Pharma July/August 12 by Paul Howells

Pharma Magazine

July/august 2012 ISSN 1746-174X

R&D

Volume 8 Number 4

Anaemia Drugs

Sample Storage

Increasing Productivity

Tabletting

The global magazine for the pharmaceutical and biopharmaceutical industry

Challenges and Solutions

July/August 2012 Volume 8 Number 4

COMMUNICATIONS

ISSN 1746-174X

DRUGDELIVERY Trends and Techniques

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Contents FOCUS TOPICS Tabletting

Contributing Companies: Gebrüder Lödige Maschinenbau,

Powder Systems Ltd, Quay Pharmaceuticals Ltd and Fette Compacting

The authors present a variety of technologies that help to overcome some of the challenges facing today’s tablet manufacturers.

Drug Delivery Contributing Companies: Molecular Profiles, Aptar Pharma, epr,

Astech Projects, Stable Micro Systems and Adhesives Research

Industry experts discuss a variety of innovations and trends shaping the drug delivery sector.

FEATURES

Supply Chain: Making Money out of Pharma Supply Chains

Richard Powell — Crimson & Co.

If the challenges facing the pharma industry are similar to those found in other industries, then segmentation may be the way forward.

Sample Storage: The Future of Sample Management — Part I

Wendy Gaisford — TTP Labtech

Using automated sample storage facilities and automated laboratory management processes to increase productivity and sample throughput.

Nutraceuticals: ‘Designer Foods’ to Grow Through M&A Activity

Leonard Fuld - Fuld & Company

Which industry — food or pharma — and which companies are best‑positioned to win the Battle for Designer Foods?

R&D: A Breath of Fresh Air for Anemia Drugs

Chris Schofield — University of Oxford

The author describes a new field of research that could lead to novel drug targets for diabetes and heart disease.

Clinical Trials: The Role of Mobile Technology in Value-Based Healthcare

Mark Brincat and Hannah O’Gorman — Exco InTouch

As the healthcare industry shifts into a new phase of value‑based healthcare, mobile technology will play a key role in facilitating this transition.

Generics: Is the Greek Healthcare System on the Right Track?

Ioannis I. Valvis — NovoSynth Pharmaceuticals LLC

Encouraging the use of generic and OTC drugs could trim billions off Greece’s pharmaceutical spending. JULY/AUGUST 2012

REGULAR Comment: It’s Life Sciences Jim, but not as we Know it

Paul Gershlick — Matthew Arnold & Baldwin LLP

If less money is needed on patented blockbuster drugs, what will come in their place? pharma-mag.com

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STAFF

Contributors Editor Corrine Lawrence +44 (0) 771 517 7767 corrinelawrence@viacommsgroup.com

Sales Steve Robinson +44 (0) 1372 364 127 steverobinson@viacommsgroup.com

Editorial Director Kevin Robinson +44 (0) 1392 202 591 kevinrobinson@viacommsgroup.com

Joshua Nathan +44 (0) 1372 364 124 joshuanathan@viacommsgroup.com

Art Director/Production Paul Howells Tel. +44 (0) 1372 364 126 paulhowells@viacommsgroup.com

Financial Officer Cherelle Saunders +44 (0) 1372 364 123 cherellesaunders@viacommsgroup.com

Content/Marketing Manager Claire Day Tel. +44 (0) 1372 364 129 claireday@viacommsgroup.com

General Manager Miranda Docherty +44 (0) 1372 364 125 mirandadocherty@viacommsgroup.com

Editorial Advisory Board

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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Patrick Crowley Vice President Product Line Extensions GSK (US) Enric Jo Plant Director Reig Jofre Group Maik W. Jornitz Senior Vice President Global Product Management, Bioprocess Sartorius North America Inc.

Alan Lahaise Key Account Executive Patheon

Ray Rowe Chief Scientist/Prof of Industrial Pharmaceutics Intelligensys/Uni of Bradford

Carlos Lopez Relationship Director Healthcare & Pharmaceuticals Lloyds TSB Corporate Markets

Harald Stahl Senior Pharmaceutical Technologist GEA Pharma Systems Kurt Speckhals Gino Martini Senior Director, Director, Strategic Technologies Supply Chain Pfizer Inc. GSK (UK) Jim McKiernan Chief Executive Officer McKiernan Associates GmbH

Geoff Tovey Visiting Professor Dept of Pharmacy King’s College

Maireadh Pedersen Head of Business Development Quay Pharma

Wes Wheeler President, WPWheeler LLC

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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 © 2012, Via Communications 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).

JULY/AUGUST 2012

COMMENT

IT’S LIFE SCIENCES, JIM, BUT NOT AS WE KNOW IT

Big Pharma dominates today’s pharmaceutical industry in the developed world; for years, it has designed blockbuster drugs, which have bankrolled the next stage of R&D and have, in turn, led to further blockbuster drugs. And so the cycle continues … that was, until now.

e are currently in the early stages of the patent cliff — the period between 2011 and 2016 when many of Big Pharma’s blockbuster drugs come off patent and are opened up to competition from much cheaper generics. Now, however, there is not the product line coming through to replace them to keep the cycle going. It is becoming more costly to bring drugs to market and many are failing during late-stage clinical trials. There are ‘me too’ products, but these are not significantly differentiated from the drugs already available. Customers are becoming more discerning — looking for better value — and end patients are becoming less deferential. Other social changes shaping the industry include a change towards products and services aimed at healthier lifestyles and a more diverse set of customers with different needs — both within a territory and across borders in different regions with varying cultures. Meanwhile, the rise and impact of technology on the sector are apparent; for example, health apps and telemedicine. The change in landscape is so dramatic that Big Pharma, because of its size, may struggle to quickly and effectively adapt with the change. This is not to say that there will not be a place for Big Pharma, but it will need to work harder to adapt to find a place in the new environment. We recently held a seminar at which Professor Brian Smith presented “The Future of Pharma” (based on his book). 1,2 Drawing upon his extensive industry knowledge, as well as great knowledge of economics and evolutionary theory, Prof Smith talked about a new and greatly changed environment during the next few years. The account he gave was challenging, because imagining and accepting such an altered picture can be difficult. To help, he asked delegates to consider the industry 150 years ago, which looked completely different to today. The same applies now when we consider how the pharmaceutical industry and environment will look in the future. JULY/AUGUST 2012

According to Professor Smith, the future will involve fewer, but much bigger generics companies that will be able to produce drugs even cheaper than they do today; successful pockets of innovators; consumer goods products that focus on functional foods/nutraceuticals, and trusted suppliers for certain branded drugs that consumers would be willing to pay a bit more than for the generics. We can also expect to see service companies managing people’s health in a more personalized and sophisticated way. He clearly identifies several habitats in which suppliers will need to live. The key is not to consider what today’s suppliers will be doing tomorrow, but what will tomorrow’s environment look like and who will populate it. Can today’s players adapt quickly enough to survive and evolve? For people operating in a conservative industry who prefer to see small peripheral changes rather than radical change, Professor Smith’s book is not easy reading. Yet, if people do not adapt quickly enough, other entrepreneurs or newer players from the emerging markets will march into the new environment. Undoubtedly, the one-hat-fits-all approach to treatment, which may have once worked for society, has already started to change. People want more personalized healthcare in a way that helps and suits their own bodies and lifestyles … and the technology is rapidly developing to enable that. Already, there is demand for specials, catering for patients’ personal needs, and orphan drugs is a growing area as more resource is used to treat severe conditions that affect smaller sections of the population. I firmly believe that health spending will continue to rise, to enable the continuity of life and quality of life; but that does not mean that the nature of the spending will stay the same. If less money is needed on patented blockbuster drugs, what will come in their place? Something efficiently produced, specialized and personalized. It will still be “life (sciences), Jim, but not as we know it.”

Paul Gershlick

References

1. B. Smith, “The Future of Pharma, Professor Brian Smith,” Seminar held by Matthew Arnold & Baldwin LLP in conjunction with Watford Chamber of Commerce (23 January 2012). 2. B.D. Smith, The Future of Pharma: Evolutionary Threats and Opportunities (Gower, UK, 2011).

For more information

Paul Gershlick Partner Head of Pharmaceuticals and Life Sciences Sector Matthew Arnold & Baldwin LLP www.mablaw.com

pharma-mag.com

TABLETTING

A COATING SYSTEM FOR THE MANUFACTURE OF HORMONE PREPARATIONS

A case study describing the successful integration of a coating machine from Gebrüder Lödige Maschinenbau (GLM) into a high-containment system for the production of preparations containing sexual hormones at Pharma Münster GmbH.

harmaceutical production worldwide is subject to the most stringent safety, purity and reproducibility requirements, particularly if the substances involved are highly potent. In such cases high-containment systems must be used to encapsulate complete processes to protect people and products. Coating systems must also be integrated into these enclosed systems as part of the manufacturing process. Haupt Pharma Münster GmbH sought such a solution for the production of its preparations containing sex hormones — and was delivered by GLM. The result was a versatile coater, which achieves optimum results and is perfectly integrated into the containment system. Haupt Pharma Group is one of the largest European companies for pharmaceutical order processing and manufacture. About 2000 employees manufacture products for leading pharmaceutical companies. At the Münster plant, with a workforce of more than 230, the company’s specialties include developing and manufacturing products containing sex hormones in the form of film- and sugar‑coated tablets.

Special Containment Requirements

The handling of sexual hormones as highly potent substances requires special equipment and machines to protect employees, the environment and the product. Haupt Pharma, therefore, set up a new production department to manufacture film- and sugar-coated tablets using state-of-the-art technology.

pharma-mag.com

The new system consistently follows the closed- and high-containment principle to prevent contamination of the machine surroundings. The company thus set out in search of a manufacturer who could provide a coating solution that would fit seamlessly into this concept. The technical requirements were accordingly complex: substances with the Occupational Exposure Band (OEB) Level 4 had to be safely processed in the system, which requires system delimitation by barriers, according to the conditions laid down by BG Chemie. Furthermore, the coating system had to comply with FDA’s 21 CFR Part 11 — a prerequisite for production for the US market. In addition, the solution must satisfy the following criteria: • Suitability for film and sugar coating of very small tablets. • Batch sizes between 120 kg (starting weight) and 600 kg (final weight) for the two processes. • Compact, space-saving design, as the containment zone must be used as effectively as possible. • Energy-efficient and media saving. • Automatic production and cleaning. • Coater with partially perforated drum. On the basis of these specifications and the corresponding tests the decision was taken in favour of the Type LHC 190 coater with a partially perforated drum from GLM. In addition to compact design, the horizontal coating drum with four exchangeable perforations is the main feature of this coater type. Only approximately 25% of the cylindrical drum section is perforated; the coating drum itself is closed to the outside, thereby ensuring the coater complies with the containment principle. In the LHC 190, the prepared (the dehumidified, heated and filtered) air is introduced through an inlet in the coating drum and suctioned off by the exhaust fan through the perforations rotating beneath the product and four waste gas ducts. A rotary disc valve controls this continuous process. The maximum supply air volume is limited as consequence of this JULY/AUGUST 2012

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TABLETTING design and the resulting pressure loss. The utilization rate of the applied energy, however, is very high, as there is little waste heat in the enclosed coating drum, and the entire airflow is extracted through the product bed. Energy recovery by heat exchanger between intake and exhaust air further increases the energy efficiency of the system.

Special Adjustment to Processes and Products

Horst Spittka

Haupt Pharma required a solution that prevented the agglutination of small and thus light tablet cores in sugar-coating processes. These tend to stick to the drum wall, mixing elements and each other. The reason for this is their low dead weight, which is often unable to resist the adhesive forces that occur because of the sugar suspension on the surface of the tablet. Various measures prevent this undesirable effect: only one quarter of the coating drum wall surface is perforated (the remainder is smooth, making it ideally suited to sugar-coating processes); and special ramp-shaped mixing elements prevent the cores from sticking to the front and rear side. To achieve a better predistribution of sugar suspensions on the cores, single-substance nozzles replace the customary feed rakes, which at pressures of 6–8 bar ensure a significantly better predistribution of the suspension. By avoiding overconcentration of sugar-coating suspension on the wetted tablets, the mixing phase in sugar-coating and thus the batch times are significantly reduced. A further effect of this improved addition of liquid is avoidance of the formation of so-called ‘twins.’ As well as the specially shaped mixing elements, the nozzle arm was modified to achieve the required filling level variability. With this modification, the nozzle clearance from the tablets can be set to approximately 200 mm, even with extremely low filling levels of only 15% of the drum volume, particular for film-coating processes. Because the outflow angle of the tablets changes during the process, the nozzle angle of the spray arm can be adjusted from the outside using a gear unit.

Containment Measures Convincingly Implemented For more information

Horst Spittka Sales — Life Science Technology Gebrüder Lödige Maschinenbau GmbH Tel. +49 5251 309 208 Fax +49 5251 309 123 spittka@loedige.de www.loedige.de

pharma-mag.com

Several modifications of the coater were necessary to enable perfect integration into the high containment system. With the exception of the front door, the coating drum is securely enclosed; only the seals had to be specially designed for the high-containment level OEB 4. The coater is loaded with tablets from barrels through a containment flap and a feeder. This tablet feeder projects into the coater and is drawn after

loading into an endless plastic pouch and cleaned separately. After feeding, the dust is removed from the inside front part of the coater by a special compressed air blower and the particles resulting from the negative pressure during the entire process are suctioned off. This pneumatic dedusting can be repeated as often as necessary depending on the dust accumulation in the front zone. It is repeated prior to emptying the coater to avoid carrying out product dust upon discharge. As the coated tablets no longer release critical dusts, they can be discharged without containment measures. For this purpose, the mixing elements are modified so that with reverse rotation of the coating drum the tablets are conveyed to the front discharge and from there to a container placed in front of the coater. During the coating process, as during feeding and discharge, there is a vacuum in the coating drum to prevent the emission of product dust and thus contamination of the operating personnel or the surroundings. A filter bypass for the exhaust air filter was dispensed with for containment reasons. Emission of product dust is thus impossible. The cleaning water, however, must be more or less emptied from the system prior to drying to avoid overly moist exhaust air, which could clog the waste gas filter. To rule out an impairment of the filter function, a largely moisture-resistant exhaust air filter system was selected. The dust is removed from the dust collector under safe-change conditions. The coater is cleaned via various cleaning nozzles using a number of detergents. To avoid disturbing production, this process runs automatically overnight. Only a few parts, for example, the tablet feeder, are carried to a special washroom — sealed in a plastic hose — for cleaning.

Summary

Before it can be used to produce for the US market, the system must satisfy FDA’s 12 CFR Part 11, which applies to the system software. The system control on the basis of a SPS-PC combination fully conforms to the specifications of the US authority. It enables automatic film- and sugar-coating processes, as well as cleaning processes. The special functions of the system resulting from the containment application, such as the blow-off function, were additionally implemented. Following the successful commissioning of the coater, it fulfils all expectations regarding quality, energy efficiency and versatility. It has also been shown that with the modified LHC 190 the OEB 4 is constantly upheld. The customized solution thus exceeds the originally defined requirements. JULY/AUGUST 2012

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TABLETTING

RETROFIT SOLUTION TO AN EXPENSIVE CONUNDRUM

Reliable and efficient high‑containment systems continue to challenge the tabletting industry. This article considers the reasons for this and the solutions to help overcome some of these problems.

Figure 1: High-containment capsule filling retrofit.

apsule filling machines and tablet presses are expensive long‑term investments. The conundrum for manufacturing is how to address increased safety requirements from ever increasing drug potency. With current technology, operator exposure levels (OELs) of 10‑50 nanogram/m3 8h time weighted average (TWA) can be readily achieved and should present a reliable outcome. During the course of many years, however, some key failure modes have been observed including • The inability to achieve a pass on OEL measurement during validation. • Equipment that is too difficult to work inducing operators to take a shortcut. • Rapid system deterioration after production use. • Problems with the production rate and quality. • Dust explosion. • Lack of budget where there is a need to manufacture high potency compounds without full recognition of the costs. Considering the main influences of the containment failures helps to provide more positive and controlled outcomes.

OEL Definition and Testing

The main priority is operator safety and drug quality. When developing drugs, the risks at the early stages are not always fully understood. An ultra‑conservative philosophy has to be applied until we have established sufficient data for the product. It is not untypical for a research level of nanogram/m3 to be relaxed to 1 µg by the production stage. A common method to establish OEL performance is to use a placebo such as micronized lactose with a d50 at approximately 20 µg for which accredited laboratories can detect at 2 ng. ISPE guidelines are a useful directive to follow when measuring OEL. It also takes into account background prior to testing and potential weak points around the equipment in addition

10 pharma-mag.com

to passing traffic. It will also allow comparable performance.

So where does the Unreliability come from?

When you buy a dryer, mill system, capsule filling machine or tablet press, you expect it to work. A containment provider has to truly understand all relevant manufacturing processes to ensure practical and safe solutions. If you lack confidence in their understanding, you will have problems. Replacing existing machines with new high‑containment versions is usually unviable and sometimes a quicker solution is required if a new production demand needs to be considered. A containment provider has to be able to efficiently implement a bespoke retrofit system, designed to suit a specific model of tablet press or capsule filling machine.

