validated, such standards and tools should allow more accurate determination of drug benefits and risks in actual clinical practice compared with the limited information derived from controlled tirlas. Multivariate analysis will identify patient subpopulations in whom the benefit-risk balance is optimal or unfavourable, permitting assessment of true clinical practice effectiveness, as opposed to the “two adequate well-controlled trials” required to prove statistical efficacy in a small, relatively homogeneous patient population. Additionally, these analyses should permit comparison of the benefit-risk balance for multiple treatement options in actual clinical usage, which is almost completely lacking today. Current labelling regulations do not permit updating of efficacy information without new controlled


CLINICAL RESEARCH

Sidney N Kahn, MD, PhD, SeniorPrincipal, Pharmacovigilance SciformixCorporation.

Dr Sidney Kahn’s professional credentials include Mb, Chb (Cape Town), Ph.D. (London), FRCPath (Chemical Pathology), and MFPM. His academic career spanned 17 years in clinical laboratory medicine and basic research in neuroimmunology in the UK and USA. He spent the next 13 years at bristol-Myers Squibb and Johnson & Johnson managing drug safety groups responsible for safety assessment of medicinal products throughout their lifecycle before establishing Pharmacovigilance & Risk Management Inc. in 2002. He has been associated with Sciformix Corporation since its inception. Throughout his industry career, he was actively involved in US and global activities to enhance pharmacovigilance, risk assessment, and risk management.Email: [email protected]

from the EU is now directly accessible via the web. The FDA and EU public websites list ongoing clinical trials, the FDA posts the most frequently occurring clinical trial adverse events, and there are initiatives to make summary and even raw study data available approriately.EU Pharmacovigilance Risk Assessment Committee deliberations are posted on the web, and the FDA publishes information about ongoing activities such as unconfirmed safety signals undergoing evaluation. These actions are intended to improve clinical decision-making and enhance public confidence in the system by making source data and benefit-risk assessments available and transparent. However, this is predicated on users’ initiatives to make summary and even raw study data available appropriately. EU Pharmacovigilance Risk Assessment Committee deliberations are posted on the web, and the FDA publishes information about ongoing activities such

as unconfirmed safety signals undergoing evaluation. These actions are intended to improve clinical decision-making and enhance public confidence in the system by making source data and benefit-risk assessments available and transparent. However, this is predicated on users ability to evaluate both benefits and risks accurately.

Cost- benefit Considerations Drug development costs have been increasing steadily for many years, while the pipeline of new products continues to shrink. While the business model in which giant global companies develop a few highly profitable “blockbuster” products that are taken long-term by millions will become less prevalent, it is reasonable to assume that multiple smaller companies with particular biotechnology research expertise will emerge to develop specialised therapies for much smaller numbers of selected patients. These companies will generally not have the in-house expertise to navigate the current global regulatory maze, and will almost certainly have to obtain support from appropriate external providers or partners. If these trends do emerge, it will become more difficult, and there will be fewer opportunities, to recoup expenses and generate profits, so new models of drug development and reimbursement will be needed. Engagement of all stakeholders - patients, healthcare providers, payers, regulators, and industry – will be needed to minimise resource limitations and unnecessary costs.Demographic changes, including global population growth, increased prevalence of disorders associated with Western lifestyles, emerging infectious diseases, and the increasing proportion of elderly people who are both more susceptible to ADRs and use more medications, will also alter perspectives on cost-benefit-risk.Future PV activities will require demonstrable cost-effective public benefit, and regulatory trends towards bureaucratisation and disharmonisation be reversed.

ConclusionThe impact of 21st century technologies on healthcare delivery will create significant challenges and opportunities for all stakeholders in pharmaceuticals. PV is currently in transition, with new sources of medical information and methods for its analysis being explored to transform the current reactive system into proactive benefit-risk management fully adapted to modern technology and needs. Regulations are gradually evolving towards a more proactive approach, but remain too procedurally focused, often inhibiting innovation, while the technical resources required for effective benefit- risk assessment are still at an early development stage. In summary, PV is entering uncharted territory requiring indutsry, regulators, healthcare providers, and patients to confront multiple unknowns that will eventually lead to enhanced benefit-risk assessment, communication and implementation.

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CLINICAL RESEARCH

Cardiovascular Therapeutics Watch Column

One of the hottest areas in the treatment of hypertension concerns drug-resistant hypertension. Drug-resistant hypertension is commonly defined as blood pressure (bP) levels above a specified target despite a patient’s adherence to at least three optimally-dosed antihypertensive medications of different classes, including a diuretic.1,2 In addition to these requirements, Turner and O’brien have recently argued that a patient should be on such a regimen for a minimum of three months before the classification is made.3 The methodology by which bP measurements are made also needs to be given careful consideration in this context.

Introduction

Conventional clinical bP measurement (CBPM) in a physician’s office traditionally utilises the auscultatory technique that is over 100 years old. However, while the auscultatory technique is inherently accurate, a recent European Society of Hypertension Position Paper noted that “it is dependent on observer attention to detail, which is often lacking, and it provides only a momentary measurement of bP, usually under circumstances that can influence the level of BP being measured.”4 Additionally, even though employment of automated techniques in the physician’s office may improve accuracy,5 only a ‘snapshot in time’ of bP is obtained, and, moreover, obtained under circumstances that may elevate bP. For example, the phenomenon of white coat hypertension,6 in which an individual demonstrates higher bP levels in a physician’s office than in other settings, is problematic when using CbPM (as is masked hypertension, the phenomenon of appearing normotensive in the office while in truth having hypertension in other settings).7

In contrast, ambulatory bP monitoring (AbMP) offers important advantages. First, it provides a profile of BP behaviour over a 24-hour period. This profile facilitates assessment of the effects of an intervention not only aggregated

over the entire 24-hour period but also during specific windows of this time cycle, including daytime hours and night-time hours. Second, mean AbPM measurements during daytime and night-time periods are largely devoid of the white-coat effect and the placebo effect.4

The best way to determine if a patient truly has drug-resistant hypertension is to ensure they have been prescribed an appropriate medication regime for at least three months, make sure they are actually taking the medications as prescribed, and use AbPM to obtain bP readings.

Treatment Options in Drug-resistant HypertensionCurrent estimates note that somewhere in the range of 10-20% of hypertensive individuals are classified as drug-resistant, and there is therefore considerable current interest in several interventional techniques to treat this condition. Most attention has fallen on renal sympathetic denervation (RDN), a technique in which a catheter is passed via the femoral artery into both renal arteries and radiofrequency energy is then used to ablate the sympathetic nerve fibres.8 Another technique is baroreflex activation therapy (BAT).9 One system, the Rheos system, consists of an implanted pulse generator, two carotid leads, and a programmer system. The leads are tunnelled subcutaneously and are attached bilaterally around the carotid sinuses. The device is programmable after surgical implantation. Increased baroreceptor firing induces an increase in parasympathetic (vagal) stimulation, which leads via a cascade of physiological adaptations to lower bP.10

The Cardiovascular Therapeutics Watch column that will appear in the October issue of the Journal for Clinical Studies will take a closer look at interventional approaches, but in this column a question that should be considered first is: Are there actually some other drugs that can help patients diagnosed with drug-

resistant hypertension following the use of the standard regimen of at least three optimally-dosed antihypertensive medications of different classes, including a diuretic? The rest of this column examines the drug spironolactone.

Spironolactone The aldosterone antagonist spironolactone has been used by physicians for many years. There is also evidence in the literature that it can be quite successful in the treatment of so-called drug-resistant hypertension.Ouzan et al.11 reported a trial in which 25 participants who met the criterion of having “refractory hypertension” were prospectively enrolled. Inclusion criteria included: (1) a history of hypertension for ≥ 6 months without any apparent cause; and (2) both clinical bP and 24-hour AbPM > 140/90 mmHg despite treatment with at least two antihypertensive drugs given at optimal dosage. Across one month, 24-hour AbPM decreased by 24 mmHg systolic bP (SPb) and 8 mmHg diastolic bP (DbP). While this trial, reported in 2002, discussed refractory hypertension and its definition rather than the condition now termed resistant hypertension discussed in the rest of this column, the principles are the same: as the authors noted, AbPM was necessary “to assess the diagnosis of refractory hypertension by eliminating the white coat syndrome.” Importantly, they also commented as follows: “because the results of ambulatory bPM have a prognostic value in hypertensive patients and should be the target of the treatment, they were not only an essential inclusion criterion but were used to assess the real efficacy of the treatment.”

De Souza et al.12 conducted an open-label prospective trial examining the antihypertensive effects of spironolactone in 175 participants with true resistant hypertension diagnosed by AbPM. After seven months, 24-hour SbP and DbP were reduced by 16 mmHg and 9 mmHg, respectively (reductions in office SBP and DBP were 14 mmHg


CLINICAL RESEARCH

and 7 mmHg, respectively). A subset of 78 participants underwent AMbP again eight months later. There were no statistically significant differences in BPs at this later evaluation, “confirming the persistence of the antihypertensive effect over a median of 15 months.”12

A study reported by Václavík et al.13,14

involved assessment of both daytime and night-time AbPM. It was a double-blind, placebo-controlled trial in which participants with resistant hypertension defined as office SBP > 140 mmHg or DbP > 90 mmHg despite being treated with at least three antihypertensive drugs including a diuretic, were randomised to receive either spironolactone or placebo as add-on therapy. Results are presented in Table 1. Statistically significantly greater decreases were seen in the spironolactone group for all SbP measures (CbPM, 24-hour AbPM, and both daytime and night-time AbPM), demonstrating that spironolactone is an effective drug for lowering SbP in participants with resistant arterial hypertension.14 (It should be noted that, while this trial had the strength of employing a randomised, double-blind, placebo-controlled design, the bP entry criterion, i.e., having drug-resistant hypertension, involved CPPb and not AbPM.)

A Case StudyFinally here, consider the case study recently presented by Armario et al.15

A 53-year-old patient was referred to a Hypertension and Vascular Risk Unit for management of hypertension resistant to four antihypertensive agents at full doses. True resistant hypertension was confirmed by 24-hour ABPM (153/89mm Hg). Add-on spironolactone treatment was well tolerated, and did not adversely affect renal function or kaliemia. After 8 weeks, bP was well controlled: CbPM was 132/86mm Hg and 24-hour AbPM was 128/79mm Hg.

Although not a clinical trial report, this case study illustrates perfectly the benefits of ABPM that are of central importance to this paper: the individual was evaluated via AbPM and considered a suitable candidate for spironolactone (analogous to using AbPM to determine eligibility for participation in a clinical trial), and the therapeutic benefit of the

intervention (pharmacological in this case) was confirmed by ABPM.

References1. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment–a scientific statement from the American Heart Association Professional Education Committee of the Council for High blood Pressure Research. Hypertension. 2008;51:1403–1419.2. Viera AJ. Resistant hypertension. J Am Board Fam Med. 2012;25:487-495.3. Turner JR, O’brien E. Diagnosis and treatment of resistant hypertension: The critical role of ambulatory blood pressure monitoring. J Clin Hypertens (Greenwich), in press.4. O’brien E, Parati G, Stergiou G, et al.: on behalf of the European Society of Hypertension Working Group on blood Pressure Monitoring. European Society of Hypertension Position Paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31:1731-1767.5. Myers MG, Valdivieso M, Kiss A. Use of automated office blood pressure measurement to reduce the white coat response. J Hypertens. 2009;27:280-286.6. Franklin SS, Thijs L, Hansen TW, O’brien E, Staessen JA. White-coat hypertension: New insights from recent studies. Hypertension. In press.7. Mancia G, bombelli M, Seravalle G, Grassi G. Diagnosis and management of patients with white-coat and masked hypertension. Nat Rev Cardiol. 2011 9;8:686-693. 8. Gulati V, White Wb. Review of the state of renal nerve ablation for patients with severe and resistant hypertension. J Am Soc Hypertens. 2013, Aug 14 [Epub ahead of print]9. Alnima T, de Leeuw PW, Kroon AA. Baroreflex activation therapy for the treatment of drug-resistant hypertension: new developments. Cardiol Res Pract. 2012:587194.

10. Martin EA, Victor RG. Premise, promise, and potential limitations of invasive devices to treat hypertension. Curr Cardiol Rep. 2011;13:86-92.11. Ouzan J, Pérault C, Lincoff AM, Carré E, Mertes M. The role of spironolactone in the treatment of patients with refractory hypertension. Am J Hypertens. 2002;15(4 Pt 1):333-339.12. de Souza F, Muxfeldt E, Fiszman R, Salles G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension. 2010;55:147- 152. 13. Václavík J, Sedlák R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT)--study protocol. biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011 [a] ;155:143-148.14. Václavík J, Sedlák R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011 [b] ;57(6):1069-1075.15. Armario P, Oliveras A, de la Sierra A. Resistant hypertension. Rev Clin Esp. 2013 Jul 1. [Epub ahead of print]


J. Rick Turner, PhD,is Senior ScientificDirector, ClinicalCommunications,Quintiles. He is an author/co-authorof 130 papers, author /co-author of seven textbooks, and an editor/co-editor of five professional volumes. He is also a Senior Fellow at the Center for Medicine in the Public Interest, and a Fellow of the Society of behavioral Medicine. Email: [email protected]

TABLE 1: CPbM and AbPM Reductions at 8 weeks in the ASPIRANT trial

LAbS & LOGISTICS

Dual Usage of LEAN as a Logistics Service Provider within Pharma


Even though many industrial sectors have experienced severe economic pressure, the pharma sector still offers some of the greatest opportunities in terms of growth potential and return on investment. Since the early 1970s the pharmaceutical companies have produced profit perspectives more than twice the average of all other industries, which gives a good reason to the current players, manufacturers and service providers, to protect their market share by enhancing the traditional barriers.

However, trends in the last decade in the pharmaceutical industry have turned into real and concrete daily challenges: cost pressure due to generics, implementation of new guidelines (European GDP), the impact of counterfeiting, the weight of the pharmerging countries, temperature management, etc. This leads to an increased centralisation of purchasing, as well as more direct management of the distribution from the pharmaceutical companies.

Production and distribution have become more global and optimised, which means that the pharmaceutical industry needs to seek new solutions and providers when there appears to be no adequate solution available on a large geographical scope and for the required budget. This is in line with the fact that pharmaceutical distribution is no longer a pure domestic supply chain, and keeps on growing as a “direct model” (direct to pharmacy) with a growing number of regional platforms.

Therefore some of the traditional barriers have to be challenged to manage the margin pressure in a better way, with still the need to implement new value-added solutions in line with the evolving requirements of the end consumer.

Rather than a risk, this is perceived as great opportunity for service providers to no longer follow the demand, but to further anticipate the future required capabilities.

Competition in transport is intense, and is driven by the establishment of an innovative strategy. This implies that to successfully understand and manage some of the key challenges of the pharmaceutical industry, the following factors must be considered:

How can value for the pharma market be created?• by understanding the purpose of the

customer and the end consumer• by launching initiatives and

collaborative innovations for an end-to-end supply chain to face the challenges within the pharma sector

• by translating these wants and needs into measurable criteria for the most critical quality, delivery and cost criteria

How to reduce cost in the healthcare supply chain?• by leveraging off standard networks to

reduce cost and specialising at the last possible moment

• If an innovation uses 80% re-use of existing infrastructure, then innovation lead time can be cut and remove the risk to the business

• Express carriers touch many industries and can diagnostically assess opportunities within a supply chain

• Express carriers fit well with LEAN principles

• Smaller, quicker deliveries more often reduce the waste of overproducing and excessive inventories in warehouses and distribution centres

• Managing the pull systems within the supply chain

This fits perfectly with an integrator’s business model who has an extensive and flexible network, although the real value and differentiator is within any service wrap.

but as a service provider, it is clear that whatever you do for your own organisation has a direct impact on your customers. To define the LEAN method is a key to success in innovation, and therefore in pharma.

by having a robust innovation process, the development of new products and end-to-end services that meet specified design targets for quality, cost or delivery from the launch of the product or service without serious deficiencies or conflicts in requirements can be realised.

The innovation process makes use of the DMEDI (Define, Measure, Explore, Develop and Implement) methodology. This is different from the more commonly used DMAIC (Define, Measure, Analyse,

Improve and Control) methodology, in that DMAIC is used to improve an existing process, whereas DMEDI is used to design a product, process or service from new.

The starting point is really to understand the customer purpose and the result they are trying to achieve. by truly understanding the purpose, innovation can really flourish. This will generate lists of wants and needs from the customer. Some of these will be so basic that the customers may not even mention them.

Prioritisation should be carried out on these needs to understand which ones are so basic that the customers or consumers would only mention them when such needs are not met, which leads to complaints. These should receive the highest priority. The next step would be looking at what needs would be seen as satisfying the customer. by providing more of these satisfiers, customer loyalty and trust can be built. The final level of prioritisation is looking at the delighters. These are the features that really can be seen as competitive advantages. However, over time, these features become known and thus expected, changing their importance to satisfiers. Because of this change of importance of delighters, innovation must take place on a continuous cycle.

This is the theory if we were taking an internal position of looking at delighting our customers. However, within the pharmaceutical supply chain there is a possibility to innovate on some basic needs, if we look at the end-to-end proposition from manufacture to pharmacy and return.

Some of these specific basic needs to the pharmaceutical industry are high-quality services, respect for temperature ranges, and compliance with regulations and customs regimes.

The key tool used within the DMEDI methodology and the innovation process is

LAbS & LOGISTICS


QFD (Quality Function Deployment), also known as the “House of Quality”. The tool includes four “Houses”.

