w w w. p h a r m a - m a g . c o m January/February 2011 ISSN 1746-174X
Volume 7 Number 1
Drug Delivery Trends, techniques and technologies
Taking on the counterfeiters The global magazine for the pharmaceutical and biopharmaceutical industry
Delivering future benefits
OUTSOURCING Pharma Roundtable Review
For up-to-date news follow us on Twitter (PharmaMag) and join our Pharma group discussions on LinkedIn
Outsourcing Corrine Lawrence, Pharma
Healthcare UK and Frédéric Lemaire — Avery Dennison
which industry professionals discussed strategies to secure the success of future partnerships.
As France enforces its new traceability regulation, it is likely that other countries will follow suit. What can pharma companies do now to be compliant?
Contributing Companies: Pfizer, Aptar Pharma,
Archimedes Pharma, Adhesives Research Inc., Elan Drug
Robotics: Robots Set for a Fruitful Future in Pharmaceutical Processes
Technologies and Highland Pharmaceuticals.
Industry experts provide a snapshot of current trends, techniques and technologies defining the drug delivery sector.
Packaging: Beyond the Boundaries
Valérie Marchand — GS1 France, Roger Lamb — GS1
A review of the Pharma Outsourcing Roundtable in
Anticounterfeiting Contributing Companies: PerkinElmer
Analytical Sciences, Bosch Packaging Technology and
Nigel Platt — ABB Limited Robotics
Robots are increasingly finding their way into pharma manufacturing processes. The author examines the scope for future applications of the technology.
Analytical: A New ICP Methodology to Determine Trace Heavy Metals
Techniques to help pharmaceutical manufacturers win the battle against drug counterfeiters.
Rebekah Vine — Warwick Analytical Service
From the Editor: Resolutions and Evolutions
New methodologies using ICP analysis eliminate specificity issues, provide greater detection limits and measure an additional 21 elements.
Comment: The Race Against Drug Resistance
Rachel Nugent — Center for Global Development
Patents: Abuse of Dominance Suzanne Rab — Hogan Lovells International
The recent Gaviscon case provides some valuable lessons on minimizing potential risk regarding antitrust challenges.
Working Group on Drug Resistance
Overcoming the threat of drug resistance to ensure that future
Legislation: Personal and Regulatory Data Protection in Ukraine
generations will never enter a postantibiotic world.
World at Westminster: A New Approach for Public Health
Camilla Horwood — Portcullis Public Affairs
The UK Government’s Public Health White Paper outlines a new approach to improving the nation’s health.
Timur Bondaryev and Svitlana Postrygan — Arzinger
Advice on how new legislation in Ukraine on personal and regulatory data protection will affect pharmaceutical companies operating in the Ukrainian market.
Finance: Pension Scheme Deficits: Can Intellectual Property Rights Help?
Nostrapharmus: Quality Management: Let’s Make it Simpler
Stuart Whitwel and Serena Tierney — Intangible Business
Nostrapharmus predicts that simplification of the supply chain will be
IP, as well as tangible assets, can be valued and used to fill pension
key to ensuring future compliance and quality.
Contributors Editor Corrine Lawrence +44 (0) 771 517 7767 email@example.com
Publisher/Sales Director Fred Winsor +44 (0) 1372 364 125 firstname.lastname@example.org
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Editorial Advisory Board
The world’s leading nutraceuticals trade show • 8500 attendees • 1000s of new products & innovations • 500 exhibiting companies • 250 senior industry delegates • 1 must-attend event
10 - 12 May 2011 GENEVA PALEXPO | Switzerland www.vitafoods.eu.com/pharma
Rory Budihandojo Director, Quality Systems Audit Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd Patrick Crowley Vice President Product Line Extensions GSK (US) Enric Jo Plant Director Reig Jofre Group Maik W. Jornitz Group Vice President Global Product Management, Bioprocess Sartorius North America Inc.
• 30 free seminar sessions
The Editorial Advisory Board of Pharma comprises a distinguished panel of experts from various parts of the pharmaceutical industry. They review technical manuscripts, suggest topics for inclusion, recommend subject matter and potential authors, and act as the quality control department for the magazine’s editorial content and direction.
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Carlos Lopez Relationship Director Healthcare & Pharmaceuticals Lloyds TSB Corporate Markets
Harald Stahl Senior Pharmaceutical Technologist GEA Pharma Systems
Kurt Speckhals Gino Martini Director, Strategic Technologies Senior Director, Supply Chain Pfizer Inc. GSK (UK) Jim McKiernan Chief Executive Officer McKiernan Associates GmbH Maireadh Pedersen Head of Business Development Quay Pharma
Geoff Tovey Visiting Professor Dept of Pharmacy King’s College Wes Wheeler President, WPWheeler LLC
Ray Rowe Chief Scientist/Prof of Industrial Pharmaceutics Intelligensys/Uni of Bradford
Professionals working within the industries we cover may receive Pharma free of charge on completion of a registration card. Individuals in other industries or countries may purchase a year’s subscription by sending a cheque for £100 made payable to : Via Media UK Ltd by post to: Via Media UK Ltd, Wesley House, Bull Hill, Leatherhead, Surrey, KT22 7AH, UK.
Via Media UK Ltd, 22 Highacre, Dorking, Surrey RH4 3BF, UK. The publisher endeavours to collect and include complete, correct and current information in Pharma but does not warrant that any or all such information is complete, correct or current. The publisher does not assume, and hereby disclaims, any liability to any person or entity for any loss or damage caused by errors or omissions of any kind, whether resulting from negligence, accident or any other cause. Pharma does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take any responsibility for any losses or other damages incurred by readers in reliance on such content. Copyright © 2011, Via Media UK Ltd All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording or information storage and retrieval system, without permission in writing from the publisher. Send permission request in writing to Permissions Department, Pharma, Fax +44 870 487 3469. Authorisation to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted for libraries and other users registered with the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK (ISSN: 1742-447X).
FROM THE EDITOR
Resolutions and Evolutions
ust because we’ve made significant inroads into 2011, that doesn’t stop me from wishing you all a Happy New Year. Furthermore, welcome to the first issue of the year. For many, the beginning of a year is synonymous with making resolutions. Maybe yours was to Corrine Lawrence Editor, Pharma shed a few pounds or perhaps you firstname.lastname@example.org stubbed out your ‘last’ cigarette 5 minutes before midnight on 31 December? Whether or not you count yourself as one among those determined to make self‑improvements, it is difficult to deny the sense of a fresh start that arrives with each New Year. At the very least, you may feel the need to de‑clutter and re‑organize to help establish a little more order bring an otherwise hectic life. Unfortunately, the first week of 2011 found me attending a funeral. During the service, I felt two overwhelming emotions, each pulling in seemingly opposite directions. In one respect I was immensely saddened by the turn of events that brought me to the crematorium, which reawakened my own sense of mortality and highlighted the fragility of life — one moment a life exists and the next, it is extinguished. The other half of me wanted to celebrate because this person had led a full and accomplished life. Ill health, and indeed death, tends to help concentrate the mind to prioritize what is important and of true value. It really is unfortunate that it can take events of this magnitude or the heralding of a New Year to shake us into action. These deeds or actions are not always large, life‑changing events that require a substantial leap of faith; they may be changes that are the result of a series of small steps. Whatever your wishes or desires, I urge you to make a start in making them happen! I may not have made any New Year’s resolutions but, during the last few months, I have been working towards introducing a couple of changes to Pharma. Each issue, including this, will contain some peer-reviewed content. These articles, which will be marked as such, have been reviewed (double blind) for accuracy and objectivity, by a member of the publication’s Editorial Advisory Board (EAB). In the quest to bring you highly relevant content, I am in the process of re-invigorating Pharma’s EAB and already, I am delighted to welcome on board Wes Wheeler of WPWheeler LLC, Enric Jo of Reig Jofre Group, Kurt Speckhals of Pfizer Inc. and Carlos Lopez of Lloyds TSB whose collective expertise will help to enhance the magazine. So, best foot forward and let’s make things happen!
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THE RACE AGAINST DRUG RESISTANCE
The global community faces the dangerous possibility of heading toward a postantibiotic world. Pharmaceutical companies must join governments, donors and global health institutions in taking major steps that will ensure the lasting effectiveness of treatment.
he Drug Resistance Working Group convened by the Center for Global Development (CGD) outlined four recommendations for pharmaceutical companies and other important global health stakeholders to strengthen existing efforts and build collaborations to ensure that drugs continue to save lives in future generations: secure the drug supply chain to ensure quality products and practices; catalyse research and innovation to speed the development of resistance-fighting technologies; improve surveillance by collecting and sharing resistance information across networks of laboratories; and strengthen national drug regulatory authorities in developing countries.1 Some international efforts have begun to address drug resistance, but they remain largely fragmented, often focusing on a single disease or country at a time. The Working Group’s recommendations strongly call for partnering and networking to help address drug resistance, based on the premise that no single actor can do the job alone.
Secure the Drug Supply Chain
1. R. Nugent, E. Back and A. Beith, The Race Against Drug Resistance, June 2010.
For more information
Rachel Nugent Chair Center for Global Development Working Group on Drug Resistance email@example.com
Each step along the pharmaceutical supply chain presents the potential for breaches that contribute to drug resistance: when poor conditions such as extreme and fluctuating temperature and humidity, introduction of counterfeit products, poor packaging and inappropriate drug dispensing result in people getting poor quality and bad drugs, resistance can result. Drug resistance will be slowed only by tightening the entire supply chain, addressing both distribution and packaging standards, and certification for those who prescribe and dispense drugs. Pharmaceutical companies have the unique opportunity to influence the quality of drugs after manufacturing, marketing and sales through better packaging and inserts that inform patients and dispensers about appropriate use, as well as through better monitoring of supply chain conditions (to avoid the degradation of drugs and the introduction of poor products), and by educating dispensers and prescribers about drug resistance risks. Pharmaceutical companies, supply chain experts, prescribing and dispensing associations, and technical agencies should collaborate through an international body, such as the International Organization for Standardization, to develop voluntary protocols and standards to protect drugs from deterioration and misuse. Companies adhering to those standards would be recognized, through certification or another visible means, for their efforts to reduce the circulation of poor-quality drugs and restore confidence in the quality of the global drug supply chain. To reward companies that meet
the voluntary standards, the working group recommends that donor organizations and national governments procure medicines only from those companies that demonstrate quality assurance throughout the supply chain.
Catalyse Research and Innovation
Most researchers in infectious diseases lack adequate support — financial and an intellectual community of people working on resistance — to advance their ideas, discoveries and innovations. This is particularly true of those focusing on narrow fields, such as resistance‑fighting technology. The working group recommends creating a web‑based marketplace for resistance research and innovation that would connect researchers and match good ideas with investors. The proposed marketplace would connect researchers, lower the barriers to collaboration and promote partnerships among researchers, pharmaceutical companies, venture capitalists, foundations and public funders. The marketplace would couple an innovation showcase with a brokerage facility, which would facilitate technology transfer by providing legal and financial advice and support to those entering into research partnerships, and assist marketplace users to access additional funds, such as those available from the US National Institutes of Health, the Wellcome Trust in the UK, or private investors.
Drug Resistance Surveillance
Efforts to tackle drug resistance are complicated by enormous knowledge gaps. The CGD working group recommends improved drug resistance surveillance and laboratory capacity in developing countries. Companies should collect and share resistance surveillance across diseases. Industry scientific expertise can play a central role in establishing and defining the terms of a global drug resistance surveillance network. Longstanding and existing surveillance efforts from companies should be available to inform public health, as well as clinical care. Now, more than ever — because of the huge investments in global health, including access to treatment, and improvements in delivery systems in developing countries — the pharmaceutical industry is uniquely poised to make a significant difference in the fight against drug resistance. For the sake of all people who seek effective treatment, drug resistance must be addressed urgently and aggressively as a global health priority. With coordinated, collective action, we can overcome the threat of drug resistance and ensure that future generations will never enter a postantibiotic world.
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OUTSOURCING ROUNDTABLE REVIEW The pharmaceutical outsourcing landscape is changing. As the sector moves into a new phase, Big Pharma and CMOs met at Via Connect’s inaugural Pharma Outsourcing Roundtable to discuss how best to realign their strategies and expectations … and how to get the most out of future partnerships.
Rationalizing Manufacturing Networks
What is the role of contract manufacturers in rationalizing pharmaceutical companies’ manufacturing networks? Indeed, is there a role for contract manufacturers? Starting the debate, John Bolla of GSK explained that their external supply network is growing substantially because of the growth in the company’s commercial business model — the in‑licensing of products and assets and the inherent supply chains. The company is looking across its contract manufacturing network to find out how it can complement and manage its internal network; therefore, Bolla believes “there is a significant opportunity for contract manufacturers to help us and rationalize our manufacturing networks.” He added: “We’re working very hard to ensure that we have one network that allows our internal factories and our external contract manufacturers to augment each other.” The challenge, though, is how to do that effectively. Many pharma companies have too many contract manufacturers. The challenge is to reduce when appropriate and to grow in other areas as in‑licensing increases. Internal versus external: GSK, advised Bolla, is faced with the significant challenge of implementing a network that consists of both internal and external manufacturers. How they do that together and drive continuity around that supply base will lead them into the future, because their current work will continue
to grow as they look to maximize their assets, capabilities and internal competencies, and augment those with the third parties they work with. Limited capabilities: According to Bolla, limited capabilities is a major hurdle when outsourcing products to one contract manufacturer — it is difficult to locate a CMO that’s willing and able to take all of the complex products and manufacture them. Sometimes, CMOs are interested in only one piece of that puzzle or they don’t have the capability or capacity to deal with the other pieces. “It’s certainly a challenge from a technology transfer perspective, which is difficult, costly and time consuming. And when you open up old products to scrutiny, you sometimes find yourself in a situation where you wish you hadn’t,” explained Bolla. Tail products: One delegate explained that their biggest problems lay with small products and tail products — predominantly gained through mergers and acquisitions — or those approaching the end of their product lifecycle. The cost to move a product is sometimes greater than its value. Furthermore, moving some of these products exposes them to validation problems, which also has cost implications. This situation presents a real cost problem dynamic and explains why many pharma companies have numerous tail products that can’t be rationalized, resulting in a much bigger list of CMOs than preferred. Over capacity: Further compounding the situation is over capacity. The only way to overcome this, advised John Koelink of Bayer Healthcare, is to take the volumes out and then close the site. But, this is expensive. Koelink argued: “Deciding what to do with your own assets is the biggest hurdle, not finding contract manufacturers to do the work.” The problem of over capacity can be felt from both sides, highlighted a delegate from GSK. One solution may be to in-source, fill their own capacity and cover their own overheads. But it costs as much to in-source as it does to rationalize products to another CMO.
Many CMOs can accommodate the needs of yesterday, but today and tomorrow is the challenge; that’s the partnership opportunity.
Factory design: Most factories are built for the past, not the future. Bolla explained: “It’s difficult to find contract manufacturers based on our current needs. — to logically and sensibly rationalize the network and build flexible factories for the future. The days of blockbuster drugs have gone. Today, it’s about niche products — the flexibility and capability to manufacture them.” Tim Tyson of Aptuit spoke of factories’ love of volume and having one 7/1/11 07:16 Page 1 ‘large‑volume’ product. Getting facilities that can
produce small volumes and a variety of products is challenging. “Change operations create most of the quality issues, so we need facilities that are able to do low volumes and do changes quickly,” he added. QbD: Andreas Woppmann of Ariad Pharmaceuticals advised that flexibility lies at the centre of their ability to move manufacturing activity globally. “Quality by Design (QbD) has provided us with the flexibility to effectively move operations from one location to another because we can prequalify key parameters, critical process and performance aspects.” Another delegate explained that as they (GSK) look to rationalize and move old products — either out of their existing facilities or CMOs — it becomes an opportunity to apply QbD. During the lifecycle of an old product, they learn a lot about the process and continually apply changes. It seems that many companies view QbD as something that takes a lot longer than it does or should. “QbD and the process understanding that goes with that is something that we can do and should apply in a relatively quick timeline. The biggest issue we have is when products are with existing CMOs — how do we get the knowledge transfer, which might be tacit knowledge versus written down? That’s a big challenge, but we do know a lot about our own drug processes that we can build on,” she said.