Project Implementation Approach

A budget cost and definition are formed based on drawings and discussions on user requirements. The following also need to be considered: • Is the feed system contained and what are the alternatives? • Is the dedusting product collection system contained and what methods could be used if required? • How to access the machine safely and operate in a contained manner. • Do we need to utilize a contained internal vacuum cleaning system?

Front End Design Study

A design study is thoroughly done on the existing machine using technologies such as 3D modeling and mock‑up to assess all process requirements and ergonomics. The following points provide an opportunity for additional discussions and agreements, prior to a final cost proposal for project implementation: • Direct access to the installed machine is necessary to undertake accurate site measurements, as the JULY/AUGUST 2012

TABLETTING design detail will be based on these measurements. • Retrofit designs must be workable by an operator. All operations should be mocked‑up using full‑scale ergonomic models, when you are unfamiliar with a design. • Incorporate oval gloveports for easier operation and do not exceed 550 mm (front to back) for single‑sided ridged window access. • Containment provider should consider modification of process equipment where necessary.

Project Implementation

Safety measures are critical when reviewing the containment solution to avoid dust explosion. Most organic dust will not ignite below 8 9% oxygen. Aluminium alloys, for example, will ignite at 2–3% oxygen. Tabletting systems involve numerous machineries, which can put operators at risk of injury. The containment solution needs to incorporate safety switches to avoid windows being opened or hands being placed inside the gloves whilst the machine is operating. Glove guards and safety switches are installed to allow safety emergency shutdown of the tablet press if someone attempts to tabletting-ad-030712 half page cmyk.pdf 1 03/07/2012 13:41:57 access the inside of the containment system.

A full documentation package is provided for review prior to commencing final manufacture. The ideal situation is to ship the machine to a key service centre for final assembly and testing. Alternatively, it is possible to install on‑site; this does, however, create larger costs and take more time. Documentation packages and services up to IQ/OQ would normally be included. Figure 1 is an example of a recent retrofit containment project on a Bosch capsule‑filling machine, which was completed for a US drug manufacturer. The design includes the gloves being held in special gloveport retainers with integral safety interlocked guards. The client required containment to be retrofitted onto their existing capsule filling machine and an OEL <1 µg/ m3. A feasibility and mock‑up study on their Bosch 400 was done. The existing doors were removed and new swing‑out doors retrofitted with safety interlocks. Close detail was paid to the operational and maintenance access of the machine. If you are unfamiliar with high containment, take some benchmark visits to other manufacturers. Spending time with your supplier early in the planning stage and reviewing the design alongside a draft URS are good investments, helping you to avoid surprise further down the line and increase the success of your project.

Maurice Pitcher

For more information

Maurice Pitcher CEO Powder Systems Ltd (PSL) Tel. +44 151 448 7700 sales@powdersystems.com www.powdersystems.com

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TABLETTING

USING COMPACTION SIMULATION TO AVOID PROBLEMS DURING PROCESS TRANSFER BETWEEN DIFFERENT TABLE PRESSES

Compaction simulation can be used to identify the way in which powders deform and consolidate to form tablets, and to solve problems experienced during the transfer of tablet production between different presses.

T Figure 1: Elastic and plastic deformation.

12 pharma-mag.com

he transfer of tablet production between different types of press, for example, during scale-up or transfer of production between manufacturing sites, often leads to problems with tablet quality. These can include poor mechanical strength, capping and lamination and arise because of differences in the way in which tablet presses apply force during the compression process. Important variables include the amount of force applied during precompression (if used) and main compression, and the amount of time the compression force is applied (dwell time). Dwell time decreases with increasing press speed, and a common problem observed during scale-up is the deterioration in tablet quality as a result of the process being run faster, with insufficient time allowed for tablet consolidation. During compression, a powder’s behaviour depends on its tendency to reduce in volume under load (compressibility). The powder particles can deform elastically, returning to their original shape after the compression force is removed, or plastically, in which case the deformation is permanent (Figure 1). Powders that undergo elastic deformation do not form cohesive tablets, whereas those exhibiting plastic deformation do. Dwell time is a particularly important variable in tabletting processes where plasticity is the dominant powder characteristic. This is because enough time must be allowed for the powder particles to undergo plastic deformation so that a cohesive tablet is formed. In

addition to elastic and plastic modes of deformation, powder particles may also deform by brittle fracture, which increases surface area and improves the degree of inter-particle bonding.

Compaction Simulation

Compaction simulators can be programmed to mimic the behaviour of different types of production machines. They can apply compression forces accurately for periods of time characteristic of dwell times at different press speeds. By correlating tablet properties such as hardness and disintegration time with processing parameters, including compression force and dwell time, it is possible to determine the optimum processing parameters for a particular formulation on a specific tablet press and the main deformation mode.

Case Study 1

A manufacturer of 200 mg ferrous sulfate tablets, used in the treatment of anaemia, decided to improve the control of tablet manufacture by transferring production from a manually-controlled tablet press (48,000 tablets/h) to an automatic machine (129,000 tablets/h). Initial attempts to transfer production to the new press resulted in tablets of lower hardness that would not be robust enough for subsequent coating. The direct compression formulation contained ferrous sulfate (62.5% w/w), starch, spray-dried glucose, lactose, microcrystalline cellulose, stearic acid and magnesium stearate. Compaction properties were assessed using a Stylcam 100 compaction simulator (Medelpharm SAS, Neyron, France) set up to emulate the two tablet press types. Parameters evaluated included main compression force and press speed, using 8.2 mm normal concave tooling. With the compaction simulator set up to emulate the original press, tablet hardness decreased as press speed increased (and dwell time decreased). Tablet hardness specifications (55–87 N) were met for JULY/AUGUST 2012

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TABLETTING press speeds of 20 rpm, 30 rpm and 40 rpm using a main compression force of 20 kN. Under conditions designed to emulate the new press, tablet hardness values were consistently lower than those produced using an equivalent compression force with an emulation programme characteristic of the original press. This is because dwell time on the new press was 60% that of the original machine at the same rotational speed. The dependence of tablet hardness on dwell time suggests that the tablet formulation undergoes plastic deformation during compression. The relationship between dwell time and tablet hardness for different compression force settings is shown in Figure 2 (original press) and Figure 3 (new press). The study showed that the poor tablet hardness observed on transfer of the production process to the new tablet press was principally a result of reduction in dwell time, which did not allow long enough for plastic deformation to occur, resulting in poorlyâ&#x20AC;&#x2018;consolidated tablets.

Figure 2: Relationship between dwell time, compression force and tablet hardness for the original tablet press.

Figure 3: Relationship between dwell time, compression force and tablet hardness for the new tablet press.

Case Study 2

Mark Powell

For more information

Dr Mark Powell Scientific Manager Quay Pharmaceuticals Ltd Tel. +44 151 203 9810 m.powell@quaypharma.com enquiries@quaypharma.com www.quaypharma.com

14 pharma-mag.com

Paracetamol (acetaminophen) is a well-known analgesic and antipyretic. The polymorphic form of paracetamol commonly used in pharmaceutical manufacturing (Form I) is relatively stiff, which results in poor compression properties. This study was conducted to address an increase in disintegration time observed following the transfer of tablet manufacture to a different tablet press. This resulted in failure to meet specifications for batch release. The formulation, which was prepared by wet granulation, included paracetamol (38% w/w), maize starch, polyvinylpyrrolidone and magnesium stearate. Compaction properties were assessed using a Stylcam 100 compaction simulator set up to emulate the properties of two tablet press types. The density of the final blend was determined using helium pycnometry, and this value was used to calculate blend compaction properties by Heckel analysis. Strain rate sensitivity data were derived from mean yield stresses (the stress at which plastic deformation begins) at different compression rates. Strain rate sensitivity is a measure of the extent to which speed of compression influences the deformation and consolidation process. Materials that undergo plastic deformation have high strain rate sensitivities. The formulation was compressed on the compaction simulator using a range of speeds and precompression/main compression settings; the hardness values and disintegration times of the resulting tablets were measured. Greater main compression forces resulted in higher tablet hardness values (Figure 4) and longer disintegration times. Strain rate sensitivity was low (0.61%) which, coupled with high values for mean yield pressure suggested that the formulation underwent deformation mainly by brittle fracture.

Figure 4: Graph showing the correlation between main compression force and paracetamol tablet hardness.

This is consistent with the dominant influence of main compression force on the disintegration and hardness properties of the tablets. A reduction in main compression force resulted in robust tablets that met specification for disintegration.

Conclusion

Compaction simulation provides valuable information about the dominant mode of tablet consolidation and the compression conditions required to make good tablets. Where simulation studies are undertaken before the transfer of tablet manufacture to a different press, the conditions necessary for successful tablet production may be established in advance, thus reducing the time required for successful transfer. JULY/AUGUST 2012

INCREASE PRoduCtIoN WItH MultI-tIP toolINg

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TABLETTING

SMALL BATCHES, HUGE CHALLENGES NEW TABLET PRESS GENERATION

The development in the pharmerging markets, as well as the trend towards smaller batches and increasing product diversity pose new challenges to pharmaceutical companies. As more than 50% of all drugs are still administered in tablet form, these companies need to produce more tablets more flexibly, faster and more cost‑effectively to hold their own against international competitors. The FE product family is Fette Compacting’s answer to these varied challenges.

n the emerging economic regions in Asia and South America, economic standard is not the only thing rapidly approaching the western model. Although there is still a lot of catching up to do with regard to material goods such as cars, clothing and electronics, life expectancy and lifestyles — as well as disease patterns — seem to resemble western ones more and more. For instance, PricewaterhouseCoopers estimates that the number of people suffering from high blood pressure in developing countries will rise to one billion by 2025.1 Diabetes seems to be following the same trend. These markets, however, continue to reflect a high level of diversity: in part, the

Figure 1: The FE35 — a single rotary press that can be fitted with up to 51 punch stations to produce approximately 370,000 tablets/h.

great differences in income and life expectancy, not only within but also between these countries, make it difficult to clearly characterize the demand for pharmaceutical products.

Make to Order Instead of Blockbusters To meet these new and varied demands, pharmaceutical companies need to shape their production processes accordingly. The trend towards Lean Six Sigma and other modern manufacturing methods will continue. Currently, the possibilities for pharmaceutical production are by no means exhausted. Plant effectiveness (overall equipment effectiveness, [OEE]) of pharmaceutical producers, often runs at less than 20%. New opportunities present themselves through the optimum linking of sales forecasts and through production to order (‘make to order’) of smaller batches of high‑value pharmaceutics. According to Dr Christoph Ebensperger, Head of Business Segment Life Sciences at Horvath & Partners Germany, “Blockbusters are an outdated model. In future, the production of drugs with such large turnovers will most likely be the exception and no pharmaceutical firm will be able to base its strategy solely on the development of such products. The risk of failure would simply be too great.”

Fast Product Changeover To address these new challenges, Fette Compacting, for example, has designed the FE35 (its second machine in the new FE tablet press series) — a single rotary press that can be fitted with up to 51 punch stations to produce approximately 370,000 tablets/h (Figure 1). Furthermore, the turret can be removed within just 15 min, providing customers with particularly fast product changeover. JULY/AUGUST 2012

TABLETTING Optimized Construction and Drive With the newly developed filling unit, users can increase the product output or the production capacity with a wide array of products up to 100%. The die table segments in the FE35 are also a new development. Despite a larger pitch circle diameter of 325 mm, these segments weigh the same as those with a smaller pitch diameter. The machine has upper and lower compression rollers that can be adjusted automatically, as well as compression measurement cells with integrated measuring amplifiers and drive units with a new position measurement system. This results in much shorter refitting times — operators no longer have to move to reference marks after a turret change, and they can calibrate the measurement cells at the operations terminal using software. The mechanical design of the FE35 is also new. The optimized structural frame allows for low vibration operation and reduces noise output. The new direct torque drive features an enormous reserve capacity, easy maintenance and low heat generation. This is made possible in part by the revised cooling design of the drive compartment. Customers may choose between an integrated and an external switch cabinet. As with the FE55, the housing of the FE35 is made of an FDA‑approved high-performance polymer.

Productivity, Flexibility and Availability The FE55’s unique ratio of punches to floor space (up to 87 punches on 1.6 m2) and the new, patented first‑layer sampler for the production of two‑layer tablets ensure very high performance (Figure 2). A pneumatically adjustable compression roller reduces sampling of the first layer from 20 s to 4 s; users can, therefore, reduce product loss by a factor of six. Finally, the new, internal tablet outlet chute guarantees trouble‑free production with both systems and a special control prevents sample or reject tablets blocking the outlet.

TRI.EASY Design: Basis for Efficiency and Quick Product Changeovers Another feature FE35 and FE55 share is Fette Compacting’s TRI.EASY concept. The idea behind this concept is that technology can only be efficient when it is equally easy in operation, refitting and maintenance. The TRI.EASY design, therefore, guarantees smooth operation regardless of the experience and qualification levels of its operator. The implementation of this principle is also the foundation for quick product changeovers. The layout of the machines facilitates quick and easy access to all modules. When changing the turret, all operational steps are fully automated or can be executed tool free. Furthermore, all supply lines are connected to the machine via a single plug. Another highlight JULY/AUGUST 2012

is the new exhaust unit, which can be connected above, under or to the side of the press. The removal or installation of the unit itself, or cleaning, takes only seconds. With both models, the table on which the filling unit stands can be manually adjusted in 30‑µm steps, so that users can always position the filling unit exactly over the segments. Because the appropriate settings are stored in the machine’s control unit absolute repeat precision is guaranteed, even after product changes.

New Human-Machine Interface With regard to usability in the new machines’ human‑machine interface, users can see all press parameters via the 19‑in touchscreen. The simple and intuitive handling, and full keyboard guarantee maximum efficiency and safety. The units are embedded with Windows 7, providing a future‑proof operating system. Peripheral devices can be connected via a standardized plug‑and‑play interface, in which all the cables and the dust extraction unit are integrated.

Figure 2: The FE55’s unique ratio of punches to floor space and the new, patented first-layer sample for the production of two-layer tables ensure very high performance.

Improving the Entire Process Although competitive machinery is essential, other individual factors influence the economics of pharmaceutical production processes. Common causes of costly downtime, for example, include cleaning and tooling intervals not optimally planned or complicated maintenance. At the same time, product quality is key, as even minimal deviations during medication production lead to sorting. Tabletting technology providers would do well to offer a consulting service that includes not just tabletting, but also the upstream and downstream processes. Together with the user, the experts define which systems and processes should be optimized and consequently analyse the entire production process, the tool and machine use, as well as the skills of the operator. Training and support are additional services to look for when choosing a provider. For example, does the provider offer a 24/7 helpdesk, a technical field service with highly qualified service technicians worldwide? If not, they may be unable to guarantee a minimal response time, and a fully functioning and perfectly calibrated machine after the work is done. Combining these services with the new FE series, users receive a package that optimally prepares them for the tabletting challenges of the future.

Reference

1. www.pwc.de/de/ gesundheitswesen-undpharma/assets/PHARMA_2020. pdf

For more information

Volker Reinsch Fette Compacting GmbH Tel. +49 4151 12498 tablet@fette-compacting.com pharma-mag.com

DRUG DELIVERY

INTESTINAL LYMPHATIC DRUG DELIVERY

Drug absorption into the lymph offers many advantages in drug delivery including the avoidance of ‘first pass’ extraction in the liver as well as maximizing the effect of drugs intended to act on targets in the lymph. This article will discuss the characteristics of a drug capable of being transported into the lymph and formulations that help to promote lymphatic uptake.

rug discovery programmes in the pharmaceutical industry are continuing to generate drug compounds with increasingly high selectivity for biological targets. In many cases, however, this increased target selectivity is accompanied with high lipophilicity and poor water solubility. Orally administered drugs generally enter the systemic circulation by passage through the enterocytes lining the intestinal wall and directly into the blood capillaries surrounding the intestine. The blood from these capillaries then passes through the liver before transportation to other locations in the body. For some highly lipophilic drugs, however, a significant proportion of the absorbed drug is taken into the lymph, packaged in lipoprotein vesicles (chylomicrons) Figure 1. These drug‑loaded chylomicrons are transported in the mesenteric lymphatic system, by‑passing the liver and venting

Figure 1: Schematic showing drug absorption via the systemic circulation and lymphatic system.

