Pharma Mar 2011

w w w. p h a r m a - m a g . c o m March/April 2011 ISSN 1746-174X

Volume 7 Number 2

The global magazine for the pharmaceutical and biopharmaceutical industry

Aseptic Processes Trends, techniques and technologies

Vaccines

Novel targets for cancer vaccine development

Facility Design Plants with agility

SOLID DOSAGE Developing Textures with Polyols

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March/April 2011

STAFF

Contributors Editor Corrine Lawrence +44 (0) 771 517 7767 corrine.lawrence@via-medialtd.com

Publisher/Sales Director Fred Winsor +44 (0) 1372 364 125 fred.winsor@via-medialtd.com

Editorial Director Kevin Robinson +44 (0) 1392 202 591 kevin.robinson@via-medialtd.com

Financial Controller Catherine Swainson +44 (0) 1372 364 122

Art Director/Production Paul Andrews Tel. +44 (0) 1372 364 126 paul.andrews@via-medialtd.com

General Manager Miranda Docherty +44 (0) 1372 364 125

catherine.swainson@via-medialtd.com

miranda.docherty@via-medialtd.com

Content/Marketing Manager Claire Day Tel. +44 (0) 1372 364 129 claire.day@via-medialtd.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.

Carlos Lopez Relationship Director Healthcare & Pharmaceuticals Lloyds TSB Corporate Markets

Harald Stahl Senior Pharmaceutical Technologist GEA Pharma Systems

Kurt Speckhals Gino Martini Director, Strategic Technologies Senior Director, Supply Chain Pfizer Inc. GSK (UK) Jim McKiernan Chief Executive Officer McKiernan Associates GmbH Maireadh Pedersen Head of Business Development Quay Pharma

Geoff Tovey Visiting Professor Dept of Pharmacy King’s College Wes Wheeler President, WPWheeler LLC

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

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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.

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March/April 2011

CONTENTS

Contents FOCUS TOPICS

08

Solid Dosage

MARCH/APRIL 2011

For up-to-date news follow us on Twitter (PharmaMag) and join our Pharma group discussions on LinkedIn

Contributing Companies: GEA Pharma Systems,

Avantor and Roquette Frères.

The authors highlight microwave drying, trends and

46

developing textures with polyols.

22

Gregory Berman and Sarah Wren — PA Consulting

Aseptic Processes Contributing Companies: SCM Pharma,

Helapet, Aseptic Technologies, Reig Jofre and Top Clean Packaging/Silicone.

Generics: Generics are Dead!

Long Live Generics!

By embracing the emerging payment‑by‑results model and new technologies, generics companies stand to reap the rewards of the drive to do more with less.

Industry experts provide a snapshot of current trends, techniques and

50

technologies defining pharmaceutical aseptic processes.

Software/IT: Rhythms of Life David Munt — GenSight

Using genetic algorithms to inspire evolutionary

FEATURES

progress in pharmaceutical R&D.

TAP: Novel 32 Vaccines: Targets for Cancer Vaccine Development

54

Glynn Wilson — TapImmune Inc.

Micha Schwing — Getty Images

A promising platform for the development of a range of novel cancer therapeutics that are HLA‑specific and tumour‑specific.

36

How the use of photography can help the pharma industry to connect with patients.

Plant/Facility Design: Black to the Future: Plants with Agility

56

Wim J. Spook — Matcon Ltd

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Health & Safety: Maintaining a Glass-Free Production Environment

Chris Payne — Fotolec Technologies Ltd

Reflecting on the role of lawyers and litigation in the wake of the reports of the negative effects of the Avandia litigation on GSK’s profits.

REGULARS

05

New regulations and the use of fragment retention lamps can reduce the risk of glass contamination in pharmaceutical manufacturing.

Does making things better only make things worse?

Analytical Methods: Developing and Validating Analytical Methods for Cleaning Verification

06

Gary A. Baker, James Hamby, Brian Spencer and

44

apprehension of disclosure can be overcome, it will be

58

pharmaceutical company into a successful business.

March/April 2011

Nostrapharmus: Navigating the Perfect Storm

Nostrapharmus

Claudio Gallina — Vormittag Associates Inc. and

Implementing an automated inventory management system can turn a

Tom Beil — Sigma-Aldrich/SAFC, Rx-360

easy to draw on shared information to make better decisions.

Inventory Management: Track, Trace and Replenish

Isaac Rogers — Smith Drug Company

Comment: A Matter of Trust

Once the issue of trust can be addressed and

Stephen A. Munk — Ash Stevens

regulatory compliance in a multi‑use pharmaceutical facility.

From the Editor: A Conundrum

Corrine Lawrence

42

Designing an effective programme to ensure patient safety and

Litigation: Minimizing Litigation Pain

Luca G. Radicati di Brozolo — Bonelli Erede Pappalardo

How a two-floor design that incorporates the ‘black to white’ concept can create agile solid dosage facilities.

Marketing: A Picture Can Paint a Thousand Words

Nostrapharmus explores how life science organizations are going to have to navigate the perfect storm to shape the future of patient safety.