“Why aren’t we working together with the contract manufacturers in emerging markets?” asked Koelink. One delegate answered: “I’ve had some conversations with different CMOs who have expressed their interest in emerging markets. The opportunities are there; but, despite the apparent interest, I haven’t seen much activity.” He suggested the possible merit of talking with companies, including Big Pharma, about partnering with a CMO they can all share to enable them to gain access to a region they have yet to penetrate. Koelink believes that by partnering,
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OUTSOURCING pharma companies and CMOs must seek solutions for the future together, particularly with regard to emerging markets where pharma companies need to find a competent partner and start with small volumes. Frequently, however, local companies are not interested in the small volume on offer, so it makes sense to combine it, but without the involvement of too many people. Starting a partnership will not happen with three or four people around a table, advised Koelink. He stressed the importance of making the initial decision: “If you’re doing it, do it, despite the costs. Don’t go into the deal for the short haul, it won’t work. You need to have an 8‑year spectrum.”
“Most Big Pharmas are highly arrogant,” admitted a GSK delegate. “We think we are more technically competent than the people we deal with. Frequently, we tell companies what to do and how to do it. In fact, we often find that many contract manufacturers are more innovative than we are, they’re sharper on their feet, they’re running with lower margins, they’re slicker. To get the most out of our CMO partnerships, we need to listen more because I believe we can get quite a lot of innovation from them.” So, how should we regard CMOs; are they innovators or followers with respect to new technologies and new processes? Many CMOs have a tremendous amount of innovation to offer in particular areas, advised one delegate from Baxer Pharma Solutions. Some have worked extensively with biologics and cytotoxics and have, therefore, acquired significant and valuable experience.
For those corporations that wish to discontinue products that sell 10,000 units a year, but are unwilling to deal with closing down plants and the resultant restructure — are they just trying to put plasters/Bandaids on wounds? Are there any innovative or strategic answers Pharmpack_40x267_advert 7/1/11 07:16 Page 2 to dealing with problems that really have their origin
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we often find that many contract manufacturers are more innovative than we are. at a much higher level? Bolla highlighted the need to abandon the old way of thinking, which allows the industry to foster excuses. “We need to stop thinking that we can’t move these products. There are options. One is to return to our commercial business partners. At GSK, we’re building a different relationship between manufacturing and commercial to challenge the future need for the products because, occasionally, commercial doesn’t realize. In other cases, a tail product is part of a bigger basket of products that’s necessary to sell. Frequently, commercial is willing to take a loss to be able to provide medicines, and access to those medicines, in the markets that we’re serving.” Other options, continued Bolla, include building the right relationships with the right CMOs. “It’s a business case; it’s a total view, not a one‑off look at our products and our processes. We are now looking across a host of products, not just one
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OUTSOURCING after the other because then you do find yourselves applying plasters/Bandaids to individual cuts instead of healing the whole wound.” Reading between the lines of the complex business case being portrayed, Michael O’Brien of Pfizer identified flexibility, diversity (technological and process) and capacity as key future ingredients for an effective business model. Discussions about capacity must include ‘resources,’ he explained: “You may have plant space, but you might not have the resources to run the processes. There’s development and then there’s manufacturing (commodity manufacturing development and technological). If I have to staff and maintain the infrastructure and resources to do all of this, I lose flexibility and global diversity. Making a business case to outsource a function that you cannot accommodate is easy, but if you can’t start an external partnership because you have underutilized assets, then you’re selling your organization short.” So, how do you find a viable balance between outsourcing and making internal capacity available for pharmaceutical sales business for other clients? A company’s willingness to bring in‑licensed products to their own units is something for each company to assess, advised O’Brien. Pfizer, he explained, wants to maintain a certain level of in‑house innovation, compliance and regulatory understanding, otherwise its personnel cannot effectively manage and understand that which is external. If an innovation company sells off or outsources all of its innovation, then it is no longer an innovator.“ I/Pfizer would never ever opt to go 100% external; that would be suicide,” concluded O’Brien.
It seems that both CROs and the contractors have ‘issues’ regarding being reliable partners. Miller asked whether the contractors are addressing these issues internally, as well as creating those expectations of their partners? According to Koelink, they haven’t done particularly well. Partnerships provide data transparency. Drawing on previous experience of working for a motor company, Koelink explained that information sharing was a regular occurrence there. By contrast, companies operating in the pharma industry keep their information to themselves. By opening up all the information they need to have to operate, service providers will be able to deliver better results. Bolla spoke of ‘living up to commitments’ and of partnerships being a ‘two‑way street.’ Living up to commitments, he explained, isn’t about guarantees: “Past relationships focused too much on commitments and guarantees; they should be about creating transparency so that when things go well, we benefit together, but when there are challenges, we stand up to those together and drive solutions.”
In‑licensing and acquisitions create many manufacturing relationships. Miller asked Eli Lilly how they are addressing this. The company’s Director Alliance Management explained Lilly’s mission: first, remain independent; second, to continue a stream of innovations; and third, to outsource and collaborate. “We are going to outsource a lot of our products and contract manufacturers provide us with an opportunity to get the work done with the right quality, at the right cost and at the right delivery time.” But, he noted, the expected increase in outsourcing will place greater emphasis on the way in which it is done. External partnerships will only be successful if they are worked at in much the same way as a marriage, he explained. “At Lilly, we have a unique process called Alliance Management; when you work externally with a partnership, there are going to be issues. Alliance Management provides us with a set of tools to help us work at communication, to build trust, to set up mentoring and ensure the success of the partnership.” Illustrating the necessity of Alliance Management, he explained that 60–70% of partnerships fail to meet expected results. This does not mean that they totally dissolve, but that 60–70% of those reasons for coming together do not materialize. Given the expected increase in outsourcing, how much does Eli Lilly want to outsource during the next 5 years? There’s no set target. Instead, the company is looking at which capabilities it would be sensible and prudent to acquire if it doesn’t want to make the investment internally. Lilly also considers other opportunities, such as using a contract manufacturer for a faster launch. Currently, the company is looking deeper into local presence in emerging markets where it may want to build an asset or have the capability and presence on the ground. Ultimately, though, Lilly still intends to use its internal capabilities when appropriate to retain control.
The Supply Chain of Clinical Trial Materials in Emerging Markets
In recent years, emerging markets have become a major clinical trial activity focus. This, in turn, has sparked debate about how best to deal with the issues pertaining to the supply chain of clinical trial materials into these markets. Solutions need to be found because, as O’Brien commented: “We know that we’re going to be doing increasingly more clinical trials in emerging market countries.” There’s a logistical issue of getting supply to those countries. Currently, it’s predominantly coming from the US and Western European suppliers. “In some of the emerging countries, to gain market entry, they’re going to demand that we do local manufacturing
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OUTSOURCING rather than bring materials in from another part of the world. We can’t build a plant in every country we want to have market entry in to,” explained O’Brien. One solution, he offered, could be “captive assets, codevelopment or partnerships with companies that are already in these markets once we have brought them up to a level that meets our own standards.” Pharma must not allow countries to force them to use supply from the countries in which the trials are going to be done, stresses Tyson. “We have to advocate that it shouldn’t matter where materials are made. We’re already experiencing problems with having factories in every market and then not having enough capacity, which then results in rationalizing factories.” Tyson outlined the two major issues that they have to contend with when providing clinical trials materials for a customer. The first is meeting the regulatory requirements of the country in which the studies are done and in which the product is ultimately going to be registered. When possible, they work with their local partners. The second is logistics — import/export requirements, fees, licences, restrictions, timings, costs and then having the depot network that can supply the distribution. “Clinical trials are time-sensitive; getting material to patients is critical to executing those clinical trials within the time constraints,” explained Tyson. He concluded: “Having depot networks, having the relationships and ensuring that products can easily flow throughout the distribution chain is extremely important.” Conducting even only a small portion of clinical studies in a target market may help companies to gain market access, suggested Woppmann. From a business perspective, the investment in recruiting only five patients in a country such as China can have possible downstream benefits. Although this approach takes much longer, the time factor is only really relevant in the context of conducting the clinical study; it’s not relevant to scoping out the market. Some countries, however, may not be able to afford modern medicines. O’Brien advised that a key element to a company’s approach to entering an emerging market is to be prepared for the smaller number of companies that are at the required technological level or have the same quality of people that you may be used to with US and Western-based partners. “These companies are there,” O’Brien reassured, “but they’re smaller and we all want to find them — they’re not going to be accessible to everyone.” Based on this, O’Brien recommended that companies build 5‑year plans and have a multifaceted strategy that includes varying degrees of supplier development. One delegate, a Senior Director, Supply Chain from Pfizer, added that the clinical trial supply chain comprises three fundamental components: API manufacturing, drug product manufacturing and the
People, People, People
Koelink suggested that it’s the people rather than the company that determines and characterizes successful partnerships. Companies that were very good 3 or 4 years ago have now lost some of their pedigree. Why? Because when staff left, knowledge left and the company didn’t invest in new knowledge. “How do we ensure that the companies we partner with maintain their quality of staff to sustain the good partnership?” he asked. Value of service is a major part of what companies want from their service providers. Within the overall value of a contractor’s service, the expertise and the responsiveness of the organization are what really matter. “By identifying key colleagues in those organizations and helping them to excel in their own job in that location, we can hopefully stabilize the team we need, said Woppmann. This strategy, however, can alter, particularly if the business model changes because of, for example, acquisitions, he noted. If you want to maintain talent in an external supplier or have some say as to what that talent looks like, then there are legal hurdles that need to be dealt with, pointed out O’Brien. He added: “When we investigate an emerging market country, we talk to the heads of Human Resources (HR) of each prospective company, because we want to know about their retention policy. Understanding what the company is doing from an HR perspective regarding keeping the good talent can provide valuable insight into their commitment to you.”
clinical supply pack, label and distribution. “The challenges in emerging markets are quite different for those three components,” he said. The biggest challenge lies with drug product manufacturing: “For example, when we closed our Ann Arbor (MI, USA) R&D plant, which included a drug product manufacturing facility, we had to bring on board about 15 different vendors to replace that capacity. This demonstrates that the technical needs of the portfolio are extensive in drug product dosage forms. The challenge of building that in emerging markets is immense because the complexity continues to evolve: the product’s needs change as the product moves through the pipeline. Attempting to build capabilities around that complexity in each emerging market isn’t feasible, but there may be opportunities to partner with local suppliers.” Tyson added that it’s a good area for developing long-term partnerships and relationships with a contract supplier organization. He explained that capability knowledge (regulatory understanding, the depot network and distribution capability) is going to be essential as emerging markets develop and become a larger proportion of work that’s being done both in clinical and commercial manufacturing. “It’s going to be extremely difficult for individual companies to develop all of the capability to service a number of the markets that products are being developed in. So, it’s a good position for developing strategic relationships and long-term understanding and having an ability to develop a capability ready for when pharma companies need it,” he concluded.
OUTSOURCING Effective Business Models for Client/Contractor Relationships
Begin with the end in mind, advised Woppmann. “Are we talking about development engagement, implementing a commercial process, reducing the cost of goods or risk mitigation? We must know what we’re talking about before we start,” he said. “Can any or all of these elements be combined?” he asked. Working out an effective business model needs to start with that concept in mind, followed by prioritizing what matters. For Woppmann, risk management is foremost in his mind. He explained that proactive risk management is part of effectively designing the relationship — building flexibility into the process during the design stage: done well, this will reduce the risk in development, in commercialization and of moving programmes in the future. With regard to alliance management, Woppmann believes it “all comes down to the fully engaged management of activities in real-time and ensuring that all parties are informed and have what they need.” He also stressed the importance of the following activities: •D etailed technical project management: it requires the key engineers and scientists being available to participate. •L ifecycle Management: the engineers and scientists have to stay with the product through launch and beyond. •C omprehensive supply chain management: pharma companies have to maintain this themselves, even if it is just by supervision, guidance and direction. •C ontinuous tactical direction: pharma companies need to stay on top, and have the internal knowledge and senior competence even if they engage with external development — they can’t or shouldn’t just relinquish it. • Active performance management: having metrics, clear timelines, holding people accountable for hitting those timelines and helping them to quantify their own effectiveness. The alliance management is the core of what a small organization such as Ariad has to do on a daily basis, explained Woppmann. “If we want to effectively partner with service providers, the issues are always the same, whoever they are.” The types of relationships between pharma companies and contract service providers can vary. As Bolla highlighted, not all require ‘marriage.’ Instead, they’re just a dinner and a date, which sometimes turn into marriages. Continuing with the marriage analogy, Bolla advised: “The worst thing that can happen in a relationship is when you think you’re going out for a dinner and a date, but they think they’re going out to the wedding.” Not all partnerships have to be strategic — a partner can be required to manufacture on an acquisition or tactical
not all require ‘marriage.’ Instead, they’re just a dinner and a date, which sometimes turn into marriages. basis; and, occasionally, a contractor is required from development to drug delivery, which will determine the depth of the relationship. Relationships need to be understood at the outset: “It’s not about one effective model; it’s about understanding the model you want and then structuring the relationship in the way you understand it,” added Bolla. Adding to the list of requirements that constitute a successful partnership, Tyson spoke of ‘realistic commercial terms and expectations.’ To illustrate his point, he explained: “It has to be understood that most contract service providers are competent professionals who have come from large pharma companies. They have lots of knowledge and experience but they have significantly fewer resources and a lower financial capacity to take on risk than big pharma companies. Much time is spent negotiating the commercial terms — we (the contractor) want to be flexible to ensure we have realistic terms because we want to be successful in the partnership; we also want to be successful with delivery, in compliance with quality expectations and make a little money — our investors want us to deliver reasonable returns and it’s something that is a challenge. We have pressures on some of the constraints, liabilities and risks that we can take on, so we need some co‑operative understanding.”
the range of requirements that companies are asking CMOs to address goes far beyond just the supply of a particular material. Large organizations tend to divide up responsibilities into many little pieces, which are shared out between lots of people. In smaller companies, the responsibilities are not carved up so much so that one person may have a much broader responsibility. Miller observed: “It strikes me that that’s an easier model to work with because you don’t have orders coming at you from 20 different places.” In response, Woppmann explained that their ability to transact is much better when they can bring just a few select people to the table. These people, who understand their field very well, sometimes require internal coaching and prepping. “We have to be really careful whom we send out to do what, whether it’s to meet with FDA or to meet with contract service providers,” he admitted. Getting this right can facilitate expedited timelines. One delegate from a small CMO raised a final point: the challenge of commercial reliability. He explained that he has strategic partnerships that work very well until he receives an email advising him that he’s been invited to negotiate with a contractor of his client — not the client itself — to change the current contract. “We can’t, as small companies (or bigger companies),
try to accomplish the needs you have in the pharma industry today. We need reliability of more than 6 months because we can’t work in an environment in which we have to deliver the technical skills and then, all of a sudden, another department comes in and wants 25% discount.” In reponse, Bolla spoke of the structure at GSK: the company doesn’t have a sourcing department; external supply is an integrated team based around supply, procurement, quality and technical capability. That group comes together to deliver the best value for GSK, be it cost, quality, service or innovation at the expense of higher prices. Furthermore, he added that ‘reliability’ is “incredibly important for you and for our own factories.” Sometimes, reliability in a partnership gets challenged and decisions get made that affect the factories of both the pharma company and the CMOs. The challenge, therefore, is two-fold for both parties: to give the CMO as much reliability and transparency as can be given in a partnership, but also to have them understand from the perspective of a partner that sometimes reliability doesn’t exist in the way we’d like to have it. Wrapping up the roundtable, Miller concluded that the session’s biggest ‘takeaway’ is that the range of requirements that companies are asking CMOs to address goes far beyond just the supply of a particular material; they need to consider the full range of the supply chain and corporate strategy needs. Increasingly, major companies and smaller mid‑sized companies are looking to their CMOs to address a broad range of business needs, not just immediate supply needs.