In QFD 1, the wants and needs of the customers are defined, and the customer has to prioritise those needs. The difficulty with those wants and needs is that customers do not express these needs in any technical or measurable way. How do you measure “Easy to use”, without really testing this need with the customer to really describe in detail what it is and what it means to them? Therefore the need to find ways of measuring the level of fulfilment of that need, or a measure of success against a target, is of great importance. by assessing the levels of interaction between all of the needs against all of the measurable criteria, and applying the customer’s weighting, the priority of the measurable criteria comes to the fore. Even look at how the customers rate competing products or services and any technical assessment gaps. These will help to identify areas of competitive advantage to exploit, or gaps that need to be closed. In the “roof” of the house, conflicting measures can be identified with a view to making an informed choice not to take these conflicts through into any implemented solution.In QFD 2, take the measurable criteria and compare to the functions of the product or service. The functions describe the job to be done by the product and service, but not how it should be done. For a service, these functions are arranged into a logical sequence to become the high-level but undetailed process. It is becoming apparent that within any supply chain the functions are remarkably generic, from the function of “take order” through “collection”, “transport” and “delivery” to “manage problem or exception”. This has the benefit of speeding up the innovation process.Different methods are being used to find alternatives to perform those functions. For instance, the traditional ways of fulfilling the “take order” function would be

either a telephone call or fax, but modern alternatives could include a smartphone application.QFD 3 allows comparison of the functions of the product or service against key process elements in the process, to give a further level of detail in process design. For instance, in the function “collection”, the chosen configuration might need some piece of equipment to capture proof of handover. This equipment is considered “critical to process”. What variables might that equipment have?In QFD 4, compare the most important process variables and decide the most important inputs to control. Experimentation will decide the maximum and minimum values that are acceptable for that variable for which process controls and capability are established.

Once the detailed solution has been developed, it can be implemented with a greater degree of success than an unstructured development.

A well-known investigational medical products supplier had to redesign their supply with the main goal of reducing their supply chain costs. A slightly different approach was used in the interests of time, so a diagnostic assessment of the existing processes was undertaken.This involved the same examination of the customer and business needs to describe a successful outcome within a collaborative workshop environment. below are some of the areas identified to define these successful outcomes.

The end-to-end process was then mapped in the workshop with the customer. From this, the “touch points” can be described between the customers and suppliers within the supply chain.The touch points are the most important places where people are to interact, which create either a good or bad customer experience. The process map and touch points are used to identify “break points”. These break points are places in the process where something goes wrong and there is

The process map also identified wasteful transport, excess levels of stock, inefficient handling, waiting the process, activities that are not necessary or not needed until later or quality defects.

The team looked to find solutions to the break points which led the customer to request a complete bespoke solution, while at the same time reducing supply chain costs. TNT declined to offer this on the basis that a bespoke solution would not deliver the required target cost.

The solution offered was a generic solution that could be offered to many customers so as produce the economies of scale and leverage off the existing network that would deliver the required target costs.

In summary, by removing the traditional barriers that prevent a critical evaluation of existing supply chains, pharmaceutical companies have the potential to release a lot of value tied up in their existing setups. A traditional barrier would be just to buy transportation on cost only, and thus turn it into a commodity for which price becomes the only consideration. Once pharmaceutical companies open their minds to value and removing hidden costs, then the approach must be collaborative with their supply chain partners.Using integrators that can analyse the end-to-end process and deliver a managed solution will release that value. Innovating, whilst ensuring a strong optimisation of the existing networks, dedicated solutions inspired by the clinical sector, and where necessary partnerships for vehicles and packaging, could ensure an efficient supply chain model.

Ian Kendrick is the Process ExcellenceDevelopment Manager. Ian experiences include Process ExcellenceDevelopment Manager for TNT Express, Master black belt, Responsible for the deployment of Process Improvement techniques in TNT. 13 years experience of Lean Six Sigma, Experience of Manufacturing, Telecommunications, Rail and Transportation industries.

Sebastien Guenegan is the Corporate Sector Manager Pharma. His experiences include Corporate Sector Manager Pharma for TNT Express. Responsible for the Development of TNT in the Pharmaceutical sector. 10 years experience in Transportation, including 7 years dedicated to Pharma. Email: [email protected]

LAbS & LOGISTICS

medication. Wooden pallets that gather dust or – worse yet – bring in fungi or insects are not suitable for these cleanroom environments. Even if products are sealed in primary packaging, contaminants from wooden pallets can still infiltrate product – like in the recall incidents we have witnessed.

Black Pallets in White RoomsFor belgian pharmaceutical conglomerate Merck, eliminating wooden pallets from its logistics operation and introducing a new generation of plastic pallets has allowed the company to achieve a cleaner, safer and more economical production line.

At MSD Heist Operations in belgium – Merck’s production facility – there is no compromising on hygiene standards. Packaging areas operate a ‘no access’ policy unless you are wearing the correct white safety clothing and not a trace of dirt or dust is in sight.MSD Heist Operations makes products that are packed and shipped in more

than 150 million packaging units, and the material flow processes for pharmaceutical production are extremely complex. Receiving, production and distribution warehouses are spread across three locations. The raw materials and packaging components are transported 10km from the receiving warehouse to the production facility near Antwerp, where they are picked for each production order. From the production facility, the finished products are then transported by truck 20 minutes away to the distribution centre, from where the medications are then shipped out to customers. The receiving warehouse manages more than 8,000 different items. Producing pharmaceuticals for many countries requires many different forms of packaging, labelling and insert sheets. This means that the receiving warehouse has to deal with approximately 400 raw materials and active ingredients for pharmaceuticals, and about 7,600 different packaging


The complexity of pharmaceutical supply chains is growing exponentially, putting greater pressure on suppliers to deliver superior service and more cost-effective products. In Europe, a new generation of pallets is helping pharmaceutical companies streamline production and lower their operating budgets.

A New Generation of Pallets

Pallets have long been a staple product in the pharmaceutical supply chain, with manufacturers relying on them to transport pharmaceutical goods to wholesalers and distribution centres. Although the role of pallets today remains unchanged, the requirements of them are far more demanding than they have ever been.

A greater variety of applications and uses has increased the demand for pallets to be made from different materials and in different sizes and styles. Lightweight models for easy shipping, or strong and durable varieties for repeated use, are just a couple of examples. In the pharmaceutical industry, the specific need for pallets to be used in sterile environments has led to other innovations.

In the last few years, pallet hygiene has been put in the spotlight after a number of pharmaceutical manufacturers were forced to recall products as a result of contamination issues, thought to have been caused by the wooden pallets the goods were transported on. Some of the biggest names in the industry – Johnson & Johnson, Pfizer and Depomed – were affected, costing them dearly in lost product and tarnishing their reputations.Although the hype surrounding these contamination incidents has died down, it has led to greater scrutiny towards the use of wooden pallets in the pharmaceutical industry. In pharmaceutical production areas, there is little margin for error when it comes to hygiene. Particle-free environments are a given, as the tiniest trace of dust or dirt can contaminate

The CABKA-IPS 878 PO is a medium-duty polyolefin pallet with an extraordinary weight-load capacity ratio and is ideal for export consignments.

What if we only hired diabetics to work in the active cold chain? Would they take more care handling health-

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What if we only hired diabetics to work in the active cold chain? Would they take more care handling health-

care products? We think they would. They know what happens if they don’t get insulin.

Of course we don’t just employ diabetics. But we do share their understanding of the value of what we ship

in our containers.

We educate the members of the active cold-chain on the difference they make to the lives of diabetics

and others who rely on healthcare products. Because people do a better job when they understand

the importance of why they are doing it.

Anna Klettner is one of those people. She is a diabetic and she works for us.

Diabetics do it betterenvirotainer.com

HIL

AN

DE

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| P

HO

TO

: M

OR

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with astounding ease. They place them on a marked spot on the floor and bring them to a comfortable working height using a scissor lift. Then they are loaded layer by layer with boxes, finally to be taken by a lift truck to a central waiting area, where automated guided vehicles take them to the shipping area for exporting worldwide.

Polyolefin PalletsThe new generation of plastic pallets we’re talking about are recycled polyolefin (PO) pallets – namely the CAbKA-IPS CPP 878 PO and CAbKA-IPS CPP 875 PO1 – which we recently added to our range following the merger of pallet manufacturers CAbKA and IPS.

Hygiene benefits aside, these polyolefin pallets come with a very competitive price tag, which is perhaps why MSD Heist Operations has managed to convince many of its suppliers to use them, so that now more than 40 per cent of the goods it receives can be sent to production as complete pallets. For example, typical aluminium ointment tubes that come labelled and packaged on the polyolefin pallets can go directly from the receiving warehouse to the production facility.


Operations on various load carriers – mainly wooden pallets – which for sanitary reasons could not be sent right to production, so the products had to be inverted onto hygienic plastic pallets before entering the cleanroom environment.

Switching from using a combination of wooden and hygienic plastic pallets to using a new generation of plastic pallets throughout its supply chain has allowed MSD Heist Operations to tap into huge cost savings, and promote better hygiene, as the new pallets can be used by suppliers for delivering packaging components to the production facility, throughout production, and then to ship the finished product to its final destination.

There is no doubt that the white rooms of the production area are the most sensitive point in the internal logistics, and where the plastic pallets make their most prominent appearance: In the packaging areas at the end of each production line. At the zones downstream from the production lines, the medications are packed into larger box units, which are then stacked onto pallets.

MSD Heist Operations has reported that employees handle the plastic pallets

The new generation polyolefin pallets can be used throughout the pharmaceutical supply chain.

The white rooms of the production area are the most sensitive point in the internal logistics, and where the plastic pallets make their most prominent appearance.

Jim Hardisty is the founder and Managing Director of Goplasticpallets.com, the UK’s leading independentsupplier of plasticpallets and containers. After 18 years working in the logistics sector and six years in the pallet industry, Jim set up Goplasticpallets.com in 2001 to facilitate the supply of plastic pallets to businesses in the UK. Twelve years on, Jim has signed exclusive partnerships with a number of pallet and container manufacturers across Europe, allowing the company to establish a comprehensive and competitive product range. Email: [email protected]

In the past, we’ve found that the perceived cost of plastic pallets has put customers off using them, but this example illustrates that a shift from wooden to plastic pallets doesn’t have to be a costly one. Although the initial outlay on many plastic pallets is often higher than wooden pallets, new generation polyolefin plastic pallets are bridging the gap. Since polyolefin pallets can be used throughout the pharmaceutical supply chain – from suppliers delivering the packaging components to the production facility at the beginning of the chain, through production, to shipping the finished products at the end of the chain – they remove the cost and time implications of transferring product from wooden pallets to plastic.

Like many plastic pallets, these polyolefin models are also more environmentally friendly than their wooden alternative, as they are manufactured from 100 per cent recycled polyolefin, which is fully recyclable.

Polyolefin plastic pallets are more durable than wooden pallets; however, they are not a substitute for more long lasting polyethylene plastic pallets, which, in normal handling and loading scenarios, can have a lifespan often exceeding 10 years – up to 10 times longer than wooden pallets.

ConclusionMost pharmaceutical companies have complex supply chains that are constantly adapting to meet the demands of the fast-evolving marketplace. Pallets remain an important component in the pharmaceutical supply chain, but suppliers of the future need to be looking at ways they can help pharmaceutical companies tap into potential savings, whether it’s improving customer service and delivery lead times, or developing more cost-effective products. What is certain is that those suppliers that continue to innovate with hygiene in mind will be best placed to serve the pharmaceutical industry in years to come.

References1. The UK’s CAbKA-IPS CPP 878 PO and CAbKA-IPS CPP 875 PO pallets are known as the Eco E5 (OD-3R) PO and Eco i5 (OD-5R) PO pallets in Europe.

LAbS & LOGISTICS


Switching from using a combination of wooden and hygienic plastic pallets to using a new generation of plastic pallets throughout its supply chain has allowed MSD Heist Operations to tap into huge cost savings and promote better hygiene.

LAbS & LOGISTICS


In the multifaceted interconnected world in which we work, timeworn models of competition are becoming increasingly outmoded. Today we take for granted how the internet and intranet have developed into an integral part of the way we go about our daily lives. With the advent of new technology, offices have become virtual, the workforce is not confined to one location, and exchange of information is possible on a scale never before imagined. The lone salesman on the road is a distant memory; teamwork has progressively become the byword to corporate life; by virtue of economic necessity, corporate entities are seeking out new ways to collaborate and partner. And the term ‘supplier’ has virtually disappeared from our vocabularies.

Partnerships between service providers are vitally important to effect the change necessary to improve the strength of a company’s bottom line and, in my opinion, the wellbeing of the staff. The overriding objective is to provide a collaborative learning and engagement opportunity for all entities that are willing to engage with large and small corporate entities, thus creating an opportunity for the supply chain to learn from each other in partnering for the future.

Investing in R&D A changing economic climate, together with the patent cliff of many major products, has resulted in drastic changes in the business models of a whole industry. It’s no longer simply the repetitive, simple tasks that are outsourced, but increasingly complex, specialised tasks, including research and development, when pursuing the identification of new chemical and biochemical substances.

Nowhere is this more apparent than in the pharmaceutical industry. Innovation is crucial in a fast-changing world and, whereas once companies would have avoided assistance from external


Partnerships Herald the Future for Pharma and Biopharma Industries

sources, today partnerships are the norm rather than the exception. These days an amalgamation of in-house and external expertise applies to virtually every project undertaken. Networks can be called upon to enable individuals to work together. Scientists, for instance, may be working with similar compounds in different parts of the globe. With collaboration, the restrictions of reporting processes and boundary functions can effectively be scrapped.

Research and development is one area that benefits enormously from strategic partnering. According to the AbPI, the pharmaceutical industry invests more in R&D than any other industry in the UK – up to £12.1 million every single day. It’s a costly and lengthy process, with the development of a new pharmaceutical product taking anything from 12 to 15 years. Given that only five out of the 25,000 compounds tested in laboratories actually come to fruition, you realise how important it is to get the development process right. And that so often relies upon teaming up with appropriate partners in the first place to be able to offer a more holistic service to the client.

Drug discovery, testing and analysis and managing growth without outstripping existing infrastructure by partnering are the norm. Historically though, companies simply haven’t had the resources to offer these services. Today there is a viable alternative through collaboration. Global companies like Vindon, based in Rochdale, UK, with offices in Ireland and the USA, understand that pharma and biopharma are undergoing a paradigm shift in the methods of discovery and development of drugs, and so are endeavouring to lead the way with specialist expertise that is helping manufacturers throughout the world to reduce their costs and plan for future needs.

The Partnership PropositionVindon shares a number of unique strengths with its partners; we have

a reputation for acting swiftly and, importantly, being flexible. We are committed to working with our partners to create tailored partnerships that are structured to best achieve our mutual goals. We bring a broad range of skills and resources to every partnership including the co-ordinated organisation of analytical testing, and management and supply of storage suites for pharmaceutical and biopharmaceutical samples in a controlled environment.

We understand the need to capitalise on growth and the requirement for professional assistance at every level of the process. Ultimately, there is a change process happening; a shift from doing everything internally, to a more versatile, but multiple, faceted partnership approach. This could be in different geographical regions, as manufacturers are aligning their strategy with partners that can facilitate access to local markets. by choosing a company that already works in different regions Vindon can meet global and national regulatory standards for quality, and secure storage

Page 77 – ADVERT 32 – COOL LOGISTICS

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of APIs, biologicals, tissues, cells, solid and liquid dosage forms for local as well as established markets in North America and Western Europe.

They and their partners remain as autonomous organisations regarding their respective operational activities, but by working in conjunction with each other they are able to streamline costs. As an example of collaborative working, not only do Vindon provide traditional off-site storage, but they are also developing the capability to manage clients’ own storage suites at their own premises. In the ideal arrangement, your collaboration will give you a turnkey solution that will bring your product or service to market in the quickest time possible.

Such a partnership will enable quick acquisition of knowledge to tackle new problems; you both have the opportunity to cross-fertilise ideas, thus generating new insights and perspectives; and because a larger network has been created, project developments can be more quickly disseminated.

Advantages of PartneringPartnering selected activities can significantly ease your own pressures, by enabling people to do more. You may choose to use a partner occasionally to enhance existing in-house expertise when an unusual short-term requirement

arises. Or you might go for a more substantial partnering option.

In Vindon’s case, key services include the testing, analysis and storage of pharma and biopharma drugs through all stages of clinical development. We are also involved in DNA sequencing, clinical trial support, the expansion of cells into master and working cell banks, cell line characterisation, genetic profiling, mycoplasma and sterility testing.

Choosing your Partner/sThe flexible array of collaboration choices opens up a whole new approach to stability testing, cryobanking, biobanking, global clinical trial support, genomics and pathology services to name but a few, all changing and growing alongside your own evolving business. However, the right choice of partner is critical. A good outsourced facility should be willing to invest time to listen to and support your needs to at least the same standard and thoroughness that you would expect from your own in-house scientists. In today’s climate, flexibility is key, and you need to be able to choose whatever level of external support is best for you and your team.

Trust, approachability and flexibility are all preferable to a rigid structure that does not lend itself to reacting quickly to changing requirements. The presence of the right equipment, volume capacity,

turnaround time, quality systems and data security are all crucial factors when selecting your potential partner. You may even choose to work with multiple partners to gain the best access to specialist expertise.

Controlling the CostsPartnering with a company that can provide a wide range of laboratory services and controlled environment storage allows you to access state-of-the-art facilities while enabling significant cost reductions due to economy of scale at the outsourced facility. In addition, it can provide peace of mind, whether the goal is long-term or an interim solution. During site consolidations following a merger or acquisition for instance, partnering could well be the only option.

However, if handled badly, any type of business collaboration can unsettle your organisation, resulting in lower quality of services. The right outsourced storage organisation will seek to build effective partnerships and respond quickly to specific market requirements, giving guidance on critical aspects including laboratory processing and liaison with regulatory bodies. Choosing a partner that understands your market sector, and the pressures that are exerted on it, will ensure a more efficient process to help motivate your own plans for the future.

In drug development, cost control is a critical component of maintaining a competitive advantage. If you want to free up aspects of your own operations that might not be running efficiently, it may be worth considering the merits of partnering for some of your more routine services. This will allow your team to focus on their core competencies while enabling instant access to state-of-the-art, secure facilities without the need for capital outlay, additional space, equipment maintenance or additional training and labour costs.

Beware the PitfallsPartnering arrangements can go wrong; after all, partnerships are based on trust and have to take account of people’s foibles. It’s fair to assume that some mistakes could occur during the process, so it is important to take appropriate steps to make sure they don’t. Even though you may be of the opinion that two heads are better than one, partnering can be a risky business if you

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don’t get it right at the outset.So be absolutely clear about your objectives, and then examine your potential partner’s attributes. Do they have a proven track record and state-of-the-art facilities? Do they have full emergency back-up, including spare equipment, and dedicated service teams on call 24/7/365? Check that they have a high-security environment, including access control systems, motion detectors, smoke detectors, and CCTV surveillance. They should offer easy but secure access to your sample information, and a straightforward process for sample retrieval when required. And ensure that they have a fully documented disaster recovery plan in place.