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th D P e o lu w n C or ’t s! on ld m fe -le iss re a nc di e ng

STAFF

Contributors Editor Corrine Lawrence +44 (0) 771 517 7767 corrine.lawrence@via-medialtd.com

Publisher/Sales Director Fred Winsor +44 (0) 1372 364 125 fred.winsor@via-medialtd.com

Editorial Director Kevin Robinson +44 (0) 1392 202 591 kevin.robinson@via-medialtd.com

Financial Controller Catherine Swainson +44 (0) 1372 364 122

Art Director/Production Paul Andrews Tel. +44 (0) 1372 364 126 paul.andrews@via-medialtd.com

General Manager Miranda Docherty +44 (0) 1372 364 125

catherine.swainson@via-medialtd.com

miranda.docherty@via-medialtd.com

Content/Marketing Manager Claire Day Tel. +44 (0) 1372 364 129 claire.day@via-medialtd.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.

Rory Budihandojo Director, Quality Systems Audit Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd

The Global Nutraceutical Event 10 - 12 May 2011 GENEVA PALEXPO | Switzerland Register today: �

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Jim McKiernan Chief Executive Officer McKiernan Associates GmbH Maireadh Pedersen Head of Business Development Quay Pharma

Geoff Tovey Visiting Professor Dept of Pharmacy King’s College Wes Wheeler President, WPWheeler LLC

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

Plus FREE entry to:

Registered Office:

Via Media UK Ltd, 22 Highacre, Dorking, Surrey RH4 3BF, UK. The publisher endeavours to collect and include complete, correct and current information in Pharma but does not warrant that any or all such information is complete, correct or current.

The publisher does not assume, and hereby disclaims, any liability to any person or entity for any loss or damage caused by errors or omissions of any kind, whether resulting from negligence, accident or any other cause. Pharma does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take any responsibility for any losses or other damages incurred by readers in reliance on such content.

Copyright © 2011, Via Media UK Ltd All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording or information storage and retrieval system, without permission in writing from the publisher.

Send permission request in writing to Permissions Department, Pharma, Fax +44 870 487 3469.

Authorisation to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted for libraries and other users registered with the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK (ISSN: 1742-447X).

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Maik W. Jornitz Senior Vice President Global Product Management, Bioprocess Sartorius North America Inc.

Kurt Speckhals Gino Martini Director, Strategic Technologies Senior Director, Supply Chain Pfizer Inc. GSK (UK)

Professionals working within the industries we cover may receive Pharma free of charge on completion of a registration card. Individuals in other industries or countries may purchase a year’s subscription by sending a cheque for £100 made payable to : Via Media UK Ltd by post to: Via Media UK Ltd, Wesley House, Bull Hill, Leatherhead, Surrey, KT22 7AH, UK.

Register online now for FREE at www.vitafoods.eu.com/pharma Portfolio includes

Enric Jo Plant Director Reig Jofre Group

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March/April 2011

FROM THE EDITOR

A Conundrum

N

o doubt, we have all experienced moments of unrest at work; moments when we’d rather be somewhere else … and I’m not just talking about regular Monday morning blues. Yet, take that work away and we’re unhappy for a host of other reasons. Redundancy, alas, is still running amok, casting misery indiscriminately. It seems that no profession or industry is beyond its reach. If you haven’t been directly affected by redundancy, it is likely that you know someone who has. And its effects can be devastating — not only financially, but how it can strip people of their identity and self‑worth.

Many companies continue to consolidate, optimize and become more ‘lean’ to remain profitable and competitive. I know the feelings that come with redundancy announcements. Although I was spared, I watched while entire departments were told that they were being dispensed with. Once the initial shock dissipated, those of us that were left turned our thoughts to strategy — how were we going to maintain output levels? But here’s the thing … we did. So, what were

we doing previously? If the same amount of work can be done using fewer people, then surely the company was inefficient or has now chosen to cut corners?

Alternatively, perhaps superior technology is replacing people as the economic climate is forcing companies to focus on optimization, and concentrate on areas of expertise and innovation with a sense of urgency. But, surely the more efficient we become and the smarter our technology gets, the greater the likelihood that more people will lose their jobs? As we become more sophisticated, the issue of redundancy is ever more exacerbated. Perhaps BioCity Nottingham has the answer: in the wake of Pfizer announcing the closure of its R&D site in Sandwich (Kent, UK), the now redundant pool of talented scientists could, perhaps, strike out and forge new pharma companies.

Last year, BioCity Nottingham responded to the closure of AstraZeneca’s Charnwood plant by offering the company’s former employees practical advice and support, which has led to the emergence of several new ventures. But then, how many pharma companies can the market support?

Corrine Lawrence Editor, Pharma corrine.lawrence@via-medialtd.com

WHEATON|Roller Culture Apparatus Technology Leader in Volume Production and Flexibility > Optimum growth environment for monolayer, adherent cell production > Proven technology increases production yields and reduces cost > Link up to 255 units to optional software that monitors, controls, and records for GMP or FDA requirements > Built-in Monitoring and Alarms on R2P models > Add capacity and options without revalidating > Fully customizable from research to production For more information, call us at 856.776.4254 or email Kate Gove at kate.gove@wheaton.com 8816

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COMMENT

A MATTER OF TRUST

Sharing information that can potentially be used competitively is a commonly shared concern within the pharmaceutical industry. The real trust issue, however, is in our supply chain security.