• J oaquin Santos Benito, Senior Director External Supply Integration, Janssen Pharmaceutica • J ohn Bolla, Vice President External Supply, GSK • Tim Tyson, CEO, Aptuit •M ichael O’Brien, Executive Director Technology & Strategic Sourcing, Pfizer • J ohn Koelink, Senior Vice President Global Supply Chain, Bayer HealthCare •A ndreas Woppmann, Vice President Manufacturing Operations, Ariad Pharmaceuticals •C hairman: Jim Miller, President, PharmSource
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DRUG DELIVERY References
1. D. Bishara and D. Taylor, “Upcoming Agents for the Treatment of Schizophrenia,” Drugs 68(16), 2269–2292 (2008). 2. J.C. Garbutt, et al., “Efficacy and Tolerability of Long‑Acting Injectable Naltrexone for Alcohol Dependence” JAMA 293(13), 1617–1625 (2005). 3, J. Cortes and C. Saura, “Nanoparticle Albumin‑Bound (Nab)‑Paclitaxel: Improving Efficacy and Tolerability by Targeted Drug Delivery in Metastatic Breast Cancer,” EJC Supplements 8(1), 1–10 (2010). 4. N . Desai, “Nanoparticle Albumin‑Bound (Nab) Technology: A Nanotechnology Platform for Biologically Interactive Drug Delivery and Targeting,” Abstracts of Papers, 234th ACS National Meeting (2007). 5. M .N. Samtani, A. Vermeulen and K. Stuyckens, “Population Pharmacokinetics of Intramuscular Paliperidone Palmitate in Patients with Schizophrenia,” Clin. Pharmacokinetics 48(9), 585–600 (2009). 6. J. Shah, et al., “Development of a Ready-to-Use Parenteral Nanosuspension of a Weakly Basic Model Compound and its Salts,” AAPS Proceedings (2006). 7. R .S. Ramchandran, et al., “Fluocinolone Acetonide Sustained Drug Delivery Device for Chronic Central Retinal Vein Occlusion: 12‑Month Results,” Am. J. Ophthalmol. 146(2), 285–291 (2008). 8. F . Alexis, et al., “New Frontiers in Nanotechnology for Cancer Treatment,” Urol. Oncol. 26(1), 74–85 (2008).
THE COMMERCIALIZATION OF PARENTER AL DRUG DELIVERY SYSTEMS BASED ON MICROSPHERES, NANOTECHNOLOGY AND IMPLANTS Recent advances in nanotechnology, polymer science and ocular biology have enabled the development and commercialization of many parenteral and ophthalmic drug delivery products that have significantly improved therapeutic outcomes. With the patent cliff looming for many new chemical entities (NCEs), the development of such delivery systems to extend the life cycle of NCEs is paramount. Development, manufacturing and regulatory hurdles, however, threaten to hinder the development of these technology enabled delivery systems. This article explores these challenges because, if left unaddressed, the coming of age of the new technologies may not translate into advanced delivery systems that provide significant clinical benefit.
he last 10 years have seen the introduction of technology enabled parenteral and ophthalmic drug delivery products that provide significant clinical benefit and improved therapeutic outcomes. Such products include parenteral sustained‑release depots such as Risperdal Consta (risperidone), Zyprexa Relprevv (olanzapine pamoate), Vivitrol (naltrexone) and Invega Sustenna (paliperidone palmitate). Now, depot formulations of multiple atypical antipsychotics are available to psychiatrists to improve patient compliance — resulting in a better therapeutic outcome.1 Risperdal Consta is produced from biodegradable poly(DL‑lactide‑co‑glycolide) (PLGA) microspheres, which is a mature technology. The commercial launch of Vivitrol demonstrates that very high drug doses can be delivered with microsphere technology, which was previously considered to be unfeasible.2 Abraxane is the first parenteral (intravenous) drug product to use paclitaxel nanoparticles bound to human serum albumin. It avoids the use of a cosolvent (ethanol) and a surfactant (cremphor), which are present in an innovator product that has been claimed to be responsible for allergic reactions.3,4 Because of the nanoparticle nature of paclitaxel, Abraxane allows higher doses to be delivered in a smaller volume, resulting in improved clinical responses with fewer side-effects — thus improving the therapeutic index.3 Paliperidone depot utilizes a paliperidone palmitate nanosuspension, a hydrophobic ester derivative of an active metabolite of risperidone, 9‑hydroxyrisperidone.5 The nanoparticles no doubt enabled the paliperidone palmitate to dissolve at a fast enough rate to achieve pharmacokinetic exposure that
is safe and effective for the duration of 1 month with a single intramuscular injection. Nanotechnology has been shown to enable the delivery of a very high dose: 840 mg in a 2‑mL intramuscular injection, thus solving parenteral solubilization and delivery challenges.6 An ageing population, coupled with an increasing incidence of diabetes, has put greater pressure on the need to treat various ocular conditions — such as age‑related macular degeneration and diabetic macular edema — which can result in blindness if left untreated. This need has led to the development of drug products such as Macugen and Lucentis, which are administered by direct intravitreous delivery to the target tissues — the retina and choroid. Because these drug delivery routes are invasive and can result in associated side-effects, efforts have been made to develop implants that provide effective levels in the eye for more than 3 months upon dosing. Retisert and Ozurdex are very small implants that deliver steroids for durations of 8 and 6 months, respectively. A Phase III study has been conducted with an implant (which can fit into a 25‑gauge needle) that enables direct injection into the vitreous humour and provides 3‑year drug release.7 The technology required to make the implant both small enough to fit into a small‑gauge needle and deliver an effective dose for 1 year is more complex and difficult to manufacture. These products owe their success to the fundamental scientific understanding of the physical and chemical properties of nanoparticles, microspheres and implants, their fabrication and mechanisms of action in biological environments. The manufacturing process
DRUG DELIVERY STRAP
for these technologies, such as miniature implants and microspheres, is a complex, multistep process that must be conducted in an aseptic, particulate‑free environment with dedicated equipment and facilities. The registration and approval of these products requires preclinical and clinical safety studies spanning many years. Although this could be considered to be the coming of age for complex and advanced drug delivery systems for parenteral and ophthalmic administration routes, these products have come through long, expensive and dedicated development programmes. Paliperidone palmitate depot was developed and approved after six Phase I studies with multiple formulations followed by a Phase II study and four Phase III studies, spanning many years.5 Similarly, an ophthalmic implant delivering drug for more than 3 years would demand Phase III studies for a longer duration.7 Considering that many drugs are coming off patent during the next 5 years, using nanotechnology, sustained‑release depot and ophthalmic delivery systems for these drugs could provide both additional revenue streams and therapeutic/medical benefits to patients with either an improved pharmacokinetic (PK) profile and/or localized and targeted delivery. Additional advances in technology, such as targeted nanoparticles with tumour‑specific homing ligands, can provide significant efficacy enhancement while sparing the rest of the tissues from the side-effects of oncology drugs.8 Targeted nanoparticles can potentially change the therapeutic index of, and breathe new life into, effective chemotherapeutic agents that are limited by their adverse side‑effects profile. Although it may be tempting to develop such advanced delivery technology based drug
products, consider should be given to whether the drug is a candidate for such technology and whether there are better and simpler means of achieving the same therapeutic goal. In addition, there are numerous challenges to using these technological advances to create new drug products for parenteral and ophthalmic drug delivery. These technologies have a long development time frame because of the early‑stage research investments to identify the formulation, the need to conduct additional preclinical safety studies and a full Phase II programme similar to that required for an NCE. Whereas modified‑release oral dosage forms can be registered with bioequivalence and/ or PK bridging studies via the Abbreviated New Drug Application and/or 505b(2) path for approval, there is no clear guidance on the clinical development and filing of parenteral delivery systems; in which case, the sponsor assumes an NCE‑like development and regulatory filing. In addition, this complex technology requires large capital investments in dedicated manufacturing facilities before these products are approved, which carries a significant financial risk. From a purely financial perspective, the risks compared with the benefits may not justify the investment for developing parenteral delivery systems for a compound that has gone off patent. This may portend a “valley of death” for these promising delivery technologies that have come of age and are much needed in the future to cost-effectively improve medical outcomes with existing drugs. The efficient and cost-effective development and progression of technology enabled, advanced delivery techniques should be a key topic for discussion and debate. Both scientists and regulators need to establish a framework and strategy to realize the promise of these mature technologies.
From a purely financial perspective, the risks compared with the benefits may not justify the investment for developing parenteral delivery systems for a compound that has gone off patent.
For more information
Jaymin C. Shah, PhD Research Fellow Pfizer Global Research and Development Tel. +1 860 715 2332 Jaymin.c.shah@Pfizer.com Acknowledgements I would like to thank Phil Nixon, Kurt Speckhals and Carl Ziegler for review and comment on the article.
Nasal and Pulmonary Drug Delivery Market Future Key Drivers
he pulmonary market represents about $25 billion sales per annum — approximately 3% of the global pharma market sales ($837 billion, 2009). The main chronic therapies addressed by this delivery route are asthma and chronic obstructive pulmonary disease (COPD), which affect a patient population of 350 million. The nasal market represents $7.1 billion sales per annum, but it implies many more therapies, such as allergic rhinitis (42% share), nasal systemic therapies (for example, pain, migrain) and nasal over‑the‑counter (OTC) medications, each about 30%. Both the pulmonary and the nasal drug markets have experienced a growth in terms of units though the values of these market segments (in USD) are affected by the somehow recent generic penetration.
For more information
Pierre Carlotti Vice President Marketing & Communication, Prescription Division Aptar Pharma www.aptar.com
For asthma and COPD, there are two key portable inhaler platforms available. Pressurized metered‑dose inhalers (pMDIs) are still the gold standard representing more than two thirds of the drug products (in volume) while dry powder inhalers (DPIs) represent about 25% and the remaining being soft mist inhalers. A combination of reliability, accuracy and reproducibility of dosing, as well as patient familiarity, convenience and cost effectiveness has made pMDIs a pulmonary drug delivery success. A significant proportion of patients prefer DPIs to pMDIs, which are breath‑actuated and require ‘hand–lung coordination.’ There are, however, notable geographical and demographic variations in DPI and pMDI preferences. In addition to these two dominating technology platforms, a third portable inhaler technology called Soft Mist Inhalers is making inroads in this market segment.
Patient compliance is a major issue in the long‑term management of chronic diseases. Poor patient compliance with a prescribed drug regimen could result in ineffective therapy management and eventually dangerous health consequences with cost implications as well. When designed with a patient‑centric approach and quality-by-design principles, an adequate drug delivery device can contribute to enhance patient compliance. The development of the novel side‑actuated device Latitude for nasal sprays, which leveraged frequent medical research to drive better convenience, is one example of practical patient‑driven innovation. Another example is the development of cost‑effective dose indicators and counters for pMDIs. These are designed to meet regulatory guidelines and help improve patient compliance, which in turn increase drug effectiveness and reduce the overall cost of chronic respiratory therapy to healthcare providers.
The application of innovative IT, electronics and communications solutions to healthcare is an area of growing interest and is seen as a potential market opportunity. During the next 10 years or so, the introduction of innovative e‑health telemedicine and personal health records is expected to facilitate access to healthcare, help prevent disease, and improve the monitoring and control of chronic conditions. Realtime monitoring of pMDI use by asthma patients is on the horizon, allowing both patients and doctors to receive warning of changes in device use patterns that might indicate a change in a patient’s medical condition. In the longer term, electronics solutions are likely to enable the creation of new delivery devices with new functions and widespread connectivity.
electronics solutions are likely to enable the creation of new delivery devices with new functions and widespread connectivity.
Nasal Delivery Trends
For more information
Alan Smith Vice President, Research & Development Archimedes Pharma alansmith@ archimedespharma.com
main attribute of nasal administration is the potential rapid delivery of drug into the systemic circulation. The nasal route is convenient, straightforward and well accepted by patients, making it ideally suited, for example, to the treatment of acute and crisis conditions. Historically, the nose has been regarded mainly as a site for local (for example, anti‑allergics) delivery with limited numbers of drugs being administered intranasally for treating systemic conditions such as migraine, endometriosis and osteoporosis. Given the diverse physiochemical properties of different molecules, specific drug delivery technologies are required to create nasal formulations that will deliver the appropriate pharmacokinetic profile and address the needs of patients. Typically, simple aqueous solutions are insufficient. The recent European approval of Archimedes’ innovative fentanyl pectin nasal spray product for of breakthrough cancer pain (PecFent) is one example of a product specifically designed for purpose and there are numerous other nasal drugs in clinical development at Archimedes and elsewhere, including granisetron (nausea/vomiting), diazepam and midazolam (seizures), testosterone (hypogonadism) and apomorphine (Parkinson’s disease).
Nose‑to‑brain delivery is currently generating significant interest as direct delivery of active agents into the central nervous system via the olfactory region offers some interesting therapeutic possibilities particularly in nerodegenerative diseases (Alzheimer’s, Parkinson’s, ischemia); yet, significant challenges remain to be overcome — in particular, the delivery of formulations to the absorptive site in man continues to be problematic and the most compelling current evidence for this route of delivery is predominantly from unvalidated animal models. Of more immediate interest is that the accessible immune tissues in the nasal cavity can be used for delivery of vaccines; nasal influenza vaccines are already marketed and vaccines to various other pathogens are in clinical trials, including norovirus. Importantly, novel formulation technologies, such as absorption enhancers, gelling polymers and microand nanoparticles, and innovative delivery devices are increasingly being applied to provide optimum delivery, not only of molecules that naturally lend themselves to nasal delivery, but also those that may lack the ideal properties, including macromolecules for which the nose can now offer an alternative route to injection.
A For more information
William G. Meathrel Senior Scientist Adhesives Research, Inc. Tel. +1 717 227 3460 firstname.lastname@example.org
s drug manufacturers evaluate ways to extend life cycle applications for solid‑dose formats coming off patent protection, development work into new types of transdermal drug delivery will further expand. The capabilities of transdermal patches are moving beyond the delivery of compounds with low molecular weights for short‑term conditions such as motion sickness, or for longer‑term therapies such as hormone replacement or birth control. The next generation of patches addresses the treatment of chronic conditions. Examples can be seen in new treatments for Alzheimer’s disease including a recent US filing of a 7‑day donepezil patch and the first rivastigmine patch. In Europe, some forms of Parkinson’s disease are now being treated with the rotigotine patch. Drug developers also are investigating the patch platform as an alternative delivery system for peptide drugs that are vulnerable to proteolytic attack and that tend to undergo aggregation, adsorption and denaturation. In addition, the benefits of patches are well recognized regarding avoidance of unwanted side-effects, particularly with compromised populations of patients. Device-assisted and alternative delivery sites are areas of great interest and development; for example, needle‑free delivery of therapeutics and
vaccines can potentially address the growing global issues associated with diseases that are passed intravenously through the improper use and disposal of needles. Iontophoretic devices offer a noninvasive alternative for delivering therapeutic substances via the electro‑assisted transport of molecules that would not normally diffuse across the skin. The dissolvable oral thin film (OTF) platform technology, which is built upon the coating techniques used for decades in transdermal adhesive manufacturing, is well proven for the delivery of APIs to patients for select over‑the‑counter (OTC) medications and is now being utilized for prescription drugs as seen in the recent launches of Zuplenz and Suboxone OTFs. A number of the film’s physical properties are customizable, including dissolution rates, activated or triggerable release, thickness, material composition, taste masking and API absorption rates to broaden the potential uses for this technology. Areas of consideration for dissolvable films include topical treatment applications for delivering agents such as analgesics or antimicrobial ingredients for wound care or other applications; films for enveloping active particles in multilayer or combination systems to enable controlled release; buccal, sublingual and mucosal delivery systems; and gastroretentive dosage systems.