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into the blood circulatory system at the thoracic duct. One advantage of drug transportation via the lymph is the avoidance of ‘first pass’ extraction in the liver — particular beneficial for drugs that are prone to a high degree of metabolism in the liver. Another advantage of drug delivery to the lymphatic system is to maximize the effect of drugs that are intended to act on targets in the lymph, such as use of oncology drugs to treat lymphomas. So what characteristics of a drug dictate whether it might be transported into the lymph? In considering the possibility of oral drug delivery to the lymphatic system, Charman and Stella suggested that a candidate molecule should have a log octanol/water partition co‑efficient (log P)3 5 and a triglyceride solubility of at least 50 mg/mL. 1 A drug molecule that satisfies this criterion will be preferentially transported via the lymph following absorption into the intestinal epithelium. The processes involved in the digestion, absorption and transportation of dietary lipids and the potential for exploiting these processes for drug delivery to the lymph has been reviewed by Shen. 2 If there is a desire to specifically target the lymph then it may be possible to improve the likelihood of lymphatic uptake by producing a lipid pro‑drug — through attaching a long‑chain fatty acid to the active moiety by an ester link. Thus, the pro‑drug mimics a long‑chain fatty acid and is absorbed and transported as such. JULY/AUGUST 2012

DRUG DELIVERY What formulations can help promote lymphatic uptake? Lipid‑based formulations are the obvious choice for promoting lymphatic uptake, with the use of long‑chain triglycerides or long‑chain fatty acids (for example, oleic acid) for the lipid component of the formulation. Long‑chain fatty acids are good solvents for lipophilic drugs and are taken into the body, after ingestion, via the lymphatic system. Lipophilic drugs dissolved in long‑chain fatty acids may also be preferentially absorbed into the lymph.3 The use of unsaturated long‑chain fatty acids is particular effective in promoting lymphatic drug delivery, probably because they produce larger chylomicrons compared with those produced from saturated fatty acids. Recent research has also shown that the presence of oleic acid in the small intestine stimulates lymph production.4,5 In addition, the use of surfactants in the formulation, to promote emulsification and accelerate the rate of absorption of the drug and the lipid components into the enterocytes, can further enhance oral bioavailability. Giving consideration to the practicalities of producing a suitable oral dosage form, lipid‑based formulations can be filled into soft gelatin capsules or into hard shell capsules (followed by capsule sealing) for oral administration.

Conclusion Lymphatic drug delivery can improve the therapeutic effectiveness of certain drugs. Drugs delivered to and transported by the lymph avoid passage through the liver — particularly beneficial for drugs prone to high hepatic extraction. Also, for drugs intended to act on targets within the lymphatic system (for example, oncology drugs), deliberately promoting lymphatic uptake is an obvious strategy. As a rule of thumb, the more lipophilic the drug, the greater the likelihood of it being taken into the lymph.

Robert Harris

References 1. W.N. Charman and V.J. Stella, “Estimating the Maximal Potential for Intestinal Lymphatic Transport of Lipophilic Drug Molecules,” Int. J. Pharm. 34, 175–178 (1986). 2. H. Shen, et al., “From Interaction of Lipidic Vehicles with Intestinal Epithelial Cell Membranes to the Formation Secretion of Chylomicrons,” Adv. Drug Deliv. Rev. 50, S103–S125 (2001). 3. A.J. Humnerstone and W.N. Charman, “Lipid‑Based Vehicles for the Oral Delivery of Poorly Water‑Soluble Drugs,” Adv. Drug Deliv. Rev. 25, 103–128 (1997). 4. N. Dashti and E.A. Smith, “Increased Production of Apolipoprotein B and its Lipoprotein by Oleic Acid in Caco2 Cells,” J. Lipid Res. 31, 113–123 (1990). 5. W.A. Khan, et al., “Activation of Protein Kinase C by Oleic Acid. Determination on Analysis of Inhibition by Detergent Micelles and Physiologic Membranes: Requirement for Free Oleate,” J. Biol. Chem. 267, 3605–3612 (1992).

Innovative Filtration The LifeASSURE PNA Range of Membrane Filters by 3M LifeASSURE PNA filters from 3M are designed specifically for biotechnology, pharmaceutical and biological applications for the production of vaccines, ophthalmic products or high purity DI water and WFI systems, blood products and fine or bulk chemicals. LifeASSURE PNA features an asymmetric membrane with a 0.2µm or 0.45µm filtration rating and 3M’s Advanced Pleat Technology (APT) which maximises the useful surface area of the filter. The unique membrane design offers benefits through improved microbiological control whilst simultaneously reducing capital costs and overheads.

3M™ LifeASSURE PNA Filters ✓ are optimised for fast flowing applications for superior retention of microorganisms ✓ provide a complete solution for rigorous contaminant control ✓ use up to 50% fewer cartridges compared to some competitors; resulting in a longer service life and lower costs for you

To find out more about 3M Purification and any of our products, call 0845 6025237 or visit us online at 3M.co.uk/filtration

For more information Robert Harris Director, Early Development Molecular Profiles Tel. +44 115 871 8888 info@molprofiles.co.uk www.molprofiles.co.uk

DRUG DELIVERY

SPRAYS HIT THE TARGET! Using recent applications and drug products on the market, the author discusses the evolution of buccal and sublingual sprays, and opportunities in improving drug delivery device design to achieve a more effective, convenient and safe mode of drug delivery.

Figure 1: The sublingual Unit‑Dose Spray device developed by Aptar Pharma is specifically designed for the effective delivery of breakthrough pain medications.

he oral route is the preferred way to take drugs for many patients, so it is unsurprising that the majority of the drugs provided to patients are given through the mouth.1 With the global market for mucosal drug delivery estimated at more than $2 billion in drug sales, m a n y new oral d r u g delivery systems have been developed in the recent past; from the traditional tablets, capsules and lozenges, to solutions, films, gels and hydrogels, chewing gums and fast‑dissolving tablets.2 During the last three decades, however, oral and sublingual sprays have become a successful and valid alternative to the invasive route for systemic delivery: proving to be just as fast‑acting and effective, but much more comfortable for patients.

The Advantages of Buccal and Sublingual Drug Delivery

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The success of oral drug administration is largely a result of the physiology of the buccal cavity. The inside of the buccal cavity is lined with a mucus membrane, the oral mucosa, which possesses ideal features to ease drug delivery. Studies have shown how this mucosa is much more permeable than skin and is surrounded by a high number of blood vessels. 3 Drugs delivered to this site can easily move into the bloodstream without having to pass through the gastrointestinal tract and the liver (where some

drug’s active compounds may be broken down). The self‑repair properties of the buccal cavity prevent tissue damage that occurs with the use of long‑term medication.4 Oral and sublingual sprays are easy to use for either third‑party or self‑administration — a feature attractive notably for geriatric and paediatric patients. These qualities make the oral route a highly effective way of quickly getting drugs to their site of action in the body.

The Evolution of Buccal and Sublingual Sprays

Back in 1879, a paper was published in The Lancet describing the use of nitroglycerine to treat the symptoms of angina pectoris, severe pain caused by lack of blood to the heart. The drug was administered under the tongue, demonstrating that, even more than a century ago, physicians recognized the benefits of the oral mucosa to deliver drugs straight to the bloodstream. Since this time, many regulatory hurdles have been overcome, so that a range of conditions are now treatable via the oral mucosa, with oral sprays at the forefront of this mode of drug delivery. Oral sprays can act either locally or systemically by releasing their microsized droplets to a large surface area. Local treatments include anaesthetics such as lidocaine and systemic therapies are currently on the market for treating angina, diabetes and cardiovascular disease. One exciting area of development is in breakthrough pain management, as witnessed by the recent launch of Subsys (fentanyl), a sublingual spray indicated for the treatment of breakthrough cancer pain, as well as drug products such as Sativex buccal spray, for the treatment of multiple sclerosis.

Innovation and Future Opportunities Formulation Design

The characteristics of the drug formulation used in oral sprays can play an important role JULY/AUGUST 2012

DRUG DELIVERY in the effectiveness of sprays to treat different conditions; therefore, the amount of drug released, the bioavailability of the drug, the onset of action, the solubility of the drug in saliva and the time the formulation spends in contact with the mucosal membrane are all factors to be considered to improve drug delivery. Penetration enhancers may be useful to help the drug cross the mucus membrane. These should be pharmacologically inert and nontoxic, and have reversible effects on the physiology of the mucosa. Some examples, to date, include bile salts, fatty acids and surfactants.5

Spray device design

The optimal design of spray devices is also critical to ensure safety and efficacy of the drug product, as well as patient convenience. The Subsys device, mentioned above, uses the Aptar Pharma sublingual Unit‑Dose Spray (UDS) device (Figure 1). UDSs’ ‘primeless’ feature offers the patient a unique ‘ready‑to‑use’ convenience, unlike traditional multidose spray pumps, which need to be primed prior to first use and sometimes reprimed when used infrequently. New drug delivery devices such as this are easy to use and offer dose accuracy, which is key with potent molecules such as fentanyl (an opioid that is 100 times more potent than morphine). In

addition, a UDS, which is a disposable system, helps counter diversion, misuse or overdosing, as only one dose is available per container or treatment. Other device designs for oral or sublingual sprays include; multidose containers fitted with multidose spray pumps, special actuator or nozzle designs that generate optimal spray droplet size for oral deposition; and options that can deal with formulations of varying viscosity, surface tension and so on.

Conclusion

The evolution of electronic ‘add on’ devices to current buccal spray products will provide a novel way of ensuring patient compliance and safety in the future. Electronic devices, or ‘e‑devices,’ incorporate ‘dose counters,’ which indicate to patients how much drug product number of doses are left, when their next dose is due and even use ‘lock‑out’ systems to manage the time between actuations to prevent accidental overdose or drug abuse.

For more information Gerallt Williams Aptar Pharma Tel. +33 2 3263 7373 Gerallt.williams@aptar.com www.aptar.com/pharma

Gerallt Williams

References

1. R. Hooda, et al., “A Review on Oral Mucosal Drug Delivery System,” The Pharma Innovation 1(1), 13–20 (2012). 2. Market estimates generated internally by Aptar Pharma, 2012. 3. V. Hearnden, et al., “New Developments and Opportunities in Oral Mucosal Drug Delivery for Local and Systemic Disease,” Adv. Drug Deliver. Rev. 64(1), 16–28 (2012). 4. A.H. Shojaei, “Buccal Mucosa as a Route for Systemic Drug Delivery: A Review,” J. Pharmaceut. Sci. 1(1), 15–30 (1998). 5. M.M. Thosar, “Intra Oral Sprays — An Overview,” IJPLS 2(11), 1235–1246 (2011).

The Solution to Oral Peptide Delivery

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www.unigene.com

pharma-mag.com

DRUG DELIVERY

EMBRACING IMAGING PARTICLE ANALYSIS TO SUPPORT DRUG SAFETY AND EFFICACY With regard to the presence of nonsoluble particles in injectable solutions, pharmacopoeial standards mandate the use of visual inspection and light obscuration for detecting visible and subvisible particles, respectively. New imaging particle analysis technology offers a beneficial approach to detecting these particles in parenteral formulations, as well as for other pharmaceutical applications.

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espite the high-tech instrumentation, machinery and equipment in use throughout the pharmaceutical industry for research, development, processing and packaging, the level of technology in use for verifying the quality and safety of these drugs has advanced at a slower pace. In the case of verifying the quality and safety of injectable solutions, the adoption of new technology has been driven primarily by the requirements of United States Pharmacopeia (USP) 788 and its European Pharmacopoeia (Ph. Eur.) and Japanese Pharmacopoeia (JP) equivalents. To detect the presence of nonsoluble particles in parenteral formulations, for example, the Pharmacopoeia Particle Standards mandate use of the naked eye for inspections of visible particles 100% of the time. Typically, a vial is held up to a light and subjectively graded based on the number of visible particles. Given the potential dangers of allowing fragments of rubber, plastic, glass, cellulose and other nonsoluble particles, as well as aggregated proteins to be injected, and given their risk to efficacy, many pharmaceutical companies have stopped relying solely on this manual test to reduce the potential for human error to compromise the results. Typically, companies have added a variety of microscopes and light obscuration instruments to their testing laboratories; manual microscopy, however, is still a slow, cumbersome process that relies on human judgment to detect and count visible particles. Similarly, light obscuration provides a total count of all particles detected greater than 10 and 25 µm; but unless the shape of the particles is predominantly spherical, and the viscosity of the formulation is similar to water, it will often yield inconsistent and erroneous data. Though Pharmacopoeia requires results from both types of instruments, many pharmaceutical formulators and

quality control professionals believe more sensitive techniques need to be added.

Taking Action Beyond Pharmacopoeia

There is a growing realization that knowing exactly what particles may be hiding in formulations is vital to meeting quality specifications, minimizing risk, accelerating product development and even boosting product efficacy. GlaxoSmithKline (GSK), Abbott Molecular, Wyeth Pharmaceuticals and FDA are among the hundreds of companies and organizations worldwide that have committed to improving their understanding of how the presence of these particles may affect their products and have added the latest high‑tech instrumentation to do so. The concept of imaging particle analysis combines the imaging capability of microscopy with the high speed of modern particle analysers in an automated instrument that eliminates the time and labour involved in manual approaches whilst also freeing the data from human subjectivity for greater accuracy and reliability. Commercialized as the FlowCAM imaging particle analysis system (Figure 1), this instrumentation detects both visible and subvisible particles in the 1 µm–2 mm detection range whether opaque, translucent or transparent and takes a high‑resolution digital image of each individual particle detected, then measures each one based on the actual image itself. This is a critical issue to understand. Older technologies such as light obscuration do not measure the actual particles; rather, their measurements are based on an approximation of the equivalent spherical diameter (ESD) of the particle and, therefore, are inherently flawed. The FlowCAM is the first instrumentation that measures the actual particle JULY/AUGUST 2012

DRUG DELIVERY

JULY/AUGUST 2012

pharma-mag.com

DRUG DELIVERY and characterizes its shape and its data, therefore. It is this ability to see the actual shape of each particle that sparked interest at GSK (King of Prussia, PA, USA).

Imaging Particle Analysis Applied

Paul Entin

For more information Paul Entin Freelance Technical Writer epr paul@eprmarketing.com www.eprmarketing.com

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A project team at GSK decided to count particles from its light obscuration instrumentation whilst testing a new parenteral product formulation and compared its data to the results of visual inspection; but difficulties in detecting transparent or translucent particles left the team feeling more information was needed. Then the team used a FlowCAM and saw images of aggregated proteins; longitudinal fibers; round, silicone oil droplets; and air bubbles. By imaging each particle, the instrument not only offers accurate measurements of each particle, but, with its built‑in, proprietary pattern recognition software, it can also automatically discern one type from another, such as a protein from an air bubble. This approach enabled the project team to see exactly what was present, to determine why and to understand whether the particles detected were related to the product formulation or to the sampling technique. The images are shared with colleagues in a variety of departments all over the world. The FlowCAM data are being used as an orthogonal method to verify the accuracy of the data generated by visual inspection, and the system is being integrated into the company’s testing programme to develop protein‑based parenteral drugs. The particles may be measured by up to 32 different properties such as size, length, aspect ratio, count and ESD plus advanced morphological properties, such as perimeter, roughness, elongation and compactness. Thousands of particles may be detected in less than a minute, and all of the images and their corresponding data are saved with a date and time stamp for further review and analysis. This entire process happens automatically in real time with the push of a button and requires only 50 µL samples to yield statistically significant results. GSK was able to switch from 25‑mL samples to 1 mL samples and cut sample production from 800 ampoules per batch to three per batch.

The Shape of Things has Come

The imaging advantage is not limited to injectables — more than one global pharmaceutical company has embraced imaging particle analysis for studying

Figure 1: The FlowCAM PV Series imaging particle analyser. This instrumentation automatically detects the presence of particles in a fluid sample, takes a high‑resolution digital image of each individual particle and measures each one using up to 32 different properties including morphological.

the cancer treatment paclitaxel. The ability to image and differentiate individual particles may permit analysis of the paclitaxel and its carrier for testing and assessment of different drug delivery carriers and methods. It may also be used to monitor particle longevity when coated on stents, catheters and other medical devices, in addition to detecting aggregates in the injectable solution form. At CP Kelco (San Diego, CA, USA), the technology is being used to improve the quality and performance of pharmaceutical‑grade gums, additives and modifiers; for example, the FlowCAM was used recently to determine the optimum size and shape for producing a blend of pectin, which is fibrous, with sugar, which is a spherical particle. Compatible particle sizes are essential for ensuring they remain locked together for optimum performance and the testing process to arrive at the ideal product specifications would not be practicable via other methods.

Conclusion

Major pharmaceutical companies are embracing the latest available imaging particle analysis technology to safeguard product quality and ensure their performance. The FlowCAM imaging particle analysis system automatically detects the presence of particles in a fluid sample, takes a high‑resolution digital image of each individual particle and measures each one using up to 32 different properties including both traditional and advanced morphological properties. The results documented to date include substantial cost savings in formulation, testing and production and show great promise for enhancing the safety and efficacy of injectable solutions, additives and other products. JULY/AUGUST 2012

PROTECTING THE SUPPLY CHAIN WITH INNOVATIVE SERIALISATION METHODS CASE STUDY

The European Medicines Agency is focusing on tackling counterfeiting with new legislation on falsified medicines expected to come into force in 2013. This brief case study looks at how AndersonBrecon is working with its clients to tackle the rising problem of drug counterfeiting. THE SITUATION Dispensing and dosing errors, reimbursement issues and cases of counterfeits in the legitimate supply chain have highlighted the need to establish more clearly and effectively the identity of each single medicine pack. The European supply chain is becoming increasingly complex with billions of medicine packs moving around the EU each year. Fragmentation has resulted in decreased transparency in the supply chain and increasing difficulty in tracking and tracing medicines opening the system to the risk of counterfeiting.

THE CHALLENGE AndersonBrecon clients were increasingly looking for greater control over their products and total serialisation was becoming a viable, secure option. The company responded to the challenge by assembling a team of engineers, IT and validation experts from across its own and client businesses, underpinning the work with a full risk analysis.