T

For more information

Tom Beil Vice President, Quality & Regulatory Affairs Sigma-Aldrich/ SAFC Board member, Rx-360

6

he International Pharmaceutical Supply Chain Consortium (known as Rx‑360), which was launched in June 2009, consists of regulators, pharmaceutical executives, supplier executives and members of professional organizations, to serve patients. Rx‑360’s mission is to create and monitor a global quality system that meets industry and regulators’ expectations, and to ensure patient safety by guaranteeing product quality and authenticity at every stage of the supply chain.

Sharing appropriate supplier audit information and conducting joint audits are primary goals of Rx‑360. The consortium’s audit‑sharing process makes available the wealth of supplier audit information that already exists within its constituent companies, in an effort to make the process more cost‑effective and audits more robust, and to allow pharmaceutical companies to gain more knowledge about suppliers.

A subcommittee within Rx‑360 — The Audit Standards Working Group — focuses on standardizing audits and auditors. Last year, we launched the Rx‑360 pilot programme to share existing sponsor audits, to determine the value to Rx‑360 members of sharing existing audits and the effectiveness of the audit‑sharing process. One of the subcommittee’s functions, and that of Rx‑360 in general, is to educate and share through identifying the essential points within an audit and turning these into a ‘to do’ list. In September 2010, the US Federal Trade Commission endorsed the shared audit programme by granting a Positive Advisory Opinion, thereby further enabling the efforts of our committee.

The pilot programme will initially collect audit reports and responses associated with 30 suppliers from the US, Europe, China and India. Plans are now in place to commence these audits in the first quarter of 2011.

The first few days of a 3 to 4‑day audit typically focus on basics (for example, water purity, training), before the critical issues are addressed. When devising the audit‑sharing process, our thinking was to capture that information and leverage what we already know. From my own company’s standpoint, as a fine chemicals supplier we would save on fewer audits and the time it takes to host them; as a producer we would benefit by being part of a consortium that can do

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100 audits for the same monetary or man‑hour investment that it would take my staff to do 20–30 audits.

The work of the Audit Standards Working Group is split into six subgroups that consist of 27 participants from 19 different companies and organizations: APIs, excipients, supply chain security, basic chemicals, packaging and print. The first four subgroups are now active, with packaging and print likely to be added after completion of the initial pilot programme. All of the standards for APIs, excipients and basic chemicals have been finalized and will be used in the pilot, with their effectiveness and suitability being reviewed in early 2011 through auditor and auditee feedback.

Three standards will be used within the pilot programme — APIs, excipients and basic chemicals — in conjunction with a supply chain security checklist, which is to be used alongside all of the other standards. This list has now been reviewed, prior to launch, and the supplier and manufacturer teams have determined the balance of security and cGMP appropriate level of quality systems. An additional pilot programme is in the process of gathering the audits of eight suppliers already completed by Rx‑360 members as additional audits and these will be made available to share with members.

Spending an excessive amount of time gathering the same information in a hundred different ways is neither efficient nor helpful. It is similarly nonsensical, for example, when 100 customers audit one facility, whilst 99 facilities go unaudited. At the core of Rx‑360 is an ethos of not shying away from your responsibilities, but being able to more efficiently utilize and share information among companies. Within the pharmaceutical industry, safety is not supposed to be a competitive advantage; it is a necessity and something that we all have to achieve.

To do this we need to work together, as our needs are not unique and we can save months, if not years, in learning how best to set up the programme.

Once the issue of trust can be addressed and apprehension of disclosure can be overcome, we will be pleasantly surprised how easy it is to draw on shared information to make good decisions on quality and safety. Through collaboration, we will access more and richer data, in an increasingly efficient manner, to make better decisions.

March/April 2011

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SOLID DOSAGE

MICROWAVE DRYING

It is still relatively unknown to some, but microwave drying is an accepted drying method for pharmaceutical formulations. The author highlights the important aspects of microwaves and their relevance to pharmaceutical processing.

M

icrowaves are a form of electromagnetic energy with frequencies of 300 MHz–300 GHz, generated by magnetrons under the combined force of an electric and a magnetic field perpendicular to each other (Figure 1). In the electromagnetic spectrum they fall between radio waves and optical waves. For domestic, scientific, medical and industrial purposes

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two frequencies are allocated that do not interfere with communications frequencies: 915 MHz and 2450 MHz. In the pharmaceutical industry the most common frequency used is 2450 MHz, because of the advantages it offers in conjunction with a vacuum. 1 Microwave fields are reflected off metals, which they do not heat. For this reason metals are used as conduits for the microwaves, or wave‑guides, and

March/April 2011

SOLID DOSAGE as walls for a microwave oven. As pharmaceutical equipment is manufactured from stainless steel, the vacuum chamber acts as confinement for the microwaves by reflecting them back into the chamber.

Many materials are transparent to microwaves and do not heat; for example, quartz glass and polytetrafluoroethylene (PTFE), which can be used as microwave windows. The most important property of microwave fields, however, is the absorption of microwaves by the materials, because materials that absorb microwaves are heated. 2 Microwave heating is a direct method of heating.

In the rapidly alternating electric field generated by microwaves, polar materials orient and reorient themselves according to the direction of the field.