Nanotechnology: Disruptive Technology with Game-Changing Opportunities
For more information Dr Gary Liversidge Chief Technology Officer Elan Drug Technologies
ore than 40% of compounds identified through combinatorial screening programmes are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation‑related performance issues. Previously, the inability to achieve high drug loading, the cost of ingredients/ processing and the restricted number of suitable excipients has limited the broader use of many of the earlier formulation approaches. During the last decade, formulating poorly water‑soluble compounds using a nanoparticulate approach has evolved from the academic curiosity that it was to one that can potentially deliver real solutions. Formulating these compounds as pure drug nanoparticles has been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. The most commercially successful technology designed to overcome this poorly water‑soluble problem is Elan Drug Technologies’ NanoCrystal technology — partly because it was the first technology that was robust and easily scaleable to commercial quantities with an extensive patent estate supporting the technology — and has resulted to date in five licensed products being launched (TriCor 145 — Abbott; Emend —
Merck; Megace ES — Par Pharmaceutical; Rapamune — Pfizer; and INVEGA SUSTENNA — Janssen) with annual in‑market sales in excess of $1.9 billion. Other technologies designed by drug delivery companies to overcome problems associated with poor water solubility include Skyepharma’s IDD solubilization technology used to launch Triglide (Shionogi Pharma Inc.), and LifeCycle Pharma’s Meltdose technology used in Fenoglide (also marketed by Shionogi in the US). We have already seen that nanotechnology is having a significant positive commercial impact on a dozen or so commercialized products. Yet, this is only a tiny fraction of the number of drugs these nanotechnology approaches could potentially rescue from abandonment. During the coming years, many more poorly water‑soluble products are expected to be launched aided by these and similar technologies. It is well accepted that pharma companies have a dearth of pharmaceutical products coming through development. If pharma companies do not encourage outsourcing at the lab‑bench stage (which can often be the case), then the product is dropped purely because it has solubility issues. Pharma companies should look at their own war chest of pipeline products to see if there are any hidden gems that were discarded because of their inherent poor water‑solubility properties.
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Emilie Dolan Highland Pharmaceuticals LLC Tel. +1 314 205 9666 firstname.lastname@example.org
ithin the last 10 years, prescription drug abuse has grown by 80% in the US. 1 Educators, legislatures and healthcare professionals are seeking solutions to control and/or alleviate this problem. Most of the solutions offered thus far affect the distribution of such drugs as oxycodone, hydrocodone, hydromorphone, morphine and propoxyphene. Unfortunately, by controlling distribution mechanisms, it also creates unnecessary “road blocks” for those patients who benefit from these types of pain medications. As such, pharmaceutical manufacturers have an opportunity to positively affect this issue — by creating a delivery system that is “tamper resistant” while maintaining recommended efficacy. If the active ingredient in the medication cannot be extracted by using crushing or dissolution processes, then street abusers no longer have a vice to distribute and consume. Nevertheless, healthcare
professionals can continue to prescribe and manage these types of medications to patients in a safe and healthy environment — a “win–win” situation for manufacturers, healthcare providers, patients and drug enforcement professionals. To date, there are several pharmaceutical companies including Purdue, Pain Therapeutics/King and Endo/ Gruenthal that have developed tamper-resistant systems. Only Purdue’s OP system has reached FDA approval. Recently, Highland Pharmaceuticals introduced a novel tamper-resistant technology, that cannot be crushed into a powder‑like substance (needed for inhalation or injection) and holds great promise in addressing the issue of prescription drug street abuse. Although the public focus thus far in this drug abuse challenge has centred on distribution safety, it is evident that the onus may turn to the manufacturers. As such, pharmaceutical companies are prudent to prepare for this need and begin investing in the development of delivery system technologies.
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chemicalweek January/February 2011
ADVANCES IN TECHNOLOGY IN THE FIGHT AGAINST COUNTERFEITING
Paul Coombes examines the latest advances in anticounterfeiting techniques. he anticounterfeiting landscape has changed drastically during the past 5–10 years. Key breakthroughs include the introduction of FDA guidelines for physical chemical identifier (PCID) use, advances in on‑site analysis and increased collaboration between law enforcement, manufacturers and customs. Together, this demonstrates that the threat of counterfeit materials is now being taken seriously. One estimate from the Center for Medicine in the Public Interest (CMPI) predicted that counterfeit drug commerce would grow by 13% in 2010 — twice the rate of growth of legitimate pharmaceuticals — generating $75 billion in illegal revenue.1 Consumer education programmes are beginning to bring the issue into mainstream media and warn consumers of the potential health risks. Co-operation between various industry bodies and organizations is only a recent development. Now, a multidisciplinary approach is favoured, which takes into account everything from the legality surrounding counterfeit products to analysing their chemical makeup. The EU, US and Canada all have strict anticounterfeiting laws, but this is not true elsewhere. Uncertain legal ground drives the problem to ports and airports, resulting in minimal traceability further back in the chain. The problem of ownership can also cause issues regarding who should invest in anticounterfeiting measures — the police, governmental organizations or the pharmaceutical companies themselves.
In the US, the majority of freight undergoes spot checks using a four‑layered approach: examining the shipping paperwork, visual checks of the product packaging, on‑site chemical testing and then, if necessary, the product is sent to a laboratory for more detailed chemical testing. There, techniques such as liquid chromatography mass spectrometry (LCMS) and Raman analysis are used to confirm the sample. Anticounterfeiting operations are still in their infancy, so there is still some variation in technique preferences — the industry is yet to decide upon a ‘one‑size‑fits‑all’ approach, or even a ‘one‑size‑suits‑most.’ Among the most recent developments is radio frequency identification (RFID), which can be used to track each batch of product using a centralized database to match on‑site readings. Each individual item or carton can be electronically ‘tagged,’ which records its origins and guarantees authenticity. This traceability creates an important layer in a multidisciplinary approach.
There are, however, limitations; for example, metal in packaging — such as in blister strips — can interfere with the RFID signal and render it ineffective.
New Lines of Defence
Packaging innovations are also helping to combat counterfeiting within the supply chain. Both overt and covert technologies can be used to indicate that a product is genuine. Tamper‑evident packaging is perhaps the most easily recognizable and consumers are confident in such measures. Holograms and security seals are also commonly used, indicating authenticity as well as guaranteeing that the product inside is untouched. Colour‑shift inks, which change colour when tilted, are also difficult to replicate. Manufacturers of these inks use bespoke colour combinations and technology, and guarantee exclusivity of these combinations, which ensures no imitations. Covert packaging markers include UV images and microtext, which are invisible to the naked eye. One of the main supply chain operations that undermines packaging innovations is repackaging by distributors. Repackaging is legal and common in Europe, mainly driven by local language needs and different licensing in each country. Another difficulty is that counterfeiters move quickly when trying to imitate anticounterfeiting measures.
PCIDs, covert additions within the drugs, are a new method currently being trialled by some manufacturers. Microspheres, for example, can be incorporated into the product itself. When analysed, the appearance of these microspheres indicates that the product is genuine, while an absence of the spheres proves otherwise. Other PCIDs include inks, pigments and flavours. One shortcoming of PCIDs is that analytical interrogation is often required. High‑specificity analysis can address this issue by determining the authenticity of a sample without a PCID taggant, thus saving time and lowering the cost to the manufacturer.
Spectroscopic analysis, including near‑IR, mid‑IR and Raman are all used to analyse pharmaceutical materials. The high specificity of mid‑IR makes it a useful fingerprinting technique, which is commonly combined with user‑generated or commercially purchased spectral libraries to simplify material identification. The relatively low cost and low maintenance of mid‑IR means that it is now used in most quality assurance/ quality control laboratories.
ANTICOUNTERFEITING Mid-IR use outside the laboratory is not always the preferred method as its range of sampling options can be limited. Samples must first be removed from their containers and prepared before analysis. Aqueous solutions can present difficulties for on‑site rapid analyses. Inside the laboratory, however, mid‑IR analysts can prepare and analyse samples with a large range of sampling options. Near-IR spectroscopy provides a valid alternative to mid‑IR analysis. More suited to the non‑laboratory environment, it requires only limited sample preparation. In addition, analyses can be conducted without the removal of sample containers, such as glass bottles and plastic bags, for increased efficiency. A convenient remote triggered sampling probe can also be used. Raman spectroscopy is becoming an accepted method for on‑site and in‑field front‑line analysis. It is accepted by US and other government agencies, as well as within the pharmaceutical industry. The convenience of sampling and the high specificity of the data produced make Raman a suitable tool for the rapid and unambiguous identification of pharmaceutical materials, either in the laboratory or warehouse. Solids, powders, liquids, gels, slurries, aqueous solutions and polymeric packaging materials can all be analysed using Raman. It is a versatile technique that allows tests to be performed on incoming raw materials, process intermediates or final products. Furthermore, it is suitable for checking authenticity when a product is shipped without its original packaging.
tendency to fluoresce under Raman analysis. Strong fluorescence can mask the Raman signal and render the analysis invalid. Small, handheld analysers normally display lower performance (and higher tendency to fluorescence) than their laboratory‑based counterparts. This often results in a compromise between analytical performance and portability. Technological innovations are helping to address these problems. Portable systems that combine the superior data quality associated with laboratory‑based instruments with the convenience of a handheld probe are now available. High sensitivity results in straightforward analyses being conducted in seconds, while more demanding analyses can also be made in situ. It also means that reliable data can be obtained through packaging materials, including bottles and plastic packaging.
Growing safety concerns have led to an increased demand for 100% testing of materials on‑site, which means a rise in the number of sample analyses now required. This in turn has driven the need for a more convenient and economical, on‑the‑spot means of analysis within a goods‑in or warehouse facility. Portable devices that can deliver a pass/fail result quickly without the need for laboratory analysis are favoured.
The ultimate aim is for on-site analysis to produce 100% accurate results. Both false positive and false negative results could be costly and reduce confidence. Most technologies currently in use may generate 5–10% inaccurate results depending on the samples. Previously, many proponents, including technology suppliers themselves, believed only an ‘all or nothing’ (that is, guaranteed zero false positive and false negative) performance would be acceptable. Now, agencies understand and accept the possibility of some false positives or negatives, with the hope that accuracy will improve in the future and because they recognize the benefit of even 95%. Building a spectral database with specialized software generates a simple pass/fail result, along with technical data including spectrum correlation and discrimination values. These records are essential in tracking counterfeiting. Another benefit of using software in counterfeiting analysis is the advantages in compliance. Software that protects raw data and method audit trails and requests user sign‑off on results reduces the time needed for legal compliance paperwork procedures.
Every Last Detail
Winning the Battle
As some counterfeiters are now producing drugs that resemble the genuine product on a chemical as well as visual level, false positive or false negative results can put consumers at risk. For such a challenging application, it is important to use instruments that generate a full‑range spectrum at high resolution to improve the accuracy in differentiating between chemically similar materials. To obtain high quality spectra directly through a range of packaging materials, an instrument with high sensitivity is required. The greater the sensitivity, the quicker and more definitive the answer will be. Raman spectroscopy delivers this high specificity, but it does have limitations. For example, some materials have a
A multilayered approach is the most effective way to fight counterfeiting. Innovations in packaging, PCID and material analysis offer opportunities to block traffickers. Along with tamper‑evident packaging and seals of authentication, convenient on‑location testing can prevent counterfeit drugs from reaching consumers. For pharmaceutical and healthcare industries and regulators, confidence in the quality of the data and the performance of the instrumentation and software is paramount. Raman spectroscopy generates a simple pass/fail analysis in seconds, providing extensive data processing capabilities that generate high quality spectra from even the most challenging samples.
1. www.cmpi.org/inthe-news/testimony/ counterfeit-drugs-andchina-new
For more information
Paul Coombes Qualifications Services Europe PerkinElmer Analytical Sciences and Laboratory Services www.perkinelmer.com
STANDING UP TO THE
COUNTERFEITERS Franz Ludwig of Bosch Packaging Technology talks to Pharma about trends in counterfeiting and the technologies used by Bosch to help manufacturers win the war against the pharmaceutical counterfeiters. How big and real is the threat of counterfeiting to the pharma industry? Counterfeit APIs and medicines pose a growing threat to patients worldwide, with numbers increasing in Europe and the US. For example, seizures of counterfeit medicines at European borders have risen explosively during the last 5 years. According to a report by the European Commission, 118 million counterfeit products were stopped by customs in 2009, of which 10% accounted for medical goods.1 In addition, medication is increasingly sold via the Internet, making it much easier to put counterfeit products into circulation. As a result, many pharmaceutical companies are realizing the need to implement anticounterfeiting measures for their products. Is there a trend in the type of drugs being counterfeited? The extent of the problem of counterfeit drugs is vast. According to the World Health Organization, antibiotics, hormones, analgesics, steroids and antihistamines make up almost 60% of the drugs counterfeited.2 Currently, the most popular medicines that are being counterfeited are Sildenafil citrate, which is sold as Viagra and various other trade names, and weight-loss drugs. This is because these products are predominantly ordered online, providing an opportunity for counterfeiters to more easily disguise the fake products and sell them as originals compared with walk-in pharmacies where fake products would be quickly detected.3
What are some of the technologies being employed to combat pharma counterfeiting? Regulation of the serialization of pharmaceutical products is currently in place or being implemented in several countries, among them Turkey, France and the US, to curtail the number of counterfeit products on the market. To address this, Bosch Packaging Technology offers comprehensive anticounterfeiting solutions by using a combination of technologies, including mass serialization and tamper-evident packaging combined with 3D holograms to help manufacturers reduce counterfeiting of their products. During the last 2 years, Bosch has conducted scientific examinations and extensive trials with currently available printing systems, including thermal inkjet, continuous inkjet, drop-on-demand inkjet and laser printers. As a result, we have amassed extensive expertise in this field and can offer solutions for tracking products and for mass serialization. Our Track & Trace Carton Print System (CPS), which uses either drop-on-demand or laser printer depending on customer packaging material demands, provides superior print quality and speed and offers the highest format flexibility on the market. In addition, our engineering and development teams are evaluating other innovative possibilities to offer manufacturers a variety of additional options to further enhance their anticounterfeiting efforts. For example, we are currently running an experiment with nanoparticles to test how an infrared spectrum could be included in the matrix that is printed on the package. These nanoparticles are invisible to the human eye, but can be detected by a sensor, adding a new, highly advanced level of security to the Track & Trace solution. How do these work? With our Track & Trace system, a unique identifying code is printed onto each product after it has been packaged, which allows for the traceability of individual products throughout the supply chain and facilitates the identification of counterfeit products. It also provides manufacturers with documented proof of what has been produced at item level. The Track & Trace system uses a CPS module consisting of a printer and camera, which automatically prints and verifies products. To trace each product individually, a unique serial number and an expiration
date are printed on the package. The information also includes a batch number and global trade item number (GTIN). The system encodes the data into a machine-readable 2D datamatrix code, which is printed on the package, eliminating the possibility for human error in the tracking process. Printed tracking data is automatically checked for accuracy by the camera, which reads and verifies each printed digit (optical character recognition/verification). Within milliseconds the camera cross-checks the humanreadable text with the 2D datamatrix code. All information is then stored in a centralized database, ensuring that tracking and tracing of the product are possible after each package exits the factory. The database can also be modified to provide the printed data to regulatory bodies such as FDA or the Ministry of Health. How smart are drug counterfeiters — can they keep pace with the new technologies designed to stop them? Generally, counterfeiters are well equipped with the necessary resources to offer fake products to the market. Yet, anticounterfeiting technologies that incorporate security details on products, such as a unique serial number, are one way that pharmaceutical manufacturers can start to win the fight against counterfeit drugs. In addition, the quicker new developments can be incorporated into existing anticounterfeiting systems, the harder it will be for counterfeiters to keep pace and adapt. This will help achieve the ultimate goal of eliminating the problem of counterfeiting. How do you think Track & Trace technology will evolve? Track & Trace as an end-to-end solution will be firmly established within Europe by 2015 as many manufacturers are starting to identify the need to protect their brands and, ultimately, their consumers. The adoption of this technology would mean that every pharmaceutical drug would have a serial number, allowing each product to be authenticated in pharmacies before it is sold to the patient. I also expect to see measures put in place to protect consumers when shopping online for pharmaceutical products. For example, consumers buying medical items from online pharmacies will have the option to authenticate their purchases within seconds using web-based or mobile solutions.