THE SOLUTION AndersonBrecon designed an end-toend, point-of-dispense identification solution which incorporated a

unique identification code on each pack, generated and applied by the manufacturer. A unique-to-client server enabled secure communications between AndersonBrecon and its client. A simple 2D-data matrix bar code was applied to the packet containing a unique serial number, along with the lot number, expiry date, GTIN (supplied by client) and material code. The product verification process then compared the data held within the data matrix code with a secure product record on a database to confirm that: • The product record existed and matched the data held on the product itself • The product record had not been previously marked as ‘dispensed’ • The product record did not contain any warning or advisory notes This verification process immediately alerted the pharmacist if the packet containing the same number had already been released into the supply chain.

against counterfeiting. Moving forward, it will tailor its process to meet customer requirements. As the battle against counterfeiting remains high on the agenda within the pharmaceutical industry, serialisation is no longer just an ‘if’ or ‘when’, but a key requirement for many companies.

OUTCOMES Having conducted a client pilot study in 2010, by 2011 the total serialisation process had been implemented and rolled out across two product lines in eight SKUs. AndersonBrecon is continuing to work with many new customers who select its innovative serialisation solutions in the fight

For more information about serialisation or any of our commercial services please contact: ANDERSONBRECON EUROPE WYE VALLEY BUSINESS PARK, HAY-ONWYE, HR3 5PG, UK. +44 (0) 1497 820829 EMAIL US: info@andersonbrecon.com

AndersonBrecon is the alignment of sister companies Brecon Pharmaceuticals Ltd and Anderson Packaging Inc, a business unit of AmerisourceBergen Consulting Services which is a subsidiary of AmerisourceBergen Corporation. AndersonBrecon is a leading provider of contract packaging services to the global healthcare market. With facilities in North America and Europe, supporting pharmaceutical and biotech companies with products destined for more than 100 countries around the world. AndersonBrecon provides services for each stage of the product lifecycle – from early Phase I through commercial launch and long-term supply – and partners with customers to provide key insight and expertise in enabling successful commercialisation and bringing life saving medications to patients. For more information, go to www.andersonbrecon.com

DRUG DELIVERY

A BREATH OF FRESH AIR FOR INHALED PRODUCT ANALYSIS Orally inhaled and nasal drug products (OINDPs) comprise a dynamic, fast growing pharmaceutical sector, albeit one with its own hurdles. The mechanisms behind drug delivery via the pulmonary and nasal routes are complex and associating the performance of drug deposition with clinical efficacy (in vitro–in vivo relationships [IVIVR]) can be challenging.

Figure 1: AED apparatus.

esearchers are now investing in the cultivation of efficient and pertinent testing protocols and technology platforms, which will help the development and application of inhaled products enormously. In 2005, the Next Generation Impactor (NGI) was incorporated into the pharmacopoeias (including the United States Pharmacopeia [USP]) for inhaled product testing. NGIs are high performance, precision, particle‑classifying cascade impactors that test metered‑dose, dry powder and similar inhaler devices. Since then, the innovation of new data analysis techniques and new equipment for more representative testing has helped drive progress. Bespoke analytical technology platforms, developed using Astech Projects’ specialist automation expertise, have been implemented within the GlaxoSmithKline (GSK) inhaled testing laboratories using a quality by design (QbD) approach. R&D and manufacturing scientists identified key quality parameters and attributes for each test, with controls being specified to minimize testing variability. These scientists worked in collaboration with Astech Projects to develop analytical technologies that generate and deliver effective, safe testing, reliable data across the GSK network.

Novel Emitted Dose (nED)

To retrieve the emitted dose from dry powder inhaler (DPI) device, a manual apparatus called the DPI nED,

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is used. The DPI nED uses a DPI Dose Collector, designed from first principles, as its core technology. This dose collector is sealed to a firing station, to which the DPI device is clamped. During each nED test, the DPI is primed and an air‑flow drawn through the device via a critical flow controller, as used with NGI testing. A washing station pumps solvent through the DPI Dose Collector into a volumetric flask to recover the collected dose for subsequent analysis. Dose Collectors are then dried and re-prepared via the Dose Collector Drying Station. As well as delivering a more efficient and cost‑effective process than the manual procedure, this technology has vastly enhanced testing robustness and data reliability.

Automated Emitted Dose (AED) The technology behind the AED apparatus (Figure 1) enables the DPI product Content Uniformity test to be fully automated. Once the user loads the inhaler devices and appropriate recovery and clean‑up solvents, and initiates the correct method programme, the system waste fires and collects the dose from the defined blisters. Each dose collector is rinsed with the recovery solvents to prepare HPLC autosampler vials with aliquots of sample solution. The AED system is extensively used within the development and manufacturing process for both routine analysis and batch characterization. By minimizing human intervention, the potential for analytical error has significantly reduced.

Next Generation Dose Sampling Introduction (NDSI) Waste firing or collection of the powder within the NGI is automated through the NDSI system. Identical to the AED and nED apparatus, the device holder minimizes any potential variability in the sealing of the device to the NGI USP throat. This system complements other JULY/AUGUST 2012

DRUG DELIVERY manufacturer’s automated NGI recovery systems, improving robustness of the complete NGI procedure and again requires minimal human intervention.

Blister Sampling Analysis (BSA) The BSA apparatus is used to recover a powder blend from single DPI blisters within a strip for content uniformity or bulk assay procedures. The DPI strip is clamped onto the BSA platform, the blister is pierced, and then metered solvent is dispensed through the blister and recovered to a flask for further processing and analysis. This system has proved to be of real benefit to the DPI product development process. GSK now uses extensively several systems such as this, already having performed tens of thousands of assays in a safer, cost‑effective and more reliable way.

Improving Efficiencies A significant improvement in efficiency has been observed when these automated technologies are compared with previously employed manual techniques. Implementing these platforms has improved throughput, ICSE 2012 visitor 210x148.5 v1.pdf 1 14/05/2012 10:09 dramatically reducing the amount of time taken to

perform 100 sample preparations. Furthermore, a reduction in solvent volumes has also been facilitated, providing a more cost‑effective option, whilst reducing waste streams for an environmentally friendly procedure. A reduction in the time taken to perform the analyses with the improved technologies has also been achieved, ensuring other value added activities can be performed.

The Future The introduction of bespoke analytical technology platforms, such as those provided by Astech Projects, can improve throughput, efficiency, safety and minimize analytical variability within the inhaled product development lifecycle. The platforms also help to justify product specifications, and advance the science and understanding of inhaled products, and have become part of a first intent strategy. The implementation of the platforms across an entire network can ensure that analysis of inhaled products is completely reliable. Innovation and development of such technologies signifies the drive to meet the needs of the community to have better, more effective and easier to use inhaled pharmaceuticals.

Anthony Moran

For more information Anthony Moran Director Astech Projects www.astechprojects.co.uk

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The author considers the widespread use of gels in pharmaceutical applications, the challenges that R&D and manufacturing departments need to overcome and the important role that texture plays in determining the suitability of formulations for specific pharmaceutical applications.

hen thinking about pharmaceutical applications, tablets, sprays and liquid formulations spring quickly to mind, but gels also offer a valuable method of delivering medicines through digestible capsules, topical dermal application and parenteral delivery. Gels can offer a convenient, comfortable method for administering controlled drug release for the patient. They can also enhance bioavailability and enable medication to be targeted at specific areas of the body; for example, gels find application in ophthalmic treatment as they enable retention of medication around the eye. Similarly in dental applications the gel can be delivered to the exact site of treatment and remain comfortably in situ. The first use of gels for medical applications was reported by Wichterle and Lim in 1960 and involved manufacturing soft contact lenses and implants from hydroxyethyl methacrylate polymers.1 Gel formulations can be manufactured in many different sizes, shapes, colours and viscosities to meet patient and practitioner needs. In addition to administration method, consideration needs to be given to stability, shelf life and robustness of the finished product. In this respect, gel texture is critical to its performance.

Measuring Gels

28 pharma-mag.com

The physical properties of gels, such as elasticity and tear or rupture force, are fundamental in the development of pharmaceutical products such as coronary stents where soft, flexible hydrogel polymers mimic living tissue. Similarly, compounds with gel‑forming properties used in the manufacture of wound dressings, lubricants, contact lenses, suppositories, soft gel capsules and bacterial growth media, need to be able to withstand the rigours of daily life. Using texture analysis, gels can be assessed by measuring their mechanical resistance to stress. In a simple viscosity measurement, using, for example, a TA.XTplus, a cylinder probe typically of 2.5‑cm diameter, is lowered into the gel system at a fixed speed (Figure 1). The gel strength is reported as the peak force (PF) required to reach a chosen distance. Standard probes, such as those required for ISO

standards tests, are also available for the assessment of gel bloom or rupture.

Texture Profile Analysis — Determining Gel Properties

The intended use of a pharmaceutical gel will determine its required viscosity, strength and bioadhesive attributes. Through texture profiling, a series of measurements can be performed to assess these gel properties including hardness — indicated by the force required to attain a given deformation, adhesiveness — the work necessary to overcome the attractive forces between two surfaces and compressibility — the force needed to deform the product. These results can be used to measure product characteristics such as ease of removal from a container (for example, a tube or jar), and application and residence characteristics. Such features are key in the design of topical medications, which need to be easy to apply, deliver controlled drug release and exhibit good bioadhesion to ensure that the medication remains in place and is effective at the intended site of activity.

Dressing for Success

Today’s dressings for wounds and burns go far beyond a simple white bandage. Hydroactive wound dressings are designed to retain exudate around the wound or incorporate the fluid by gel formation, creating a local environment to support wound healing. In this moist environment the dressing must be sufficiently adhesive to remain in place, yet be removed with minimal discomfort. To determine the bioadhesion of dressings, a peel test can be performed typically against neonate porcine skin. Researchers McCarron et al. have reported the use of a peel rig in such a test. 2 One end of the patch or dressing is secured in the clamp grips whilst the remainder is applied to wetted porcine skin. A force of 10 N is applied for 30 s and the clamp then moved upwards at 6 mm/s whilst the sliding base section moves horizontally, maintaining an angle of approximately 90° between the film and skin. The peel strength is recorded as the maximal force per unit length of the separating interface. A similar JULY/AUGUST 2012

DRUG DELIVERY used to contain water- or oil‑based formulations where a failure in the encapsulation could be catastrophic. The robustness of a soft gel capsule can be determined via a particular compression test known as the bursting test. This measures the maximum force that a capsule can be subjected to and establishes whether there is a weak point in the gel film or capsule seal. Using the TA.XTplus, a small cylinder probe, typically 2–3 mm in diameter, is gradually lowered onto the capsule until it ruptures. The force recorded at this point is defined as the bursting force. Capsules can be tested under different conditions to assess the effects of temperature, humidity, storage and handling, but the integrity of the capsule may also be affected by its contents. Simple compression tests on gel capsules do not always adequately predict which formulations may result in failures related to brittleness, and hence those drugs that are suitable for hard or soft gel encapsulation. Using a capsule tensile rig, as shown in Figure 2, the effect of the formulation on the capsule integrity can be studied. Prior to testing, the capsule is emptied and the shell mounted onto a separating rod fixture on the texture analyser. The upper rod is moved vertically upwards within the sample, monitoring the tensile force being applied until the capsule is split apart. This force gives a reproducible measurement of the breaking point of the capsule and can be performed under different ambient conditions, as well as on capsules that have held different contents. The precision in force measurement using a capsule tensile rig technique is sensitive enough to differentiate between slight modifications in formulation with regard to the effect on capsule integrity. This provides a useful formulation screening tool, prior to embarking on expensive, long-term stability studies. Figure 1: A gel penetration test using a TA.XTplus texture analyser.

approach, which does not require the porcine skin sample, is to use a 180° peel test against a rigid material.

Gel Capsules

Gel capsules offer many benefits to formulators, manufacturers and patients alike, including ease of digestion, no unpleasant taste, control of bioavailability, hermetic sealing and the ability to produce capsules in a variety of shapes and colours. The brittleness, hardness and flexibility of gel capsules and their resilience to variable storage and handling conditions should be considered, along with any potential effect the contents may have on the mechanical properties of the capsule itself.

Filled to Bursting Point?

30 pharma-mag.com

Although the comfort factor of soft gel capsules is not to be underestimated, such media are primarily

20:20 Vision — Ocular Application

Some diseases are treated most effectively when the medication can be administered directly to the affected area, particularly for ocular, dermal, oral periodontal and anorectal tissue disorders. Ocular drug delivery is a challenging opportunity for pharmaceutical development, as the eye is protected by a series of complex defence mechanisms. Through tear production and the blinking reflex, solutions dropped into the eye are typically cleared within 5–10 min. Coupled with low corneal permeability, eye drops commonly exhibit low drug bioavailability of only around 1%. 3 Extending the residence time of the drug at the site of delivery in the eye or by facilitating transcorneal penetration will increase bioavailability and can be achieved through a number of delivery systems including hydrogels and ocular inserts. Hydrogels are a good choice as they exhibit excellent biocompatibility, physicochemical JULY/AUGUST 2012

optimized therapeutic profiles. better treatments. As a global leader in drug development and delivery, we have the expertise in innovative and proven drug delivery technologies to optimize the therapeutic profiles of your treatments.

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and mechanical properties, which enable them to be comfortably applied as soft contact lenses. Comfortable lenses can be manufactured using flexible hydrogels that effectively drape over the cornea, but the lens is subject to external forces both on the eye by the lids and during handling. It is important that this comfort does not come at the expense of durability as a result of low tensile strength of the gel material.

Measuring Contact Lens Mechanical Strength

To assess the durability of a contact lens, a texture analyser can be used to measure the amount of force applied in stretching a lens sample. The results can then be interpreted via a stress–strain plot. The area under the curve reflects the sample toughness, and the shape of the stress–strain curve gives indicates whether the gel is strong and tough or strong and brittle. In addition, the initial slope of the curve gives a measure of the Young’s modulus, which describes how well a material resists deformation. Hydrogels exhibit a very low Young’s modulus, resulting in a comfortable, pliable lens; but this low modulus also reflects the delicate handling characteristics of the hydrogel lens material. The modulus of a material can also be measured under compression (Figure 3). As the material is maintained in its final form, clinically relevant physical properties can be studied. Furthermore, as the sample can be recovered, the test can be repeated several times to investigate time-dependent deformation.

Mucoadhesion

Mucoadhesive drug delivery systems are designed to enable a drug to stick to mucous membranes to deliver dosage to a precise site in the body for a controlled time. They are increasingly used to treat stomach ulcers and cancers, as well as conditions in the mouth. Gel formation is a key step in the process, so the ability to measure polymer–mucin gel interactions is of particular interest in pharmaceutical development. Using the mucoadhesion rig, originally developed at the University of Strathclyde, mucin samples can be studied at near in vivo conditions. Researchers from the University of Iceland developed a further technique for evaluating the adhesion of hydrogel formulations using a gel mucoadhesion probe. 4 The end of the probe is an inverted cone with concentric grooves, which encourage the attachment of a controlled volume of hydrogel sample to the probe surface. A syringe may be used to apply a consistent Figure 2: Measuring gelatine capsule tensile strength using the capsule tensile rig.

32 pharma-mag.com

JULY/AUGUST 2012

DRUG DELIVERY Figure 3: Compression of a contact lens to assess mechanical strength.

volume of gel to the probe to ensure reproducible studies. The gel-laden probe is lowered onto the sample substrate and a compression force held for a fixed dwell time. The force needed to detach the hydrogel from the sample is recorded as a function of elongation, allowing the maximum bonding strength and area under the force/time curve to be obtained. Analysing debonding behaviour can be complex, because although peak forces for different products can be very similar, the separation process may be very different. The adhesion curve can provide a wealth of information describing the nature of adhesion and release in mucoadhesion. Mucoadhesive delivery systems have potentially harsh environments to contend with, as in the case of throat sprays where food, liquid and muscles are capable of removing medication. The area of work is, therefore, a much better measure of adhesive capability than PF, as the product must withstand dislodging forces. Few real mucoadhesive situations fail cleanly enough to generate momentarily high peak forces. For most adhesive plots, if there is a long ‘time distance’ after the PF this indicates poor cohesion within the gel. This is equally true for the area of work after the peak. Low ratios of either post PF distance:pre PF distance, or, post PF area:pre PF area indicate strong gel cohesion, whereas high ratios would indicate poor cohesion. Ideally a mucoadhesive preparation should be highly cohesive so that it remains intact as the body attempts to dislodge it. Very cohesive products typically leave no residue on the probe. Eye-drops are a commonly used bioadhesive treatment, yet are known to be poorly cohesive; they must, nevertheless, be sufficiently strong to stay in place during initial application. When poorly cohesive bioadhesives debond, they tend to deform in an ‘hourglass’ shape before failing cohesively and typically leave residue on the probe surface. JULY/AUGUST 2012

Nonetheless, for poorly cohesive products, high areas of work indicate that the product may have remained intact for long enough to allow a smaller drug dose to be administered to meet the medical challenge.