The rapid changes in the field — at 2450 MHz, the orientation of the field changes 2450 million times/s — cause rapid re-orientation of the molecules, resulting in friction and heat creation (Figure 2). This type of heating is instantaneous, uniform and penetrating throughout the material, which is a great advantage for the processing of pharmaceutical compounds. 2 As already mentioned above, different materials have different properties when exposed to microwaves, related to the extent of absorption of the microwaves. The amount of microwave energy absorbed is expressed by the following equation: 3 P = 2 π f v 2 E 0 E r tanδ Where P = the power density of the material = energy absorbed (W/m 3)

f = frequency (Hz)

v = electric field (V/m) E 0 = dielectric permissivity of free space (8.85 x 10-12 F/m)

E r = dielectric constant of the material

tanδ = loss tangent.

For a given material and a given electric field, 2 π f v 2 E 0 is constant, and the absorbed microwave energy is proportional to the term E r tanδ, called the loss factor. Materials with a high loss factor will readily absorb microwave energy, whereas materials with a low loss factor are either reflecting or transparent for microwave energy.

Given the characteristics of the materials commonly used in pharmaceutical production (Table I), microwave energy is particularly well suited for the drying of pharmaceutical formulations.

The liquids most frequently used for wet granulation (water, alcohol) have much higher loss factors than the other standard ingredients for a wet granulation (lactose, cornstarch), leading to higher absorption of microwave energy and thus preferential heating of the liquids. For many materials these properties

March/April 2011

Figure 1: An electromagnetic wave in free space.

Figure 1

Given the characteristics of the materials commonly used in pharmaceutical production, microwave energy is particularly well suited for the drying of pharmaceutical formulations. have been investigated and are published in tables and monographs. 4 It is important to note that the loss factor changes with the temperature of the product. This phenomenon is related to the relaxation frequency of materials — the time required for build‑up and decay of the order induced by an electric field.

This frequency increases with the temperature of the material. As the efficiency, or the amount of energy converted into heat by each cycle of dipole rotation, is optimum when the microwave frequency coincides with the relaxation frequency, the amount of microwaves absorbed by a material — and thus the loss factor — will differ with the temperature of the material. In Figure 3, the change in loss factor with the temperature of some food products is

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SOLID DOSAGE

The History of Microwave Technology

The first applications of microwave energy for heating and drying date back to the 1930s. 15 The development of the magnetron during the Second World War presented a challenge to the engineering and scientific world to develop industrial applications for this technology. During the decades that followed major developments in the design of magnetrons and extensive investigation of material properties have led to the adoption of microwave applications in several industry sectors, such as the food, rubber, ceramics, paper and other industries.5 Medical applications for microwaves were developed as early as the 1950s.16,17 Compared with other industry sectors, the pharmaceutical industry has been a late adopter of microwave technology. Only in 1979 the initial concept of combining microwave and vacuum was proposed by ICI, and the first static‑bowl microwave‑dryer prototypes were developed in collaboration with T.K. Fielder. In the same year, Dr Schwabe and IMI developed a microwave vacuum belt dryer for drying plant extracts. 6 Although the static microwave dryer proved the potential qualities of microwave drying for the pharmaceutical industry, problems such as caking and local overheating led to the development of agitated microwave dryers in the mid-1980s and the first combined high‑shear granulator‑microwave dryer (Spectrum) was introduced by T.K. Fielder in 1987, followed by N.V. Collette in 1989 with the Vactron.6,18 The interest in microwave technology was high, as demonstrated by the fact that as early as 1989, an FDA workshop was held during which four major US pharmaceutical companies presented their experiences with the technology to more than 100 FDA staff, and AAPS dedicated a symposium to this new technology at their Annual Meeting.19 During the following decade, microwave drying gained a strong foothold in pharmaceutical production, despite its slower‑than‑expected adoption rate and now, more than 100 microwave dryers are in use at pharmaceutical companies worldwide to manufacture a variety of drugs, many of which many are FDA approved. 6

Water

Molecular polarization

Figure 2

Figure 2: Di-pole rotation in a microwave field.

10

illustrated. As can be seen, the loss factor of water decreases with increasing temperature, because at room temperature, the relaxation frequency of the small water molecules is already larger than the microwave frequency, and with increasing temperature it moves further from the microwave frequency, resulting in a lower absorption of microwave energy.

For larger molecules, however, the relaxation frequency at room temperature is often lower than the microwave frequency, and with increasing temperature it moves closer to the microwave frequency, resulting in more energy conversion. This increased absorption of microwave energy will result in an increased temperature, which in its turn will again lead to increased absorption. This phenomenon is called thermal run‑away, and is illustrated in Figure 4. As most pharmaceutical processes are executed at a temperature lower than the critical temperature of the most common pharmaceutical ingredients and the modern microwave dryers are executed with accurate product temperature control,

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the risk of encountering thermal run‑away in a pharmaceutical process is minimal. 2,5 Another important characteristic of microwaves, particularly regarding the combination with vacuum drying is the breakdown electric field of gases. This characteristic is the electric field at which a discharge of the gas will take place. At atmospheric pressures, the risk of a breakdown is low, because the high frequency breakdown electric field is high. When the pressure is reduced, the breakdown electric field is significantly lowered, thereby increasing the risk for a breakdown.

A discharge of the gas can be observed as a glow or arc, and is disadvantageous because of possible damage to the product or the equipment and because it represents loss of power. 5 Many precautions have been taken to avoid such discharges in modern microwave dryers.