Getting it Right
The current buzz topics within the pharmaceutical industry are authentication, serialization and Track & Trace. This is a result of a combination of legislative initiatives and advances in technology convincing people that unique item level marking is possible and will allow consumers, healthcare professionals and brand owners to identify an individual product and where it has been. Yet, despite what some companies would have brand owners believe, serialization without security is not authentication and serialization without aggregation and integration is not Track & Trace. Some companies purport the idea that placing a unique and checkable code onto a product provides authentication. This is not so. Codes can be copied, sequences can be guessed and databases can be stolen. For ‘true’authentication you need to have security built into the serialization programme. Codes, therefore, need to be difficult for counterfeiters to replicate. Brand owners need to consider systems that work via encryption and potentially include other security features that support each other, providing a ‘lock and key’ approach. Serialization can only really be seen as true authentication if other factors are involved and it is not the only means of defence. Track & Trace involves the monitoring of products as they go through the supply chain, such as checking the progress of courier packages online (tracking) and finding out where a product has come from (tracing). There is an erroneous notion that serialization effectively acts as a Track & Trace system. Serialization provides no such facilities in its own right. A unique code can only be used as a Track & Trace device when monitored and recorded at each point along the supply chain. For this to work, the unique code has to be associated with each packaging unit so information can be aggregated. For example, the code on the pack is associated with the carton it goes into, which in turn is linked to the shipping case it enters. A better understanding of these issues will result in increased efficiency and security for the pharmaceutical industry.
For further information Richard Burhouse Business Development Manager Payne Security www.payne-security.com
1. E uropean Commission, Report on EU Customs Enforcement of Intellectual Property Rights (2009). 2. w ww.who.int/medicines/ services/counterfeit/ overview/en/ 3. w ww.policynetwork. net/sites/default/files/ keeping_it_real_2009.pdf
For more information
Franz Ludwig Product Manager Track and Trace Bosch Packaging Technology
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BEYOND THE BOUNDARIES
With France’s new traceability regulation now in enforcement, how likely is it that other countries will follow suit? Valérie Marchand of GS1 France and Roger Lamb of GS1 Healthcare UK talks to Pharma about their views of the wider impact of rule, and Avery Dennison’s Frédéric Lemaire advises on the technology available to facilitate compliancy.
ith the new traceability regulation now enforced in France, it is likely the rest of the world is considering adapting a similar rule that ensures all medical products are labelled with a GS1 Data Matrix 2D barcode. To allow for complete visibility, France’s production lines, as of 1 January 2011, contain the new CIP 13 standardized GS1 code, a batch number and the medicine expiry date.
Valérie Marchand believes the new regulation will greatly benefit the French pharmaceutical industry, as manufacturers will posses a thorough knowledge of the products they have supplied. France is the first country to adopt this ruling for medicine, with Italy, Spain and Germany likely to be the next to follow suit. “The decision to implement this regulation depends entirely on each country’s budget, and from this how they can successfully migrate an international code into their own system — they need to decide what will work for them in terms of which details will be included in the barcode,” she adds. “I believe France’s decision to adopt this system has not only affected the UK and the rest of Europe, but may also have had a global impact. Never before has there been such a strict regulation on the marking of drug products, and the advantages involved cannot be ignored. It is highly likely that this system will be considered by most countries throughout the next couple of years.” According to Valérie, despite the regulation’s many benefits, the costs incurred mean the majority of pharmaceutical manufactures, throughout the world, are unlikely to begin using a 2D barcode on their production lines until a law is enforced in their country. “Manufacturers who wish to sell their medicines in France, however, must ensure
that products are labelled with a GS1 Data Matrix 2D barcode — all the required information needs to be included to comply with the French regulation. Therefore, companies who use this code on their production lines for France will certainly reap the benefits if they then choose to continue doing so on the remainder of their produce not intended for France.”
Commenting on the UK’s stance on the likelihood of adopting a similar system, Roger Lamb advises: “The Department of Health’s Procurement, Investment and Commercial Division (PICD) in the UK is currently discussing the adoption of GS1 Data Matrix with the pharmaceutical industry. There is a Datamatrix working group, which is a subgroup of the GS1 UK Healthcare User Group, and discussions are taking place with manufacturers, trusts and solution providers regarding a similar regulation.” Roger states that work is ongoing in the UK and the Department of Health’s PICD aims to consult widely and thoroughly before any decisions are made. He adds: “France’s decision to enforce the GS1 Data Matrix 2D barcode has certainly stimulated a debate within the UK pharmaceutical industry. Although there will be substantial costs involved in implementing such a system, equivalent benefits will be derived by companies. For manufacturers in the UK wishing to learn more about implementing a GS1 Data Matrix 2D barcode I would advise that they contact GS1 UK and join the work programme, which will ensure they are kept up to date with any progress.” Roger urges manufacturers to plan in advance and seek professional help if a regulation is implemented: “It is extremely important for pharmaceutical companies to be fully prepared for the new system in every way possible.”
France’s decision to enforce the GS1 Data Matrix 2D barcode has certainly stimulated a debate within the UK pharmaceutical industry. Datamatrix at a glance
Constitution: 2D matrix made up of juxtaposed points and squares. Capacity: Able to encode up to 2300 alphanumerical characters (3116 digital characters) on a reduced surface. Reading: Distance of 15 cm to approximately 1 m (progress underway)/visibility of the label essential Price: Label — from €0.01 to €2; reader — €1000 to €10,000.
Datamatrix Bar-Coding Technology
The three types of information required by the new French regulation — a new CIP 13 standardized GS1 code, the batch number and expiry date of the medicine — would need an extremely large label if traditional unidimensional barcodes were used. Many pharmaceutical products do not necessarily have the space to host this information. The beauty of Datamatrix marking is that is has a major storage capacity on a minimum size, thanks to 2D coding. Furthermore, this system is cost effective and requires a traditional implementation (for example, laser, inkjet). The main problem encountered by the project managers concerns a lack of space on the production lines. Furthermore, to guarantee good quality Datamatrix marking, it is essential to ensure products are correctly packaged. This is compounded by the multiple interfaces and systems that exist between various elements of the production line (marking,
control, automation, line supervision, and so on). Many marking and labelling companies offering Datamatrix have had to re-evaluate their products to ensure they enable pharma manufacturers in France to be complaint with the country’s traceability regulation. Avery Dennison now offers three solutions that meet the aforementioned constraints. Upgrade One solution upgrades an existing labelling machine, without affecting the dimensions. The update of the AVL labeller is a cost‑effective upgrade of a proven labelling machine, but with new features added. The machine is equipped with a unique interface that centralizes the management of all functions of the machine: marking, labelling and Datamatrix control. Update The second solution updates the production line by adding a compact (600 mm) and dedicated Datamatrix module. The accurate and consistent movement of product cases through the labelling area ensures superior print quality. Integrate Finally, for manufacturers wishing to install and establish a completely new production line, Avery Dennison’s AVL-DM labeller integrates the printing of the Datamatrix and control over the Datamatrix code, in addition to the classical functions of deposition and inspection of the social security label. Using a single interface makes it possible to easily manage the different functions of the machine and maintain a reasonable load (1000 or 1300 mm). Frédéric Lemaire, states: “Pharmaceuticals manufacturers recognize the importance of the Datamatrix system and the potential impact on their production procedures. 2010 was a busy year in preparation for the new Datamatrix standard, both in France and internationally. At Avery Dennison, with our integration solutions and trusted expertise, we are ready to help every stakeholder reach full compliance.”
For more information
Valérie Marchand Healthcare Manager GS1 France email@example.com Roger Lamb Healthcare Sector Manager GS1 Healthcare UK Frédéric Lemaire Southern Europe Manager Avery Dennison frederic.lemaire@ eu.averydennison.com
ROBOTS SET FOR A FRUITFUL FUTURE IN PHARMACEUTICAL PROCESSES The food and beverage and pharmaceutical
industries have often mirrored each other in the way they use similar technologies in their respective production processes. Automation is one such area, particularly robotics. Having been embraced in increasing numbers by food manufacturers, robots are increasingly finding their way into many pharmaceutical manufacturing processes as well. Nigel Platt explains the benefits that robots have already been proven to deliver in the pharmaceutical sector and examines the scope for future applications.
lthough the characteristics of food, beverage, and pharmaceutical products may be very different, they do have several things in common. First is the overriding need for hygiene, with both industries operating equally high standards that must be met to eliminate product contamination. There are numerous examples of process techniques that are common to both industries, including aseptic filling, sanitization, sterilization, isolator technology, containment and cleaning in place. Both industries are also governed by similar standards for validation and traceability, particularly when it comes to ensuring that their production processes meet strict regulatory requirements. FDA requirements, for example, whilst originating in the US, impact any company importing food or pharmaceutical goods into the US, consequently affecting companies worldwide. Meeting these standards can be a challenging and time consuming process, particularly as, technically, there is no such thing as an FDA approved or compliant product. Instead, FDA reviews the validation of each production process and considers the combined ability of all the equipment, manufacturing and quality systems employed to ensure that the end product will be safe for human consumption. In meeting these requirements, it makes little sense for companies to develop solutions from scratch, which make the availability of a proven production solution from a closely related industry highly attractive. With robots still largely considered to be new technology in many quarters, even despite their more than 50 years of heritage, it has taken a while for robotic equipment to be accepted as part of the Good Manufacturing Processes (GMP) set out for the production of food and pharmaceutical products. In recent years, however, there have been major advances in robotic technology that have made it increasingly suitable for both food and beverage, and pharmaceutical processes alike. Foremost amongst these has been the development of specific hygienic design models for these industries, rather than just the adaptation of existing models developed for other applications. This targeted focus has been partly driven by the need for robot suppliers to look for alternative markets to the traditional bastion of automotive manufacturing, particularly during
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Today’s robots can handle the full range of tasks inherent in the screening process, spanning everything from sample preparation and shaking samples through to transporting samples between different experiment points.
the last 2 years when many large automobile manufacturers have had to downscale their operations. As new specific models have become available, such as stainless steel versions for use in clean‑in‑place processes, so too have new applications been found for them, which in turn has helped to secure their acceptance. The following are just some of the key processes in which robots are already being deployed.
The R&D stage has historically been a complicated, time‑consuming process that has invariably led to delays in time‑to‑market and increased costs to cover testing and evaluation. With steady advances in robotic technology during recent years, this situation has now changed, such that thousands of potential pharmaceutical products can now be developed and tested in a fraction of the time previously required. One example is high‑throughput screening (HTS). Using robotic technology, coupled with data processing software, liquid handling devices and sensitive detection equipment, HTS enables research teams to conduct millions of tests, in turn leading to the much faster discovery and development of new pharmaceutical products. The improvements that this technology has brought has meant that up to 100,000 samples per day can now be tested and evaluated, as compared with the 30 samples per day previously achievable with manual screening. With ultra high‑throughput screening (uHTS) also in development, robots could soon have a part to play in processing even greater numbers of samples. Another important benefit of utilizing robotic technology has also been the elimination of the negative impact of human tedium on test results. Today’s robots can handle the full range of tasks inherent in the screening process, spanning everything from sample preparation and shaking samples through to transporting samples between different experiment points. Robots have also proved useful in temperature‑controlled processes, where samples need to be incubated in special ovens for specific periods of time.
In these applications, the robot can automatically insert and remove samples to ensure they are incubated under the correct conditions.
There are several areas in which the demands on robots in pharmaceutical processes differ from those in standard industrial applications. One key difference is the need for faster cycle times. Time constraints on the screening processes, for example, where each part of the experimentation process needs to be performed for a set duration, mean that robots have to move at faster speeds without any negative impact on precision. With recent developments in robotic control technology, coupled with advances in handling accessories, such as grippers, robots have proven to be highly adept at delivering fast, repeatable performance with few or no production errors. Developments in vision technology, such as the arrival of colour and three‑dimensional capabilities, have also helped to add an extra element of intelligence. Areas where this is proving beneficial include the scanning of barcodes to enable the recognition and tracking of specific batches through to production and packaging, crucial for meeting traceability requirements. Vision capabilities can also assist at the packaging stage, where the ability to ‘see’ enables robots to visually weigh and fill products much more effectively, and thereby greatly reduce packing errors. As mentioned earlier, another pressing requirement inherent in pharmaceutical production is the demand for the highest levels of hygiene and cleanliness. With a choice of specially designed robots now available, it is now increasingly possible for pharmaceutical companies to find new ways of achieving the ideal situation of a production process where products are ‘untouched by human hands.’
The benefits that robots can bring in the packaging of pharmaceutical products are well illustrated by an
ROBOTICS installation at Novartis in Italy. The plant produces and packages up to 35 different vaccines for shipment to more than 70 countries worldwide. Various robots are used at the plant. The first of the robots to be supplied to the plant handles the palletizing of packaged products, with the flexibility to handle different package sizes and shapes when required. This robot uses two scanners to read barcodes on boxes arriving via a conveyor belt and sorts them according to their shipment destination. The robot proved to be so fast and reliable that it was subsequently moved to a larger area where it now loads up to six pallets at a time. The improvements brought by this robot led to the acquisition of a second robot, which is used mainly for packaging oral vaccines for polio. Incorporating an advanced vision system, this robot ensures that each individual polio cartridge is correctly lifted and placed into boxes of 20 cartridges at a time. The most innovative robotized application at the plant is a robot denester, which came into operation in 2008. The robot is part of a 40‑m packaging line for flu and meningitis vaccines that handles up to 500 syringes/min. This process entails three separate stages, which were previously handled manually, risking potential contamination and repetition‑induced error. The process begins with ‘nests’ of 100 flu syringes arriving from the aseptic department in lidded plastic tubs. The robot removes the lid of each tub by vacuum, before lifting each nest and placing them individually on a conveyor belt, ready for the next stage. With each nest costing potentially thousands of euro, it is vital that any errors are avoided. Once the tubs are emptied, the robot places each tub and its lid onto a pallet. This placement too has to be carefully controlled to meet pharmaceutical GMP requirements, which stipulate strict separation of packaging materials and products. As several million tubs and lids will be handled during the course of a year, it is, therefore, critical that the robot ensures the correct procedures are followed. The robot also incorporates a telecamera, which matches each tub and its contents through datamatrix code reading, to ensure that the correct vaccines have arrived in the correct tubs and eliminates the risk of potential cross contamination. As a security measure throughout the entire process, the system performs three verifications on the tub contents, with any irregularities immediately reported to the operator.
Dispelling the Myths
Despite the many benefits that robots have been proven to bring, and a heritage spanning more than 50 years, robots are still often deemed to be ‘new technology’ by many users, anxious about perceived complexity or cost. Smaller companies that have limited financial
and technical resources, and are consequently more risk‑averse, often tend to view robots as the preserve of larger companies. In fact, it is precisely these smaller companies at which the developments in robotic technology, particularly in the areas of programming and operation, have been aimed. With time, the technology has been steadily tweaked with a whole raft of improvements aimed at reducing complexity and increasing the range of applications where robots can be used.
For users of robotic equipment, a key development has been in the area of remote monitoring technology. With developments in communications, it is now possible for a robot to relay up‑to‑the‑minute data on its performance, which can be used to identify potential issues before they occur. When coupled with a remote service agreement whereby a robot supplier takes total responsibility for robot maintenance, this technology can yield considerable benefits regarding asset availability and maintenance resource allocation.