Jo Smewing

Periodontal Applications

Mucoadhesive drug delivery systems are beneficial for the treatment of periodontal disease, because of their high retention within the periodontal pocket. For optimum performance, the medication should be a highly viscous, yet syringeable formulation. The ease of expressing a formulation can be measured by correlating mucoadhesive strength and syringeability, and used to optimize periodontal formulations. Identical plastic syringes are filled with gel samples, then, using a texture analyser in compression mode, the syringes are fully emptied. The area under the resultant force–time plots is a measure of resistance to expression. The greater this area, the harder it will be to syringe the medication.

Conclusion

Pharmaceutical gels find an abundance of applications across ocular, periodontal, topical and internal applications. They also offer a range of packaging options to formulators in terms of capsules, dressings, gels and liquid formulations. This enhances convenience and comfort for patients, as well as enhanced efficacy through specifically targeted delivery and controlled release rates. Texture analysis has a vital role to play in understanding the viability of a formulation from early drug development to quality control of the end product at the full‑scale manufacturing stage.

References

1. O. Wichterle and D. Lim, “Hydrophilic Gels for Biological Use,” Nature 185, 117–118 (1960). 2. P.A. McCarron, et al., “Evaluation of a Water Soluble Bioadhesive Patch for Photodynamic Therapy of Vulval Lesions,” Int. J. Pharm. 293, 11–23 (2005). 3. I.K. Reddy and M.G. Ganesan, Ocular Therapeutics and Drug Delivery: An Overview (Technomic Publishing Company, UK, 1996), p3–29. 4. S. Skulason, T. Kristmundsdottir and W.P. Holbrook, “A Technique for Evaluating the Adhesion of Hydrogel Compositions,” Proceedings of the International Symposium of Controlled Release Bioactive Materials (Paris, France, 11–13 July 2000).

For more information

Jo Smewing Applications Manager Stable Micro Systems Tel. +44 1483 427 345 Fax +44 1483 427 600 www.stablemicrosystems.com pharma-mag.com

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DRUG STRAPDELIVERY

SKIN-FRIENDLY ADHESIVES

As transdermal products evolve to include treatments for chronic conditions and long-term wear (LTW) applications, pharmaceutical product developers turn to adhesive manufacturers for the latest skin-friendly adhesive technologies to improve patient compliance and the therapeutic outcome of their products.

Wong Baker FACES FACESpain Painscale Scale Wong-Baker

uman skin is an extremely variable substrate; factors such as age, race and overall patient health can affect the condition of the skin’s bonding environment. The skin’s structure, as well as surface energy and viscoelastic properties, influences how well an adhesive will bond to this unique substrate. These factors also determine how the skin will respond to removal of a bonded patch or device following treatment. As a general rule, adhesives for transdermal patches are formulated to present aggressive bonds with flexibility and conformability to assure the patch remains firmly in place without lifting or fall off to assure a therapeutic dose. The adhesive/skin bond must withstand physical activity, constant friction from clothing, periodic moisture exposure, and varying degrees of skin porosity and oil levels without shifting or moving. The majority of transdermal patches available today are daily‑wear

Figure 1: Pain self-assessments utilizing the Wong-Baker Faces Pain Scale illustrate the gentle removal experience of the skin‑friendly adhesives developed by Adhesives Research when compared with silicone tapes.

36 pharma-mag.com

devices that are typically removed within 24 h of application. Formulators are, however, developing extended wear for multiple-day use.

Skin-Friendly, Aggressive Adhesives for LTW

More products are becoming available requiring wear times of multiple days; in the case of insulin pumps, the adhesive must reliably attach a device to skin whilst bearing load. Although aggressive adhesion assures a secure bond to skin for addressing dosing concerns, it can potentially cause discomfort upon patch removal — the adhesive can remove skin cells and/or hair when the device is pulled away. In addition, an adhesive that releases uncleanly may leave behind an unwanted residue on the skin that is difficult to remove. A tailorable, pharmaceutical‑grade acrylic adhesive technology that meets the critical design parameters required for adhesives in LTW applications requiring a more aggressive adhesive to secure a patch/ Adhesive removalPain pain assessment Adhesive Removal Assessment device for periods up to 7 days has been designed by Adhesives Research. The 5 LTW technology offers high moisture vapor transmission rate (MVTR) for Silicone tape Tape Silcone 4 breathability, particularly good wear AR’sLTA-1 LTA-1adhesive Adhesive AR’s properties with minimal edge lift, no AR’s AR’sLTA-3 LTA-3adhesive Adhesive edge residue and tolerates radiation 3 AR’sLTW LTWadhesive Adhesive sterilization techniques. In spite of the AR’s aggressiveness of the LTW adhesive, pain experienced upon removal of the 2 tape is tolerable and demonstrates a pain index of <2.5 on the Wong-Baker 1 FACES pain rating scale. Moreover, the formulation can be tailored to customize the wear time and pain Low Medium High 0 level depending on the needs of the Silicone LTA -1 LTW Silcone LTA-1 LTA-3 LTA application. Studies have also shown tape Tape that removal of the adhesive tape Adhesive Type does not cause disruption of stratum Adhesive tape corneum. JULY/AUGUST 2012

STRAP DRUG DELIVERY Low-Trauma Adhesives for Short‑Term Wear

As more patch products become available for diverse consumer populations with skin of varying ages and conditions, product developers are seeking adhesive technologies that continue to demonstrate high levels of reliable adhesion, but with a more gentle removal experience for the user. Another factor is the emergence of transdermal treatments for chronic conditions that require repeated patch placement to a specific skin site, or mechanical preparation of the skin. The need for more adhesive choices providing low- to no‑pain removal is growing. The growing need for skin-friendly adhesives whilst overcoming the thickness issues of gel formats through the development of a low‑trauma adhesive (LTA) technology for gentle removal is being addressed. This high‑MVTR, customizable pressure‑sensitive adhesive (PSA) technology maintains intimate skin contact for up to 5 days with painless and residue‑free removal. The adhesive is formulated to cleanly release from hair and the top layer of skin with a pain index <2.5 on the Wong‑Baker FACES Pain Scale, compared with a standard‑skin friendly adhesive, which, based in internal studies, has a pain index rating of 4–5

ON THE INSTRUCTIONS OF

(Figure 1). Some LTA formulations exhibit good to excellent ratings for resistance to gamma sterilization techniques, which is an important consideration in active patch designs utilizing microneedles, abrasion, or other techniques to prepare the skin prior to, or as a step in the proper application of a patch device.

Conclusion

Transdermal drug delivery systems continue to deliver increased compliance by providing predictable and reliable therapeutic dosages without limiting a patient’s normal daily activities, driving drug manufacturers to continue to expand the scope of this drug delivery system. As the scope widens, adhesive manufacturers are responding by developing a range of skin‑friendly formulations for improved comfort and wear with less discomfort during removal. Versatile in their chemistry and form, PSAs are critical components in achieving intended outcomes such as reliable, sustained skin adhesion. Whilst pharmaceutical product developers explore new methods for delivering a wider range of drugs through passive and active systems, PSA manufactures will continue to push the capabilities of their technologies to meet the unique challenges of new and emerging transdermal applications.

For more information

Gozde Karabiyik, PhD Product Development Chemist Adhesives Research, Inc. Toll-free 800 445 6240 Tel. +1 717 235 7979 Adhesives Research Ireland Ltd Tel. +353 61 300 300 www.adhesivesresearch.com The Wong-Baker FACES Pain Rating Scale is a trademark of the Wong-Baker FACES Foundation.

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SUPPLY CHAINS

MAKING MONEY OUT OF PHARMA SUPPLY CHAINS Pharma supply chains can be complex and highly regulated, leaving plenty of opportunity to gain competitor advantage and raise the share price.

onventional wisdom says pharma supply chains are different from those in other sectors; but are they really that different? In reality, the biggest winners are often those who recognize that a combination of supply chains are needed to meet their business needs, and each one has parallels and lessons for best practice in other sectors.

risks; these are easy to introduce and hardly ever reviewed. More needs to be done to ensure practices stay relevant and deliver the real needs of patients, licencing authorities and customers. Few pharmaceutical companies realize how much these ways of working drive the high cost bases that make it very difficult to compete with emerging competitors.

Pharma Challenges

The need to be much more successful outside the US and Western Europe highlights the need for pharma supply chains to deal with supply chain shocks, which could be environmental, economic or demand‑related. How does a pharma supply chain deal with these risks? Ultimately, this is part of a business’s segmentation and agility strategy, which needs deep contingency planning. Agility comes in many guises, but pharma’s ‘network agility’ — the ability to reconfigure quickly networks in response to political and economic shocks — needs further development. Although there are no miracle cures, pharma companies would do well to spend more time looking at contingencies, qualifying suppliers and locations, and ensuring the regulations can be flexed to respond as fast as possible.

Before looking at the solutions, what, exactly, are the challenges in the pharma industry?

Increasing the Reach

The first is the need to increase reach to the 80% of the world population that are not buyers from Big Pharma. This will require building the service models (physical logistics, payments systems, customer touch points) to reach these customers — taking the fragile products into increasingly challenging environments — and supply chain capabilities to challenge the generic producers and even the consumer goods‑style pharma businesses. Pharma companies are going to be fighting on a wider battlefield and have many handicaps to overcome.

Operating Effectively

Second, the need to operate effectively in a highly regulated environment is driving towards remote planning and direction. This often results in operating sites’ challenges not being properly understood and poor plans being produced, which pushes them to fatalistic “can’t do anything” attitudes. This can undermine performance improvement efforts.

Challenging Regulation

There is often a lack of challenge to regulation. The industry has to cope with a variety of requirements created by the formal licensing process and by the often quite arbitrary needs of end‑markets and individual customers. The mindset that goes with these requirements results in a relentless tendency to introduce more standard operating procedures to cover one‑off and, in some cases, entirely theoretical

Supply Chain Shocks

Margin and Cash Pressures

The reality for most pharma companies is that the variations in product handling requirements, costs to make and move, value, channels to market, geographic peculiarities, customer requirements, regulations and other influencing factors mean that multiple supply chains are needed. Margin and cash pressures, however, dictate that whilst a responsive supply chain is needed, companies cannot afford to run separate supply chains for each value stream. How do businesses design their supply chains, therefore, to balance financial and strategic pressures with the needs of the different customers? The answer will often lie in segmenting the supply chain: the ability to manage the supply chain differently depending on specific customer, product, geographical and profitability drivers JULY/AUGUST 2012

SUPPLY CHAINS whilst maintaining one consistent global supply chain. This has been talked about for many years and tested by many people, but the solutions are proving to be elusive. Everybody understands the difference between ‘lean and stable’ and ‘agile and responsive,’ and highly focused trials often generate promising results. The problems come with scaling this up across a global business with hundreds of products and thousands of combinations of technology, customer segments, cost structures and geographies. Such wider implementations have not typically had great success.

Segmenting a Supply Chain

What is meant by ‘segmenting a supply chain’ and what approach works? The key is to take a wide‑ranging, data‑driven approach to identify the key segments in each supply chain and decide how they should be prioritized and what to do about them. Figure 1 shows an example of a segmentation based on customer type and delivery mechanism, with example sectors for comparison. Grouping common characteristics and assessing each product against them at a low level of detail allows a business to consider their products in a new way. Best practice in each grouping will often be outside the pharma sector, and so lessons can be learned from how those nonpharma companies manage their supply chain; for example, ‘fast food’ restaurants are fantastically good at configuring products quickly and exactly fitting the requirements of the customer every time; utility companies are strong at monitoring usage and billing remotely. Do you need to segment your supply chain? Not necessarily. Most supply chains have multiple tasks, which can be seen as segments, but a legitimate supply chain‑driven business model for the future could be based on being exceptionally good at one thing; for example, next day parcel delivery or providing the cheapest, most basic product on

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the market. Few big pharma companies can be this focused, but they can exploit this logic, outsourcing more of their business activities to those with this level of focus. This means looking at each aspect of the business and finding specialists who can do the task more simply, better and cheaper. Traditionally, companies do this with their distribution. The irony and look‑out for all pharma companies is that having outsourced distribution to multi‑user pre‑wholesalers, complexity has frequently been passed along the chain to those pre‑wholesalers. They are then expected to do delivery to pharmacy, billing, order placing, labelling and more rather than leaving them clear to focus on what they were originally good at. High quality segmentation needs high quality collaboration, both internally and externally. Some businesses have gone too far in ‘virtualizing’ themselves, with lots of complex relations with service providers; one of the trends we may see is a re‑integration of some operations back into the core business. Intriguingly, more and more businesses are recognizing that they need to re‑integrate logistics and all customer fulfilment activities, whilst considering outsourcing their manufacturing operations; the important aspect of this turnabout in strategy is the realization that the customer relationship is core and, therefore, not something to be outsourced without careful consideration. The diversity that drives a segmented solution will also drive a ‘plug and play’ approach to internal and external operations, and so collaboration will happen in many and varied guises. A key requirement of a successful segmentation approach, therefore, is the ability to effectively collaborate in some markets and some parts of the supply chain, but less in others, and to be able to turn this collaboration on and off as needed. This needs to be done in a controlled, secure way to appropriate standards.

Car fleet supply

Turbines

Roads

Military capital equipment

One-off demand

Consignment stock service

Trade counters

Stationary supplies

Personal computers

Packaging supplies

Construction

Continuous demand

Electricity, water

Retailing

Mail order

Fast food restaurants

Expensive furniture

Bathrooms/ kitchens

Continuous demand

Utility

Off shelf

Deliver to order Configure to order Make to order

Figure 1: A segmentation based on customer type and delivery mechanism, with example sectors for comparison.

Design to order

Delivery mechanism JULY/AUGUST 2012

pharma-mag.com

SUPPLY CHAINS

Richard Powell

For more information

Richard Powell Managing Director and Co-Founder Crimson & Co. information@crimsonandco.com www.crimsonandco.com

Successful collaboration needs a difficult mix of hard‑nosed self‑interest, and an open and accommodating attitude to the partner. In many cases, collaboration seems an easy way out of a confusing situation, such as “we don’t know about distribution in sub‑Saharan Africa, so let’s work with someone.” This can work well only if the time has been taken to thoroughly understand the issues and choices, and to see how a partner will specifically add value. Why else might creation of a segmented supply chain fail? As with poor quality outsourcing, poor quality segmentation can occur when businesses stop taking an end‑to‑end view. At one level, there is much to be said for focusing on what you know and becoming particularly good at it. In many cases, though, this can be suboptimal both within a company and beyond it: within, this can put you at a competitive disadvantage; beyond, as part of the wider value chain, it can hamper creativity and the ability to anticipate what is round the corner. If other parts of the value chain are planning to change the way they do things — for example, as a result of a segmentation strategy — and you haven’t anticipated it, you will struggle to

participate on your terms. This is how the fast moving consumer goods companies, many with great brands that were thought unassailable, lost power to the retailers. Will pharma companies make the same mistake? Even if companies choose to focus on a specialist area, they should be aware of the entire value chain and their part in it, as well as ongoing influences, changes in market perceptions, technologies and competitive threats. What will the value chain look like in 5 years’ time? What will be the key determinants of success? Where will the margin be made? These are questions that successful niche players consider, which, in turn, keep them at the top. Pharma has many challenges that are deemed unique, but are they? Temperature control, geographic spread, strict regulations, emerging market growth, multiple product lines, innovation complexity, multiple channels to market, stringent customer expectations; many other sectors face these challenges, albeit in different ways. How do they cope with them and where are the bright stars of best practice that can show pharma companies how to beat their competition? Segmentation, done properly, can provide the answers.

Wheref d meetsPharma YO

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CASE STUDY

HAUPT PHARMA AT ICSE

Leading contract developer and manufacturer Haupt Pharma is a true veteran of ICSE and CPhI, exhibiting since the 1990s. In this interview, Hans‑Wolfram Hardtke, Vice President of Business Development, explains how the firm uses ICSE as a key opportunity to bring staff from multiple sites together with clients from around the world. Please tell us a little about Haupt Pharma Haupt Pharma is one of Europe’s leading contract drug developers and manufacturers. We provide a technology that covers most pharmaceutical dosage forms. In addition to conventional APIs, we handle various special products; for example, cytostatics, hormones, beta‑lactam antibiotics and controlled drugs. Our portfolio includes pharmaceuticals (ethical and OTC products), veterinary medicinal products, dietary supplements and cosmetics. We offer a full end‑to‑end service, from pharmaceutical development and materials procurement through to commercial production, packaging and distribution. Haupt Pharma has a total of nine production sites — six in Germany, and one each in France, Italy and Japan — and a sales office in the US. We have more than 2000 employees and serve more than 200 international pharma companies, including many of the global players. What sort of presence do you have at ICSE? We are located very centrally on the ICSE floor, with a stand of around 150 m2, which makes ours one of the largest in the area of contract manufacturing for finished dosage forms. Between 35 and 40 people are present on our stand. Last year, we offered a Bavarian buffet for the first time. There’s a lot of competition to attract visitors with social events, but nevertheless it was clear that it was a positive move, so we’ll be repeating it this year. What are your hopes and expectations of ICSE? In the 1990s, there was no major European event focused purely on contract manufacturing; we therefore attended CPhI, which focused on APIs, with the aim of meeting potential customers. Now, our primary motivation is networking and meeting existing customers. Haupt Pharma is quite well

JULY/AUGUST 2012

known around the world, and we feel that potential clients of our service will either know about us already, or discover us very quickly when they start their search for a for an outsourcing partner. What benefits do you realize from ICSE? The main benefit is the chance to meet clients from all over the world in a single location. We discuss a huge range of topics with them, from troubleshooting and performance data to ongoing contracts and day‑to‑day projects. I spend all my time in customer meetings, but some colleagues who are not so deeply involved take the opportunity to check out new competitors and their stands. We don’t have much time to listen to speakers or attend conferences — for us, it’s all business. It’s impossible to give a true figure for our return on investment from ICSE, but one way to consider it is in terms of travel costs. We have colleagues from all our sites on our stand available to meet clients, which reduces the need for business trips. If we avoid 50 trips, each of which might cost €1000, that represents a good saving, which we can offset against the cost of exhibiting. Overall, how would you rate your experience? The practical side works perfectly for us. We have an external supplier who handles everything on a turnkey basis — we just look around the day before to check everything’s OK, then we’re ready to go. In Europe, we mainly exhibit at local events in France and Italy, where we have production sites. Sometimes we attend specific fairs such as biotech events. We also attend Interphex, CPhI Japan and Contract Pharma in the US. ICSE is by far the largest and most important of the exhibitions we visit. Even though ICSE represents a significant investment for us, we’ll definitely be going again. As far as we know, there is no better event in the world!