Microwave Drying Systems

Although microwaves are used in different types of equipment, for example, microwave vacuum belt dryers, this paper will only discuss the so‑called single-pot systems, or high shear granulator dryers, equipped with microwave drying capacity. 6 Magnetrons are the source of microwave energy and have either a fixed or a variable output. Fixed output magnetrons regulate the forwarded power to the processing vessel by cycling on and off. Usually, they have a low power and several magnetrons are mounted on the lid of the bowl to allow step‑wise control of the microwave input into the product.

Variable output magnetrons control power directly by adjusting wattage and usually have a higher

March/April 2011

March/April 2011

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SOLID DOSAGE Figure 3: Loss factor versus temperature.

Loss factor

Figure 4: Thermal run-away phenomenon.

Temperature (ºC) Figure 3

Figure 4

Early reports on experiments with the prototypes of microwave dryers often reported problems with temperature control of the product.

12

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output level. They are located in a separate area and the microwaves are guided to the processing vessel by wave‑guides. This setup facilitates easier access for servicing, but requires proper tuning of the wave‑guides to avoid the reflection of microwaves to the magnetron. As magnetrons generate heat, they have to be cooled using either air or water. The latter is the most efficient way given the greater heat capacity. 1 Modern microwave dryers are equipped with several features to ensure safe operation of the system for the operator, the product and the equipment. All microwave equipment has to comply with the guidelines for microwave leakage specified by the Center for Devices and Radiological Health within FDA and by the American National Standards Institute, which is 5-mW/cm 2 maximum exposure at a distance of 5 cm from any surface of the microwave cavity and at a frequency of 2450 MHz. 7,8 The equipment manufacturers include safety features such as microwave chokes and conductive seals into the design of microwave processors to avoid any microwave leakage from the vessel. Furthermore, the available microwave systems are designed with safety interlocks to avoid accidental exposure; for example, microwaves can only be activated when the process vessel is operating under vacuum and all bowl openings are sealed off.

Early reports on experiments with the prototypes of microwave dryers often reported problems with temperature control of the product, arcing, local overheating and even burning of the product. These problems were predominantly related to design issues or lack of experience with microwave drying.

All modern microwave dryers have an optimized design for microwave drying; for example, sharp edges and loose contacts between metal parts are avoided, because discharges could occur there. In addition, the control systems have been optimized to include different process controls, such as temperature control, microwave reflection control and arc detection. Important parameters, including forwarded power, reflected power, product temperature and energy added, can be monitored in real‑time and maximum limits can be set to control the process. Finally, to avoid local overheating of the product the option to mix at low speed or to use a swinging bowl to move the product is offered.

Process Considerations

Directly connected to the early observations mentioned were concerns about a possible influence of microwave drying on the granule characteristics and stability of the product. Many studies have

March/April 2011

SOLID DOSAGE Table I: Loss factors of commonly used ingredients for pharmaceutical formulations.

15. R.A. Moss, AAPS Annual Meeting (Washington, DC, USA, November 1991).

16. R. Poska, Pharm. Eng. 11(1), 9–13 (1991).

17. K. Van Scoik, AAPS Annual Meeting (Washington, DC, USA, November 1991).

18. Fed. Reg 60:6163861643, FDA (Washington, DC, USA) November 1995.

19. P. Robin, L.J. Lucisano and D.M. Pearlswig, Pharmaceut. Tech. 18(5), 28–36 (1994).

For more information

Griet Van Vaerenbergh Product Manager Single Pot Processing GEA Pharma Systems nv Tel. +32 3 350 1211 griet.vanvaerenbergh@geagroup.com www.geapharmasystems.com

Commonly used excipients Commonly used solvents Maize starch 0.41 Methanol 13.6 Avicel 0.15 Water 12.0 Carbonate 0.08 Ethanol 8.6 Manitol 0.06 Isopropanol 2.9 Calcium Phosphate 0.06 Acetone 1.25 Calcium Carbonate 0.03 (Ice 0.003) Lactose 0.048 (Polypropylene 0.0027) (Teflon 0.0003)

Table I

temperature slightly above or below the product temperature to avoid caking of the product.

Endpoint control of the drying process is another important aspect of the microwave drying process. All microwave dryers can use product temperature as an endpoint for microwave drying.

Product temperature is a good indicator for the end of the drying process if the formulation contains ingredients with a relatively high loss factor such as cornstarch. If, however, the formulation contains only ingredients with a low loss factor (for example lactose), product temperature will rise very slowly, and over‑drying could occur if the endpoint of drying is only based on product temperature. In those cases, the amount of reflected power gives a good additional indication

for the endpoint, as reflected power will increase towards the end of the process, because less microwave energy is absorbed into the product.

In addition, some systems are equipped with a calibrated power measurement (forwarded and reflected), which allows the calculation of the exact amount of energy added to the product.

This added energy amount can then be used as a validated endpoint for drying if a known amount of liquid has to be evaporated.

Conclusions

Although microwave technology has been around since the Second World War, its application in the pharmaceutical industry is relatively recent.

Single–pot processors equipped with microwave drying were only introduced 15 years ago.

The properties of microwaves, however, make them particularly suited to dry pharmaceutical formulations quickly and elegantly. The modern microwave drying systems are all equipped with the necessary safety measures to ensure completely safe processing for both operator and product. Nevertheless, careful design of the process parameters is necessary to obtain optimal results from the microwave technology in pharmaceutical production.