It seems obvious but, above all, check that you can actually afford their services. It’s imperative that your partner has the financial stability to match the continued investment needed for your own requirements. Get an assurance that your long-term requirements will be met.

If the answers to all of these questions are in the affirmative, you’ve found your ideal partner. The chosen company must also have a comprehensive quality assurance programme with best practice standard operating procedures, as well as systems in place to demonstrate the use of regular internal audits for compliance with appropriate regulatory bodies. The company should be able to provide security, absolute visibility of process, and reliable access to the materials using current compliant procedures.

Foolproof Administrative ProceduresIf your partner is providing controlled environment storage, a comprehensive information quality management system is at the heart of all storage solutions. Their inventory management process should enable the user to record all data associated with samples, recording all user-defined information. Every sample handled must be given a unique barcode label and then recorded on the compliant database system.

This significantly simplifies handling, tracking and processing. Supplementary information relating to individual samples in terms of movement within the facility, time and duration of storage chamber openings and who accessed

the chamber must also be available as part of a comprehensive audit trail. All staff should be fully accountable and provide a service that complies with regulatory requirements. Samples must be handled at all times according to cGMP guidelines. Clearly the cGMP service provided by your partner should always meet legislative obligations.

Effective Disaster Back-upSome organisations may still prefer total control of their own storage. but there is no better example of the need for collaboration than establishing a comprehensive disaster recovery facility. back-up secondary storage is considered to be an effective insurance policy against the various mishaps that are beyond your control, and is an alternative to total partnering. In parallel with the primary in-house storage facility, a third party in a secure second geographical location should retain a set of duplicate samples. A disaster recovery plan ensures that potential economic loss is minimised and it counteracts any disruption to, or loss of, stability storage activities at your own premises.

This approach is well worth considering on the basis that it virtually eliminates the risk of a disaster scenario destroying your valuable stability storage samples and causing commercial damage to the organisation.

A Better OutcomeAs the pharmaceutical industry undergoes major changes, this could be the ideal time to reassess your current facilities and to carry out a cost-benefit analysis of partnering for stability testing, cryobanking, biobanking, global clinical trial support, genomics and pathology services, controlled environment storage, and cell culture services for your organisation. Collaboration isn’t right for everyone but it is well worth consideration, bearing in mind that you can pick and choose exactly which activities make sense for you to outsource.

Partnering can be strategic, cost-effective, efficient and productive – all of which are tempting incentives. When it’s handled competently, the results are well worth the effort. The blending of efficiencies and synergies can result in a renewed vigour within all the partnership companies. We’re living in an age when resources and finances are stretched. So collaborations in the pharma and biopharma industries can help scientists, inventors, laboratories, education and the academic world all pull together to make life science projects more effective.

Working together, the prospect of better healthcare in the future will become a reality for all of us.

Patrick Jackson - business DirectorVindon. Patrick Jackson - business Director, has been part of Vindon’s management teamsince 2005 and is responsible for developing systems to sustain growth in this highly competitive market by formulating working relationships with clients and major sub-contractors and negotiating exclusive trading agreements with major clients by developing a client and supplier partnership philosophy.His focus at Vindon is the development of new products and markets both in the UK and overseas.Email: [email protected]

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AbstractMolecules reaching the market in recent years present an ever-growing complexity. In the meantime, purity criteria are more important than ever to ensure patient safety. The combination of these two facts represents a big challenge for the manufacturing industry, where the right combination of state-of-the-art synthesis and advanced purification is necessary to meet the demand in a cost-effective and time-efficient manner. Membrane filtration and chormatography are presented as efficient technologies to reach the required purity level. The use of these technologies at industrial scale is illustrated through a case study including a complex biocatalysis reaction and the complete downstream processing yielding the final, pure product. The scale-up from gram- to hundred- kilogram-scale, process efficiency and timelines are also considered.

IntroductionThe complexity of APIs reaching the market has been increasing over the years, as the new synthetic molecules developed in the pharmaceutical industry have become larger and more challenging to synthesise. This trend is driven by two major factors:1 the development of more and more targeted therapies, leading to specifically designed, highly functionalised molecules and2 the intellectual property minefield, commanding innovators to look for unpatented molecular structures to protect their future markets. In addition, specific and inflexible purity targets have to be met to ensure patient safety and to comply with ever-tougher regulation, while minimising the costs of production. The combination of complexity and purity represents a real challenge for the chemical and biochemical manufacturing in-dustry which is to master smart

Smart Synthesis, Membrane Filtration and Chromatography

synthesis and advanced purification technologies to deliver high quality products. In its first part, this article will present selected purification technologies. In the second part, their use to reach the required purity while optimising the recovery yield and production costs will be illustrated with a case study, demonstrating that the combination of advanced purification technologies and smart synthesis guarantees meeting tough timelines and purity specifications

TechnologiesMembrane Filtration: A Mild Process to Isolate Molecules from Complex Mixtures Membrane filtration (Figure 1) allows for mild downstream processing to separate the components of a complex mixture depending on their size, to carry out a buffer exchange (diafiltration) or to concentrate a solution. Depending on the size of the membrane pores (also called the membrane cut-off), different particle sizes are excluded andthis determines the type of filtration: microfiltration (MF), ultrafiltration (UF), nanofiltration (NF) or reverse osmosis (RO), as depicted in Figure 2. This technology is well adapted and

routinely used in the food industry to isolate a food ingredient from complex natural mixtures or in the bio-pharma industry to purify compounds obtained by fermentation or cell culture. However, this technology can also be implemented to synthetic processes when similar conditions are met and more conventional processes cannot apply. This is the case for biocatalytic processes where the reaction is carried out in aqueous buffers, the molecules involved are often fragile and temperature-sensitive, or the resulting mixture can be complex and presents molecules of very different sizes to separate (enzyme, cofactor, product, by-products, etc.). As a result, a series of filtration steps with carefully selected membrane cut-offs can be fully integrated within the production process of small molecules, and enable the recycling of expensive biocatalysts (enzymes).

A Chromatography Solution for Every Purification Challenge, from Lab to Commercial ScaleSeveral options are available to purify complex mixtures in a large scale, among which three preparative chromatography technologies are

Figure 1: Filtration unit: 4000 L reactor (foreground) and UF membrane filtration units (background, on the wall behind the operator).

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phase is constituted by supercritical

CO2; the technology is mostly suited to small scales (up to a hundred kilograms) and allows for improved separation and process throughout. It is particularly well adapted to early-stage production.Finally, continuous chromatography is operated with several columns in a loop and is particularly well suited for medium to commercial production (up to 100s of tons per year) due to low product dilution and low operating costs.

It is routinely used in pilot and commercial scale for the separation of binary mixtures (such as racemic mixtures), and also as a two-step process for purifying complex mixtures in large-scale applications. Preparative HPLC is based on the same principle as analytical HPLC,

Spring / Summer 2013 Volume 5 Issue 3

only on a considerably larger scale, with increased injection volumes and stacked injections to maximise productivity. A common misleading belief states that chromatography cannot be evaluated precisely unless pilot runs are implemented on larger-scale equipment. It must be affirmed thatthe main advantage of chormatography is the very predictive assessment of the results over a large scale based on automated screening results obtained from just a few experiments and sub-gram amounts of material, due to direct scalability (a 1-million-fold linear direct scale-up has been demonstrated).1 As a consequence, an accurate estimation of large-scale productivity and costs is obtained very early in the process development phase. In addition, advanced simulation tools allow for a rapid, reliable development and straightforward validation of the process. Nowadays, chromatography has proven to be robust and reliable for the production of commercial APIs. It constitutes the purification method of choice, as illustrated in the case study developed below.

Combining State- of - the - art Synthesis and Advanced Purification TechnologiesThe coupling of chemistry, high- performance chromatography, and membrane filtration enables the efficient synthesis and purification of highly charged or polar molecules that are somewhat thermally labile. because of their charge or polarity, these molecules tend to be water- soluble and can or do exist as salts.

Their purification necessitates the use of ion exchange and reverse osmosis or nanofiltration. The organic structure is purified by classical chormatography and membrane filtration allows for the concentration of the purified product under extremely mild conditions, and prevents any issues to thermal instability. Final drying is drying is achievable with spray drying, for instance. This type of combination can, for example, be used for saccharide derivatives, nucleotide derivatives, complexes with metals, or other species. Applications can include various pharmaceuticals, like contrast

highly competitive for synthetic molecules: high performance liquid chromatography (HPLC, Figure 3), supercritical fluid chromatography

(SFC) and multi-column continuous chromatography (often referred to as SMb or simulated moving bed techniques). The critical choice of a chromatography technology for a given purification often depends on the scale at which the separation is to be carried out (Figure 4) and on the nature of the mixture to purify. More fragile biomolecules are often separated on resin-based stationary phases, with medium or low pressure liquid chromatography (MPLC or LPLC). Preparative HPLC is well suited for small to medium scales (up to metric tons).With SFC, the major part of the mobile

Figure 2: Filtration technologies and their size-based molecular selectivity

Figure 3: Prochrom® DAC LC300 HPLC column (in front of the operator) with Hipersep® L system (behind the operator) for production under cGMP conditions.

Figure 4: Chromatography technologies and their application span as a function of scale and development stage.

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saccharide derivatives, nucleotide derivatives, complexes with metals, or other species. Applications can include various pharmaceuticals, like contrast agents; cosmetics; certain functional ingredients and other high-end chemi-cals, such as electronic chemicals.

Case Study: How to Obtain 100s of kg of a Pure Polar Functional IngredientThe production of pre-commercial quantities of a highly polar functional ingredient required an expert in purification. The initial project included the full process development for a chromatography step, and the scale-up of the complete process from lab-scale to commercial-scale, including a complex biocatalysis step and the downstream process. Chromatography was part of a multi-step downstream process to isolate a chiral compound from a complex enzymatic reaction mixture. Due to a good technology and competence fit, the entire scale-up and manufacturing project was achieved on a single manufacturing site, from the enzymatic stereoselective reaction to the isolated final product. After the technology transfer, the process was implemented and scaled up from a few grams to a few hundred kilograms.

Biocatalysis: A Complex Reaction Yielding a Complex MixtureThe chiral active ingredient targeted resulted from a complex enzymatic process. This bioreaction conversion resulted in a complex mixture of biological material, reagents, intermediates, and desired product. The isolation of pure product required a series of advanced purification steps (downstream processing) includ ing membrane filtration and HPLC chromatography (Figure 5).

Functional Ingredient Isolation at the Required PurityThe biocatalyst material was removed from the reaction mixture by ultrafiltration (UF) using a 10,000 Dalton molecular weight cut-off membrane, meaning that no selection was obtained on the smaller molecules: their concentration was expected to be the same in the permeate and retentate. However, thanks to a retentate volume 30 times smaller than the permeate

volume, the recovery of small molecular weight compound was maximised, and reached 95% for the valuable desired product.2

At this stage, the product remained in dilute solution within a complex aqueous mixture, together with seven undesired compounds. The mixture was concentrated by nanofiltration (NF): impurities were partially removed while the overall volume was reduced in preparation for the HPLC step. This step was very important since it determined the quality of the feed for the chromatography, which in turn impacted the quality of the separation. A concentration close to 45 g.L-1 of the desired product was obtained with a 90% recovery yield over the two filtration steps.

The HPLC process development and optimisation was carried out on site and fully benefited from long experience with this technology. The target was to reach a purity over 95% with a maximal recovery and in a cost-effective manner. The HPLC purification was the key step to meet these requirements, and numerous parameters were optimised to

comply with the specifications: the bed length (amount of stationary phase used), the stationary phase stability (i.e. its lifetime), the minimisation of the volume of eluent required by batch, the volume of solution injected and the collection time. With optimal parameters, the elution volume was halved compared to the initial process and the recovery reached 90% of the desired product injected (against 50% for the initial process). The desired compound was obtained at the required purity in a dilute aqueous solution, which was concentrated 30 to 40 times by reverse osmosis to reach the targeted 180 g.L-1 concentration. This step was performed with a 90% recovery yield and performances higherthan initially expected were reached. Finally, the product was isolated by spray drying with a recovery of 87%. The bio-conversion equilibrium afford-ed the desired product within a complex crude mixture of biomaterial and smaller molecules. A multi-step downstream processing was implemented to reach the 95% purity target with maximum recovery, and a purification yield of 52% was obtained over the five purification steps (three filtrations, one HPLC chromatography and the final spray drying).

Scale-up in Three Steps to Reach 100s of kg Production in Four MonthsThe process initially provided by the developer had been optimised up to a three-litre scale, which corresponded to the production of a few grams of product per batch. The production was scaled up in three phases to obtain several hundreds of kilograms in the final phase (Figure 6). Phase I consisted ofa technology transfer to ensure the reproducibility of the initial process at the CMO production site.

Figure 6: Global project timeline, including production phases and the design construction of a dedicated workshop.

Figure 5: Process overview with the key technologies involved.

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The workshop was designed by the CMO, which benefited from strong expertise in engineering, especially for purification systems in pharma and industrial biotechnology industries. The workshop was fitted with four reactors (1000 to 4000L) for the biocatalysis itself and the work up, aProchrom® HPLC column (800mm internal diameter) com-plete with its chromatography system (Hipersep® XL), three filtration units: UF (15m2), NF (36m2) and RO (36m2) and a spray dryer (3kg.h-1 capacity) to accommodate the full process at pilot and pre-commercial scale. Within this new facility, more than 500kg of product were manufactured over four months (Phase IIIb), exceeding the customer’s expectations.

ConclusionOverall, a complex process was implemented and scaled up thanks to the availability of a broad range of technologies: the expertise in advanced synthesis permitted a straightforward technology transfer for the enzymatic reaction. Strong know-how in various filtration (UF, NF, RO, diafiltration) and chromatography (HPLC) technologies ensured a smooth and reliable downstream processing, including the development and optimisation of the HPLC process using proprietary chromatography technology. Finally, a new workshop was designed and purpose-built using the engineering capacity gained by building turnkey purification units for the pharmaceutical and industrial biotechnology industries. The project was completed in a record time of 15 months, including the scale-up from a gram-scale to a hundred- kilogram scale and the design and construction of a dedicated work-shop. The combination of advanced purification technologies enables one to obtain purity levels and recovery yields unattainable by classical purification; it may be used to increase the purity of intermediates to improve the yield of difficult or expensive downstream chemistry steps, which sometimes dramatically reduces the manufacturingcost. The combination of biocatalysis, membrane filtration and

chromatography is a specific example: the functional ingredient present-ed here required a moderate purity of 95%, which enabled high recovery at the HPLC unit operation. However, specification as strict as 99.9% purity can be met with chromatography: the product is delivered at the required purity, whatever the threshold. Combined with smart synthesis, the choice of purification technologies best suited to the crude mixture is definitely the key to a time-efficient and cost-effective production.

References1. Welch, C.J., Sajonz, P., Spencer, G. et al., Org. Process Res. Dev., 2008, 12, 674–677.

2. All the yields and purity data correspond to the average data over the entire commercial-scale production campaign (Phase IIIb: four months, 30 batches).

agents; cosmetics; certain functional ingredients and other high-end chemicals, such as electronic chemicals.

Case Study: How to Obtain 100s of kg of a Pure Polar Functional IngredientThe production of pre-commercial quantities of a highly polar functional ingredient required an expert in purification. The initial project included the full process development for a chromatography step, and the scale-up of the complete process from lab-scale to commercial-scale, including a complex biocatalysis step and the downstream process. Chromatography was part of a multi-step downstream process to isolate a chiral compound from a complex enzymatic reaction mixture. Due to a good technology and competence fit, the entire scale-up and manufacturing project was achieved on a single manufacturing site, from the enzymatic stereoselective reaction to the isolated final product. After the technology transfer, the process was implemented and scaled up from a few grams to a few hundred kilograms.

Biocatalysis: A Complex Reaction Yielding a Complex MixtureThe chiral active ingredient targeted resulted from a complex enzymatic process. This bioreaction conversion site. The process was applied and minor improvements to the existing process were carried out. A major part of this step was to fully develop and optimise the HPLC purification step, which was completed within only three months (including stationary phase screening, phase stability testing, and operating condition optimising). The complete manufacturing of the pure, dry product was fully mastered and 50g of product was obtained.

The process was scaled up to pilot scale (batches of a few kilograms each). All unit operations were scaled up without major issues, and Phase II afforded 35kg of product over a two-month campaign.The final phase aimed at production of hundreds of kilograms, and required a purpose-built workshop (Phase IIIa).

Aline Devoille,Technical MarketingManager - SyntheticMolecules, NovasepAline Devoille received a Master degree in OrganicChemistry and

Chemical Engineering from ECPM (European Engineering School of Chemistry in Strasbourg, France) and a Master degree in Molecular and Supramolecular Chemistry from the University of Strasbourg, France. She obtained a PhD in Inorganic and Coordination Chemistry from the University of Edinburgh, UK. Through her studies, she has worked as medicinal chemist for GSK in Harlow, UK for a year. She has joined Novasep in 2011 where she is in charge of Marketing for the Synthetic Molecules business.Dr Devoille is the author or co-author of several peer-reviewed articles and has given lectures at several scientific conferences.E-mail: [email protected]

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Page 89 – ADVERT 38 – LYOFAL

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Last year, the World Health Organization revised its guidelines regarding the manufacture and distribution of water for pharmaceutical use, emphasising the appropriate specification and design of water purification systems. By utilising the latest purification technology and techniques, pharmaceutical companies can meet such requirements and make considerable improvements in water quality and delivery, says Steve Mines from Purite.

IntroductionWater is one of the most important raw materials used in the pharmaceutical sector. It is used for drug dilution, as a transport agent in analytical work, cell cultures and DNA sequencing, and is also essential for equipment cleaning and wash-down.

The chemical composition of raw water drawn from boreholes or direct from mains supplies can vary considerably in terms of the quantity and the variety of dissolved minerals and particulate matter. As a result, the correct water purification techniques are essential to ensure a consistent supply of high purity or ultra-pure water.

Producing a water feed stream to a consistent quality, and at competitive cost, can be very difficult. In addition, the cost of raw water is steadily rising, making it increasingly important for manufacturers to consider ways of minimising waste and improving the opportunity for recycling.