For more information Tel. +31 20 40 99 507 icsesales@ubm.com www.icsexpo.com

pharma-mag.com

SAMPLE MANAGEMENT

THE FUTURE OF SAMPLE MANAGEMENT: Part I

Using automated sample storage facilities and automated laboratory management processes for the routine handling of large sample numbers, can increase productivity and sample throughput.

he automation of laboratory processes in the pharmaceutical industry has revolutionized the drug discovery industry during the past 20 years, leading to a rapid increase in the number of compounds identified as potential drug targets. Alongside an increase in chemical compound libraries, the number of biological samples resulting from the expansion of collaborative programmes such as The Human Genome Project and cancer screening has also escalated. This rapid increase has put a strain on traditional manual methods of sample storage and, as a result, the automation of sample storage and retrieval is an essential requirement for fast and efficient laboratory protocols.

Automated Sample Storage Solutions

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With an escalating number of compounds, small molecules, fragments, and RNAi libraries requiring safe storage, the use of traditional methods, such as freezers and refrigerators with manual labelling, rack organization, logging and placement, becomes a time-consuming, labour-intensive and error‑prone process. Pharmaceutical companies typically maintain libraries of 5000–500,000 compounds and with such large sample numbers it is unfeasible to expect completely accurate manual storage and retrieval for large‑scale, high content and genetic screening assays. As a result, it is essential to have efficient automated storage facilities with robust tube identification, computer‑based tracking and efficient sample retrieval. Early automated storage systems developed for storing large sample numbers were introduced as room‑sized stores. In such stores, sample racks or

plates logged by 1D bar coding were transported in and out of temperature‑controlled rooms (ranging from ambient to –20 °C) via large robots able to move between rack aisles. Many research establishments and drug discovery companies, however, found that the acquisition of such automated storage facilities was not viable because of the size of investment and the need to commit upfront to a large library. As such, laboratory‑based, modular compound tube storage systems have been developed, making automated sample storage and management available to research groups and easing the initial financial outlay and impact on space requirements. 1 With such modular storage units it is now possible to specify the minimum requirements for an automated storage system before investment, enabling research groups to easily upgrade and expand their storage facilities. During the conceptual development of modular storage systems, a number of fundamental requirements — including sample storage, and retrieval and the maintenance of sample integrity — were addressed. In addition to requirements for samples to be easily logged, placed and rapidly accessible, compounds need to be stored in a controlled environment to ensure sample integrity is maintained. Safe and secure storage has been successfully achieved using mechanical, or even pneumatic, transport technology for sample placement and removal within the store. By combining 2D bar code and computer technology it is possible to achieve 100% sample verification on a tube per tube basis. To date, storage systems coupled with intelligent software, which is easily integrated into lab information management systems (LIMS), provide a robust, secure and error‑free solution for sample management.

SAMPLE MANAGEMENT

% H 2O

Figure 1: Tubes purged with argon to form an inert barrier reduce water uptake within the sample during storage and freeze/thaw cycles, protecting the sample from potential moisture induced degradation. Figure courtesy of DrÂ H.Â Fayez, formerly of Wyeth Pharmaceuticals, now Pfizer Inc.

Cycle: Time (h):

Sample Integrity The maintenance of sample integrity is an essential requirement for any longâ&#x20AC;&#x2018;term store, regardless of size. Traditional manual storage methods can prove problematic, because during the placement and removal of samples freezer doors are opened to allow for rack removal. This opening exposes all stored samples to an increase in temperature

as the internal chamber is exposed to warmer, external conditions. Furthermore, the removal of an entire rack exposes each sample within the rack to ambient conditions, essentially causing it to begin to thaw. Resulting freeze/thaw cycles can be detrimental to the stability and viability of the sample. Numerous other factors may affect the quality of stored samples: contaminants, which can enter the storage chamber when as the door is opened, decomposition as a result of light exposure; concentration changes because of evaporation; and reactions with oxygen or water and precipitation. To minimize the risks of sample degradation, samples should be kept in dry, dark, cold and inert conditions.

SAMPLE MANAGEMENT

The design of automated storage and retrieval using internal robotic or pneumatic handling devices and intelligent software makes it possible to cherry‑pick individual samples from storage, thereby minimizing exposure of samples to external conditions. Sample storage under nitrogen or dry air in hermetically sealed chambers has now become the standard for sample storage facilities. In addition to storing racks in hermetically sealed chambers, it has been shown that plugging tubes with an inert gas such as Argon during the preparation of samples for storage reduces the potential risk of sample degradation resulting from moisture uptake. 2 In a study done by the Wyeth Research Liquid Sample Management team, tubes containing Dimethyl sulfoxide (DMSO) (700 µL) were subjected to multiple freeze/thaw cycles during aliquot removal. Using the Karl Fischer titration method to measure low levels of water, a comparison between DMSO samples with and without a plug of Argon demonstrated a significant difference between samples within tubes containing this inert barrier compared to air after 16 freeze/ thaw cycles during a period of 13 h (Figure 1). 3 Wendy Gaisford PhD

References

1. www.technologynetworks. com/hts/news.aspx?id=123215 2. P.E. Ilouga, et al., “Investigation of 3 Industry Wide Applied Storage Conditions for Compound Libraries,” J. Biomol. Screen. 12, 21–32 (2007). 3. H. Fayez, Lab Automation (Palm Springs, CA, USA, 23–27 January 2010). 4. S. Michael, et al., “A Robotic Platform for Quantitative High Throughput Screening,” Assay Drug. Dev. Technol. 6, 637–657 (2008).

For more information Wendy Gaisford PhD Scientific Writer TTP Labtech sales@ttplabtech.com www.ttplabtech.com

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Tube versus Plate Storage

Since the launch of low footprint modular storage systems 10 years ago, sample stores have been developed for use with tubes and plates. These stores cater for the high‑density storage of low volume samples in multiwell plates and satisfy a requirement for the handling of ‘ready to assay’ plates. Such plate storage was initially considered to be the only way to support the throughput requirements of primary screening. 2 Plate storage, however, although ideal if the entire plate is to be screened, can limit the flexibility of a library subset. Similar to the potential downfalls of freezer‑based rack storage systems, to gain access to an individual sample the entire plate must be thawed. This poses potential risks with regard to maintaining sample integrity, making plate storage less suitable for potentially unstable and delicate samples. The identification of false positives and negatives from plate‑based samples, which are not picked up until the secondary screening stage, has also raised concerns. A more efficient approach to primary screening is to screen only against library subsets that are chemically relevant to the target. Tube storage systems facilitate larger sample volumes, have the ability to select individual samples and can perform ultra‑high throughput cherry‑picking of tubes, making them an ideal sample storage method. Although multiformat

storage systems can be advantageous, it is often thought that this combination is inefficient. Adding to the complexity of these repositories, they are expensive to implement, maintain and, more importantly, difficult to expand or relocate. Furthermore, new sample submission often becomes a protracted process, which can lead to long delays before the samples are available for high‑throughput screening (HTS). These storage systems, however, are generally larger, but tend to involve slower processing times for sample input and retrieval.

From Storage to Analysis

The process of automated sample retrieval from compound or biological stores involves more than just automated sample selection and removal. Chilled or frozen samples need to be brought up to room temperature and centrifuged to maximize sample recovery. Tube caps need to be removed and samples dispensed for further analysis. The return of the remaining sample to store involves vial sealing and recapping, and the vials often need to be purged with inert gas to ensure sample integrity is maintained during storage. Automation of these processes can substantially reduce manual effort and sample handling time. In a large research unit, these processes are an important part of automated sample storage management. A number of establishments employ automated decappers and recappers, which are either used independently or integrated into sample handling platforms.

Conclusion

The manual set up of compound screening assays or high‑content screening is a time‑consuming process with repetitive serial dilutions and plate set up being required. Robotic liquid‑handling devices are used for a number of pharmaceutical applications, including chemical analysis, HTS assays, ELISA and immunoassays. With such large sample libraries present today, the elimination of manual logging, placement, removal and aliquoting reduces the potential for error, allowing scientists to concentrate on their research. The introduction of automated storage and retrieval solutions into sample management provides significant savings (cost and time), whilst increasing accuracy, throughput and laboratory productivity. The ability to automatically transfer samples from storage with plate or tube handlers to automated liquid dispensers and onto analytical or cell‑based assay workstations enhances modern drug discovery programmes today. JULY/AUGUST 2012

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NUTRACEUTICALS

‘DESIGNER FOODS’ TO GROW THROUGH M&A ACTIVITY

A business war game on 30 April between Oxford University’s Saïd and Cambridge’s Judge Business Schools, run by Fuld & Co., predicted the outcome of the so‑called ‘Battle for Designer Foods’ (nutraceuticals).

he world of food is about to change, and the companies represented by the MBA students in the war game (Abbot Nutrition, Danone, GlaxoSmithKline and Nestlé) are amongst those that will be part of the revolution. It is uncertain whether consumer packaged goods or pharmaceuticals will take control of this new space. Can the food companies compete against the pharmaceutical companies? Pharma companies, looking for growth opportunities as drug patents expire, may be better equipped to endure the costly and time‑consuming clinical trials for products. So which industry — food or pharma — and which companies, were best‑positioned to win “The Battle for Designer Foods”? A strategy game, or ‘War Game,’ is an enlightening and engaging analytical exercise that can lead to truly creative strategies. Briefly, two sets of MBA student teams represented the companies mentioned. Working in breakout rooms they created a picture of the company and developed strategic options it expects to pursue. The teams reassembled and presented their company’s marketing strategy. Teams, judges and observers had an opportunity to analyse Dr Todd Abraham, Senior and critique each others’ Vice President, Research strategies. Based on what & Nutrition at Kraft Foods and judge of “The Battle for they learned they retreated to their breakout rooms Designer Food” to refine their strategies “Having served previously as a judge for Fuld & Co.’s war games, I have seen the value a war game brings to the companies involved. then returned for a further It forces companies to strategize about alternative scenarios and critiquing session. be better prepared for the future as the dynamic competitive The facilitators then environment continues to change. “In the growing nutrition and consumer wellbeing space, the offered a fictional, but overlap between foods and supplements or even drugs continues plausible, surprise event for to get blurred. This allows companies firmly planted in the food the teams to consider. At industry to anticipate competitive threats from sources not usually considered. Competitive intelligence — anticipating what others that stage, they could talk may do based on publicly available information — is critical to to each other if they wished, preparing for the future and identifying areas where advanced and negotiate deals. scientific and business exploration should target. “In addition, as a judge for this event, I have a wonderful One of the war game’s opportunity to evaluate potential candidates for employment, as predictions include the well as hear how outsiders view our industry and its threats. Both of fact that giant consumer those benefits have made participating in the business school war games extremely valuable and rewarding.” packaged goods companies

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are likely to join forces with their pharmaceutical counterparts to catapult the nutraceuticals business in Europe and in the US into a major market, projected to be worth $250 billion in just a few years.1 With the European Food Safety Agency beginning to regulate designer foods, the war game arguments made it clear that this category will be subject to increased regulatory scrutiny on both sides of the Atlantic, requiring some of the clinical trial expertise and capabilities pharmaceutical companies bring to the market with consumer companies adding their knowledge of customer segmentation and mass market resources. “We are confident about this prediction, as past competitions have accurately forecasted events and competitive activities in a number of industries,” commented Leonard Fuld, Fuld & Company president. “This is the ninth such event run in as many years and the first between these universities with a centuries’ old rivalry.” In addition to the above general prediction, other key insights emerged, including • Tailored foods will be coming to a grocer near you: a ‘one size fits all’ model will be supplanted in the future nutraceuticals market. Consumers present many nutritional challenges and will require companies producing variety in their nutraceutical portfolio to fulfil the need for each consumer segment. • R egulators will impose stricter requirements, forcing producers to demonstrate either a product’s efficacy or health claims: currently, the designer foods industry offer products that are not required to be put through advanced, scientific testing to prove more than the basic health claims. As the interest in companies of designer food products increases, companies will migrate to issuing products that may contain compounds offering specific medicinal value; for example, treating diabetes or cardiovascular disease. Although the games’ judges cited the difficulty in adding drug compounds to foods because of dosing and other issues, companies JULY/AUGUST 2012

NUTRACEUTICALS Andrew Lake, Managing Director of Health at Vivactis Global Health and judge of “The Battle for Designer Food”

“The importance of getting into the minds of your competition, and understanding their market position and their potential future moves, cannot be understated. In the real world we often find ourselves mired in day‑to‑day fire‑fighting and the challenges of succeeding in our own space. “When food manufacturers go head‑to‑head with the pharmaceutical industry, the outcome is far from a foregone conclusion. One business sector is exceptionally talented at communicating directly with consumers, the other has unrivalled skills in the generation of robust evidence and communication to the healthcare profession. “The battleground will be (in my opinion) one of consumer branding versus healthcare recommendation and health branding. That is to say that the segment of nutraceutical consumers who do not seek medical advice (the healthy or health conscious) will likely gravitate towards brands that are available through food manufacturers as a result of their innate ability to establish trusted consumer brands. “The segment of consumers who are seeking medical advice for a condition or ailment (patients) will likely be most influenced by their doctor: patient interface, where physician or nurse recommendation for a specific brand or product will result in its use and adoption. There may well be two ‘theatres’ of war: the winning of consumer ‘hearts and minds’ and the winning of professional ‘hearts and minds.’ Who wins and who loses in each of these areas cannot be predicted, but the favourites for each customer group are clear.”

that do seek to differentiate with drug‑like treatments to achieve higher value and possibly higher prices for products in this category will find regulators likely to require firms to conduct rigorous and far more expensive clinical trials — particularly for designer foods sold by consumer package goods companies. • T he greatest advances in designer foods will come from firms with highly focused objectives and highly focused portfolios: large multinational players are likely to be at a disadvantage by having to manage too wide a portfolio of products, which will not allow them to focus on the designer foods segment. Smaller — perhaps start‑up — companies will be the ones to discover breakthroughs in this industry sector. In the “Designer Foods War Game” Fuld conducted in the US in 2011 on the same topic, risk, or fear

of risk, was a central theme, but this was less of a discussion point between the Oxford–Cambridge participants. In the Oxford–Cambridge game, teams demonstrated some concern about the risk of investing in functional foods, but chose instead to form alliances and propose acquisitions.

When do you need a War Game?

War games are about anticipating competitive moves before your rivals make them. A war game is a structured strategic exercise. It allows companies to understand unexplored, or unforeseen, strategic options. Most important, a war game shows the implications of corporate decisions months or years ahead. Typically, companies consider a war game when they face one or several of the following: • a threat from current competitors • imminent entry of new rivals • industry consolidation • change in the external environment • a threat for a new technology of a similar discontinuity.

Conclusion

War games never truly end. Although the game itself stops, the player often learns a great deal about its rivals and the competitive forces that drive the industry. Management also learns is what it does not know! If this game were run privately for one of the companies portrayed in this public event, inevitably management would identify the knowledge gaps that arise, including questions about rivals’ R&D initiatives, ability to go to market, lack of information about promotional strategy, new products in the pipeline … the list goes on. War games reveal strategic options, as well as your own flaws. They are clear mirrors for anyone wishing to see the competition and the opportunities that lie ahead. And, as this war game revealed, the nutraceuticals space certainly offers an intriguing opportunity for all those who wish to compete in it.

Leonard Fuld

Reference

1. P. Malik, “Value-Added Nutrition,” Can. J. Cardiol. 23(12), 956 (2007).

For more information Leonard Fuld President Fuld & Company www.fuld.com

pharma-mag.com

R&D

A BREATH OF FRESH AIR FOR ANAEMIA DRUGS

By studying how our bodies sense oxygen in the environment researchers at the University of Oxford have opened up a new field of research that could lead to novel drug targets for conditions including diabetes and heart disease.