Trends in Solid Dosage Forms

T

For more information Liliana Miinea Senior Research Chemist Avantor

Nandu Deorka Director, R&D Avantor www.avantormaterials.com

16

he pharmaceutical industry’s desire to reduce cost, innovate and commercialize value-added products demands new approaches to how it makes and delivers drugs. Solid dosage forms, the most established and preferred administration route, offers opportunity for innovation through the utilization of novel materials such as performance excipients and efficient manufacturing processes. In fact, orally disintegrating tablets (ODT) are quickly becoming mainstream as they gain acceptance as effective product life-cycle management tools.

The ability to combine novel excipients with taste masking technologies are making ODT solutions cost effective and broadly appealing. The last few decades have also seen a surge in controlled-released solid dosage forms given their ability to control the rate of drug release over an extended period of time and/or target specific sites. The advances in oral controlled-release dosage forms made possible by

www.pharma-mag.com

new coating technologies (tablets; multiparticulate systems), matrix systems, slowly eroding devices and osmotically controlled devices are all based, in part, on the progress achieved in designing novel functional polymers and/or coating and manufacturing technologies. Although the future prospects of these dosage forms are encouraging, major hurdles remains.

These include in vitro–in vivo correlation, improving bioavailability of poorly soluble drugs, prolongation of gastric residence time, dependence of drug delivery rate on the gastrointestinal tract hydrodynamic conditions, effect of drug solubility on the performance of the delivery system, tablet size limitation, oral delivery of biologics, and complex manufacturing techniques and equipment that render current technologies expensive.

A lot of work is ongoing to overcome these barriers.

Further, progress will be achieved by addressing drug delivery in an interdisciplinary manner where cell biology, biochemistry, physiology, pharmaceutics and material science will be major contributors.

March/April 2011

Big Business

March/April 2011

in China

www.pharma-mag.com

13

SOLID DOSAGE References

1. H. Püschner, Wärme durch Mikrowellen, Philips Technical Library (Eindhoven, The Netherlands, 1964).

2. A.C. Metaxas and R.J. Meredith, Industrial Microwave Heating, Power Engineering Series 4 (Peter Peregrinus Ltd, London, UK, 1983).

3. J.E. Roberts and H.F. Cook, Br. J. Appl.

Phys. 3(2), 33–40 (1952).

4. B.W. Clark, Trans.

Am. Acad. Ophth.

Otolaryngol. 56(4), 600–607 (1952).

5. H. Stahl, Pharmaceut.

Tech. Eur. 12(5), 23 (2000).

6. M.S. Waldron, Proceedings of the 2nd Single Pot Processing Workshop (Collette, Wommelgem, Belgium, 25–26 February 2002).

7. L.J. Lucisano and R.P. Poska, Pharmaceut.

Tech. 14(4), 38–42 (1990).

8. T.P. Garcia and J.L. Lucisano, Handbook of Pharmaceutical Granulation Technology, Drugs and the Pharmaceutical Sciences, Vol. 81 (Marcel Dekker, New York, NY, USA, 1997) pp 303–331.

9. B. Krieger and R.D. Allen, Annual Meeting of the Rubber Division of the American Chemical Society.

10. M.S. Waldron, Pharmaceut. Eng. 8(1), 9–13 (1988).

11. A. Wade, Handbook of Pharmaceutical Excipients (The Pharmaceutical Press, Washington, DC, USA, 1994).

12. 21 CFR Part 1030 (Washington, DC, USA, 1 April 1988), 461–464.

13. ANSI C.95.1‑1982; American National Standards Institute (New York, NY, USA) 1982.

14. T.K. Mandal, Drug Dev. Ind. Pharm. 21(14), 1683–1688 (1995).

14

Vacuum and microwave power levels are also important regarding the porosity of the granules. since been published showing no difference in either stability or physicochemical properties of the granules dried with microwave–vacuum processing compared with other drying methods such as tray drying or fluid bed drying. As microwaves are non‑ionizing and lack the necessary amount of energy required for the formation of free radicals or the liberation of bound water, there are no conditions created during microwave drying that foster product instability. 1,9–12 The fact that many drugs, manufactured with microwave–vacuum processing, have been approved

by FDA and other regulatory bodies worldwide without requiring additional stability or analytical testing — apart from that normally required for other manufacturing methods — corroborates the safety of using microwaves for drying pharmaceutical formulations. 1 It also refutes the fear of many companies that in the case of a change of the manufacturing process to microwave drying the regulatory bodies would require extensive validation, stability and analytical data. A conversion from an approved manufacturing process to a microwave drying process for an immediate release solid oral dosage form in the US is governed by FDA’s SUPAC IR Guidance document, similar to any other change in such a manufacturing process. 13 In 1992, a survey was conducted by Robin and colleagues of eight European regulatory bodies to determine the implications of converting an approved fluid bed drying process to a microwave drying process.