Tightening LegislationLegislation and guidelines continue to be refined, too, raising the bar for safety. Last year, the World Health Organization revised its guidelines regarding the manufacture and distribution of water for pharmaceutical


Water Purification that Stays Ahead of Legislation

use. As reported by the website Good Manufacturing Practice, the revision emphasises that, “the design of a water system is important for avoiding microbiological growth in the system. Where previously only the sanitisation was mentioned.

The authors also emphasise the importance of the appropriate capacity to ensure a sufficient re-circulation. Another new development is that the pharmaceutical manufacturer is now responsible for ensuring that the feed water has drinking water quality. If this is not the case they [the pharmaceutical manufacturer] have to take suitable measures in a step prior to the actual treatment to guarantee this quality.”

The report goes on to say, “In the chapter “Qualification” it was added that the quality of the feed water needs to be inspected as part of the validation and that this testing is supposed to be continued as part of the routine monitoring.

In the chapter “Inspection of a Water System” it was further added that an on-site inspection of the treatment as well as of the distribution system and the sampling points should be part of the inspection.”

This recent revision only goes to emphasise what market-leading manufacturers and suppliers such as Purite have been saying for some time; that the appropriate specification and design of water purification systems is key to meeting legislation, delivering efficiency and ensuring safety.

Purification Requirements for the Pharmaceutical SectorThe requisite degree of water purity will vary from task to task, with the highest levels typically being required in cell culture, media preparation, DNA

sequencing, and genome research. For these applications, water purity is usually measured in terms of either resistivity, expressed as Megohms per centimetre (MΩ.cm), or conductivity, measured in microsiemens per centimetre (µs/cm), as the concentration of ionic contaminants will determine how electricity is conducted; the purer the water the higher the resistivity, as lower concentrations of ions are less able to conduct current.

There are three main grades of water – purified water (PW), water for injection (WFI), and highly purified water (HPW) – with water quality being regulated by various national and international bodies. For example, Europe, Japan and the United States each publish official documents listing drugs and explain how to achieve specific quality attributes. These publications are known as pharmacopoeia.

A pharmacopoeia specifies parameters and measuring criteria for water to be used for certain applications; however, they do not necessarily prescribe the design or maintenance regimes required to achieve these requirements repeatedly. This falls

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within the remit of a number of validating bodies; in the US, for example, it is prescribed by the Food and Drug Administration (FDA), which aims to ensure compliance with standards through ensuring that system design, installation, monitoring and maintenance procedures are in place to facilitate consistent and traceable performance to standards.

It should be noted that the need to design water systems to meet legally enforceable standards can have far-reaching consequences, as system designers, engineers and operators tend to concentrate on solutions that have a proven validation track record. However, the standards are regularly updated to ensure that the benefits from new technological advances are incorporated in system design after an appropriate period of validation and documentation.

System DesignOne of the main design and operational criteria for pharmaceutical companies is that the water purification system, from generation through to the distribution network and storage vessels, can be successfully validated to ensure that it consistently produces water that meets the necessary standards.

The design of any water treatment system is generally based on a number of variables, including the quality of the source water, the required output quality, and other considerations such as operating costs. A PW system is generally fed from a potable water source, while a WFI system is usually fed by a PW system with a resistivity of between 0.5 and 5.0 MΩ.cm. by contrast, an HPW system is normally fed by a primary loop with a resistivity of between 16 and 18 MΩ.cm and a TOC of 30 ppb or less. Highly purified water will, therefore, require more treatment stages than a WFI or PW system.

Most systems designed to generate purified water comprise a number of process stages:

1. Pre-treatment – to remove particulate matter from the mains / borehole water, and to remove any contaminants that would impair the RO stage of the process or damage the RO membrane.

2. Reverse osmosis (primary deionisation) – to remove 98% of contaminants and bacteria from the supply water using membrane technology.

3. Secondary deionisation – to remove the remaining ions.

4. HPW would require a polishing deionisation stage to take the water up to maximum theoretical purity utilising re-circulation through a bed of nuclear grade resin.

Maintaining QualityPurified and HPW in particular are extremely difficult to store and any system should be designed to minimise the length of pipework between the source of HPW generation and the points of use. In the part of the system where the purified water is generated,

careful consideration must be given to the material of all wetted parts, as contaminants can leach out of most metals and plastics.

Achieving Microbiological ControlEven within HPW systems, where theoretically there is little to support micro-organisms, biofilm growth on pipework remains an issue. There are a number of important design considerations that must be considered to minimise microbial contamination, including the use of an RO membrane, a UV light and filtration. Furthermore, effective system construction is fundamental for maintaining microbiological purity.

Choosing, operating and maintaining an RO system to provide a high purity of supply should be straightforward, but systems are often incorrectly specified for the application or subject

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bacteria and fine particulate matter. However, although the selection of the deionisation cartridges is relatively straightforward, the specification of RO systems that can achieve these enhanced levels of performance can be complex if optimum levels of performance, energy efficiency and operating costs are to be achieved.

Even though there is potential to raise the quality of purified water supplies delivered by stand-alone units, there are situations where it is more efficient and economical to install a centralised system. For example, as most purification systems will have to comply with bS EN ISO 3696 and provide water on demand wherever they are needed throughout the lab, the nature of the work may dictate that one or more self-contained units need to be positioned at different locations. Space being a valuable commodity in most laboratories, the chosen water purification solution needs to be as unobtrusive as possible whilst still delivering the required quantity and quality of water. In these situations, a centralised system feeding a ring-main may be more appropriate.

Once the benefits of stand-alone or centralised water purification systems have been considered, it is time to choose and specify a system that will

of purity, 0.01mS/m (0.1µs/cm), with Grade 2 being 0.1mS/cm (1µs/cm) and Grade 3 at a level of 0.5mS/m (5µs/cm).

However, it is also possible to achieve higher levels of purity by employing a combination of reverse osmosis and deionisation. In addition, pre-treatment of the feed stream will protect and extend the life of reverse osmosis membranes, especially in areas where the feed water contains high levels of organic contamination, hardness and free chlorine.

As an alternative to resin-based deionisation systems, larger integrated laboratory systems can incorporate an electro-deionisation system (EDi), for secondary purification when fed with permeate from the RO system, producing water with a quality of greater than 10 MΩ.cm. Essentially (EDi) is a purification technology that uses a combination of ion-exchange membranes/resin and electricity to deionise water.

For stand-alone systems, there are further measures that can be taken to enhance the quality of supply. For example, where Grade 1 water with enhanced microbial quality is required, the RO/deionised purified water is further processed using UV irradiation at 254nm and sub-micron filtration between 0.2 and 0.05 microns to remove

to improper use. However, a well-specified water purification system from a trusted and experienced supplier will provide an exceptionally high level of purity and, coupled with ongoing technical support and advice, will ensure that your laboratory or production area receives an efficient, economical and reliable supply of purified water.

SpecificationThe first stage in the specification process is to ensure that everyone involved fully understands the grades of water purity that have been standardised, the available methods of delivering them and the requirements of the laboratory itself.

Reverse osmosis is capable of producing purified water, in large volumes, from a supply fed under pressure into a module containing a semi-permeable membrane, which removes up to 98% of inorganic ions, plus virtually all colloids, micro-organisms, endotoxins and organic macromolecules. Depending on the quality of the feed water, RO systems are able to provide typically Grade 3 purity purified water. There are three grades of water purity, expressed in terms of conductivity, defined in the current standard, bS EN ISO 3696:1995 ‘Water for analytical laboratory use’. Grade 1 represents the highest level

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achieve the right level of water purity and the most effective balance between cost and efficiency. A common cause of inefficiency in water purification systems is oversizing, so it is important to specify equipment that can deliver only the volume of purified water that you need. Oversized systems require extra space, greater expense and, because RO is potentially less efficient when the laboratory is only operational for short periods, can suffer degraded performance. Likewise, a realistic estimate must be made of the number of take-off points that will be in use at any one time; if it is simply assumed at the installation stage that all points will be in use at once, the result can be a dramatically oversized and expensive system. To maximise efficiency, it is essential to consider whether a given water quality is required throughout the laboratory, or only at a limited number of work areas. Similarly, the volume of water needed should be analysed based on the patterns of daily use to highlight peaks and troughs in water requirements over extended periods.

Steve Mines is the DivisionalSales Manager at Purite.Steve Mines is the Divisional Sales Manager at Purite.

His scientific background started as a Lab Assistant, then progressed to Shift Chemist with Synthetic Resins and later Laporte Industries. In 1992 he moved to Sales which included roles with Abb Kent Taylor and P&R Laboratory Supplies, followed by Hamilton Company as European Sales Director. He joined Purite in 2008.Email: [email protected]

To achieve the best specification it is advisable to work with a supplier who is willing to assist you on-site and help you to specify the best solution for your needs, one that also has a capacity not only to supply but to plan, specify and install a system, rather than delegate to outside contractors. With the right help and advice, an efficient, economical and reliable supply of purified water is available for your laboratory that will remain cost-effective throughout its lifespan.

ConclusionPerhaps the most important fact of all to bear in mind is that although there are many companies with the ability to supply, install and commission RO systems, there are far fewer with the resources and expertise to help end-users maximise the return on their investment once the installation and commissioning engineers’ work is complete. To help you make the right decisions regarding specification and maintenance factors from the outset, choose a supplier who is willing to work with you on-site and

MANUFACTURING

help you to specify the best solution for your needs. by utilising the latest purification technology and techniques, pharmaceutical companies can make considerable improvements in water quality and delivery while potentially reducing both capital and operating costs.

MANUFACTURING


Pharmaceutical manufacturers are under continuing pressure to bring product to market faster and at a high level of quality. This pressure has driven pharma manufacturers to look to lean principles and automation as a means to streamline operations and enhance efficiency. One area where these principles are starting to find traction is microbial quality control testing.

Microbial quality control testing can often be a gating factor to the final release of products for manufacturing of pharmaceuticals. The culture method, the mainstay of microbial testing, is manual and time-consuming. As a result, quality control teams have begun to look for other methods to accelerate the time to results. As part of that search, many businesses have concluded that automation of these methods brings a significant value to the organisation in the form of process standardisation and reduced resource requirements.

The search for the best rapid microbial method (RMM) can be daunting. There are many resources available to help guide companies to determine what RMM best fits their needs. However, the company needs to find the best way to put that data together. The goal of this article is to identify one method of measuring the value of RMM technologies, as well as to offer some points of consideration to help create the appropriate questions for both internal business analysis and investigation of rapid method suppliers.

Beginning the Search for an RMMWhen beginning the search for an automated method, the following points should be included in the list of information requirements to be gathered as part of the initial analysis of the RMM project. • What is driving the need for the RMM (financial, quality improvement etc)• What RMM methods are available • What are the key parameters for the evaluation, e.g. alternative technology, reagent required, non-destructive, automated, training required, etc.• How appropriate is the technology as it relates to unique business requirements e.g. product type

MANUFACTURING

Choosing an Automated Rapid Microbial Method

• What are the results of a basic ROI calculation• Based on the parameters defined, how does each technology score in the initial phase.

Developing and Using a Decision MatrixA useful tool to help compare and contract different methods is a decision matrix. by taking the systems under consideration, creating a key parameter list based on the identified requirements, and scoring each method against the parameters, data will be created that can be plotted to determine what system best addresses all the identified needs. Some of the items that could be included in a decision matrix are listed in the below table.

Once decision criteria have been determined and the matrix developed, scores can be assigned to each parameter, with 1 for low, and 3 and 5 for higher benefits, as seen in Table 1. Parameters 1 through 8 are summed for technology benefit and 9 through 13 for ROI benefit. The values for each can be plotted for a visual representation of the data and to facilitate the selection, as seen in Table 2.With the initial analysis completed, the methods scoring the highest, usually the top two or three, can be examined in closer detail to determine the best fit. When commencing with a more detailed analysis, the following points should be included in the investigation and decision-making process.

What is the Technology?When evaluating the technology used to provide detection, consider parameters such as the signal system being affected by the product type, or the availability of colonies at the end of the assay for identification. In addition, it is important to determine if the method generates a CFU or a signal that will be difficult to relate to CFU during validation.

What Applications does the Method Support?Current microbial testing involves sample preparation, incubation and detection for air, surface, personnel and water testing, sterility testing, and bioburden testing. To minimise the amount of cross-training needed, and allow for technicians to move from one method to the other, the technology should support as many of the current sample tests as possible. A consistent test across all applications eases the burden on the technician to learn one test method for environmental monitoring, and another test method for sterility, for example.

What do the Regulatory Organisations Think of the Technology/Method?While it can be argued that rapid methods are in their infancy, regulatory agencies have been quick to point out that these technologies have value and that the agencies are open to their adoption. An excellent example is the recent update to 21 CFR part 680 with regard to sterility test requirements for biological products1. The intent is “…To promote improvement and innovation in the development of sterility test methods, to address the challenges of novel products that may be introduced to the market in the future, and to potentially enhance sterility testing of currently approved products. This proposed revision would provide manufacturers the flexibility to take advantage of modern methods as they become available, provided that these methods meet certain criteria.” While working with automated rapid method suppliers, clearly understand their relationship with regulatory agencies, if their method has been validated, and how it was validated. Will their technology and validation method be accepted by the regulatory authorities?

Table 1: Sample decision matrix (note: Data is entered only to illustrate and does not represent any particular method or supplier)

Table 2: A sample decision chart plotting the data from Table 1.

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Time to ResultSome rapid methods operate similarly to the existing method, where a sample is not read until a specific time point representing the final read. In the case of automated rapid methods, samples are often read at pre-defined time intervals, allowing for an interim result within hours. In the case of a test failure, this can accelerate the investigation by weeks. A clear understanding of the automated technology can determine if this benefit is available.

What are Level of Automation and Integration to Business Processes ?The term “automated” can mean many things to many different organisations. A truly automated technology should minimise the amount of interaction that the user has with a sample, including the reading and reporting of results. This eliminates the types of errors that can occur as a result of human interaction. For example, forgetting to move a plate from one temperature to another for serial incubation can result in an incorrect result and generate an investigation. Or, accurately reading CFU counts on a plate but incorrectly recording them into the LIMS system can generate an investigation. These investigations often end with the need to train the user, but could be virtually eliminated with automation.

An automated technology should minimise or eliminate manual steps and integrate results to the LIMS system, such that a user prepares a sample, loads it into the automation, and the rest is performed by the technology. The user is only required to intervene when a sample is found to be out of specification.

How Much Analyst Retraining isRequiredWhile the current method has limitations, users and operating procedures are designed around the method for sample capture, analysis and result reporting. An automated method that can operate within the current operating procedures, but meets the requirements for sample capture and reporting, will likely require fewer updates to documentation and procedures. Technologies that require a number of manual actions may be suitable for low numbers of tests or niche applications, however if the new method does not replace the current method and requires similar processing time, then more staff may be required. ThroughputThe method should support your daily


MANUFACTURING

throughput needs. It is important to analyse your entire daily testing to clearly identify your number of samples per application and the resource currently required for each application. This will help appropriately determine if the technology can support your volumes.

Size of the TechnologyWith the implementation of a new technology, the size of the instrument can be important if space is limited. Manual systems typically require less bench space, while automated systems may require floor space as well. When reviewing the size of an instrument, consider two points. First, will the introduction of the instrument allow for the removal of another piece of equipment (i.e. an incubator) or multiple pieces of equipment? Second, is the technology designed in such a way that it does not need to reside in the QC lab, but could be in adjacent space or in the manufacturing area?

Sole SupplierMany companies require that when any piece of equipment is sourced that it is not from a sole supplier. For RMM, unfortunately that cannot be accommodated, as each technology and the consumables designed to run on that unit are dedicated to one company. The risk can be mitigated by determining if the company has multiple manufacturing sites for the consumables. This will support continued supply should one facility fail.

System SupportWith the modern RMM methods there is generally a piece of complicated equipment or dedicated reagents that will require rapid response from the company in the event of any issues. For RMM there is also the requirement for validation, and the further the method is from the compendia method, the more support is required from the organisation to facilitate the validation and answer regulatory questions. Smaller companies with small product ranges generally have better customer care/response than larger organisations. Review of the service package and referral by customers with the systems can be useful data to add to the matrix.

System and Consumables Cost The total cost for the system and consumables will need to be determined; however, the weighting of this needs to be tied to manpower required as well. A higher-priced system around $200K may

initially seem a negative score compared to a unit at $50K, however if the manpower required to run the lower-priced unit is high then the balance shifts.

ConclusionRapid microbial methods can revolutionise microbial quality control testing for manufacturing. Automation adds to the value of the method and can provide tangible benefits through the reduction of human error and increased efficiency. Selection of an automated rapid microbial method includes the analysis of internal needs, initial scoring of methods against those needs, deeper investigation of the top methods and final selection of the best technology for the business.

References1. Federal Register. Amendments to Sterility Test Requirements for Biological Products. Vol. 77, No. 86;

May 2012

David Jones,Ph.D., has more than 20 years experience in analytical method development,validation and equipment

Mark Severns,is Senior Marketing Manager at RapidMicro biosystems.For the last 15 years,he has worked closely withbusinesses to help

optimisation in the diagnostics industry, with a number of start up companies including Unipath. David then spent six years at Chemunex where he introduced rapid microbiology methods to the market as Director of QA and Regulatory Affairs. More recently David was at Wyeth biopharma leading the evaluation and validation of rapid micro methods and new technologies to improve laboratory efficiencies. David has a bSc in biochemistry and a PhD from London University in steroid endocrinology.Email: [email protected]

them automate their manual processes. Mark has worked with a number of start-up companies in the technology space, helping businesses in industries such as life sciences automate their manufacturing, warehousing and distribution processes. He holds a bachelor’s degree from the University of Delaware (Newark, DE, USA). Email: [email protected]

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Formulation for Improved Liquid Biotherapeutics

Many biotherapeutic drug products are prepared as lyophilised powders, but there is a growth in the number being formulated as liquid presentations for prefilled syringes. This move towards prefilled syringes is driven by the user-friendly and cost-effective attributes of these devices. Providing a prefilled syringe format minimises potential dosage errors by reducing the number of steps involved in administration. An example of a key step that is removed is the reconstitution of a lyophilised biotherapeutic. Removing this reconstitution step reduces the risk of contamination and speeds up the administration, providing an assurance of sterility of the product. Due to the simplicity in administering a prefilled syringe injection there is potential for patients to self-administer the biotherapeutic, resulting in better patient compliance. The manufacturer also benefits from prefilled syringe devices because it is no longer necessary to overfill vials with the costly biotherapeutic to counter loss from liquid transfer.