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umans are able to live at an impressive range of altitudes, from below sea level to the heights of the Himalayas. This is made possible by the body’s ability to sense changes in oxygen levels and adjust its metabolic activities to suit local conditions. These oxygen‑sensing pathways are also important in a number of diseases; for example, cancer tumours are usually hypoxic (that is, they use lower than normal oxygen levels) because they are rapidly dividing. Similarly, ischaemic heart disease, such as occurs after a heart attack, can result from lowered oxygen levels in heart tissues, and diabetes sufferers can be forced to suffer limb amputation as a result of impaired oxygen delivery to tissues. With funding from the Biotechnology and Biological Sciences Research Council (BBSRC), I have been working with Peter Ratcliffe, Chris Pugh and other colleagues at Oxford to tease apart the mechanisms that allow the body to sense and respond to low oxygen levels. We have found a mechanism by which the activity of a transcription factor called hypoxia inducible factor (HIF), which is a master regulator of our body’s response to low oxygen levels, is regulated. Transcription factors are proteins that bind to DNA, controlling which portions of the genetic code are read. In response to low oxygen levels HIF turns on genes that trigger a cascade of proteins and metabolites, which, in turn, can lead to increased red blood cell and blood vessel formation. As we have shown, HIF regulates a cell’s stress response to low oxygen levels in organisms ranging from the simplest animal, Trichoplax adhaerens, all the way to humans.1 Our major discovery was identifying a mechanism by which HIF levels and activity can be changed in response to changing oxygen levels. We found that under normal atmospheric oxygen levels HIFs are broken down in a process regulated by enzymes called the HIF hydroxylases.2–4 HIF hydroxylases work by adding an oxygen atom to HIF causing it to degrade. As oxygen levels drop, fewer oxygen atoms are available for the

HIF hydroxylases and so HIF is not broken down as rapidly. This allows HIF hydroxylases to act as an ‘oxygen sensor.’ As the extent of hydroxylation drops, HIF accumulates in cells and switches on a set of genes that work to counteract the effects of hypoxia. These genes include a number that regulate red blood cell and blood vessel production. As such, we immediately realized that this process could offer new targets for drugs to treat anaemia and a range of other diseases associate with hypoxia. The next step was to produce recombinant enzymes that allowed us to deduce the crystal structures for HIF hydroxylases along with details of their mechanisms of action.5 In addition to its obvious medical applications, this work was exciting from a scientific perspective as this was the first time that the hydroxylation of a transcription factor had been shown to play a role in cell signalling. Once we had identified the HIF hydroxylases and understood their importance we then set to work on demonstrating that they could be inhibited by small molecules. We hoped that by inhibiting the action of HIF oxygenases with small molecule drugs, it would be possible to improve the body’s natural defence against damage from low oxygen concentrations by boosting blood vessel and red blood cell formation.6,7 Currently, the natural hormone erythropoietin (EPO), which is banned in sports because of its ability to boost blood cell formation, is a standard treatment for ischaemic heart disease. By blocking the HIF hydroxylases using small molecules it should be possible to achieve similar effects to EPO, possibly without causing side‑effects. To allow our early findings to be commercialized we filed a number of patents with Isis Innovation, a commercial branch of the University of Oxford founded to exploit intellectual property arising from research. In due course we formed a spin‑out company called ReOx, which set about developing selective inhibitors for HIF hydroxylases for use in animal models or cellular studies. After ReOx had been running for a couple of years, we attracted the interest of a number of JULY/AUGUST 2012

R&D pharmaceutical companies. Eventually we chose to partner with Amgen, a US California‑based company, as their major product was EPO, which, as an important treatment for anaemia, has annual sales of about $12 billion. Amgen paid a fee to gain a licence to take the technology in‑house and try to develop a new generation of EPO‑like drugs and inhibitors that will safely do the same job — EPO is a natural hormone in the body after all. Hence, we worked with Amgen to help them develop potent and selective HIF hydroxylase inhibitors. In recognition of our work setting up ReOx to develop our work on HIF hydroxylase inhibitors we were recently shortlisted as finalists in BBSRC’s innovator of the year competition. The focus of most of our work is on understanding the molecular details of fundamental biology; however, realizing that the HIF pathway had an important medical dimension we worked hard to ensure that our findings were put to good use. A key element of the work has been the close collaboration between scientists trained in chemistry and medicine. The story of our work on the HIF system has not ended with ReOx though. Our findings have raised questions regarding how big a role oxygenases play in

controlling the expression of genes in other pathways and indeed biology as a whole. Our recent work has shown that the human HIF system is present in the simplest known animals and we are pursuing the paths by which animals evolved their oxygen sensing mechanisms. The work has led to the discovery that protein hydroxylation by oxygenases is quite common in animals. Indeed in recent work, we — and others — have been working on nucleic acid hydroxylation. Aside from the HIF hydroxylases, other human hydroxylases have been associated with diseases, including cancer, and are being pursued as medicinal targets. Our long‑term goal is to contribute to comprehensive functional studies on all human oxygenases, in part out of scientific curiosity and in part to help enable the medicinal exploitation of them. A decade or so ago when there were few researchers in the field, this seemed a rather fanciful objective, but now it seems realistic.

References

1. www.nature.com/embor/journal/v12/n1/full/embor2010170a.html 2. www.sciencemag.org/content/292/5516/468 3. www.cell.com/retrieve/pii/S0092867401005074 4. www.nature.com/nature/journal/v417/n6892/full/nature00767.html 5. www.pnas.org/content/103/26/9814 6. www.jbc.org/content/278/3/1802 7. www.jneurosci.org/content/29/27/8828

Professor Chris Schofield

For more information

Professor Chris Schofield University of Oxford http://research.chem.ox.ac.uk/ christopher-schofield.aspx

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CLINICAL STRAP TRIALS

THE ROLE OF MOBILE TECHNOLOGY IN VALUE-BASED HEALThcare With the healthcare industry shifting into a new phase of value‑based healthcare, electronic patient reported outcomes (ePRO) solutions will play an increasingly vital role in providing accurate and sustained reporting on the benefits and impact of a treatment. This article will study the evolution of electronic data capture technology, paying particular attention to the rise of mobile technology, following its development in clinical and late phase, through to its emergence into the mHealth arena.

ome research reports published during recent years such as Stone and Shiftman’s “Patient Non‑Compliance with Paper Diaries” have expressed growing concern about the use of paper methods for data collection in clinical trials.1 The risk of error associated with these methods has led to a shift towards electronic data reporting within the industry. Clinical researchers are now finding electronic methods of data collection increasingly appealing to generate reliable, real‑time data. This industry shift is being recognized and embraced in industry regulations, with FDA’s 2010 Draft Industry Guidance document on Electronic Source Documentation for Clinical Investigations recommending the preferred use of electronic means of data capture, to ensure quality, reliability and traceability. In response to this movement towards electronically captured data, the industry has seen a significant evolvement in the use of technology during the past few years. Researchers are now seeking complementary methods to collect data, with mobile technology rapidly replacing traditional tools such as personal digital assistants (PDAs) because of its familiar, fast‑paced and universal nature. As the Internet can now be extended far beyond stationary PCs and onto mobile devices, users can record their experiences easily, from convenient locations. In line with this, recent reports demonstrate that 84% of the world’s population owns a mobile phone, with the total worldwide number recorded as 5.9 billion in 2011. 2

The Increasing Value of the Patient Voice

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Increasingly, the success of a drug development programme is dependant on understanding the ‘patient voice.’ The industry’s shift towards a more patient centric approach is driving the automation and simplification of patient data capture through the development of complementary technologies. An area currently benefitting from this transformation is PRO, which has seen a rise in the variety of ePRO tools that are available to study sponsors.

With recent regulatory support (evident through both FDA and EMEA guidelines) firmly behind PRO, drug developers have become increasingly open to the use of ePRO devices for data capture in clinical trials.3 The use of ePRO is seen by clinical research organizations (CROs) and sponsors as a way of streamlining the drug development process, by improving data quality and the efficiency of the regulatory submission process. ePRO tools hold the promise of higher validation of results as a result of data being captured directly from the patient without additional processing. Improving compliance and accuracy, ePRO captures the objective voice of the patient in their own environment in real time, leading to decreased patient burden, bias answers and human interference. In addition, the real‑time nature of ePRO studies enables sponsor companies to monitor patient adherence to protocol requirements, as well as a sense of how a study is progressing.

Capturing Real-Time Data with Mobile Technology

The simplicity of the data collection method is key for patient compliance. Greater trial complexity and the demand for increasing levels of data make it vital that the patient (the data source) remains responsive. Patient compliance rates can be seriously affected if the collection of PRO data becomes too complicated. As the most pervasive (universal and highly accessible) communication tool across the world, the cell phone could be key to achieving successful patient engagement throughout a trial. The increasing presence of mobile technology has resulted in technological advancements that have seen the introduction of advanced cell phone‑based solutions for electronic data collection. These solutions can significantly enhance compliance and retention rates by providing a simple and effective data collection interface. By offering a real-time, easy-to-use data capture solution that can be customized to suit the requirements of the trial, mobile‑based ePRO technology offers sponsors and CROs a unique way to collect reliable, unbiased results. A familiar user JULY/AUGUST 2012

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Answers Through Innovation

CLINICAL TRIALS interface provides easy navigation that enhances the user experience, positively affecting patient adoption and compliance, regardless of age and demographics. Questionnaires can be delivered via a series of text messages to a patient’s personal cell phone and if a response is not received within a certain timeframe, a text message reminder can be automatically sent. This is particularly valuable for late‑phase trials running for long time frames, ensuring that participants remain engaged throughout. In addition, the ability to capture real time patient data means that investigator site staff can be alerted to abnormal patient data and react accordingly to ensure patient safety. To enable users to independently record their data electronically during trials, eDiaries can be used via fixed line and the mobile Internet (on a PC or mobile device) or as a Smartphone App when more complex patient data or lengthier questionnaire responses are required. Within these methods, questionnaires can be customized to improve ease‑of‑use for the patient by including widgets such as radio buttons and check boxes. Real‑time reporting can also be easily built into the system, which enables the sponsor to view eDiary responses as they are submitted and respond quickly to any issues. As the patient‑centric approach in clinical trials becomes increasingly important, the use of mobile technology becomes more important because it is easy to use and is accessible.

Case Study — Pfizer

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Highlighting the potential of using mobile technology for PRO in clinical trials is Pfizer’s recent Research on Electronic Monitoring of OAB (overactive bladder) Treatment Experience (REMOTE) study. The Phase IV Patient Participatory Centered (PPC) clinical trial is being conducted by Pfizer and demonstrates how mobile technology can overcome hurdles such as distance to site, duration of trial and frequency of visits. With the use of mobile technology in collaboration with other technologies, patients whose location previously meant that they would be excluded from site‑based clinical trials can now participate remotely in the study. This home‑based approach enables sponsors to use otherwise untapped patient resources, thereby increasing accessibility to clinical research, and improving the overall success and accuracy of a trial. The adoption of mobile ePRO diaries is enabling Pfizer to evaluate the hypothesis that direct and personalized interaction empowers patients to actively manage their own trial remotely and report results directly to a trial investigator who keeps close oversight of patient eligibility and safety. The anticipated benefits of this approach include time savings, improved patient engagement and compliance, lower withdrawal rates, real‑time data collection and the reduction of costs associated

with the management and co‑ordination of running multiple sites.

ePRO Collection in Late‑Phase Studies

In postapproval research, which focuses on monitoring product safety, and establishing the clinical and commercial benefit of a drug in the ‘real world,’ the collection of accurate and real‑time PRO data is essential. In addition, findings in late phase can often be used to support labelling and marketing claims, local requirements, health economics data and market readiness. PRO data plays a key role in providing the information to ensure these goals can be realized. Late-phase trials often take place for a longer and undefined duration for the purpose of collecting more safety‑specific data from a large and diverse group of patients. Data is collected in a real life setting with minimal ‘touch points’ from the data collector, enabling better determination of the factors leading to treatment impact. The minimal intervention associated with late‑phase trials, coupled with their lengthy duration and the risk that the patient could become disengaged means that compliance rates are frequently low, which can result in inaccurate and incomplete PRO data. In comparison to the large budgets allocated for preregistration studies, late‑phase trials are often compounded by lower budgets. This cost issue is a key driver in late‑stage research, and usually results in low levels of technology adoption for the collection of PRO data, because of the associated hardware costs and complex logistics. As a result of the real life setting and broad patient diversity of late‑phase studies, sponsors often struggle to find and implement a PRO model that is flexible and accessible enough to be customized for use in individual participants’ lives.

Value-Based Healthcare and the Role of ePRO

As the patient voice remains a top priority in healthcare, the pharmaceutical industry is recognizing the importance of adopting healthcare outcome solutions that address the clinical and economic value of drugs across their lifecycle. The industry shift towards focusing on value‑based healthcare, with increased emphasis on health outcomes will have significant influence on the drug development process. Confirming this industry shift is the Patient Protection and Affordable Care Act (Public Law No. 111–148). This recently passed US legislation highlights the need for comparative effectiveness research, which seeks to evaluate and compare the implications and outcomes of healthcare strategies, such as medical procedures, medicines and other approaches to address a particular medical condition. JULY/AUGUST 2012

CLINICAL TRIALS Following the patient‑centric approach, the benefits and impact of a drug on a patient are rapidly becoming the main drivers in successfully moving a drug from trials to market. Where previous healthcare solutions have focused predominantly on improved medication adherence, the industry now requires integrated, personalized devices that fully support the patient through the management of their condition. mHealth solutions, which include functions such as assessments and diaries, target setters, reminders and educational information, are ideally placed to support the patient‑centred approach to healthcare through a multilayered approach. To a certain degree, these solutions are a repackaging of an already existing functionality, with their components being remarkably similar to those used to build ePRO products for pharmaceutical companies. A successful mHealth solution, however, must consider the specifics of each condition and be designed in line with the requirements of that therapy area. These complex products allow pharmaceutical companies to identify areas — patient education, helping patients meet their own health goals — that need to be addressed, while seamlessly collecting patient report information.

Mark Brincat

Conclusion As the healthcare industry increasingly shifts into a new phase of value‑based healthcare, mobile technology will play a key role in facilitating this transition. Transcending all phases of the drug development process, mobile technology offers a familiar, universal device with a simple user interface, and gives patients a voice by allowing them to participate in studies regardless of age and demographics. mHealth solutions also provide sponsors and CROs with more control of the study plus reduced costs, and increased patient engagement and compliance, regardless of the duration of the study. Addressing the challenges of collecting PRO data in the real world, mobile ePRO offers customized solutions to patients and sponsors, which can help reduce medical costs, remove geographical disparities, enhance patients’ access to medicines and, fundamentally, improve accuracy of patient reported outcomes.

References

1. www.bmj.com/content/324/7347/1193.full 2. www.itu.int/ITU-D/ict/facts/2011/material/ICTFactsFigures2011.pdf 3. www/fda.gov/ohrms/dockets/98fr/06d-0044-gdl0001.PDF

Hannah O’Gorman

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Mark Brincat Product Development Director Exco InTouch Hannah O’Gorman ePRO Project Manager Exco InTouch www.excointouch.co.uk

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GENERICS

IS THE GREEK HEALTHCARE SYSTEM ON THE RIGHT TRACK?

Pressures from the European financial community have triggered favorable reforms in Greece’s healthcare system. With some corrective actions already initiated, Greece can be back on track reducing pharmaceutical spending; a lot more work, however, needs to be done.

n response of the new austerity measures imposed by the European financial community, Greece’s healthcare is now targeted for significant reform. This was catalysed by an extraordinary spending on medicine that placed healthcare in Troika’s (European Commission, the International Monetary Fund and the European Central Bank) radar scope. According to statistics reported by the Organisation for Economic Co‑operation Development (OECD), Greece’s pharmaceutical spending both on a per capita basis (approximately $700/person) and as a percent of the total healthcare budget (25%) exceed that of most European countries, in 2010.1 The pharmaceutical spending reached alarming levels in 2007 and continued to ascend through 2010, when Andreas Loverdos became the Minister of Health. Mr Loverdos embarked on a series of policies to control the physician’s prescribing authority and reduce the budget to that in the early 2000s … which begs the question: what has changed during the last 10 years that led such an exuberant spending on medicine in Greece and how can it be fixed? This article analyses the drivers that led to this situation and raises points

for consideration that could enable a sustainable recovery in the immediate future. In addition, four basic principles that are fundamental in today’s healthcare climate — preventive care, compliance, safety and cost containment — are discussed.