None of the agencies required more data than could

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be expected for similar types of manufacturing changes (change in process or equipment). Most of the agencies required only process validation data and three suggested limited stability data (up to 6 months of accelerated data). 14 The design of a microwave drying process, however, still requires careful consideration of the different parameters involved and their interaction to arrive at an optimal result. The interaction between the pressure in the bowl and the microwave level is a particularly important considerartion. As explained above, the risk of electric breakdown increases when the pressure in the bowl decreases; yet, when a higher pressure is used for the process, the evaporation temperature of a granulation liquid is also higher, leading to the fact that in the initial phase of the drying process, the microwave energy will probably be used to heat up the product instead of for evaporation. Depending on the temperature sensitivity of the product, an optimal balance between pressure and microwave level needs to be determined. To avoid any adverse effects of the use of microwaves outside the practical range of pressures, most manufacturers of microwave single-pot processors have restricted the pressure range in which microwaves can be activated to 30–100 mbar.

Vacuum and microwave power levels are also important regarding the porosity of the granules.

As microwaves are instant and penetrating, the granulation liquid inside the granules can evaporate immediately after the microwaves are switched on. If the evaporation rate exceeds the migration rate of the vapour towards the granule surface, a pressure build-up inside the granule can occur, possibly leading to granule explosion and the creation of fines. Lowering the microwave power level or increasing the working pressure may eliminate this effect.

Other parameters to consider are the method and frequency of product agitation. Agitating the product is necessary to ensure an even power distribution throughout the product bed: too much agitation can lead to attrition of the granules and creation of fines. For this reason, very low mixer speeds and the option for intermittent mixing are available for all single-pot processors. Using a swinging bowl to agitate the product is an alternative to the mixer arm.

Finally, the control of the jacket temperature during microwave drying can affect the yield of the process. As the microwaves supply most of the energy needed for drying, the heated jacket of the bowl does not need to act as an energy source.

Its temperature, therefore, can be controlled to a

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15

SOLID DOSAGE Table I: Loss factors of commonly used ingredients for pharmaceutical formulations.

15. R.A. Moss, AAPS Annual Meeting (Washington, DC, USA, November 1991).

16. R. Poska, Pharm. Eng. 11(1), 9–13 (1991).

17. K. Van Scoik, AAPS Annual Meeting (Washington, DC, USA, November 1991).

18. Fed. Reg 60:6163861643, FDA (Washington, DC, USA) November 1995.

19. P. Robin, L.J. Lucisano and D.M. Pearlswig, Pharmaceut. Tech. 18(5), 28–36 (1994).

For more information

Griet Van Vaerenbergh Product Manager Single Pot Processing GEA Pharma Systems nv Tel. +32 3 350 1211 griet.vanvaerenbergh@geagroup.com

www.geagroup.com

Commonly used excipients Commonly used solvents Maize starch 0.41 Methanol 13.6 Avicel 0.15 Water 12.0 Carbonate 0.08 Ethanol 8.6 Manitol 0.06 Isopropanol 2.9 Calcium Phosphate 0.06 Acetone 1.25 Calcium Carbonate 0.03 (Ice 0.003) Lactose 0.048 (Polypropylene 0.0027) (Teflon 0.0003)

Table I

temperature slightly above or below the product temperature to avoid caking of the product.

Endpoint control of the drying process is another important aspect of the microwave drying process. All microwave dryers can use product temperature as an endpoint for microwave drying.

Product temperature is a good indicator for the end of the drying process if the formulation contains ingredients with a relatively high loss factor such as cornstarch. If, however, the formulation contains only ingredients with a low loss factor (for example lactose), product temperature will rise very slowly, and over‑drying could occur if the endpoint of drying is only based on product temperature. In those cases, the amount of reflected power gives a good additional indication

for the endpoint, as reflected power will increase towards the end of the process, because less microwave energy is absorbed into the product.

In addition, some systems are equipped with a calibrated power measurement (forwarded and reflected), which allows the calculation of the exact amount of energy added to the product.

This added energy amount can then be used as a validated endpoint for drying if a known amount of liquid has to be evaporated.

Conclusions

Although microwave technology has been around since the Second World War, its application in the pharmaceutical industry is relatively recent.

Single–pot processors equipped with microwave drying were only introduced 15 years ago.

The properties of microwaves, however, make them particularly suited to dry pharmaceutical formulations quickly and elegantly. The modern microwave drying systems are all equipped with the necessary safety measures to ensure completely safe processing for both operator and product. Nevertheless, careful design of the process parameters is necessary to obtain optimal results from the microwave technology in pharmaceutical production.

Trends in Solid Dosage Forms

T

For more information Liliana Miinea Senior Research Chemist Avantor

Nandu Deorka Director, R&D Avantor www.avantormaterials.com

16

he pharmaceutical industry’s desire to reduce cost, innovate and commercialize value-added products demands new approaches to how it makes and delivers drugs. Solid dosage forms, the most established and preferred administration route, offers opportunity for innovation through the utilization of novel materials such as performance excipients and efficient manufacturing processes. In fact, orally disintegrating tablets (ODT) are quickly becoming mainstream as they gain acceptance as effective product life-cycle management tools.

The ability to combine novel excipients with taste masking technologies are making ODT solutions cost effective and broadly appealing. The last few decades have also seen a surge in controlled-released solid dosage forms given their ability to control the rate of drug release over an extended period of time and/or target specific sites. The advances in oral controlled-release dosage forms made possible by

www.pharma-mag.com

new coating technologies (tablets; multiparticulate systems), matrix systems, slowly eroding devices and osmotically controlled devices are all based, in part, on the progress achieved in designing novel functional polymers and/or coating and manufacturing technologies. Although the future prospects of these dosage forms are encouraging, major hurdles remains.