The key challenge to enabling a prefilled syringe product is the development of a stable liquid formulation of the biotherapeutic. The stability of a biotherapeutic is a function of a large number of parameters, including the formulation, interactions with the container-closure system, and stress conditions. A large number of these stress conditions must be applied during the development of a robust biotherapeutic, such as storage at different temperatures for different periods of time, shaking, freeze-thaw and light exposure stresses. The instabilities exhibited by the protein biotherapeutic to these types of stresses fall into two key categories: physical instability and chemical instability1. The main physical and chemical stability issues affecting biotherapeutics are shown in Table 1. Determining the relative importance of each of these stability issues and defining a successful biotherapeutic target product profile are important parts of the

formulation development process. Often the formulation requirements

for reduction of each degradation pathway differ from one another, so need to be finely balanced. Formulation is a very powerful tool for controlling biotherapeutic stability and achieving the target product stability profile. Formulation is defined by the nature and quantity of specific excipients in a composition that determine important parameters such as pH, ionic strength and viscosity. Many of these parameters have optimum working ranges with limits set to minimise adverse side-effects. For example, there is an optimum level established for formulation ionic strength or osmolarity to minimise the risk of injection site pain (typically ~300 mOsm/L for a subcutaneous administration). Each component of the formulation serves a specific purpose in

Table 1. Major degradation pathways of biotherapeutics.

Table 2. Key excipient types in biopharmaceutical formulations.

controlling these parameters (Table 2). It is strongly preferable to use excipients with a history of use in approved drug products because of their established safety profile. Ideally the excipients should be used within the approved concentration limit for the intended route of administration as defined, for example, in the US Food and Drug Administration list of substances Generally Regarded as Safe (http://www.fda.gov/Drugs/InformationOnDrugs/).

Often the first step in the formulation design process is the determination of the optimum pH and selection of an appropriate buffer. Near-neutral pH around 7 is preferable, but generally pH 5-8 is seen as safe. However, a number of successful products are formulated outside of this range, for example Lantus (Sanofi Aventis, pH 4.0) or Enfuvirtide (Roche, pH 9.0). The tonicity modifier

is typically the dominant component in a formulation, and its key purpose is to adjust osmolarity to a required level. The two types of tonicity modifier are charged, such as a salt (e.g. sodium chloride) and non-charged, such as sugars or alcohols (e.g. trehalose or mannitol). Charged tonicity modifiers can be used to modulate the short-range interactions in protein solutions. This property allows charged tonicity modifiers to be used to effectively reduce the viscosity of concentrated biotherapeutic doses (>100 mg/ml) facilitating ease of injection2. Surfactants, especially non-ionic surfactant (e.g. polysorbate 20 and 80) are often added to protein formulations to prevent or minimise the surface interface-induced damage, particularly in the presence of shaking or agitation stress. Antioxidants such as methionine or metal chelating chemicals such as EDTA can be used to prevent chemical changes due to oxidative stress. Although not usually found in prefilled syringe formulations, preservatives (e.g. phenol or benzyl alcohol) must be included in multi-dose device formulations to prevent microbial growth.

Some biotherapeutics require an additional stabilising component to help maintain their structural integrity. For example, metal cations such as Ca2+ can have a stabilising effect, particularly on proteins that contain a structural metal ion. Stable formulations of Factor VIII, for example, contain a small amount of calcium chloride, as the calcium ion binds within the structure of Factor VIII and improves its conformational stability. Amino acids, including histidine and arginine, have been described to stabilise proteins by a variety of mechanisms, including preferential exclusion, direct protein binding and prevention of oxidation. Some proteins have also been used as stabilisers, for example, human serum albumin is often used in virus particle-based vaccine formulations. Design of Experiments software can be used to effectively explore excipient compositions across a large formulation design space in a manageable-sized screening experiment.

In the first buffer selection stage of formulation development, the buffer is typically chosen to have a pKa value near the pH of the formulation3, for example,

phosphate at pH 7, citrate at pH 6, or acetate at pH 5. It has been found that this approach can be detrimental to certain aspects of protein stability, including aggregation. This may be due to the rapid proton exchange that occurs between the surface of the protein and the buffer species if the formulation pH is near the buffer’s pKa. This increased exchange results in an increased likelihood of a hydrophobic patch appearing and protein aggregation being triggered. A “displaced buffer” buffer system has been developed to address this problem, in which two buffer species, “buffer A” and “buffer b”, are used in combination4. buffer A has a pKa value >1 unit lower than the pH of the formulation, and buffer b has a pKa value >1 unit higher than the formulation pH. Under these conditions, the proton exchange between the buffer species and the protein is reduced, resulting in a lower likelihood that a hydrophobic patch will appear and thereby improving protein stability.

Figure 1. Retention of monomeric EPO in a marketed liquid formulation and in a reformulated product based on a TRIS/benzoate anion displaced buffering system4,5.

An example application of this type of displaced buffer technology can be found in the development of a temperature-stable liquid formulation of erythropoietin (EPO). Figure 1 compares the stability of an existing marketed liquid product formulation containing a conventional phosphate buffer with the new formulation

study7. This new vaccine formulation has the potential to be used outside the cold chain for part of its shelf-life. The new capability conferred to the product by the improved formulation enables distribution to geographic areas with limited cold-chain infrastructure, improving immunisation coverage.


based on the displaced buffer technology consisting of benzoate (buffer A) and TRIS (buffer b). It can be seen that the change in formulation resulted in a considerable improvement of stability with respect to aggregation. In addition to the displaced buffer, another formulation technology that was found to substantially improve stability was the use of a small amphiphilic species (in this example, the benzoate anion) which under specific salt conditions acts to non-covalently cover hydrophobic patches on the surface of the protein, reducing aggregation5.

Displaced buffer formulation technology has also been applied to stabilising vaccines6. The histidine/phosphate displaced buffer was successfully used to develop a temperature-stable liquid formulation of a Hepatitis b vaccine at pH ~5.0. This formulation showed a considerably improved stability at elevated temperatures compared with the currently marketed product, Shanvac-b (Figure 2). The stability and efficacy of the product was further confirmed in an animal

Tyagi A, Perkins S, Sylvester D, Guy M, Lal M, Priddy S, Plzak H, Kristensen D, Chen D. Characterization of a thermostable hepatitis b vaccine formulation. Vaccine (2009), 27: 4609- 14.

MANUFACTURING MANUFACTURING


Successful liquid formulation involves the intricate design at the molecular level of a composition of chemical excipients to stabilise protein biotherapeutics. Ultimately every component in the optimised formulation has a role in controlling a particular aspect of protein stability, either individually or in combination with other excipients. The concentration of each excipient component added has to be carefully balanced to achieve the best target product stability profile by addressing degradation pathways with different optimal formulation conditions. Formulation optimisation will be further improved by new discoveries in protein folding and protein-excipient interactions, aided by increasingly powerful analytical technologies. As the resulting picture of protein stability becomes more detailed, formulation design will become even more effective. Precise formulation development can provide a new level of stability to a liquid biotherapeutic to, for example, enable cold-chain free shipment. In this way formulation can help biotherapeutics reach a wider community, as well as

improve patient experience by enabling a prefilled syringe format for home use.

References1. Manning MC, Chou DK, Murphy bM, Payne RW, Katayama DS. Stability of protein pharmaceuticals: an update. Pharmaceutical research (2010), 27: 544–75. 2. Jezek J, Darton NJ, Derham bK, Royle N, Simpson I. biopharmaceutical formulations for pre-filled delivery devices. Expert Opinions on Drug Delivery (2013), 6:811-28.3. Sek D. breaking old habits: Moving away from commonly used buffers in pharmaceuticals. European Pharmecutical Review (2012), 7: 37–41. 4. Arecor Ltd. Stabilization of aqueous of proteins with displacement buffers. WO2008084237A2; 2008.5. Arecor Ltd. Stable formulation of Factor VIII. WO2011027152A1; 20096. Jezek J, Chen D, Watson L, Crawford J, Perkins S, Tyagi A, Jones-braun L. A heat-stable hepatitis b vaccine formulation. Human Vaccines (2009), 5(8), 529-35.7. Jones-braun L, Jezek J, Peterson S,

Figure 2. Recovery of antigenic activity of hepatitis b vaccine formulations7 at 45°C. The formulations were: (A) original Shanvac-B formulation; (B) 40 mM phosphate, 40 mM histidine, 100 mM NaCl, pH 5.2.

Nicholas DartonPlatform Manager at Arecor LtdNicholas Dartonis responsiblefor leading the

development of new formulation technologies. Currently a key focus of Nick’s work is on developing new formulation approaches to reduce viscosity in concentrated biologics. Nick joined Arecor in 2012 from a Research Associate position in the Department of Chemical Engineering at the University of Cambridge. In this previous bioprocessing Research Industry Club bbSRC-funded position Nick developed and tested a new chromatography platform technology.Email: [email protected]

A Partnership approach With more than 27 years of experience supporting clinical trials, BARC is your independent global central laboratory of choice. Belonging to one of the largest diagnostic networks in Europe, the Cerba European Lab group, BARC provides central lab services of the highest standard whilst maintaining the necessary flexibility our clients have become accustomed to.

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Turning Your Smartphone into an Authentication Device

PACKAGING


The Smartphone as an Authentication Device Counterfeit drug incidents continue to increase1, predominantly in developing countries, but also in developed ones, as the recent counterfeit cancer drug cases attest.2 At the same time, a new forecast from the International Data Corporation (IDC) Worldwide Quarterly Mobile Phone Tracker expects that “…2013 will mark the first year that smartphone shipments surpass those of feature phones”.3 There are already more than 1.08 billion smartphone users in the world, out of which, 91.4 million are from the United States.4 Among them, one-fifth has health apps.5

Although these applications are typically used to track and manage personal health, it is not unreasonable to imagine using them to authenticate pharmaceutical products along the supply chain, at the point of dispense, or at home. Many anti-counterfeiting suppliers have already jumped on the bandwagon, offering various applications capable of authenticating pharmaceutical products and packaging using overt, covert or forensic authentication elements. This trend not only highlights a clear interest in using commercially available authentication tools, but also in simplifying the authentication process.

This article examines the smartphone as an authentication device to combat drug counterfeiting; provides real-world examples on various products and packaging; and discusses questions of security, capabilities, and responsibility.

Authentication Using a “Non-smartphone”:SMS-based Authentication “Non-smartphones” or feature phones have already been adopted in several African countries as an identification device6: their penetration rate is on average higher and they allow consumers to verify the authenticity of pharmaceutical products via simple text message. Despite these advantages, SMS-based authentication systems require network access, are generally more

expensive for the manufacturer (a unique serial number is printed on each item, increasing production costs) and are not highly reliable.

With respect to this last point, the consumer authenticating a genuine product may get an “authentic” response on the first try and a “fake” response on the tenth, because the server automatically assumes the code has been copied. but what happens on the fifth verification text? Likewise, if a fake product with a genuine serial number gets distributed and checked, the consumer will automatically receive an “authentic” message on the first few tries. As a result, while this authentication platform is more widely available and generally free to the consumer, the probability of a “false positive” (the product is fake, but the authentication result is positive) or a “false negative” (the product is genuine, but the authentication result is negative) is also higher. This article focuses therefore solely on smartphones as an authentication device, rather than feature phones. by the same token, this piece does not apply to smartphones designed for tracking and tracing of pharmaceutical products, but for authentication applications. Whereas track-and-trace technologies concern a process of determining the current and past locations of a product, authentication is the “act of establishing whether a material good is genuine or not”.7

Smartphone-based Authentication Levels As with authentication elements (overt, covert, and forensic), we have identified three ways the smartphone can be used as an authentication device. In the first case, the smartphone is simply utilised as a documentation system. This method generally relies either on a product-specific application or on a custom two- dimensional (2D) barcode printed with visible ink on the package or product. In the first instance, the inspector launches the app and accesses information, such as package features (including authentication

elements), drug ingredients and expiration dates, allowing him or her to determine whether the product is genuine or fake.

In the second, scanning the code links the inspector to a standard URL, displaying the data. While this technology is easy to implement, it requires a trained eye to compare and contrast the product in hand with its description. It also gives counterfeiters access to the same information as the consumer, increasing the risk for look-alikes and raising security concerns.

In the second case, the smartphone is used as a sensor. A common anti-counterfeiting technology is microprinting. This technique involves printing very small text or characters onto an item.8 These micro-security features cannot generally be seen with the naked eye and require a magnifying lens or microscope to be located and analysed. In this case, the smartphone operates as a loupe or magnifying glass to help determine whether the packaging is genuine or fake. While the smartphone eliminates the need for a dedicated decoder, it only provides a higher resolution image of the text, leaving the inspection and final outcome once again up for interpretation.

In the third case, the smartphone is used as a stand-alone, automated device. In this instance, smartphones do not rely on human interpretation to establish the authenticity of products. Instead, they “…integrate the functions required to be able to verify the authentication element independently.”9

For example, Near Field Communication (NFC), a form of challenge-response authentication, is a wireless technology that establishes radio communication between two NFC-enabled devices, allowing for the transfer of data. Smartphones equipped with NFC can read an NFC tag, such as a sticker, to validate a pharmaceutical product. While this technology does automate the authentication process, not all smartphones are NFC-enabled, notably Apple’s iPhone. In addition, NFC

Turning Your Smartphone into an Authentication Device

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PACKAGING

technology necessitates close proximity, usually no more than a few centimetres, between an NFC-equipped smartphone and an NFC tag to trigger product authentication, possibly compromising the exchange of data. Most importantly, smartphones equipped with NFC must be paired with an NFC tag to operate, which increases production costs. Indeed, an NFC tag costs on average between 15 cents and 30 cents, whereas most pharmaceutical companies will pay no more than a fraction of a cent for a safety feature.

A more cost-effective solution “fades” a pattern of invisible micro-dots in the fabric of the printed material using regular visible ink and standard printing processes (offset, flexography, rotogravure).10 When it’s time to authenticate a package, the consumer launches an app, positions the smartphone over the item and if the pattern is present, receives a positive authentication message within seconds. Automated, this system eliminates interpretation and training, significantly reducing human error. Stand-alone, it also decreases thephone or code hacking. Most notably, this solution does not require any additional consumables, allowing brand owners to maintain the same costs of production while increasing product security. This said, very few smartphone-based authentication solutions combine the user-friendliness of an automated authentication process with the security of a covert brand protection technology, making them less widely available. because the


authentication process is completely automated, reliability may also be an issue. Finally, because the smartphone performs the authentication in a local computing environment, security concerns, such as unknowingly using a fake application, reverse engineering a cryptographic algorithm, or finding it out by trial and error, may also arise.

Local Vs. Remote Smartphone Authentication As described in the examples above, smartphones used as an automated, stand-alone authentication device allow inspectors to verify the authenticity of pharmaceutical products anywhere, at any time, maximising the overall efficiency of the verification process. However, an application developed for local authentication is also often platform-dependent and will need to run on a proprietary mobile operating system, such as iOS. Moreover, it will not have the adequate computing power to

provide any other information but the authentication result.

One approach to overcoming these limitations is to build a web-based application that allows inspectors to perform remote product authentication. While the verification process is considerably slower, remote authentication allows inspectors to receive real-time reports, as well as connect with and market directly to experts in the field, supply chain agents, and consumers. This capability is important as it will help rights holders report key performance indicators for their anti-counterfeiting strategy, such as frequency of application deployment and usage, and number of items protected.

Today, it is possible to build a hybrid app, which would allow the inspector to perform a local authentication, and then connect to a wired or wireless network to send and receive authentication statistics. What’s the solution? It will depend on the brand owner’s unique authentication needs, but experience tells us that users want fast,

Figure 2: Micro-holes (40-80 microns) in the standard varnish layer coating the pharmaceutical package are detectable using a smartphone

Figure 1: Authenticating a pharmaceutical bottle label with a smartphone

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easy-to-use applications that do not necessarily require access to a network to function. As a result, hybrid apps might be the preferred solution.

Is Smartphone-based Authentication Secure?So what is more secure: local or remote authentication? Since data processing and storage occur on a protected server, remote authentication is naturally more secure. Indeed, any data, such as images, text or characters, sent to the server is generally public information. However, provided that minimal sensitive information is stored locally, we believe that today’s encryption technologies ensure adequate smartphone security.

Real-world Smartphone-basedAuthentication ApplicationsDriving smartphones forward as an authentication device has not only been their automation, but also their convenience. Concurrently, anti-counterfeit solutions offering high levels of security are also often costly to implement, making them difficult to afford. It is therefore highly desirable to consider technologies that are both secure and cost-effective, and do not require special readers to be detected.

One of these solutions leverages the standard varnish layer printed on most pharmaceutical packaging and labelling to add a glossy finish. A digital image file containing encrypted information

PACKAGING


is integrated during the prepress process. When it’s time to print, the file embeds a pseudo-random pattern of micro-holes (40 to 80 microns) into the coating. Non-intrusive and totally invisible, these micro-undulations cover the entire surface of the packaging or label without changing its design. A smartphone application specifically developed for this technology enables users to confirm authenticity without a network connection. Entirely automated, the application generally takes less than three seconds to verify the authenticity of the product, including time to pick up the item and position the smartphone over it.11

Another solution uses the concept of fingerprinting to authenticate moulded products, such as vials, containers and lids, test tubes and caps. This technology leverages the surface irregularities naturally occurring in a mould and uses these unique features as the means of authentication. The process simply requirescapturing a digital image of the moulded product and storing it in a database. To perform the authentication, the inspector launches an app, positions the smartphone over the item, and upon image correlation, instantly receives a positive authentication message.12

These technologies satisfy some key requirements for the modern pharmaceutical industry and its consumers. Non-intrusive, they are easily integrated into any printing process or product line at

no additional production costs. Encrypted and totally invisible, they are also highly secure. Lastly, they are easily detectable with a smartphone, an everyday consumer electronic.

Who Should Perform Smartphone-based Authentication?While advantageous, using a smartphone as an authentication device also raises questions of responsibility: Who should authenticate pharmaceutical products? The answer is debated at length and depends on the category of authentication elements (overt, covert, and forensic) used to protect medicines.