Diagnosis: “Over-Spending on Medicine”

Healthcare in Greece is based on a mixture of public and private services funded by the state budget, social insurance contributions and private spending. Public and private expenditures together reached $30 billion or approximately $2700 on a per capita basis by 2010; nearly double that of year 2000.1 In an effort to stop further ascent, Loverdos implemented a number of policies to control the number of prescriptions issued by physicians, which resulted in a 5.4% reduction of the overall healthcare budget by the end of 2011.1 That year, spending on medicines fell sharply by 27%, to €$4.1 billion ($5.5 billion), still about 8% above Loverdos’s target of €2.8 billion ($3.7 billion). 2 The target was higher than Troika’s recommendation for 1% of the gross domestic product (GDP) or $2.8 billion — lower than what

Figure 1: Health expenditure as % of GDP in OECD countries, 2008.4

54 pharma-mag.com

JULY/AUGUST 2012

STRAP GENERICS Germany and France spent: 1.9% of GDP in 2009 per OECD. 1 Between 2000 and 2011, Greece’s healthcare spending has been increasing steadily at a compound annual growth rate (CAGR) of about 8.5%, exceeding the country’s GDP growth rate, currently in a negative territory.3 According to OECD Health Data, the fastest growing contributor for such increase has been out‑of‑pocket payments (CAGR +11.5%), accounting for 37% (about $11 billion) of the total spending (Figure 1). 4 Typically, these monies include payments for physicians, diagnostic centers and medicine, which are not reimbursable by the national health insurance or employers. The percentage is among the highest in Europe: the average among EU27 states is 25% and for developed countries such as Germany and France out‑of‑pocket payments account for approximately 20% from total spending. According to the World Health Organisation (WHO), the balance of the healthcare expenditures is covered from taxation (29%) and social insurance (31%) (Figure 2). 5 Together the two components reflect the total public spending of Greece’s healthcare system. Greece’s public spending reached $19 billion in 2010, which is double that in 2000.1 Troika deemed the increase as significantly higher than that of most developed European countries; yet, on a per capita basis it was (20–40%) below that of the EU5 states, no particular concerns were raised. As a result, out‑of‑pocket spending and restructuring of the public healthcare system received the greatest attention and became the target of Loverdos’s reform efforts. To achieve such targets, understanding the root cause of the problem and finding viable and sustainable solutions are paramount. The medical profession and pharmacies have been key in Loverdos’s reforms and rightfully so. According to OECD, there are six physicians and 0.9 pharmacies for every 1000 inhabitants in Greece. 1 In Germany and France, there are on average 3.5 physicians and 0.3 pharmacies, respectively. The impact of such ratios has been an ever‑decreasing profitability for healthcare providers, and higher costs for patients and the overall health system. How? The presence of an overcrowded medical market has led physicians to overprescribe, frequently placing emphasis on the most lucrative and best‑promoted brands. The problem is more pronounced in smaller cities where physicians tend to work with select pharmacies and medical centers. Being commission driven such relations ultimately lead to an overprescribed environment, too. The situation is similar for pharmacists who support their own network of preferred relationships. Although there is nothing illegal about recommending a customer to friends, the patient and the healthcare system end up JULY/AUGUST 2012

becoming burdened with an irrationally excessive amount of prescriptions and spending.

The Prescribed Treatment: Generics

In the past, the costs of overprescription were considered irrelevant, as it was absorbed by the social insurances and the state. Now that the funds have dried, the cost is passed straight to the consumer — who is now left to absorb the premiums paid for branded drugs (70–80% higher than those for generic) — the inflated margins to wholesalers and retailers (50–60%) and commissions to physicians (25–30%).6 It is estimated that combined, the cost to the patient is approximately 3.8x of the manufacturer’s price, after the customary discounts. 6 Assuming a 75% use of generics, the cost to the patient could drop to 2.3x of the manufacturer’s price. 6 In reality, the cost is expected to be lower, as the margins and commissions along the value chain would be inherently controlled. Shift toward generics is simply the smart thing to do, particularly now as medicine worth 10s of billions in sales go off‑patent each year. Between 2003 and 2013, medicine with value of $137 billion will have lost patent protection in eight key markets (Figure 3). 7 On average, therefore, more than 20% of the branded market is turning over to the generic side. Of course, this has resulted in tremendous losses for the pharmaceutical innovators but, it has brought great savings for the consumer — typically a 70% drop in price occurs, only few months following loss of patent. Table I lists some of the most known brands that have just turned or will turn generic by the end of 2012. The shift to generics will not deprive any physician of their popular treatment choice. It is estimated that 50% of today’s prescribed medicines are considered primary therapies (for example, hypertension, osteoporosis, asthma, depression); such medicine will enter the generic stage in the next 5 years, becoming available at 50% or below the manufacturing cost.7 Today, only 18% off the prescribed drugs in Greece are generic.8 In the US and Germany this number reaches 80%, whereas the average use among the remaining European states approaches 50%. The savings from

Figure 2: Components of health expenditures in Greece.5

Figure 3: Value of products at risk (2003–2013).7

pharma-mag.com

GENERICS

Table I: Patent expirations 2011–2012.

Brand name

Generic name

Actos

Pioglitazone

Type 2 diabetes

Takeda

Piogitazone & Metformin

Type 2 diabetes

Takeda

Caduet

Amlodipine & Atovarstatin

High blood pressure

Pfizer

Combivir

Lamivudine & Zidovudine

HIV

Glaxo Smith Kline

Concerta

Methylphenidate HCl

ADHD/ADD

Johnson & Johnson

Enbrel

Etanercept

Arthritis

Amgen

Geodon

Ziprasidone

Schizophrenia, bipolar disorder

Pfizer

Levaquin

Levofloxacin

Antibiotics

Johnson & Johnson

Lexapro

Escitalopram

Depression, anxiety

Forest laboratories

Lipitor

Atovarstatin

High cholesterol

Pfizer

Plavix

Clopitrogel

Myocardial reinfarction

Bristol-Myers Squibb

Protonix

Pantoprazome

Acid reflux

Pfizer

Provigil

Modafinil

Sleep disorders

Cephalon

Seroquel

Quetiapine

Antipsychotic

AstraZeneca

Singulair

Montelukast

Asthma

Merck

Solodyn

Minocycline

Moderate/severe acne

Medicis Pharmaceuticals

Tricor

Fenofibrate

High cholesterol

Abbott

Zyprexa

Olanzapine

Antipsychotic

Eli Lilly

% Generics Total Generics scripts spending ($) ($) 18 25 32 39 46 53 60 67 74 81

pharma-mag.com

Innovator company

Actos plus Met

using generics can be impressive, but many have chosen to undervalue. According to IMS, in the US the savings from choosing the same drug as a generic versus brand amounted to $121 billion or about $382 per capita in 2009. 9 With many generics ultimately becoming available over‑the‑ counter (OTC), the US patient has increased their savings further by avoiding the cost of repeat physician visits. Most frequently consumers use OTC products as a preventive care remedy, to treat mild chronic health conditions or to respond to a nonlife‑threatening emergency. Of course, the use of OTC medicine requires an informed consumer who can read the product’s label and if needed with help of the pharmacist select the most relevant formulation for him. Table II: The impact of higher generic utilization on total spending ($ billion).

Condition

5.50 5.23 4.98 4.75 4.54 4.34 4.15 3.98 3.82 3.67

0.99 1.04 1.08 1.13 1.16 1.20 1.23 1.27 1.30 1.32

Brand ($) 4.51 4.19 3.90 3.63 3.37 3.14 2.92 2.71 2.52 2.35

In the US, initial information regarding which OTC to use may be obtained from the family physician, the neighborhood pharmacist or public media. Medicine such as Omeprazole, Ranitidine, Loperamide, Benadryl, Neosporin, Ceritizine and others are available at lower cost relative to prescribed branded or generic products. Such medicines are readily accessible on the shelves of most pharmacies and supermarkets. With the OTC market rapidly growing (estimated to be 10% of the overall pharmaceutical market), patients can benefit from the additional savings. 10 Why? To ensure proper use, OTC products are properly labeled so that the patient can select the supplier with the proper formulation for him. So, to reduce spending costs across the pharmaceutical chain reforms must encourage the use of generic and OTC drugs, and limit the number of prescriptions issued by physicians. Taking such direction could trim billions from Greece’s pharmaceutical spending and provide significant financial relief to consumers. Simple maths suggest that, for every $1 spent on generic medicine $5 dollars can be saved, which would be spent on branded medicine. The savings would be even greater if OTC medicine were used, when available. It is the author’s opinion that the use of generics would drive competition across the value chain, lowering margins and commissions across the value chain and increasing savings to the patient by another $0.5–1.0. Translating this into JULY/AUGUST 2012

GENERICS total savings for the Greek healthcare system, the $5.5 billion in Loverdo’s pharmaceuticals spending could be reduced to $3.7 billion by increasing the use of generics from 18% to 80% (Table II). 6 Such shift would require at least 4 years to implement as it would require associated structural and cultural changes in Greece’s healthcare system. To ensure compliance, commission to physicians from pharmaceutical companies will have to be declared illegal and margins for branded medicine at pharmacies must be capped according by therapy categories; a specially commissioned governmental team reporting through the ministry of health should control compliance. Most people are intentionally led (by healthcare professionals showing preference on branded products) to believe that generics and OTC are not safe. Perhaps it is time for the government to step in and change such mistaken notion. Generic manufacturers are subject to same EMEA regulations as branded drugs. Besides, more is information is available for generic and OTC drugs (versus branded), as they have at least 10 years in the market and their safety profile is elucidated by millions of users. The use of generic and OTC medicine has far reaching impact that goes beyond cost saving for the consumer or reduction of the healthcare budget; it benefits the country’s pharmaceutical industry, which currently focuses on exportation for revenues. Increased revenues from domestic use would reduce importation, create job opportunities and result in the reduction in Greece’s soaring trade benefit. To harvest the economic benefits from using Generics and OTC medicine, the government’s efforts need to go beyond compliance and influence the development of a culture of preventive care. A governmental body should be established to drive the dissemination of useful information on health to the public and stakeholders across the healthcare value chain. Such information should address drug safety, comparative treatments and practices, epidemiology alerts and other preventive care subject matter. Preventive care should also be promoted through employers and reinforced in public education. The goal would be to promote well‑being through better living and by doing so contribute to the sustainability in healthcare spending. As a result, diabetes driven by early‑age poor eating habits, respiratory diseases catalysed by smoking, hypertension problems from lack of exercise and inadequate uptake of nutrients can be controlled and dealt with before requiring extraordinary and expensive treatments. Given today’s advanced IT, the task promoting preventive care and should be easy to attain. JULY/AUGUST 2012

Accessibility and affordability is another important aspect in healthcare, as it affects the largest and weaker part of the population. Given the state of the unemployment and aged population in Greece, accessibility and affordability require special attention. The author suggests that a national warehouse of commonly used medicine, including immunizations is established. Medicine stored in such a warehouse would be for consumption by public hospitals. Low‑income citizens could buy such medicine with a special discount from such hospital select pharmacies, too. The procurement and distribution of this medicine would be managed by professional supply chain managers in the field, under the oversight of the Greek ministry of health. The managers would have the additional responsibility to set national guidelines on procurement against which the private sector (pharmacies and wholesales) would be audited to ensure consumer safety (that is, drug producer’s regulatory compliance), cost containment and security of supply. This would be particularly important with the sourcing and distribution of generic and OTC medicine. Together with the compliance team, the supply chain management team would set the golden standards for the safe, cost‑effective and secure procurement and distribution of medicine.

Conclusion

That healthcare in Greece should no longer be left to the hands of special interests; it should serve the consumer. To do this, measures to ensure accountability and performance should be set by the Greek ministry of health and expected by every stakeholder in the pharmaceutical value chain. The use of generics and OTC medicine should increase to more than 80%. To reduce dependency on imports of generics, Greek companies contributing to the production of medicine for domestic consumption would be given special tax benefits with the requirement that part of the profits be reinvested to drive growth, competition and value for the society. The government should play a leading role on preventive care, which should be the main lever to sustainability. Though this article, the author hopes to stimulate some thinking around the effective development of regulations and business practices that will put Greece’s healthcare on a sustainable track. Loverdos’s efforts need to be on the right path, but much more needs to be done on meet the targets he set. In business terms “a plan for superior execution” needs to be put in place, where the tasks and responsibilities are transparent and all parties involved take ownership on the benefits and losses from the successful implementation of such plan.

Ioannis I. Valvis

References

http://stats.oecd.org/Index. aspx?DataSetCode=SHA 2. www.genengnews.com/ gen-news-highlights/withprogress-on-debt-accordgreece-scrambles-to-cutpharma-costs/81246345 3. www.tradingeconomics.com 4. www.janssen-emea. com/sites/default/files/ The%20Future%20Of%20 Healthcare%20in%20Europe. pdf 5. www.euro.who.int/__data/ assets/pdf_file/0004/130729/ e94660.pdf 6. Author’s analysis (2012). 7. www.imshealth.com/ imshealth/Global/ Content/Document/ Market_Measurement_TL/ Generic_Medicines_GA.pdf 8. www.fiercepharma.com/story/ greece-adopts-more-drugbudget-cuts/2012-03-01 9. www.optometricmanagement. com/articleviewer. aspx?articleid=106424 10. IMS, “Health The Rising Tide of OTC In Europe” (2010). For more information Ioannis I. Valvis Director, Supply Chain Management NovoSynth Pharmaceuticals LLC Tel. +1 302 598 8644 ioval@novosynthpharmaceuticals.com www.novosynthpharmaceuticals.com

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BUSINESS SHOWCASE Compact, High Efficiency Cold Trap & Freeze Dryer Genevac has announced a new version of its miVac SpeedTrap™ frost-free cold trap that not only provides unmatched volatile solvent recovery but now also enables freeze drying of up to 250ml of aqueous samples. The new generation SpeedTrap™ is suitable for use with a wide range of solvents, from volatile organic solvents through to water and even higher boiling point solvents. While it is designed to complement the miVac series of concentrators it can also be used with other manufacturer’s concentrators, provided that the solvents concentrated are compatible. The new SpeedTrap is very small in size and requires little bench space, being only 212 mm (8.3 inches) wide. The SpeedTrap operates with the cold condenser coils suspended directly in the vapour path - solvent vapours condense directly on to the coils and run off into the collection vessel below. The benefits to this method are: highly efficient, with more than twice the condensing power of similar cold trap systems ; users can quickly see the solvents in the trap and emptying the trap is easy, requiring no defrosting. An automatic defrost mode ensures that the user does not need to spend time defrosting the system, even when using water. Visit www.evaporatorinfo.com/info4.htm, www.Genevac.com/movie/miVac or contact Genevac on +44-1473-240000 / +1-845-255-5000 or salesinfo@ genevac.co.uk

Innovative Sample Storage Technologies Thermo Fisher Scientific brings you a complete range of sample storage products to give you peace of mind. • Assured storage and superior tube tracking - Thermo Scientific Nunc Cryobank Tubes are available in 0.5, 1.0, 2.0 and 5.0 mL capacities, supplied in standard ANSI microplate footprint racks. A unique, laser etched 2D code allows superior sample tracking with sample management software. The Cryobank™ low binding surface allows maximum recovery of low concentration samples. • Perfect labels, time after time - The Thermo Scientific ID Scribe Labware Identifier permanently and legibly marks and color codes your storage tubes and general labware, preventing sample loss and misidentification from label misreads. The ID Scribe™ minimizes your sample handling time and reduces the risk of repetitive strain injuries from manual tube labeling. Visit www.thermoscientific.com/idscribe to see how Thermo Fisher Scientific can help give you peace of mind.

Measom Freer Goes Metric

Measom Freer has added 2 NEW sizes to its popular Metric bottle range, the 60ml and 1 Litre options are UK manufactured in clear PVC with other materials and colours available to order. The range now consists of 17 sizes ranging from 2.5 ml to I Litre, with Measom Freer also stocking a wide variety of caps, closures and pumps to complete the product. Whether you are looking for a dropper cap for reagents and samples, a screw cap bottle for specimen storage or a more functional gel/ spray pump for cleaning solutions , they have a huge variety of closures available from stock. Why not try our new ecommerce website where you can order direct from stock for a fast, efficient delivery. Contact their Sales Team to find out more about how these great value packaging products can enhance your brand image and shelf presence. In addition, their stock packaging has a minimum order quantity of just a single box which means minimal lead-times, optimising your cash flow and stock management.

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Tel +44 (0)116 2881588, Fax +44 (0)116 2813000, sales@measomfreer.co.uk or you can now buy online at www.measomfreer.co.uk

Rockwell Automation Extends PlantPAx Process Automation System to Capture Motor Control Investments, Driving Higher Asset Availability and Significant Energy Savings PlantPAx process automation system optimises user uptime and improves profitability by integrating motor control devices into a plantwide control system Rockwell Automation has extended the reach of its PlantPAx process automation system to integrate critical rotating assets, such as compressors, pumps, turbines and fans, giving users the ability to manage plantwide operations with a single platform. The PlantPAx system combines the company’s core process automation capabilities and technologies with those of partners and acquisitions to deliver an integrated control and information solution for customers. For more information about Rockwell Automation’s process solutions, visit the dedicated portal at http://www.emea.rockwellautomation.com/process/en/ index.aspx Users now can tie intelligent motor devices into this unified-control architecture, making an immediate and measurable impact on asset availability, operational efficiency and energy management. The tight integration between process automation and motor control is especially beneficial in heavy industrial applications with considerable mechanical investments, such as: metals, mining, cement, power, oil and gas, water/wastewater, and pulp and paper applications. PlantPAx system users will have access to diagnostic information on any device in the system from any location – including: motor control centers, drives, compressors, pumps, fans and instrumentation. Leveraging the EtherNet/IP network, engineers can monitor process conditions such as electric motor current, vibration signatures of key rotating assets and torque signatures of variable speed drives. This allows plant engineers to predict potential problems and help avoid equipment downtime – resulting in improved productivity and reduced maintenance costs.

For more information email aburt@ra.rockwell.com or visit www.rockwellautomation.com To advertise here call +44 (0) 1372 364 124 or email sales@via-medialtd.com pharma-mag.com 58

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