Compared with even 5 years ago, when the role of automation in pharmaceutical processes was still being widely debated, the progress made by robots in the pharmaceutical market has already been impressive. The 2010 International Federation of Robotics (IFR) report identifies the ‘tremendous potential’ for growth in the pharmaceutical sector between 2011 and 2013 as more manufacturers embrace the possibilities of the technology.1 The rate of adoption of automation in general, and robots in particular, is likely to continue to grow dramatically both up to and beyond 2013. The benefits of improved product quality and consistency, coupled with enhanced profitability and product throughput, provides a strong case for the implementation of robots that often far outweighs any lingering concerns regarding their introduction. For both UK and European companies, it is also worth considering the impact of the long‑term demographic, which shows an ageing population with fewer younger people filling the employment gap as older workers retire. Already there are concerns about a shortage in the availability of skilled pharmacologists. Automation is an ideal insurance policy against the consequences this will have on both skills and resource availability. With robots also in the ascendancy in the food and beverage industry, it will also be interesting to see whether some of the projected growth in both the food and beverage, and pharmaceutical sectors might stem from greater collaboration regarding developing shared solutions. All in all, the future for robotics in the pharmaceutical sector is likely to be a fruitful and interesting one.
1. IFR Statistical Department, World Robotics 2010 — Industrial Robots.
For more information
Nigel Platt Sales & Marketing Manager ABB Limited Robotics UK and Ireland Tel. +44 1908 350300 firstname.lastname@example.org www.abb.co.uk/robotics
A NEW ICP METHODOLOGY TO DETERMIN TR ACE HEAV Y METALS
Metal catalysts and reagents used in the synthesis of pharmaceutical products can result in trace levels of metals in the final product. The non-specific method that has been in place for more than 100 YEARS has, at last, been replaced by methods that use the latest instrumentation and methodologies. New methods involving closed‑vessel digestion processes and quantitative measurements using inductively coupled plasma (ICP) analysis are far superior to the previous laborious method. The new methodologies using ICP analysis will eliminate the specificity issue, provide greater detection limits and will measure an additional 21 elements. Figure 1
T Figure 1: ICP-OES spectrometer ‘in use.’
he human body requires trace levels of a range of metal elements for numerous biological activities, including enzyme function, cell processes, protein synthesis and the uptake of other trace elements, to name but a few. At higher levels, however, these metals can be toxic to human life. For certain classes of metals there are strict limits that food and drug manufacturers must adhere to. The European Medicines Agency (EMA) has published guidelines on daily exposure amounts, which are given in Table I. Metal catalysts and reagents used in the synthesis of food and pharmaceutical products can result in trace levels of metal residues or impurities in the final
product: therefore, stringent testing for these metal impurities is vital for the safety of public health. One of the current pharmacopoeia methods for testing trace elements or heavy metals is the Heavy Metals Limit Test (United States Pharmacopeia [USP] method — General Chapter <231>). This is a qualitative, colorimetric test. Metals that respond to the test are lead, mercury, bismuth, arsenic, tin, antimony, cadmium, silver, copper and molybdenum. In this USP method, trace metals in samples are identified by the colour of the metal sulphide and the test solution is compared against a lead standard calibration solution depending on the limit specified for the test. This USP method has been used for more than 100 years and has recently become a highly debated topic.
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It is widely recognized that the General Chapter <231> test has its limitations. The method is a subjective test that detects only a select range of metallic elements. It is not sensitive enough to detect metals at levels that are toxic and fails to detect certain elements including mercury. The test has three sections; mercury should respond to the test but, as it’s a volatile element, it is easily lost — especially using open vessel digestion techniques. As a consequence, the USP has revised its standards for metal impurities to protect public health. Their focus concentrates on two main areas:
• A n update to methodologies used by manufacturers, regulators and other bodies that test for metal impurities in drug and food products. These methodologies include procedures that rely on modern‑day analytical instrumentation. • To outline limits for acceptable levels of metal impurities in medicines and food products.
The New Methodology
The current General Chapter <231> will be replaced by three other chapters:
It is widely recognized that the General
Chapter <231> test has its limitations. The method is a subjective test that detects Figure 2: Schematic of dual view ICP-OES spectrometer.
only a select range of metallic elements.
• <232> Elemental Impurities — Limits • <233> Elemental Impurities — Procedures • <2232>Elemental Contaminants in Dietary Supplements (SGS Bulletin). As discussed in Pharmacopeial Forum, the new standard procedure uses closed‑vessel microwave digestion for sample preparation. Following sample preparation, quantitative analysis using ICP instrumentation in the form of ICP‑OES (optical emission spectrometer) or ICP‑MS (mass spectrometry) is suggested. An alternative choice of instrumentation is at the discretion of the user and will require demonstrating they are equivalent to the standard (ICP) methods for quantitative determinations.
Trace elements can be measured at ppm, ppb or sub‑ppb levels depending on the sample matrix and techniques used. For ICP analysis, the sample must be successfully digested within an acid medium and the stability of the acidified sample solution measured (Figure 1). Microwave digestion is a consistent, well‑controlled and advantageous method that retains volatile elements such as mercury that would have been lost previously. Sample preparation by microwave digestion is an ideal solution for ‘difficult to digest’ samples and saves time compared with laborious wet chemical digestions. Using the microwave digestion method, followed by measurement using ICP analysis, will vastly improve the analytical process and will be a welcomed replacement to the time‑consuming USP <231> method.
The instrument detection limits for most of the target heavy metal elements by ICP‑OES is 1–10 µg/L.
This can be improved 5–10 times using an axially viewed plasma technique as the method allows measurement over a longer path length, therefore increasing detection limits. 1 Using an ICP-OES with the ability to view analyses both axially and radially would, however, be beneficial to any laboratory tasked with measuring trace impurities; it improves both sample turnaround and increases detection limits (Figure 2). There are many advantages to using the new methodology yet some organizations might be discouraged by the initial purchase and running costs of an ICP-OES. Some analytical service laboratories, therefore, enable pharmaceutical and food companies to gain the full advantages of testing for heavy metal impurities using the new ICP‑OES methodology by offering the measurement as a new service.
Although still widely accepted and used in the pharmaceutical industry, the USP <231> method based on the intensity of the colour of sulphide precipitation is increasingly viewed to be non-specific, insensitive, time consuming, labour intensive and does not provide an adequate recovery of the elements being tested. The new proposed ICP‑OES methodologies will test for Al, Sb, As, Be, B, Cd, Cr, Co, Cu, In, Ir, Fe, Pb, Li, Mg, Mn, Hg, Mo, Ni, Os, Pd, Pt, Rh, Rb, Ru, Se, Sr, Tl, Sn, W and Zn. The proposed revision will eliminate the specificity issue, provide greater sensitivity down to ppb levels and will evaluate the drug sample for an additional 21 elements.
Oral exposure Parenteral exposure Inhalation exposure Classification PDE Concentration PDE Concentration PDE (µg/day) (ppm) (µg/day) (ppm) (ng/day) Class 1A: Pt, Pd 100 10 10 1 Pt 70* Class 1B: Ir, Rh, Ru, Os 100** 10** 10** 1** Class 1C: Mo, Ni, Cr, V 250 25 25 2.5 Ni 100 Cr (VI) 10 Class 2: Cu, Mn 2500 250 250 25 Class 3: Fe, Zn 13,000 1300 1300 130
1. C .B. Boss and K.J. Fredeen, “Concepts, Instrumentation & Techniques in Inductively Coupled Plasma Optical Emission Spectrometry, 3rd Edition Perkin Elmer, Inc. USA (2004). 2. E lemental Impurities — Information: Stimuli to the Revision Process, Pharmacopoeial Forum, 36(1), Jan–Feb (2010). 3. E uropean Medicines Agency (EMEA), EMEA/ CHMP/SWP/4446/2000, Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents. 4. w ww.de.sgs.com/de/ sgs-usp-elementalimpurities-v2-en-10.pdf
For more information
Rebekah Vine Laboratory Manager Warwick Analytical Service Tel. +44 2476 323 223
Table I: Class exposure and concentration limits for individual metal catalysts and metal reagents (EMEA, 2008).
(PDE – Permissable daily exposure, * Platinum as hexachloroplatinic acid, ** the total amount of listed metals should not exceed the indicated limit)
ABUSE OF DOMINANCE
Reckitt Benckiser has agreed to pay a £10.2 million for abuse of dominance by withdrawing and delisting Gaviscon Original Liquid from the NHS prescription channel. The case involves a novel theory of antitrust harm and adds to the growing body of UK and EU cases where the pharmaceutical sector has been under the regulatory spotlight.
n 15 October 2010, the UK Office of Fair Trading (OFT) announced that Reckitt Benckiser (RB) agreed to pay a £10.2‑million fine for abuse of dominance by withdrawing and delisting Gaviscon Original Liquid from the NHS prescription channel. The case addresses a controversial theory of harm in the UK and in Europe, although there have been antitrust cases in the US that involve allegations of shifting consumers from an old version of a drug to a new version, with the alleged effect that this will undermine the ability of generic versions of the original drug to compete. The case raises difficult factual and legal issues, and will be important in defining the future direction, at least in the UK,
of competition law probes into pharmaceutical life cycle management and similar practices.
The OFT issued a Statement of Objections (SO) to RB in February 2010, alleging that RB had abused its dominant position in the market for the NHS supply of alginate antacid heartburn medicines. The OFT alleged that RB deliberately withdrew Gaviscon Original Liquid (which no longer has patent protection) from the NHS prescription channel before the product was assigned a generic name within the channel, with the result that doctors searching for Gaviscon would be presented with Gaviscon Advance Liquid — a second‑generation product still protected by a patent — rather than a competing generic product. When a patent for a drug has expired and a generic name has been assigned to it in the NHS channel, UK doctors are able to use the NHS prescribing software to search for a branded product and then provide a prescription that lists the generic name. The OFT considers that the choice given to pharmacies to dispense either the relevant brand or the generic (cheaper) medicine is important for consumer choice and price competition in the UK. RB co-operated with the OFT under the “early resolution” procedure. To reflect this co‑operation, the fine imposed was reduced from an initial £12 million.
EU Antitrust Perspectives
The pharmaceutical sector has been under a sustained antitrust spotlight by the European Commission (the “Commission”) at least since its recent pharmaceutical sector inquiry. While the Commission’s Final Report in July 2009 highlighted potential concerns with certain practices by dominant pharmaceutical companies that might be regarded as contributing to delayed generic entry, it stopped short of condemning as abusive the practices that were involved in the UK Gaviscon case. Echoing similar concerns to those raised by the OFT, however, the Commission stated in its Final Report: “The launch of a second‑generation product can be a
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PATENTS scenario in which an originator company might want to make use of instruments that delay the market entry of generic products corresponding to the first generation product. The companies have an incentive to do so to avoid generic exposure for the second‑generation product.” The 2005 case involving AstraZeneca provides the only example of the Commission finding conduct by an allegedly dominant pharmaceutical company to amount to an infringement of EU competition law. AstraZeneca was fined €60 million for two allegedly abusive practices: (i) making misleading representations to obtain Supplementary Protection Certificates in respect of Losec; (ii) selective withdrawal of Losec so that generic suppliers lacked a reference product to support their authorization. On 1 July 2010, Europe’s General Court rejected AstraZeneca’s appeal against the fine for anticompetitive practices, but did reduce the penalty instead to €52.5 million. AstraZeneca, however, has since lodged an appeal with the Court of Justice of the EU, highlighting that important principles as to the correct application of EU competition law to practices by allegedly dominant pharmaceutical companies remain to be determined.
US Antitrust Perspectives
1. Abbott Laboratories v Teva Pharmaceuticals USA, Inc., 432 F. Supp. 2d 408, 415 (D. Del. 2006). 2. W algreen Co., et al. v. AstraZeneca Pharmaceuticals, 534 F. Supp. 2d 146 (D.D.C.) 2008.
For more information
Suzanne Rab Counsel, Antitrust, Competition and Economic Regulation Hogan Lovells International LLP Tel: +44 207 296 2382 email@example.com www.hoganlovells.com
The issue of successor products has been addressed in antitrust litigation in the US. Tricor (Abbott Laboratories v Teva Pharmaceuticals USA, Inc.) concerned a challenge to a patent covering Abbott’s Tricor capsules.1 Abbott allegedly introduced a tablet form of the drug, ceased selling the capsules and changed the code for Tricor capsules in the National Drug Data File to “obsolete.” Teva claimed that Abbott had manipulated the regulatory framework to prevent generic competitors from having an opportunity to enter, contrary to section 2 of the Sherman Act (the broad equivalent to the UK and EU abuse of dominance provisions in Chapter II of the UK Competition Act 1998/Article 102 of the Treaty on the Functioning of the European Union). The court denied the motion to dismiss, however, and concluded that an antitrust inquiry into the benefits provided by Abbott’s new formulation was required. The court proposed to balance the benefits of the new formulations against the impact of change on competition from generics. The Prilosec and Nexium case (Walgreen Co., et al. v AstraZeneca Pharmaceuticals) involved the heartburn drugs Prilosec and Nexium.2 As the patent for Prilosec was nearing expiration, AstraZeneca introduced and marketed a successor drug, Nexium, which was an isomer of the active ingredient in Prilosec. AstraZeneca introduced a
new over‑the‑counter version of Prilosec. The original prescription version of Prilosec remained available. The court, however, dismissed the antitrust complaint and found that the fact that the new product siphoned off some of the sales of the old product and in turn depressed sales of the generic alternative, did not give rise to an antitrust cause of action. Unfortunately, these cases fail to clarify the question of whether a pharmaceutical company is obliged to assist generic companies by continuing to make available a product that is subject to generic substitution.
Comment and Conclusions
The Gaviscon case is the first time that the OFT has fined a company for abuse of dominance since 2003, when it imposed a £6.8‑million fine against the pharmaceutical company, Genzyme (the fine was later reduced to £3 million on appeal). The case adds to the docket of investigations where the EU competition authorities have focused their attention on practices by pharmaceutical companies that risk hindering the availability of generic drugs. A key issue for antitrust purposes is what obligation, if any, an allegedly dominant pharmaceutical company may have to take steps to enable its (generic) rivals to compete. Putting the question differently, what obligation does such a company have to refrain from adopting a course of conduct that will foreclose rivals from the market? When examining strategies in relation to successor products (which was the focus of the Gaviscon case), where the change in conduct involves a product switch that appears to have at least some benefit for patients, courts and regulators are likely to be reluctant to get involved in weighing that benefit against the potential foreclosure effect of the new product. This is particularly the case where the complainant is not absolutely excluded from the market and could take steps (albeit expensive steps) to continue to compete. Determining whether incremental improvements are “significant” enough to avoid an infringement may, however, be virtually impossible in practice, even with economics input. Such an approach could also constrain innovation with brand owners being reluctant to withdraw old products or release new drugs based on incremental improvements, even where protected by a valid patent. It would not be surprising if, in the short term at least, the Gaviscon case and other pending EU competition cases in the sector strengthened the resolve of EU competition authorities in pursuing individual competition cases against allegedly dominant pharmaceutical companies. While there remains some uncertainty regarding the legal status of certain life cycle management practices, this does suggest, however, that pharmaceutical companies concerned about antitrust challenges could minimize potential risk by documenting the actual therapeutic or other benefits of their successor products and even leaving the original product on the market.
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PERSONAL AND REGULATORY DATA PROTECTION IN UKRAINE
New legislation in Ukraine on personal and regulatory data protection has attracted many questions and much debate. The authors offer some clarification as to how this legislation will affect pharmaceutical companies operating in the Ukrainian market.
ersonal data protection (PDP) and regulatory data protection (RDP) or data exclusivity are critical issues for the pharmaceutical industry. They are, however, distinct and separate forms of protection that must not be confused with each other. PDP protects individuals from wrongful disclosure of data relating to them; RDP prevents disclosure by regulators of confidential data submitted by a company to obtain and maintain marketing approval. The importance of PDP and RDP for Ukraine doesn’t constitute an exception: while PDP is a relatively new concept for Ukrainian legislation, RDP is the subject of regular discussions and is a “struggle tool” between innovative and generic companies operating on the pharmaceutical market of Ukraine.