The European directive 2011/62/EU as regards the prevention of the entry into the legal supply chain of falsified medicinal products stipulates that wholesale distributors and persons authorised or entitled to supply medicinal products to the public shall verify the authenticity of the medicinal product.13 Likewise, the international norm ISO 12931 specifying performance criteria for authentication solutions used to combat counterfeiting of material goods recommends that “…authentication elements should not be accessible and controlled by all types of inspectors.” Rather, “…rights holders have… to define who will have access to what.” 14

Today, these guidelines ring true with smartphone-based authentication. While most pharmaceutical companies strive to educate patients and consumers

Figure 3: Authenticating a pharmaceutical bottle closure using a smartphone

Authenticationmade simple

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We Are Packaging Coordinators, Inc.

3001 Red Lion Road, Philadelphia, Pennsylvania 19114T. (215) 613-3600F. (215) 613-3601Europe Wye Valley Business Park, Hay-On-Wye, HR3 5PG, UK. Tel +44(0) 1497 820829

North America 4545 Assembly Drive, Rockford, IL, 61109, USA. Tel +1 815 484 8900

Packaging Coordinators, Inc. offers unparalleled expertise in a range of proprietary pharmaceutical and biotechnology packaging innovations for healthcare clients across all markets. PCI leads the field in providing cutting-edge customized healthcare packaging solutions that

improve patient adherence and uphold the most stringent safety requirements. For more information about PCI and its state of the art facilities in Philadelphia, PA and Woodstock, IL, Rockford, IL and Hay on Wye, UK visit the company’s website at www.pciservices.com.

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about the dangers of counterfeit drugs, they are often reluctant to publicly share the authentication element or combination of technologies they have selected to protect their products (particularly if they are covert or forensic), let alone give them the tools to authenticate them.

The World Customs Organization’s Interface Public-Members (IPM) is a good case in point. Recently, the WCO introduced the new mobile version of IPM, its online tool which serves as an interface between frontline Customs officers and the private sector. 15 On this occasion, the WCO adopted an entirely automated smartphone-based authentication solution, which allows Customs officers to instantly verify the authenticity of products at the border.16 Although IPM is made freely available for all 179 Member Customs administrations, only rights holders who have joined IPM can give Customs officers access to the tool. As this example illustrates, smartphone-based authentication is still today generally reserved for authorised

distribute a fake one. Moreover, with over 20 mobile operating

systems available in the world today, anti-counterfeit suppliers must opt for the one that will not only fit the brand owner’s unique authentication needs, but also be easily portable.

Lastly, mobile authentication providers are constantly on the lookout for the next better, faster, and more powerful smartphone, for fear of device obsolescence.

but despite these challenges, the smartphone is also, in many ways, a natural candidate for pharmaceutical product authentication and counterfeit protection. Since 2007, it has witnessed continuous progress and includes dedicated hardware for signal processing (DSP). For instance, an iPhone 5 processor is, for some specific tasks, as powerful as a standard PC. A Fast Fourier Transform (FFT) of a 128x128 pixel image will take about 480 microseconds, and 23 microseconds for a 32x32 pixel image. These numbers are comparable to a Pentium III processor, which, a decade ago, treated 128x128 pixels in 454 microseconds and 32x32 pixels in 15 microseconds. Although PCs are currently about six times faster than their mobile counterparts, smartphones have nevertheless enormous computing power. Combined with a compact display and lightweight shell, this power ultimately optimises the authentication performance and improves user experience.

In addition, brand owners can now remotely install/uninstall and update their authentication application, reducing the risk of phone hacking and information theft.

by the same token, because smartphone manufacturers often offer backward software compatibility with older models, authentication applications developed for next-generation smartphones will likely run on previous versions.Most importantly, unlike special reading devices, smartphones provide true portability and rapid deployment, making it possible to develop an authentication application that will work in different environments and be distributed in multiple markets, without adapting the hardware or the source code.

personnel and experts in the field.At the same time, a recent poll revealed

that about 80% of respondents believe that “…manufacturers or customers have most of the responsibility to take anti-counterfeiting measures.” The same survey also showed that “...there are very few if any anti-counterfeiting technologies available for customers”. 17 In light of these answers, a fully automated smartphone-based authentication solution might provide rights holders reasonable assurance of reduced human intervention and thus increased consistency of output, swaying them to give patients the ability to authenticate drugs at the point of dispense or at home. All they would have to worry about is the technology working…

Where Are We Headed Next? As with any other technology, smartphones are not a universal panacea for drug counterfeit detection. Indeed, sophisticated counterfeiters could possibly reverse-engineer the application or create and

We Are Packaging Coordinators, Inc.

3001 Red Lion Road, Philadelphia, Pennsylvania 19114T. (215) 613-3600F. (215) 613-3601Europe Wye Valley Business Park, Hay-On-Wye, HR3 5PG, UK. Tel +44(0) 1497 820829

North America 4545 Assembly Drive, Rockford, IL, 61109, USA. Tel +1 815 484 8900

Packaging Coordinators, Inc. offers unparalleled expertise in a range of proprietary pharmaceutical and biotechnology packaging innovations for healthcare clients across all markets. PCI leads the field in providing cutting-edge customized healthcare packaging solutions that

improve patient adherence and uphold the most stringent safety requirements. For more information about PCI and its state of the art facilities in Philadelphia, PA and Woodstock, IL, Rockford, IL and Hay on Wye, UK visit the company’s website at www.pciservices.com.

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Ms Jennifer Yribar, Corporate Communications Coordinator, AlpVision.Ms Yribar has been responsible

for corporate communications at AlpVision since January 2012. She manages all external communications and media/public relations, coordinates conferences and exhibits in Europe and the United States, and assists in sales and marketing activities. Previously, she served as Director of Communications of the Utah Council for Citizen Diplomacy, a private sector partner with the U.S. Department of State’s International Visitor Leadership Program. A dual citizen (Swiss-American), she holds a Master’s degree in Communication from the University of Washington in Seattle, USA and a Master’s degree in French Language and Literature from the University of Geneva in Switzerland. Email: [email protected].

Dr Fred Jordan, CEO, AlpVision.Dr Jordan is co-founder and CEO of AlpVision, a world leader in digital solutions for

product authentication and counterfeit protection. He is the author of numerous scientific publications and patents, including Cryptoglyph and Fingerprint, two covert anti-counterfeit technologies. Along with his colleague, Dr Martin Kutter, he contributed significantly to the scientific development of the Digital Watermarking technology in the late 90s. Dr Jordan received his PhD from the Swiss Federal Institute of Technology (EPFL) – Signal Processing Lab in Lausanne, Switzerland, and has work experience in the United States and in France. Email: [email protected].

2 . h t tp ://www.c l in i ca lonco logy. com /ViewArticle.aspx?d=Current% 2bPractice&d_id=155&i=June+2013&i_ id=968&a_id=23400, visited on 27 Jun 20133 . h t tp : //www. idc . com/ge tdoc . jsp?containerId=prUS24143513, visited on 27 Jun 20134. http://www.go-gulf.com/blog/ smartphone, visited on 27 Jun 20135. Fox, S., Duggan, M. Mobile Health 2012. Pew Research Center’s Internet & American Life Project. 11 (2012).6. http://www.fastcompany.com/1707667 /fighting-counterfiet-drugs-mobile- technology, visited on 28 June 2013 7. International Standard ISO 12931. International Organization for Standardization. 2 (2012). 8. “Microprinting.” Wikipedia. Retrieved July 22, 2013, from http://en.wikipedia. org/wiki/Microprinting. 9. International Standard ISO 12931. International Organization for Standardization. 2 (2012).10. http://www.alpvision.com/cryptogly ph-covert-marking.html, visited 28 Jun 201311. http://www.alpvision.com/cryptogly ph-covert-marking.html, visited 28 Jun 201312. http://www.alpvision.com/fingerprint- product-authentication.html, visited 28 Jun 201313. Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011, Official Journal of the European Union, 01.07.2011, L 174/8014. International Standard ISO 12931. International Organization for Standardization. 27 (2012).15. http://ipmpromo.wcoomdpublications. org, visited 9 Jul 201316. http://ipmpromo.wcoomdpublications. org/Contents/Item/Display/310, visited 7 Jul 201317. http://www.inksure.com/ethics/270- who-is-responsible-the-anti- counterfeiting - industry speaks, visited 4 Jul 2013

Conclusion

As we have seen, smartphones are starting to take centre stage in pharmaceutical product authentication. To take full advantage of this new tool, mobile authentication applications should be automated in order to avoid the need for training or interpretation; hybrid, to allow instant verification without network access, yet with remote synchronisation capabilities for reporting; and, as dictated by regulatory bodies, remain in the hands of inspectors, rather than consumers. This said, with consumer empowerment on the rise as a result of the digital revolution, the smartphone has more potential than any other authentication tool to change this trend.

References

1. http://www.safemedicines.org/ counterfeit-drug-incident-encyclopedia. html, visited on 27 Jun 2013

Solutions & Innovationt. +34 91 814 91 44f. +34 91 814 90 96Ctra. Navalcarnero a Chinchón (M-404), km 21,2. 28971 Griñón (Madrid). Spain

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Anticounterfeiting featuresTamper evidenceTrack & TraceSerialization

FOLDING CARTONS FOR THE PHARMACEUTICAL INDUSTRY

The more valuethe contents have,the more importantthe package becomes.

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Andrew Revel from the packaging and innovation consultancy, Faraday, recently commented on how the consumer will interact with packaging in the near future: “Packaging will talk to us, provide us with information on its storage and tell us when it is the best time to eat or use the product. The drivers for developing unique consumer experiences are very strong and, in most cases, the technology to deliver these changes is already here or just around the corner.”

Pharmaceutical packaging has many functions to perform, including information conveyance, aiding patient compliance and product protection. Increasingly, however, the value of packaging in brand identification and protection via anti-counterfeiting technologies is being realised. The application of new techniques and technologies could aid this functionality and also enhance the consumer experience and empathy with a brand.

Over-the-counter packs need to provide a strong consumer connection, and the first point in the process is the visual impact of a product. This is also becoming more relevant to ethical drugs as consumer choice increases. Increased competition is driving innovation and the introduction of new print finishes and effects to create packaging that is eye-catching is growing. This can involve everything from complex print through to the use of specialist holographic lens board, metallised board or adding a micro-embossed finish to a pack or label’s varnish. Several large brands have recently used these techniques to support the premium image of high-value over-the-counter products such as toothpastes and vitamins. This has given packs 3D qualities which have provided the impression of depth and movement and helped to make a point of difference in a crowded marketplace.

PACKAGING

Packed with Innovation

New materials such as mouldable cartonboard will provide new ways of providing further pack differentiation. The board, providing a truly 3D quality to any pack, is formed by using a specialist low-energy process which makes it possible to form a paperboard material into a complete range of distinctive shapes. This exciting development can help to promote and complement a brand – from tactile profile lines to replicating the distinctive shape of a bottle or jar. The material can be formed to a depth of 2-4mm, and compared to standard embossing of less than 1mm, it certainly gets noticed. The depth of the embossed feature can also be achieved using standard carton conversion equipment. The result is a strong visual and tactile effect that demands consumer attention. It also has the added advantage that the material is a more sustainable alternative to plastic packaging.

Consumer trends are also shaping and driving pack-related innovations. During the last few years, there has been a general move to retro styles reflecting a wave of nostalgia that has seen a surge in demand for mid-20th-century-style homewares, vintage clothing and books. It seems ‘quality’ is associated with things

of the past, so as well as colour and design for packaging, textures have also been important. This has seen cartons incorporate print finishes and effects that include techniques that provide tactile qualities such as ‘soft-touch’ varnishes or in-line reticulation processes that add prominent varnish lines.

‘Natural’ aesthetics, which have been ‘on trend’ for a while, have been reflected in an ‘unprocessed’ look. Uncoated cartonboards with a natural uneven finish or cartons subtly enhanced with micro-embossing have been favourites. Micro-embossing combined with varnish techniques have been developed to produce the effects that mimic nature, such as leather, stone, feathers or snakeskin.

The type of future interactive packaging alluded to above, however, is likely to come from developments in printed electronics. Many brand owners are exploring this technology but market adoption has, so far, been limited. In the healthcare sector, adoption of new technology needs to be tempered by the ease of application, patient understanding and the need to always provide a failsafe…and, of course, cost. Developments will come

Packed with Innovation


PACKAGING

European legislation has recently dictated the application of product information in the form of braille for an increasing range of healthcare products. Cartons provide the ideal substrate for braille embossing – dots can be precisely placed at speed on any or all of the carton’s faces, improving patient safety.

Innovation is also taking place in print technology, with digital beginning to assert its presence. Already well established for the production of self-adhesive labels, digital technology is now becoming commercially viable for folding carton production. This has required a new approach and operational setup, but it will be ideal for small order quantities and short lead-time products. The digital route also has the potential to offer reduced inventory and write-offs. At the moment, there is limited interest in using this technology for personalisation, promotional activity, or date/batch code application due to the additional SKU management this would require. However, the application of the technology is expected to expand into new areas in the coming years.

brand owners and retailers are adopting new technologies and approaches to maximise the efficient use of their products and to enhance the emotional experience their consumers get from the product. Developments in these technologies will impact on everyday products to engage with all the senses.

though. A printed carton containing conductive tracks linked to a product blister and integral electronics module is already possible. This will allow a pack to play a pre-recorded message that can highlight a product’s details and dosage requirements, or record the exact time when the blister pack was opened.

The adoption of such technology is likely to need a strong proof-of-use platform to progress, and this is one area where the link between the food & drink and healthcare sectors is strong. Many new packaging technologies that are being adopted by the FMCG sector can then be applied to the healthcare sector. Printable barrier coatings are now being developed that can protect a product from external compounds that can migrate through the packaging, as well as environmental-related conditions such as moisture. In order to meet the ever-increasing legislative and regulatory requirements of the pharma sector, there is a strong focus and desire for guidance on ‘extractable and leachable’ compounds. These new barrier coatings are being developed with an eye to the future and an aim of optimising sustainability, and where possible will incorporate non-petrochemical renewable substances, thereby reducing the amount of plastic needed to facilitate this barrier.

Security features can easily be added, such as tamper-evident closures and designs to make cartons childproof.

Contact West today.

North America +1 800-345-9800 Europe +49 2403 7960

Asia Pacific +65 6860 5879www.westpharma.com

West and the diamond logo and By your side for a healthier world™ are registered trademarks or trademarks of West Pharmaceutical Services, Inc., in the United States

and other jurisdictions. Copyright © 2013 West Pharmaceutical Services, Inc. #7902

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Your customers expect total care!You should expect nothing lessof your suppliers!

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When it comes to pharmaceutical packaging, we aim to meet every expectation.

We offer an unmatched range of products and

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CSK_PMPS_Jan13.pdf 31/1/13 16:15:36

PACKAGING


Carol Hammond, Head of R&D at Chesapeake an Applied Chemist by training, entered the packaging sector

through a job in plastic packaging. Several other manufacturing-based roles followed, with a technical focus in both the plastics and paperboard sectors covering quality, product development and packaging design. Carol has commercial experience too, and was sales director for several years before returning to a technical development role focused on the pharmaceutical sector.Currently, Carol is Head of R&D for Chesapeake - a role which has two objectives: developing new materials and processes, and adapting and broadening the application of existing processes and materials. Carol is responsible for a small team of science and engineering experts focused on packaging improvement and development to enhance consumer experience, as well as add value to the packaging and product. Central themes throughout each project are legislative compliance, sustainability, manufacturing efficiency and product safety.Email: [email protected].

Side Story:The building of brand loyalty is becoming increasingly important but difficult in today’s information-rich, fast-changing, time-constrained society. New methods to engage and interact with the consumer increasingly involve the use of innovative applications such as 2D

data matrix or unique item coding. These codes can be linked to secure portals or promotional websites depending upon the application, such as track and trace product security or product promotion.The use of these systems can help to verify the authenticity of a product and track its global distribution, as well as deliver product and promotional information direct to the customer. Unique alpha-numeric character identification codes can now be used by the consumer, via a mobile phone or a website, to access further tailored product or complementary promotional information. This process also offers the manufacturer the ability to track products and build information on a product’s distribution, life-cycle and use, as well as provide valuable market data. The increasing use of social networking sites by consumers to post product experiences - both good and bad - and the growth of internet sales make two-way communication and loyalty-rewarding even more important. The unique codes can be applied in multiple formats and systems, including human-readable, data matrix, SGTIN and electronic track and trace. They can be generated and checked in secure databases or open systems depending on the application – product security or product and brand promotion.

Your customers expect total care!You should expect nothing lessof your suppliers!

We protect and promote the world’s great brands

R

www.chesapeakecorp.com/pharma

When it comes to pharmaceutical packaging, we aim to meet every expectation.

We offer an unmatched range of products and

services through a global network of 23 dedicated

factories. Valuable too, our drive for creativity

shows in innovative solutions such as our unique

Easipak™ leaflet-cartons - just one of the many

ideas we have to offer. We ensure total security

of supply - locally, regionally and internationally.

We also take a holistic view of our service

responsibility, from sophisticated anti-counterfeiting

technology to supply chain management.

Chesapeake …a global leader in pharmaceutical packaging - leaflets, labels, cartons and a whole lot more.

CSK_PMPS_Jan13.pdf 31/1/13 16:15:36

PACKAGING

Internet pharmacies provide consumers with the ability to purchase prescription drugs online. There are thousands of internet pharmacies, yet only 16 have been accredited by the National Association of boards of Pharmacy (NAbP). Many unaccredited internet pharmacies entice unsuspecting consumers with deep discounts on medications. In addition, they offer a false sense of security when in fact the operation is based elsewhere and the product may be coming from a region without stringent regulatory standards. The NAbP states that medicine is counterfeit in over 50% of cases when the drug is purchased from internet sites that conceal their actual physical address. Unfortunately, many consumers are not aware that many of these low-priced drugs may contain substandard active ingredients, or that they are coming from an unregulated region. The FDA has released a consumer safety guide entitled ‘buying Prescription Medicine Online: A Consumer Safety Guide,’ which cautions consumers of the dangers of purchasing pharmaceutical drugs from internet pharmacies that are not VIPPS-accredited. In Europe, there have been several associations and initiatives, usually formed by a cross-section of European stakeholders from a variety of backgrounds, giving advice about buying medicines on the internet. Their key activities include campaigning for the safer use of unlicensed or off-label medicines and also the exclusion of counterfeit and substandard medicines from the supply chain, raising public awareness around such issues, and promoting effective legislation and enforcement in relation to falsified medicines.

But in fact, the key is to find an internet drug source that is legal, safe and meets your needs, such as convenience and pricing. There are good, bona fide businesses out there, but there are also


Medicines Online: The Control of a New Channel

“rogue” sites - online pharmacies (really pretend pharmacies) that are out to scam you. Fake online pharmacies and the products they sell are an escalating public health threat. While studies suggest that over 50% of medicines purchased from unregulated websites are falsified, counterfeit or substandard, the number of online pharmacies has increased in recent years to meet consumer demand. A recent review by the National Association of boards of Pharmacy (NAbP) has shown that as few as 3 per cent of websites selling prescription drugs are legitimate pharmacies, and up to half offer foreign or non-FDA-approved drugs. Many pharmaceutical companies have launched projects to meet the needs of consumers who are increasingly going online to purchase prescription medications, and public institutions are taking measures to make buying drugs online secure, for example, by looking for Verified Internet Pharmacy Practice Sites® (VIPPS®). To become VIPPS®-accredited, an online pharmacy must meet several privacy, security and quality-assurance requirements. buying from a VIPPS®-accredited site will help

ensure patients are getting legitimate medication and that personal health information is kept confidential.With the proliferation of fake online pharmacies, it is important that consumers know which sites are legitimate. After a recent review of more than 10,000 internet outlets sellingprescription drugs, NAbP listed almost 97 per cent of the sites as “Not

Recommended” because they did not appear to meet criteria for legitimate online pharmacies.

On the other side, consumers recognise the difficulty in distinguishing between legitimate and fake pharmacies, yet they still may behave in ways that put them at risk of receiving counterfeit medicines. A 2011 survey of 1000 men found that more than four in five men (82 per cent) believe it is difficult to determine if an online pharmacy is legitimate, yet more than one in three would consider purchasing ED medicines based on an online search.

In health, as in other sectors, the internet has changed our purchasing behaviour: we are now able to compare prices easily, get advice from blogs, and buy drugs from other parts of the world. but when buying medicines online, it is even more important to be careful, because our health can be put at risk by a wrong click. before we buy a medicine online, we should check at least if: 1. The online pharmacy is asking for a prescription. It is common to find a questionnaire, but this should not be enough. 2. The pharmacy is licensed in the state where is located. 3. They offer the possibility of a phone conversation with a pharmacist. 4. They have a person to talk to if you have a problem.

As people usually think that online prices will be lower than those at the local pharmacy, it is also important to compare prices, because they often vary between different pharmacy chains, websites, and even a single chain’s stores and website. For instance, the costs of brand-name drugs in many other countries may be substantially less than they are in your own country. On the other hand, some drugs are also available in other countries and not in your own country, or do not require a prescription in other parts of the world. In such cases, although it seems that

Danapak Flexibles is supplying innovative pharma packaging for Medical Devices, Transdermal Systems, Liquids, Creams and Powders. We offer tailor-made solutions with high barrier properties, childproof openings, peel properties, solutions for sterili-zation and for aggressive substances.

In our fully equipped Product Technology Centre including a Pilot Plant and Laboratory we develop the next generation packaging solutions for pharma products fulfilling the growing demands regarding use and legislation. New products are thoroughly tested in our pilot plant, in close cooperation with our customers, before starting up serial production. We manufacture according to ISO 9001, ISO 22000 and BRC.

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Medicines Online: The Control of a New Channel

PACKAGING


the patient has the responsibility to buy securely, there should be other measures to take from the public institutions.

EU Directive 62/EU/2011 introduces tougher rules to improve the protection of public health, offering, among other things, an EU-wide logo to identify legal online pharmacies. This would make it easier to distinguish between legal and illegal online pharmacies throughout the European Union. Also, there are other signs of an unsafe website: • It sends drugs with unknown quality or origin.• It gives the wrong drug or another dangerous product for your illness.• It doesn’t provide a way to contact the company by phone.• It offers prices that are dramatically lower than the competition.• It may offer to sell prescription drugs without a prescription—this is against the law!• It may not protect your personal information.

buying fake medicines online is not only a question of health, which is the more important topic, it also increases the risks of credit card fraud, identity theft and malware viruses. In addition, users may not be aware that when buying these medicines they directly support organised criminal groups.

There are other initiatives like Operation Pangea, which is an international week of action targeting websites which illegally supply dangerous medicines.

Operation Pangea VI is the largest internet-based action of its kind targeting the international black market of illicit medicines. This year, it spanned 100 countries and resulted in 58 arrests worldwide and the seizure of 9,895,926 million potentially dangerous medicines worth some USD $41,104,386. The global endeavour involved police, border security and national regulatory authorities with the support of internet service providers, payment systems providers, and delivery services.

Of particular concern are websites that use questionnaires to determine the appropriateness of prescribing drugs that patients have not received before. Unlike in the traditional relationship between a patient and his or her physician, many online practitioners issue prescriptions to a patient for the first time without a physical examination or any form of direct contact. Patients are therefore more likely to receive an inappropriate drug and to place themselves at greater risk of side-effects and drug interactions. by avoiding the inconvenience of an office visit or overtly seeking to obtain a drug without having to see a practitioner, a patient may sacrifice the opportunity for a correct diagnosis or identification of a contraindication to the drug. To address this concern, in June 1999 the American Medical Association formally adopted the position that any healthcare practitioner who offers a prescription to a patient solely on the basis of an online questionnaire without having ever examined the patient generally has not met the appropriate medical standard of care. Therefore practitioners can play an important role by educating their patients about dangerous practices on the internet and encouraging their state law enforcement and regulatory officials to take action against physicians who engage in illegal and unethical online practices. The FDA encourages physicians and patients to report potentially illegal websites to the FDA or to the National Association of boards of Pharmacy. The internet can serve as an important tool for providing health-related products, services, and information. However, as with any tool, new or old, consumers must use it wisely.

Until appropriate safeguards have been implemented, patients and practitioners should be cautious.Foreign websites pose other potential difficulties. Drugs offered by foreign sites are more likely to raise safety concerns about contamination or subpotent strengths resulting from poor manufacturing or improper storage conditions during distribution.

Drug packages only equipped with barcodes are not unique for each product and they are easy to copy. RFID tags, on the other hand, are unique for all items and significantly harder to copy or tamper with. by using RFID tagging as well as tracking and identifying the drugs on an individual basis, the likelihood of a counterfeit drug travelling all the way to its final destination is reduced significantly.

Authorised drug ingredient manufacturers tag all their ingredients with RFID tags before distribution to the pharmaceutical companies. As the drugs are manufactured, the tags of the ingredients are scanned and reported. Information about medicament ingredients as well as a serial number and other essential product information are added to an RFID tag that is attached on the package of the drug. Now the drug package tag contains information not only about its own origin, but also about the ingredients and the amount of each ingredient in the drug. The information on the tag can be converted into a so-called ePedigree (electronic pedigree), which will be filled

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PACKAGING

with more and more information about the events on the drug’s journey through the supply chain - all the way from the factory to the pharmacy or hospital.Scanning the tag and analysing the ePedigree allows the wholesalers and pharmacists to determine the identity and composition (and dosage) of ingredients in the drug, as well as its route in the supply chain. Specific information like colour, size, weight and shape of the pills can be helpful in detecting counterfeits. Information on the tag about manufacturing date and expiration date makes it hard to re-label products with a later expiration date. The RFID reader will give an alert if the drug has expired. Last but not least, if a suspected counterfeit drug is detected and reported, the product recall can be conducted in an efficient manner thanks to the RFID tracking system. Tagging drugs with RFID will make the supply chains safer and ensure that patients get

Marga RomoInternational Sales Manager Nekicesa.Marga Romo iscurrently International business Manager in Nekicesa and is responsible for the expansion in Europe and the online strategy of the company. She has experience in the sales and marketing area in many sectors such as FMCG, automotive and pharmaceutical. She belongs to the innovation committee of Nekicesa, leading projects concerning external communication. Email: [email protected]

the right treatment. And, as a bonus, RFID will also be an effective weapon against theft and shrinkage, both in the supply chain and at the end destination.

Although efforts by public-private partnerships such as IMPACT have improved the enforcement of antipiracy regulations against online drug sellers, the future of such enterprises are bleak in the face of the seemingly inexhaustible and expanding criminal enterprise. Instead, what is needed is comprehensive global health policy that advocates for active and real-time online surveillance, regulation of marketing by illicit sellers, coordinated global health governance amongst private and public sector entities, consumer education and awareness regarding potential risks, and a commitment by industry and national health systems to improve equitable medicines access. Without comprehensive interdisciplinary efforts, the global online threats to health will

continue to grow and put patients at considerable risk of avoidable harm.


Vetter is a leading contract development and manufacturing organization (CDMO) that specializes in the aseptic filling of syringes, cartridges and vials. With approximately 3,000 employees worldwide, Vetter holds numerous patents and has extensive experience with biologics and other complex compounds, including monoclonal antibodies, peptides, interferons and vaccines. Collaborating with pharma/biotech clients worldwide, Vetter supports products from preclinical development through global market supply. Through its U.S. and European facilities, Vetter Development Service provides state-of-the-art support for early-stage products, with seamless transfer at Phase III to Vetter Commercial Manufacturing for large-scale production. The company offers state-of-the-art technology and innovative processes to promote product quality and maximize API yield. As a family-owned, independent company, we do not manufacture our own drugs. Our focus is solely on our customers’ success.

Vetter Development Service

Preclinical through Phase III is a pivotal and unpredictable period for new molecules. Vetter Development Service helps smooth the path to clinic with dedicated support for key stages of development, testing, clinical manufacturing, and regulatory approval. We also help you integrate thoughtful, efficient life cycle solutions for long-term growth and success.

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Vetter Packaging Solutions

Material compatibility. Patient convenience. Market differentiation. There are many factors to consider in the selection of your primary and secondary packaging materials. Which ones matter most to your compound’s performance and long-term potential? Vetter’s packaging experts help you find the right solutions throughout your product’s life cycle.

It takes a unique blend of expertise to deliver the right results

At Vetter, we look at your product from every angle. And help you find answers that make a difference in efficiency, productivity, safety, quality, and growth. From initial process design through high-speed fill and finish, learn how a partnership with Vetter will keep your product moving smoothly towards success.

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For US inquiries please contact [email protected] • For EU, Asia and other international inquiries, please contact [email protected]

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Visit us at AAPS Annual Meeting, San Antonio, Texas at Booth # 2745

Vetter_Ad_IPI_Journal.indd 1 25.09.13 11:08

PACKAGING

SynopsisAnalytical laboratories, whether on-site or off-site, perform qualitative and quantitative analysis on samples, testing and packaging each drug. They provide the pharmaceutical market with a niche and technically specialist service that will always be a necessity. These labs are required to meet high levels of governmental approvals and copious amounts of testing, as the determination of the safety of a drug lies with the company. Alongside this challenge, the financial and time constraints facing these companies has created a strong need for a solution that can eradicate all of these issues at once.

Analytical laboratories will always play a vital role in the breaking down and analysis, packaging, development and commercialisation of drugs. These labs aid drug manufacturers in their overall drug development process and offer continual testing support through the lifecycle. To maintain the highest level of quality, these labs require state-of-the- art equipment that is close at hand, trusted employees to ensure maximum levels of communication, and a wide timeframe. but do off-site analytical laboratories provide all of these elements?

ChallengesThe process of testing and packaging is a vital part of releasing a new clinical drug, yet it can be time-consuming, geographically difficult, and expensive for the company releasing it. Analytical testing laboratories which are situated off-site, whether overseas or not, create another boundary for the drug companies to overcome. They produce a huge physical distance between the testing site and the people who have ordered the laboratory’s facilities. Looking into the process time slot, it can take a total turnaround time of three to fourteen days, depending on the sample1. If a company required a job to be completed in half the time, they would most likely be


Analytical Laboratories

required to pay double the price. The sensitive nature of these services and the amount of pressure on the testing labs means that the premise of being able to visit the facility in which your drug is being processed quickly not only creates confidence in the analytical laboratory and in their personal handling of the drug, it also allows the drug company to personally oversee the process their product is going through. With an off-site laboratory, the geographical implications create a distant relationship between the drug company and the testing company that can result in a lack of a close communication exchange between the two.

In connection with the geographical issues, off-site laboratories can also create time constraints. For example, when selecting a laboratory, a drug company must dedicate time to research the laboratory provider to ascertain if they meet certain regulatory requirements, that they have thrived in that particular drug sector before, and how successful their work is. This process can be extremely resource-intensive, in terms of both time and money. Furthermore, whilst testing and commercialising a new drug, problems and issues may arise that can take weeks to solve. In some cases a question can be posed to the lab, but a response isn’t received until the next business day at the earliest, leaving a time gap in which the issue could be resolved. This delay in communication can impact the entire production process and ultimately postpone the finale release date.

With the costs of drug transportation and delivery continually rising, alongside the often slow nature of the entire testing and packaging procedure, the act of sending away drug samples seems like an unnecessary expenditure in the release process. The American Department of Transportation’s decision to ban the air transportation of concentrated nitric acid2 has shown drug and pharmaceutical companies

the current declining state of scientific shipping. The FDA presents yet more hurdles to overcome with strict regulations not only on the actual shipping of drugs, but also on issues such as the storage of the product and its labelling requirements.

This all adds additional resource requirements, on top of the overall priority to deliver a product with precision and quality. The added cost of the courier, recorded delivery to ensure the products’ safety and shipping, could be deemed as an unnecessary cost.

Independent laboratories use their own analytical technicians to test, process and present a drug company’s product. The staff handling the product will not have been chosen by the drug manufacturer, nor will they have direct contact with them. This can create a hindrance for the drug company in regard to trust, quality assurance and monitoring, control and consistency. However, it should be highlighted that an off-site lab will provide independent results. The problem arises in the presentation of such results, which can differ from the requirements of the manufacturer, an additional requirement to be agreed at the start of the project.

Bringing a Lab Closer to HomeMany of the challenges mentioned above are being resolved with the introduction of on-site analytical laboratories. These can be tailor-made to one individual company’s requirements from the layout, design and equipment, right through to staff hired to work for the laboratory in it. This allows a manufacturer closer, direct access and insight into the entire process and the results.

Turnaround times are greatly minimised when using an on-site laboratory, as there is no longer a need for transportation time. Problems can often be resolved in a matter of hours, rather than days. Similarly, the ability to make adaptations becomes much easier and cheaper.

PACKAGING

by investing in an on-site analytical laboratory, the financial benefits are clear. The high costs associated with shipping and safety checks are eliminated, saving the company money for every sample that would require testing. The financial savings can also be linked to the staffing quality. For example, instead of funding an independent company with its own staff to process and commercialise a product, the drug company can select the individuals who work on the project which, in turn, can nearly guarantee a higher level of trust, security and overall quality.

In addition, situating an analytical laboratory on-site means the geographical implications are also taken care of. The drug company can meet the staff testing their product personally and discuss the process in detail on a daily basis, rather than having to wait one business day to be updated. Again, this aids the company by offering full transparency into the status of the project. Additionally, there are no time difference issues to consider because everything takes place in the same location.

With the safety of the drug being of utmost importance for the analytical laboratories, being able to oversee the development and therefore evaluate the quality of work is vital to a company. An on-site lab generates a stronger sense of

supervision over the process. Finally, another benefit of building

an on-site analytical laboratory is the minimisation of information loss or miscommunication between the drug company and the testing site. There are guarantees of system, process and reporting related to in-house activity that can rarely be matched.

ConclusionWith the pharmaceutical industry increasingly looking at ways to improve time-to-market whilst reducing costs and meeting the increasing regulatory frameworks, there is a clear argument for investment in an on-site analytical laboratory. These labs provide critical operational and environmental data, and establish the value of the product they are given, so will always be a requirement for the market, yet focussing them on-site lets a company have a site that exactly meets its requirements, and maintain control of the entire process.

References1. www.analytical-lab.com2. http://wwwsci.seastarchemicals.com/ safety/01NitricMSDSRev2013.pdf

Tim Roberts, Associate Director Clinical Services, Packaging Coordinators, Inc. (formerly Anderson brecon). Working within the late phase clinical trial industry for the past twelve years, Tim has specialized in global clinical trial management and strategy development. Tim is a Pharmaceutical business Development Professional, with multi-national experience in Europe, Asia and America’s and a track record of sales growth, offering clients unique solutions in accelerating compund development. As Associate Director for Clinical Services at Packaging Coordinators, Inc., Tim holds responsibility for PCI’s Clinical Supplies European business operation, ensuring that both new and existing clients have access to innovation and experienced staffing resource, when outsourcing Clinical Packaging, Storage and Global Distribution.Email: [email protected]

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CONFERENCE & REVIEWS


In the not-too-distant past, the Polish pharmaceutical industry focused on the production of generic drugs on the basis of small molecules. The arrival of the epoch of innovative biotechnological drugs has led to dynamic changes in this sector – it is a process that is still in progress. Polish pharmaceutical companies began to develop research and development (R&D) departments dynamically and invest in R&D projects aimed at elaborating new innovative drugs, most of which are biotechnological drugs.

Polska Bio and Pharma

Currently, Polish pharmaceutical companies are carrying out around 40 R&D projects. Their value is over 318,000,000 PLN (approx. 90,000,000 USD), including around 168,000,000 PLN (approx. 48,000,000 USD) from public financial support under the Innovative Economy Operating Programme. In addition, more than 120 research teams are currently implementing R&D projects in the field of biotechnology in Polish public research centres.

Changes in the pharmaceutical sector were accompanied by the dynamic development of biotechnology in Poland. It is easy to notice, for example, a rapid increase in the number of biotechnological companies. During the past five years, the number of Polish biotechnological companies has risen more than threefold (from approx. 20 in 2007 to approx. 70 in 2012). Almost 40% of these companies are working on new drugs. Fields of modern biotechnology, such as medical materials (including biocompatible materials), diagnostic tests and tools of molecular biology, are also being developed.

In order to accelerate the development of the process of introduction of biotechnological products onto the market and increase the effectiveness of R&D works under way, both in biotechnology and pharmacy, modern

companies and research institutions have created clusters aimed primarily at scientific co-operation. The largest Polish clusters grouping together companies and research institutions from the pharmaceutical and biotechnological sectors are LifeScienceKraków, the Polish Platform of Innovative Medicine, biobaltica, Innobiobiz and bioTechMed.

biotechnology plays an increasingly important role in the development of the innovative economy in Poland. The main centres of its development are located in academic institutions having large research potential in the field of biological and medical sciences; they are supported by local authorities, according to which the development of this sector is of key importance for the economic development of the region. These regions, called “bioregions”, are Pomerania (Gdańsk), Małopolska (Kraków), the Łódń Region (Łódń), Lower Silesia (Wrocław) and Wielkopolska (Poznan). Technology transfer centre offices operating in academic institutions stimulate their involvement in the development of the innovative economy.