Personal Data Protection
Until recently there was no special legislative regulation on PDP in Ukraine. On 1 June 2010 the Parliament of Ukraine adopted the Law “On protection of personal data” (hereinafter — the PDP Law), which became effective on 1 January 2011. The PDP Law regulates relations between individuals and business entities regarding the protection of personal data being processed; stipulates the basic principles of personal data processing and the main terms relating to such processing; and stipulates the rights and obligations of
the persons involved in personal data processing (both those processing the personal data or those to whom the personal data relate). The “personal data,” to be protected under the Law, is information about an individual (data subject) who has been identified or can be identified. Unlike the European legislation (European Parliament and Council Directive 95/46/EC of 24 October 1995), the PDP Law doesn’t differentiate between general personal data (such as name, citizenship, residence place) and sensitive personal data (racial, ethnic or national origin, health condition, sexual life). The definition of personal data under Ukrainian law is deliberately broad, so that almost any information about an individual is treated as personal data. Furthermore, according to Article 5 of the PDP Law, only personal data being processed in personal databases fall under legal protection. Personal data processing is for the precise and lawful purposes determined upon by consent of the data subject, or in cases stipulated by laws of Ukraine — as per the procedure established by legislation. If the purpose of processing changes, the consent of the data subject must be received. For example, a patient provides their written consent to a hospital for the collection of his/her personal data gained during his/her hospital stay for the purposes of the respective hospital. The hospital has to transfer this patient’s personal data to another healthcare institution
LEGISLATION for further examination of the patient. The purpose of data processing has changed compared with the initial purpose for which the patient gave his/her consent. Respectively, new patient consent for a new data processing purpose shall be obtained. All personal databases are subject to compulsory registration by the special authorized body — State Service for Personal Data Protection Issues (hereinafter, the PDP Service) established according to the Decree of The President of Ukraine as of 9 December 2010 Nr. 1085/2010 — with the State Register of personal databases. The registration shall be performed via the notification of the authorized body. To secure the proper operation of personal data the PDP law provides for the adoption of the following bylaws: Typical Procedure of Personal Data Processing in Personal Databases (shall be adopted by the PDP Service); Procedure of Personal Data Processing Constituting Bank Secrecy (shall be adopted by the national Bank of Ukraine); Regulation on State Register of Personal Databases (shall be adopted by the Cabinet of Ministers of Ukraine); Procedure of Keeping the State Register of Personal Databases. To date, no bylaws adopted have been adopted, so it is still impossible to register personal databases in Ukraine. Yet, the above legal acts are at the stage of elaboration and we may assume that the launch of the registration procedure of personal databases is soon expected. In practice, the PDP Law may impose certain obstacles to individuals and legal entities processing personal data, because after adopting the legal basis supporting the PDP Law they will only be allowed to do so once they have gained the consent of each individual and have registered their databases as stipulated by the Law. Moreover, the PDP Law may cause certain difficulties for foreign pharmaceutical companies that have business sites in Ukraine because the transfer of personal data to foreign persons (individuals and companies) is subject to providing reliable personal data protection and to the appropriate permit, as well as in cases stipulated by a law or an international treaty of Ukraine, as per the procedure stipulated by the legislation. The Law, however, does not clearly determine the nature of such permit and a person authorized to issue it, as well as the respective procedure. In the absence of practical experience and insufficient regulatory base, the implementation of PDP rights will raise many questions. It has been necessary for companies operating personal databases in Ukraine to take appropriate measures; for example, to elaborate or amend internal personal data processing procedures, to appoint a person responsible for PDP, to obtain written consent for the personal data processing from each respective subject of personal data; and to notify each respective subject of the personal data of his/her rights with regard to his/her personal data protection within 10 days.
It can be concluded, therefore, that starting from the moment the respective legal acts will be adopted almost all information constituting a personal database being processed, and established for whatever purpose, shall be respectively recorded and registered with the authorized body. The new PDP legislation will affect all participants of the healthcare industry — manufacturers, distributors, retailers, medical institutions and insurance companies.
Regulatory Data Protection
When entering the healthcare market in Ukraine, it is crucial that innovative pharmaceutical companies consider RDP and the enforcement of RDP rights. Article 9 of the Law of Ukraine “On Medicinal Products” (Drugs Law) grants 5 years (regardless of the validity of any patent that is relevant to the drug) of data exclusivity to innovative companies. The current wording of this Article reads that if a drug is authorized in Ukraine, it is prohibited during the 5 years starting from the registration date (regardless of the validity of any patent that is relevant to the drug) to use the registration information for the registration submission of another drug, except when the right to use such information is obtained in a due order. Considering the economic situation in Ukraine and the political will to open the way for the domestic generics industry, the draft law, “On Amendments to the Drugs Law,” aimed to implement changes to Article 9 of the Drugs Law has been introduced for public discussion. The draft law suggests reducing the term of registration application for a new drug from 5 to 3 years and indicates that such an exclusivity regime concerns only medicines containing a new active substance and registered in Ukraine as innovative ones based on a full registration dossier. It also stipulates that the registration of such a drug is possible after the 5 years since the state registration of medicines containing a new active substance. The possibility to extend the above 5‑year period to 6 years under certain circumstances is provided by the draft law as well. In accordance with the draft law, the time limits mentioned above apply only if the application for registration in Ukraine has been filed within 1 year from the date of the first registration of medicine containing a new active substance in any country. Compared with the European Directive (2004/27/ EC) providing for ‘8+2+1 principle’ (that is, a generic application for marketing authorization can be submitted after 8 years of market authorization of a reference product, but a generic drug can not be marketed until expiry of 10 or 11 years since the authorization of a reference drug), the proposed amendments to the Ukrainian legislation are not favorable for innovative companies. The share of generics in the Ukrainian pharmaceutical market is approximately 90–95 %
Timur Bondaryev Svitlana Postrygan
LEGISLATION and the presence of innovative drugs in Ukraine will be significantly reduced through adopting the abovementioned draft. Notwithstanding the above and contrary to the latest legislative initiatives, judicial practice in Ukraine proves positive examples of RDP rights enforcement by an innovative company. Similar to other countries, if an innovative company considers a generics marketing authorization to be contrary to the legislation in force, it has the right to challenge the decision of the authorization body before the respective court. A recent example is the proceedings of the regional commercial court of Ukraine (the Court) confirming the position of an innovative Danish company, which claimed for infringement of its RDP rights by the marketing authorization body (State Pharmaceutical Centre of Ukraine). During the course of market monitoring, the above innovative company detected a draft order of the Ministry of Healthcare of Ukraine on marketing authorization of its drug’s analogue with the same active substance (memantyn hydrochloride), which was authorized in 2006. The marketing authorization should have been done based on the abridged authorization procedure using the above innovative medicine as a referent one. It is stated in the Court decision that there are no analogues of the plaintiff’s medicine in Ukraine and the authorization of an analogue medicine would violate provision of the procedure of materials expertise submitted for market authorization providing for the innovative medicine to be used as a reference one it shall be well known and exist of the on the Ukrainian market for at least 10 years. The Court took into account Article 39 of TradeRelated Aspects of Intellectual Property Rights treaty stating that member states of this agreement shall protect confidential data submitted to them, Article 9 of the Drugs Law and provisions of some other Ukrainian regulatory acts. Significantly, during recent court proceedings the Court suspended the procedure of the generic’s marketing authorization until its final decision had been made. With its final decision, the Court ordered the State Pharmaceutical Centre of Ukraine to stop the marketing authorization of the analogue medicine.
Conclusion For more information Timur Bondaryev Managing Partner Arzinger
Svitlana Postrygan Associate Arzinger Svitlana.Postrygan@arzinger.ua
Despite the PDP Law’s imperfections, its adoption is a positive step towards improving Ukrainian legislation and harmonizing with European standards, provided that it is implemented with efficient procedures, transparently (that is, within clear time limits) and on the basis of objective and verifiable criteria. As things stand, unlike PDP Law, Ukrainian legislation on RDP is going to move the opposite way compared with that of the European Union, giving preferences to generics companies. The positive signal for innovative companies, however, is that existing judicial practice proves the enforcement of RDP.
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PENSION SCHEME DEFICITS
CAN INTELLECTUAL PROPERTY RIGHTS HELP? Intellectual property (IP) valuation expert Stuart Whitwell and IP solicitor Serena Tierney explain how IP such as brands, patents, copyright and contracts, as well as tangible assets such as property and shares, can be valued and used to fill pension scheme deficits.
ompany pension deficits are near an all time high. According to the Pension Capital Strategies report, November 2010, in the UK, the FTSE 100’s combined deficit is estimated to have hit £66 billion as at September 2010. Even the pharmaceutical sector is not immune and some major companies have significant deficits. Reducing these deficits is now a major issue at boardroom level. Scheme trustees will push for fully funded schemes as soon as possible, but company directors need to use their capital for the company’s operations and to get through the investment phase of each product’s life cycle and come out at the other end in good shape. Even if there is no final salary trustee breathing down the necks of the directors in that situation, there can be other powerful incentives to put a valuable asset into a company pension scheme: • Future-proofing capital gains tax liabilities. • Protection from insolvency risk. Pension schemes usually do not fall into the hands of a company’s bankers or liquidators if the company fails. • Corporation tax relief possibly using carried forward losses. One option is to use non-cash tangible assets, such as property, to fund the scheme. The company transfers the asset to a special purpose vehicle and then leases the asset back. The pension scheme has an interest in the same vehicle, which gives it a right to the future rental payments. The discounted net present value of those future payments is an asset of the pension scheme and the deficit is reduced by the value of the asset. Usually, there is a mechanism that provides that, in event of default, ownership and, therefore, the value of the asset(s) is transferred to the trustees. Increasingly, for many companies the majority of their assets are intangibles — most particularly intellectual property (IP). So the question arises of whether there is scope to use IP assets in a similar manner. In practice, most of the same considerations apply to IP assets as to tangible assets used in the day‑to‑day business of the company. So, if a company
r Pee ed w e i rev ticle ar
has valuable intellectual property rights (IPR) how could it (and when should it) consider putting those rights into a pension scheme? As with all things pensions-related, this is a heavily regulated area. To prevent a pension scheme being subject to Enron style “double jeopardy” when a company becomes insolvent, there are strict rules about the extent to which UK pension schemes can hold assets (such as IPR) that are used in the business of the sponsoring employer. The idea is that, if the company goes bust, the pension scheme should not be heavily exposed to that failure. In very broad summary, most pension schemes can only hold up to 5% of their assets in “employer‑related investments” (ERIs); and ERIs would include things such as shares issued by the company, property occupied by it and assets including IPR used in the company’s business. To avoid the 5% restriction applicable to most schemes, it is possible to structure investments of this kind through a special purpose vehicle (SPV), such as a Scottish limited partnership (LP) or a Dutch Stichting. These SPV structures do work and have been used for this purpose by companies such as Marks & Spencer and GKN. They are still new, but are becoming less exotic every month. There are some specific legal issues that arise when transferring IP in this manner and they are discussed below.
Recent examples of use of IP or other rights to reduce deficits
IP • Diageo — £500 million worth of maturing whisky stocks (July 2010). • GKN — assets including its trademark valued in total at £331 million (March 2010). • Interserve — 13 public finance investment (PFI) contracts worth £61.5 million (2009). Shares • ITV — shares in its digital channel operator, SDN (May 2010). • John Lewis — 29% share holding in online retailer Ocado (January 2010). Real property • Sainsbury — £750 million of property (May 2010). • Marks and Spencer — property totalling £1.1 billion (three tranches in 2007, 2008 and 2010). • John Lewis — £150 million of property (January 2010). • Whitbread — property worth £228 million (May 2010).
FINANCE are paid in one lump sum. This can be a considerable gain making the scheme immensely attractive. For some pension schemes, there may be an argument that their deficits are currently artificially high. Contributing assets through the SPV mechanism can be structured to allow for the income stream to be returned to the company in the future if the current level of contributions is no longer required to fund the scheme. This mitigates the risk that, if asset values return to something approaching previous levels, schemes might be over‑funded with too much cash having been contributed, which cannot then be retrieved for the company.
To the trustees
There are many benefits of such a solution both to the employer company and to the pension scheme trustees.
To the company It is currently unusual for a company to recognize the value of its IP on its balance sheet unless it has been acquired. Internally generated IP may be the company’s most significant asset, but its value may only be reflected in the general estimate of the value of goodwill. The value inherent in a company’s IP, therefore, may be either guessed at or ignored and it may well represent an underused capital asset. Using IP to reduce pension deficits is an effective way of using the capital value of that asset and of communicating its value to shareholders. A key benefit can be the immediate reduction in the company’s pension deficit, which in itself can be a significant burden on the company’s performance. This reduced deficit lowers the scheme’s Pension Protection Fund (PPF) levy payments, which the sponsoring company usually pays. Transferring IP to the scheme in lieu of cash lowers annual contributions as deficit payments are spread over a longer period, thereby improving cash flow. Enhanced cash flow provides increased funding for the company’s business operations with consequent financial benefits. It can have a beneficial effect on the share price as what was previously a significant liability is now being managed more effectively. Another key benefit is that there is an acceleration of corporation tax relief as future pension contributions
Pension scheme members and trustees benefit from the immediate reduction in the scheme’s deficit. The key benefit is the improved security position that the trustees have as a creditor of the sponsor. Whereas previously they might have been an unsecured creditor, this structure often gives trustees control of an asset they can sell if the company fails to meet its obligations. This, of course, is enhanced further if the asset increases in value. It is also a major benefit for the trustees, even if one not readily accounted for in cash terms, for the employer company to have more free cash to support its day‑to‑day operations.
All very well in theory. But, in practice, how does one go about selecting and valuing the IPR that would be used in setting up one of these advantageous structures? First, the IP must be separately identified. It may be a brand, technology or ‘content’ — typically audio‑visual or musical works. It can make sense to use a brand alone; for example, where the company’s name or brand is — or is one of — its major trading assets. Similarly, a specific piece of technology such as magnetic resonance imaging may be distinct from the rest of the company’s business. Often, though, it will be a product stream — such as a drug — where the bundle of IP rights that protect that income stream include not only the patent and supplementary protection certificate rights protecting the formulation itself, but the associated bundle of trade mark and trade dress rights that together drive the commercial revenue. The key consideration is to have an identifiable capital asset (or bundle of assets) and an associated revenue stream. Next, the IP must be valued. For some time now well‑established valuation methodologies have existed, both for brands — which are now enshrined in the ISO brand valuation standard — and for patents. There are an increasing number of experienced specialists in valuing IP for various
Use of a company’s IP rights may be an opportunity to put to work a capital asset that is currently undervalued (or even unvalued) on its balance sheet.