One of the most important factors stimulating the dynamic development of modern biotechnology and (bio)pharmacy in Poland are large resources of highly-qualified specialists. The field of biotechnology or medical biotechnology exists at 36 schools of higher education. Every year, these studies are completed by over 1400 students with a b.Sc. diploma and by over 1200 students with an M.Sc. diploma. Many of them continue their education in doctoral studies. The second source of highly-qualified staff is the Polish scientific circle. Over 8000 Polish scientists conduct research projects in the field of biological and medical sciences. A large number of these scientists are interested in direct co-operation with biotechnological and/or pharmaceutical companies.

The change that may be decisive for the success of Polish biotechnology and

pharmacy in Poland is the change of awareness concerning the importance of the protection of intellectual property in the research process. This results in, among other things, a substantial increase in the number of patent applications submitted by Polish research institutions. The increase in the number of R&D projects with adequate protection of intellectual property is one of the most important factors that provide optimistic prospects for the development of the biotechnological and pharmaceutical sectors in Poland.

Polish biotech & Pharma is a Sector Promotion Programme under the project system implemented by the Polish Ministry of Economy entitled: “The Promotion of the Polish Economy in International Markets”, Sub-measure 6.5.1 of the Operational Programme Innovative Economy (OPIE).The project is implemented by a consortium of the companies Ageron Polska and Ageron Internacional in collaboration with bio-Tech Consulting. It would be a pleasure to assist you with any questions concerning Polish biotechnology and pharmaceutical companies.Should you need more information about the Polish biotech & pharma sector or contact to Polish biotechnology and pharmaceutical companies, please visit:www.biotech-pharma.pl

Meet with Polish biotech & Pharma Industry leaders at biotechnica (8-10.10.2013 Hannover) and CPHI (22-24.10.2013 Frankfurt).

biotechnica Stand F75, CPHI Stand 30H48

Exhibiting Companies: biovico, bestpharma, Genomed, Hasco Lek, IPO Pszczyna, Komtur Polska, Polpharma, Unia Farmaceutyczna


On the 13th of June 2013 the Anglonordic Biotech Conference celebrated its 10th anniversary at 1 Victoria Street in London. In total 240 decision-makers attended this popular event and set a record for the number of pre-booked one-to-one meetings. The conference started in the evening before the event, with an exclusive drinks reception at Canada House on Trafalgar Square.

The conference continues to grow, and this year it was also the first time it was held in conjunction with the Anglonordic Medtech Conference that was held in the same venue (12th of June).

‘The outcome of this year’s event was very successful, and many companies took advantage of the opportunity to attend both conferences. The conference committee will continue to merge the two conferences into one with the aim to have a two-day conference [in] 2014, with [a] focus on Medtech day one and biotech day two,’ says Mattias Johansson, Director, Anglonordic Life Science Conferences.Next year’s conference takes place in

The Success of the Anglonordic Biotech Conference Continues

London on the 10th of April. Entering its eleventh year, the Anglonordic biotech Conference XI provides the ideal one-stop opportunity to discover, collaborate with and invest in the Anglo-Nordic life science community. by invitation only, the select audience is restricted to decision-makers representing drug discovery and medtech companies from the Anglo-Nordic regions and international pharmaceutical and investment firms. Service suppliers can only attend as sponsors.‘Every year we receive the same positive feedback from the delegates. They are very happy with the format and the size of the conference. It would be easy for us to increase the number of delegates substantially, however, the feedback we receive is that we should stay with the

number of approximately 250 delegates and continue to work on the quality instead of the quantity,’ says Mattias Johansson.

The Anglonordic biotech Conference XI (10 April 2014) will be held in connection with the Anglonordic Medtech Conference III (9 April) at the same venue. For more information about the conferences,visit www.anglonordicbiotech.com and www.anglonordicmedtech.com.

Contact: Mattias Johansson, Director,Anglonordic Life Science Conferences;email: [email protected]


CONFERENCE & REVIEWS CONFERENCE & REVIEWS


CPhI Worldwide event preview

(22-24 October 2013):

Last year CPhI Worldwide once again delivered an exceptional platform for both innovation and growth in the pharmaceutical industry. With more than 30,000 visitors and over 2,200 exhibitors, this year’s edition provides the opportunity for attendees from more than 133 countries to meet under one roof. There will be 20 d edicated zones covering ingredients, APIs, excipients, finished dosage, contract services, packaging, machinery and more.

Running alongside the pharmaceutical ingredients halls are three sister brands, which help visitors to quickly identify the right halls for their needs. ICSE is an outsourcing focussed area designed to connect the pharmaceutical community with contract service providers in the field of clinical trials, CRO, logistics, data management and CMO. InnoPack brings together buyers and specifiers from the packaging and pharmaceutical industries. Finally, P-MEC Europe features exhibitors from traditional large-scale capital equipment to companies focussed on instrumental analysis, measuring and testing technologies, materials testing, quality control and laboratory.

As you prepare your itinerary to attend this year’s CPhI Worldwide, make sure you factor in attending the CPhI Pre-Connect Conference on 21 October. Comprised of 6 modules featuring Drug Delivery Systems and biosimilars and biobetters, the Pre-Connect Conference offers the exclusive opportunity to join senior executives and influential speakers from across the pharma industry. Representatives from Wockhardt, Novartis, Merck and PwC to name just a few, will help you get a head start on your networking in an informative and interactive environment.

Additionally, the show features a constant stream of informative content on the latest key developments via the CPhI Pharma Awards and free exhibitor sessions in the Speakers Corners. You will have the opportunity to hear first-hand from exhibitors across the globe about the latest trends within the Pharma industry whilst also finding out about their latest products, innovations, services and more!

Since visitors are increasingly operating in the biopharmaceutical sector, there will be a specific biopharma zone and a bioservices zone at Messe Frankfurt this October.

CPhI Worldwide holds a unique position in hosting the largest number of traditional pharmaceutical suppliers and buyers, alongside an array of top biopharmaceutical companies, including Therapeutic Proteins International, biosidus, Amega biotech, Mabion and Toxicon Corporation.

Within the biopharma zone and throughout the wider show, exhibitors and visitors should set some time aside to take advantage of key biopharmaceutical presentations taking place. Topics on this year’s schedule include:• The future of manufacturing technologies: promoting innovation in complex biopharmaceutical manufacturing • Challenges of biopharmaceutical development, manufacturing and commercialisation • Development of protein engineering platforms to improve stability, safety and productivity of biopharmaceuticals • Outsourcing as viable R&D and manufacturing strategies: adapting business models to maintain the market position

Attendees will also be able to take advantage of CPhI’s unique matchmaking programme to help make the most of their time at the event. It allows for direct access to individual exhibitors that meet your needs. The customised program facilitates high quality meetings, boosting ROI for all participants, across the 3 show days.

CPhI Worldwide 2013 will, undoubtedly, provide a high-quality platform to help in further augmenting growth and driving innovation within the pharmaceutical and biopharmaceutical markets. To register for CPhI Worldwide 2013 please visit: http://www.cphi.com/register-your-interest-2013


Page 61 – ICSE Preview

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Investor Optimism at the 10th Anniversary EPIC (European Partneringand Investment Conference)

This year’s EPIC biotechnology conference, sponsored by Johnson & Johnson in London, proved to be another successful mix of opinion, business meetings and hard-nosed appraisal of the worth of the European biotechnology companies presenting. As usual, the day opened with industry opinions and this year also an overview of Cell Therapy Catapult. This is a government initiative to develop cell therapy research into products for the clinic and hospitals, and how the improvement in scaling-up of cell manufacture is helping to drive this branch of medicine.

big pharma’s view on developing products with biotech companies was put forward by Klaus Mendla of boehringer Ingelheim. The theme of investment by big pharma in biotech companies was carried on during the panel session of VCs and big pharma investors. Debbie Harland, director of GlaxoSmithKline investment arm SR One, viewed this type of investment as becoming more prevalent in the next 5-10 years, although conceding it had not made a significant impact on biotechnology company development yet. The question ‘Is investment in European biotechs still conservative in comparison to their US counterparts?’ was taken up by Kate bingham of SV Life Sciences. She said that the mainland European VCs were still more cautious than their UK counterparts, and in comparison with the States. Warming to the theme, she carried on to say that the UK was in fact a better place for biotechs to do business in Europe, and would encourage companies to relocate to the UK to develop their business. The panel were asked about what are the hot sectors in biotech investment today, and some areas were mentioned, such as companion diagnostics and platform technologies. Kevin Johnson of Index Ventures thought that in fact VCs were much more opportunistic – choosing

simply what they thought was the right mix of technology and management in a company, rather than looking at any particular therapy area. The debate was lively, educational and great fun, with a good deal of audience participation in the discussions.

The main body of the event was the showcasing of 60 UK and European biotech companies in three streams: Pre-Clinical, Clinical and Platform Technology/Diagnostics. Companies varied in size between start-ups and listed ones, and some that caught the eye were:

Dutch company to-bbb is a clinical stage biotechnology company focusing on enhanced drug delivery across the blood-brain barrier. The company is developing novel treatments for devastating brain disorders, such as brain cancer, neurodegenerative diseases and lysosomal storage diseases.

Out of Trinity Collge, Dublin, TriMod Therapeutics’ technology is a combination of two new molecular entities – a TLR agonist and a PI3 kinase inhibitor – which synergistically enhances the patients’ immune response to target tumours.

Elasmogen is a new spin-out from the University of Aberdeen, and is an antibody drug discovery company based on a

unique, shark single-domain antibody (VNAR) platform, and is exploiting the power of proteins as drugs.

based in Germany, immatics are producing therapeutic cancer vaccines designed to redirect the immune system so that it recognises and controls tumours. Their most advanced product is directed at renal cell cancers and is in a worldwide Phase III clinical trial.

Feedback from the some 250 delegates has been overwhelmingly positive with the partnering meetings cited as being extremely productive. Another successful conference, with the one-day format being popular and making EPIC a very cost-effective way to meet biotech companies.

Next year’s conference will be in early October:

Simon TarpeyDirector00353 86 [email protected]

CONFERENCE & REVIEWS CONFERENCE & REVIEWS


Location, Location, LocationNow in its thirteenth year, by creating an efficient and dynamic conference in central London, the annual Genesis Conference was established to provide a complementary forum to the plethora of bio-partnering, investment and policy-led events in the life science sector calendar such as, biotech Showcase, JP Morgan, bioEurope, Chinabio, bIO Investor Forum, bIO and bioEquity. As one would expect, many of the global events listed above take place in key international locations, however few take part at the heat of a World city, where R&D scientists, financial and deal building executives and Government policymakers not only rub shoulders, but are trained and highly networked. Genesis is one such conference, located in Westminster, London, next door to Parliament and a stone’s throw from three of the World’s top medical teaching and research centres and neighbouring one of the most globally successful financial centres. One should not forget also, that in an age of convergence in healthcare delivery where mobile apps, big data and electronic patient records play an ever increasing role, London also provides a leading ICT sector base with which the bioPharma and Healthcare industry can interface daily.

Highlights of Genesis 2013• 700 delegates from across the life

sciences spectrum• Opening Plenary Session

Genesis Conference 2013: Where scientific, economic and healthcare success converge

• 12 tailored breakout leadership sessions

• The SCRIP – One Nucleus Plenary Debate

• Online 1-2-1 partnering facility• Careers, recruitment and training

strategy hub• 70 Exhibitors• Pre-Genesis Seminar, bioNewsRound

Award Final and Welcome Reception on 11 December 2013

Who’s leading who?The programme at Genesis this year is packed with opportunities for delegates to engage in debate about their hopes and fears for the sector and how they feel the opportunities can be grasped. The main day will commence with a breakfast policy session led by the bioIndustry Association (bIA) setting out the way in which they are working with One Nucleus, bionow and biopartnerUK to develop a compelling Life Science Manifesto ahead of the next parliamentary elections. The following Plenary Session of key opinion leaders will include Louise Wood (Department of Health), Sir Salvador Moncada (UCL), Roel Bulthuis (Merck Serono Ventures), providing insights into how the interactions between the public sector payers, Academia, industry and corporate venture funds will enable improvements in healthcare outcomes on a global scale. The session will be completed by Mike Ward presenting new data from the Informa Group’s suite of products describing the state of the

industry and what we may expect in the following twelve months.The single stream format will be returned to in the afternoon, but this time in the form of a Plenary Debate. Taking a bbC Question Time format and chaired by John Hodgson (SCRIP Intelligence) a panel of experts will debate ‘The Industry in 2018: Predictions, Hopes and Fears’. I am delighted to have panellists confirmed that include George Freeman MP the Government’s Life Science Champion, Shaun Grady, VP of Strategic Partnering and business Development at AstraZeneca, David Philips, Partner at SROne and Mike Ward, Head of Content, Informa.

Breakout Leadership SessionsThe middle section of the conference programme will include sessions focussing on the technologies and strategies behind innovative product development. Each session will include two keynote speakers followed by a Q&A panel discussion with additional experts from the field. Sessions will include ‘Managing Big Data in R&D’ with John Parkinson (MHRA) and Kat Zarychta (HistoIndex); ‘Biomarkers in oncology: lessons from other therapeutic areas’ with Richard Pither (Cytox) and Hanns-Georg Klein (IMGI Labs, Munich); ‘Imaging in CNS’ with Kevin Cox (Imanova) and John O’brien 9university of Cambridge); ‘Antibody-based therapeutics’ with Martin Welschoff (Opsona Therapeutics) and Matthias Grossmann (Parexel), ‘Natural Product Development’with Andrew Casey (bioteCanada) and Meredith Lloyd-Evans (biobridge), 4 Case Study Deals selected and analysed by SCRIP Intelligence, 2 Pharma Partnering Showcase sessions looking at recent trends and innovations led by TranScrip Partners and a UKTI Showcase highlighting strengths of the UK offer. The international faculty of 60+ speakers including executives from Academia, biotech and Pharma Industries, expert advisers and regulators will provide insights and debate that will enable all delegates to engage, learn and depart better equipped to perform their day jobs.



Meeting the right targetsIt is human nature to wish to be as efficient as possible in our various roles. The immense growth of the bio-partnering conference capacity is testament to both the need for collaboration and deals within the life sciences industry as well as the desire of delegates to target their key contacts at events. Even with highly efficient partnering facilities, which work extremely well when you know who you need to meet, selecting those targets and why you need to meet them is still a challenge in this era of converging technologies sector. The lighter touch approach to partnering at Genesis complements the agenda and delegate mix which is designed to enable delegates to maximise their networking opportunity to gain knowledge and insight. The added efficiency of pre-scheduled 15 minute 1-2-1 meetings via Howdi to ensure high quality contacts are met in order to share those insights, test the feasibility of working with new partners or solution providers and arrange follow up meetings thus provides an ideal springboard for future developments.The partnering facility is located within the UKTI International Zone where key market and geographical Commercial Officers of UK Trade & Investment from over 20 countries are available to share data on territories of high potential to the attending companies. Further details of which Commercial Officers will be attending are available on the conference web site and via the online partnering system. Since the introduction of a partnering facility into Genesis in 2009, there has been a consistent rise in the number of face-to-face meetings scheduled with 2012 delivering almost 1000 such connections over the course of the single day.

Pre-Genesis Seminar, BioNewsRound Award and Welcome Reception We delighted once again to be returning to Canada House again for a pre-conference afternoon and evening sessions that is available to all Genesis delegates subject to capacity when reserving their place. The afternoon will feature a seminar format with Andrew Casey the CEO of bioteCANADA describing the strengths and collaborative opportunities in the Canadian Life Sciences sector. Chris Farmakis of GLE will detail the funding and support programmes available to all companies raising capital and partnering on the international stage and Jo Pisani, Partner, Price Waterhouse Coopers who will share insights from the November Pharma Integrates conference on emerging strategies between Pharma, CROs and biotechs in the pursuit of product and commercial success. The main outcome of any awards ceremony is to ensure success is celebrated and the audience leaves enthused about being a part of the industry. Of course, showcasing great things also builds investor and wider stakeholder confidence which in turn generates more resource and, hopefully, even more successes to celebrate. The 2013 BioNewsRound Award final will follow the popular format introduced in last year, where selected finalists are given just 4.5 minutes to describe why one of the announcements they have made in the preceding year was significant to their company, the sector and patients. The details of the announcement are pre-released ahead of the final so the presentations need to focus on explaining why the subject matter is exciting. A small panel of expert judges then selects the winner, to be announced during the Welcome Reception, based upon their assessment of the significance of the announced development and the quality of the presentation. The evening session is dedicated to a theme that is often overlooked in the conferences that focus on product development, finance and deal making, that aspect of selling the sector to the wider community. It is vital that the life science and healthcare sector have effective engagement with the public, patient groups and emerging bright sparks in science. Through showcasing good practice in public engagement the session will highlight the benefits in terms of better healthcare outcomes in general. We will also hear from guest

speaker Ricky Martin, founder of Hyper Recruitment Solutions and winner of the bbC Apprentice in 2012, on what it takes to attract top class talent into the sector through education and careers advice as well as how to attract non-specialist business leaders such as Lord Alan Sugar to back the sector as a business opportunity.

It’s a people thing!We all know that success comes through building the right teams, yet do we pay sufficient attention to ensuring the training, recruitment and career path strategies across our sector are fit for purpose. This year’s exhibition hall will feature a physical hub where delegates can seek 1-2-1 expert advice on matters affecting their personal and company futures in terms of talent management. Our most recent recruit to the One Nucleus Partner Programme, Nature Publishing Group will be on hand to discuss scientific recruitment trends and, with colleagues from the editorial side of MacMillan Press strategies to successful science writing and publication. Pharma Training International, another One Nucleus Partner who offer significant discounts to One Nucleus members, will be on hand to discuss training needs and strategies. Completing the human capital jigsaw will be a number of our executive search members who will be very happy to advise on recruitment and rentention strategies for emerging life science companies.

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Documents

Ipi volume 5 issue 3 2013