For more information
Stuart Whitwell Joint Managing Director Intangible Business Tel. + 44 207 089 9236 stuart.whitwell@ intangiblebusiness.com www.intangiblebusiness.com Serena Tierney Solicitor and consultant to the Intellectual Property team Wragge & Co. Tel. +44 207 864 9539 email@example.com www.wragge.com
types of corporate transaction whose valuations have proved to be robust when tested in a range of situations including by the courts and by tax authorities. Provided that the methodology used is one of the usual ones and its application is transparent (required for compliance with the ISO standard), pension scheme trustees may have confidence in it when reaching their investment decisions. An analysis of the potential for triggering an exit charge for capital gains tax purposes is also needed. It is usually possible, particularly in circumstances where the purpose of the transfer is to benefit the employer company’s pension scheme, to avoid triggering such a liability, but care must be taken in establishing the structure. The IP will then be transferred to the SPV to be used. Different structures will reflect differing corporate considerations, but at its most basic, this
will be to the vehicle in which the pension scheme trustees will invest. As the transferring company will need to use the IP rights in its business, it will take licences of those rights and pay in return a royalty. This provides the income stream that is fed through to provide the cash flows to the trustees, upon which they base the value of their interest in the SPV. The licences-back must be at an arm’s length value and these transactions often provide a useful opportunity for groups of companies to ensure that their licensing practice complies with the requirements of the transfer pricing tax regime. As mentioned above, special considerations do apply to the use of brands or trademarks in this way. As a matter of trademark law, only the registered owner exercises control of the use of the trademark. This requirement may be met in many ways, but if the transfer is taking place to (or via) a jurisdiction with an advantageous tax regime, it may be necessary to transfer those of the company’s personnel responsible for managing the brand to become tax‑resident in the same jurisdiction. This extreme step is usually unnecessary because most SPVs are established through a Scottish LP. The trustees are under an obligation to monitor the value of the assets of the scheme on an ongoing basis. Depending on the ‘headroom’ between the value of the trustees’ interest in the SPV and the value of the underlying IPR, it might be necessary to put in place policies to measure the impact on the value of the IP of the company’s regular trading activities, as well as any relevant external events occurring after the transfer. Finally, as with all corporate assets, it will be necessary that it is not subject to any prior restrictions on its use in this manner. If it is, then those restrictions will need to be removed before the transaction can proceed. Typically with IP assets, the problem tends to be a floating charge over all the company’s undertaking and assets. As the IP has not usually been accorded a specific value, but has been included without either party giving any thought to the value concerned, frequently no real difficulty arises in freeing it from that charge.
Use of a company’s IP rights may be an opportunity to put to work a capital asset that is currently undervalued (or even unvalued) on its balance sheet and which can relieve the company of the need to make cash contributions to fund its pension scheme deficit. It is now well established that the legal and regulatory obstacles are surmountable, safely and properly; and the financial, asset protection, tax and accounting benefits of doing so can be considerable.
WORLD AT WESTMINSTER
A NEW APPROACH FOR PUBLIC HEALTH
The Government’s publication of the Public Health White Paper marks a new chapter for England’s healthcare, as it outlines a new approach to improving the nation’s health and attempting to eradicate inequalities.
For more information Camilla Horwood Associate Director Portcullis Public Affairs Tel. +44 207 368 3100
he end of November saw the Department of Health publish its long anticipated proposals for a new approach to Public Health management in England ‘Healthy Lives, Healthy People.’ The White Paper is the Government’s response to the 2009 Marmot Review into health inequalities in England, which highlighted several challenges facing the population. The White Paper presents what Health Secretary Andrew Lansley has labeled a “radical new approach,” better equipped for the task of fighting the public health problems faced by the nation. It is hoped that this alternative approach “will empower local communities, enable professional freedoms and unleash new ideas based on evidence that works.” This represents a steadfast commitment to the Government’s mantra of localism and a focus on outcomes rather than processes. It also ties in with the Coalition’s Programme for Government, which suggested that freedom, fairness and responsibility were the keys to fixing what the Government called ‘broken Britain.’ By improving public health through self‑esteem, confidence and personal responsibility, the White Paper proposes that this new approach will “reach across and reach out,” addressing the root causes of poor health and well‑being. The White Paper also claims that the new approach will be responsive (by being led by local communities), resourced (through use of a ring‑fenced budgets), rigorous (by being professionally led and focused on evidence) and resilient (by strengthening and streamlining the current system). Whilst maintaining that the key to improved public health will be through local endeavour it is confirmed that central Government will retain a role in improving public health, specifically in intervention, when it is clear that a national programme would be more effective than various local alternatives. This will take the form of a ‘ladder of interventions’ adapted from the Nuffield Council’s Bioethics intervention ladder and influenced by the concept of “nudge” first devised by Chicago academics Richard Thaler and Cass Sunstein. Essentially, this means the government will guide people into healthier lifestyles by making healthier options the default option. The new body, Public Health England (based within the Department of Health), will streamline the current public health management system. It will have responsibility for nationally required health solutions and be responsible for funding, provision of evidence,
data and professional leadership for local services. Public Health England will also be able to instruct general practitioner (GP) commissioning consortia to commission services on its behalf. There will be ring-fenced funding from the National Health Service (NHS) budget for spending on public health. This is estimated to be about £4 billion initially. Public Health England will allocate local budgets, weighted for inequalities, to local authorities for improving the health and well‑being of local populations. There will also be a new health premium, funded from within the overall public health budget, to reward local authorities for progress against the proposed public health outcomes framework, which are yet to be determined. Directors of public health will in future be employed by local government and jointly appointed by the relevant local authority and Public Health England. They will be the strategic leaders for public health and health inequalities in communities. It is hoped that charities and voluntary organizations will act as “advocates for excluded groups and catalysts for action” feeding into the notion of responsibility that is key to the government’s philosophy and is most evident in its calls for a ‘Big Society.’ The Government has also called for businesses to take increased responsibility for the impact their practices have on people’s health and wellbeing, which will form part of the Government’s new Responsibility Deal. The core elements of the proposed system will be set out in the upcoming Health and Social Care Bill, which will have to go through parliamentary approval. Subject to this, the government has pledged to have the proposed system in place by April 2013. Further details of the arrangements needed to make this happen are expected to be set out in a series of planning letters to be released throughout 2011. Initial reaction to the proposals from health opinion formers has been mixed, with many responding positively to the direction of travel and the principles contained, however, expressing concern regarding the lack of detail and the potential for disparity across geographical locations. Co‑operation between relevant services and activities will be the key to making sure the Government’s plans for public health work, but more clarity is needed before people will feel confident that these reforms can provide the improvements to public health outcomes, which are so needed.
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To advertise here call +44 (0) 1372 364 125 or email firstname.lastname@example.org Intrinsically Safe Flame Sterilization...
A new white paper from INTEGRA describes the security features of modern safety Bunsen burners in relation to the inherent dangers of flame sterilization using alcohol burners, gas cookers or a traditional Bunsen burner connected to a gas distribution system. Safety Bunsen Burners were developed to ensure high safety by eliminating the risk of gas leaking and explosion inherent in using alcohol burners, gas cookers and traditional Bunsen burners. With this new generation of Safety Bunsen Burner the gas ignition is both immediate and safe as no lighter or matches are needed. Unlike traditional burners, the gas supply flows only if a gas flame is detected by the flame monitor. Advanced temperature protection, user-defined maximum burning time and alarm display features serve to protect both the operator and operating environment. A copy of this new white paper may be downloaded from http://www.integra-biosciences.com/pdf/sterilisation/Modern_Bunsen_burners.pdf.
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Porvair Sciences Announce 2010/2011 Microplate Catalogue… Many scientists around the world rely upon previous editions
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or interested in using microplates. For a copy of the new 2010 / 2011 Microplate Catalogue please visit www.porvairsciences.com/camera_promotion.php or contact +44-1372-824290
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Innovative results entry solution offers LIMS users greater flexibility to manage test sample data Innovative LIMS developer, Two Fold Software
Limited, is releasing new user-friendly software that enables the company’s intuitive Qualoupe LIMS user interface to display results parameters with a clarity and flexibility not available in other commercial LIMS. Qualoupe has been designed to provide LIMS users with greater flexibility when entering test sample results. Results entry in most commercial LIMS is designed to allow input of basic types of results such as numeric value, calculated value and text but does not take into account other types of data that could be recorded as valid results. Qualoupe enables the following types of results parameters to be used to record test sample data: Numeric Free Text Calculated Value Date Colour Time Upload File Date and Time Pick List T: +44 (0) 845 8055182 E: email@example.com W: www.twofold-software.com
SMP40 melting point – the automatic choice Stuart’s SMP40 melting point apparatus speeds up purity and identification testing by offering automatic, walk-away operation. The unit is available with optional full installation qualification and operation qualification (IQ/OQ) documentation, for regulated laboratories needing to comply with cGMP audit requirements. The SMP40 uses digital video imaging technology to detect and capture accurately the melting point of up to three samples simultaneously. The melt process can be viewed in real time or retrospectively on the full colour 5.7” VGA screen. Maximum footprint flexibility is ensured by the split design so, for example, the sample side of the apparatus can be placed at the back of the bench or even in a fume cupboard, while the control side detects whether it is being used upright or on its side and adjusts the screen orientation accordingly. Rob Skehens, Marketing Director, Bibby Scientific, said, ‘The SMP40’s intuitive touchscreen interface and innovative split design concept provide excellent ease of use, as demonstrated in a series of short videos at www.thebestmeltingpoint.com
To advertise here call +44 (0) 1372 364 125 or email firstname.lastname@example.org Automated Filling of 2-Compartment Petri Dishes Using a MEDIAJET vario Automatic Media Preparation
System from INTEGRA - leading Danish healthcare provider - Herlev Hospital has drastically increased the efficiency and reliability of preparing its 2-compartment agar plates. Anette Banke, Senior Pharmaconomist at Herlev Hospital commented “We have had our MEDIAJET vario with biplate option up and running for two years filling over 70,000 biplates annually. We also use
Telstar Puretech, Complete Solutions For Pharmaceutical Water Production
Telstar Group and Puretech Process Systems have joined forces to create an alliance that provides the Pharmaceutical and biotechnological industry with a new worldwide source for Turnkey Pharmaceutical Water Systems. In this field, Telstar Puretech becomes one of the few key global pharmaceutical partners specialized in GMP Water Systems and Pure Steam, with total in-house capability from equipment manufacture to complete turnkey solutions. Telstar Group is today one of the main international company with the ability to offer
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and it is by far the most reliable instrument we have ever had for Petri dish filling. You could
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providing turnkey solutions. www.telstar.eu - www.puretech.uk.com – More information: email@example.com
One Green Tottle…
Elfab awarded US patent for Opti-Gard SoLo rupture disc
Measom Freer have added a brand new bottle shape to their stock bottles
British pressure relief specialist Elfab (www.elfab.com) has been
range. The ‘Fosse’ range will launch
awarded a US patent for its reverse-acting rupture disc Opti-
with both 125 and 250ml options and
Gard SoLo. Opti-Gard SoLo is now both a registered trademark,
is manufactured in house from natural MDPE, other polythenes and clarified & natural polypropylene with colours to order. The bottles come with their own flip top closure giving them a unique look to help with product identity and shelf prominence. The tottle option, meaning it can stand on its cap, makes this versatile bottle ideal for the laboratory and pharmaceutical markets where every drop counts! Screen printing in one or several colours is also available to complete the product. With a minimum of 10% PCR (post production regrind) used throughout their stock bottle ranges, Measom Freer are tackling the recycling issue head on. In fact they are so committed to
and has been granted patents, in the UK, EU and US. The latest addition to Elfabs industry-leading Opti-Gard range, Opti-Gard SoLo was developed specifically for lowpressure applications from two psig. Featuring a 95 per cent operating-to-burst-pressure ratio and a performance tolerance of just three per cent, Opti-Gard SoLo offers the highest performance characteristics available for liquid, gas or vapour applications. Tested to over 100,000 cycles, SoLo provides excellent cycle life and leak tightness. The addition of SoLo to Elfabs existing Opti-Gard range gives customers the opportunity of rationalising stock holdings by a typical 65 per cent.
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detectors, Flo-Tel is fail-safe and operates only when a disc has ruptured, eliminating both false alarms and downtime in the event of a disc functioning. www.elfab.com
IDT enters exclusive agreement with 454 Life Sciences to provide custom primers for GS FLX Titanium Chemistry
Finding it difficult to source talented senior Pharmaceutical candidates? Look no further than Pharma’s Via Recruit service. We can promote your vacancies to a target sector of 100,000 qualified and experienced Pharmaceutical professionals. For more information contact: Paloumi Bhattacharya E: email@example.com, T: +44 (0) 1372 364 124
Integrated DNA Technologies (IDT), the custom biology company, has signed an exclusive agreement with 454 Life Sciences, a Roche company, to provide researchers with custom primers for the GS FLX Titanium Chemistry, used on the company’s GS FLX System and GS Junior System. Available as FusionPrimers or Rapid Library MID (Molecular Identification) Adaptor Oligos, these products are used for amplicon or shotgun sequencing. IDT’s unique design software enables users to create specific primers to target individual or multiple exons from one or more genes. Through the use of HPLC-purification techniques, IDT significantly reduces the potential occurrence of mis-priming and identity is guaranteed with 100% mass spectrometry quality control. The Standard FusionPrimers, GS FLX Titanium FusionPrimers and GS FLX Titanium RapidLibrary MID Adaptor Oligos are all available to order via IDT’s free online suite of design tools, SciTools. For further information, please visit www.idtdna.com.
QUALITY MANAGEMENT LET’S MAKE IT SIMPLER
Simplification of the supply chain will be key to ensuring future compliance and quality.
magine that it is your job to sign the form that releases the product to market. You’ve checked that everything is in place — the batch records, the signatures, the test results — so there’s no reason why you cannot sign. The sales people need the revenue, the pharmacists need the inventory and the patients need the drugs. The supply chain is secure, compliant and safe. So sign. Are you sure? Do you really have sufficient confidence in the quality of production throughout the whole supply chain that you can put your signature on the release form? Since globalization has become a feature of the industry, maintaining that oversight has become increasingly challenging. Between 2001 and 2007 the number of manufacturers in India increased by a factor of 25, and in China by a factor of seven. It will almost certainly be true that some of your supply chain will exist in countries with less well‑developed regulatory systems than, for example, Europe or the US. How do you know what’s really going on in your suppliers, or their suppliers, or theirs? Your company probably won’t have audited them all — you won’t have enough auditors in‑house, and renting that kind of capability is expensive. Of course you’ll have Quality Assurance Agreements (QAAs) in place for your third‑party contractors, and those that you have negotiated recently will be good. But what about the older ones? Do they ensure total transparency? What about your raw material supplier network? Do your suppliers (and theirs, and theirs etc.) fully disclose every Out of Specification (OOS) measurement, every deviation, every change? How do you know? Are you still going to sign? And we haven’t even considered counterfeiting or theft yet! With supply chains spread out akin to old‑fashioned caravans strung along an ancient trade route, the opportunity for modern day piracy is extensive. Is the next
For more information
Melamine disaster going to erupt just as soon as the ink is dry on your signature? With fears such as these it’s a wonder any drug gets released to market at all. But of course, all of these challenges are well known, and pharmaceutical companies and regulators work hard to minimize them. A risk‑based approach to auditing and clear accountability for ownership of quality along specific supply chains means that a company can be more certain that both quality and compliance are under control. New regulations are emerging that impact cGMP, particularly with regard to contract manufacturing. FDA set priorities for the human drug cGMP programme in 2010, focusing on knowing the whole supply chain, up to and including original manufacturers, and enforcing greater packaging and security features and test requirements, all designed to ensure that when that release form is signed it is done so knowing that all is well. Technology, particularly integrated tracking systems, tamper‑proofing and radio frequency identification (RFID), will help ensure supply chain integrity, as will an increased focus on auditing, checking and testing. But this does seem to be a little more of the same only more complicated than before. Is there another way? Specifically, what can be learnt from other industries with similar global supply chains and high quality products? The automotive sector makes cars of mind‑boggling complexity and with demands on quality of the highest order that are designed to protect its end users. (If you doubt the potentially lethal effect of using a car with a quality imperfection try driving one with no breaks. No, don’t!) How has this industry overcome comparable challenges (it is not regulation‑free either, by the way!)? The key principle that it has deployed is that of simplification. In contrast to pharmaceuticals it has moved to fewer and fewer suppliers, thereby simplifying its supply chain and quality management, even within a globalized framework. It may well be the case that the regulations will limit how far life science companies can go down this path, but one thing is for certain; supply chain simplification will have to be part of the industry’s quality management approach if it is to ensure compliance and quality in the future. Nostrapharmus predicts that ‘in 10 years’ time there will be a reduction in the number of pharmaceutical suppliers, along with geographical consolidation, to simplify and enhance quality management. Without this the risks, and costs, become unsustainable.’ In the meantime, there’s a form to sign...
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