These include in vitro–in vivo correlation, improving bioavailability of poorly soluble drugs, prolongation of gastric residence time, dependence of drug delivery rate on the gastrointestinal tract hydrodynamic conditions, effect of drug solubility on the performance of the delivery system, tablet size limitation, oral delivery of biologics, and complex manufacturing techniques and equipment that render current technologies expensive.

A lot of work is ongoing to overcome these barriers.

Further, progress will be achieved by addressing drug delivery in an interdisciplinary manner where cell biology, biochemistry, physiology, pharmaceutics and material science will be major contributors.

March/April 2011

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17

SOLID DOSAGE

DEVELOPING TEXTURES WITH DC POLYOLS The authors propose different methodologies for assessing the feelings of brittleness, crunchiness and melting in the mouth upon chewing tablets formulated with polyols.

T

he development of solid dosage forms that can be chewed or easily dispersed in the mouth is particularly attractive for the paediatric and geriatric markets. 1 A key challenge for the final patient’s acceptance is in the design of tablets having an appealing texture, as well as an acceptable taste and mouthfeel. 2,3 The selection of excipients is critical in achieving a tablet’s disintegration in the oral cavity, a pleasant mouthfeel, and robust tablets that can withstand processing and transportation.

Our DC polyols range displays a palette of different textures as a result of their inherent physicochemical properties, such as enthalpy of dissolution and crytal shapes. 4 For instance, Xylitol exhibits a cooling effect upon dissolution in the mouth and tablets containing maltitol provide a ‘crunchy’ sensation when chewed. 5–7 The purpose of this study was to propose different methodologies for assessing the feelings of brittleness, crunchiness and melting in the mouth upon chewing tablets formulated with polyols.

Materials and Methods Materials

The directly compressible polyols used in this study were maltitol (SweetPearl P300DC; Roquette Frères, France), xylitol (XYLISORB DC; Roquette Frères, France) and sorbitol (NEOSORB P300DC; Roquette Frères, France). Magnesium stearate as a lubricant was purchased from Bärlocher (Germany).

Preparation of Tablets The polyols and the lubricant were blended in a Turbula T2C blender (Willy A. Bachofen, France) for 5 min (Table I). The tablets were prepared by direct Polyol (qsp 100 %w/w) XYLISORB DC NEOSORBP300DC SweetPearl P300DC Table I: Formulas.

18

Table I

www.pharma-mag.com

Magnesium stearate (%w/w) 1.2 0.8 1.2

compression using single punch tabletting press FETTE Exacta 21 (FETTE Compacting, Germany) equipped with 16‑mm flat beveled‑edge punches whilst applying increasing compression forces (10–30 kN). The press was set to achieve identical tablet weights (1200 mg).

Physical Properties of Tablets The prepared tablets were evaluated for physical parameters, such as thickness — using a standard micrometer and hardness — using an ERWEKA TBH 30 GMD hardness tester (ERWEKA GmbH, Germany).

Development of an In Vitro Sensory Evaluation Test The test was developed using a texture analyser that records applied forces through probes. Two tablet quarters were placed side by side in a specially designed cup. Then a 10‑mm diameter probe on contact with the top of the tablet pieces went down at a constant rate. The resulting variation of the force was recorded along 3.5 mm of the displacement of the probe inside the tablet. The fragmentation process of the tablet upon collapsing appeared as multiple peaks (Figure 1). Each test was repeated four times. The overall quantity and frequency of the peaks would be a good indicator of the sensation of “crunchiness” during chewing of the tablet.

In Vivo Sensory Evaluation Test A panel conducted sensory evaluations. The panel comprising 23 people was trained to perceive three sensory descriptors: • B rittleness — the breakdown of the tablet into two to four pieces after one bite.

• C runchiness — the persistence of solid individual fragments after one bite.

• M elting of the crystals — the quick melting and disappearance of crystals in the mouth.

The perceived intensity of these three sensory attributes was rated by each individual on a scale of 0–7 (where 0 = not apparent and 7 = very apparent).

The statistical analyses were performed with ANOVA Friedman and Wilcoxon tests.

March/April 2011

SOLID DOSAGE

Results and Discussion

1 – Number of peaks

Figure 1: Schematic representation of a fragmentation profile recorded by the Instron Texturizer.

Force (N)

Study of the Compression Settings on Tablet’s Properties NEOSORB P300DC, SweetPearl P300DC and XYLISORB DC were compacted at increasing compression forces of 10, 20 and 30 kN. The hardness of the tablets increased with the compression force until 20 kN. NEOSORB P300DC tablets exhibit the maximum hardness at 20 KN and gave higher hardness values than SweetPearl P300DC and XYLISORB DC tablets for all compression forces (Table II).

The compression profiles for SweetPearl P300DC shows also the maximum hardness at the compression force of 20 kN above which there is a decrease of hardness. For the compression profile of XYLISORB DC, it can be observed that the hardness is still increasing at 30 kN and this product could be compressed at a higher compression force than 30 kN. For texture evaluation, tablet hardness of 250 N and 100 N were selected.

2-Height = pF Each peak = a break or a ‘micro-break’ of the tablet

Displacement (mm)

Figure 2: In vivo sensorial analysis of 100 N tablets.

Figure 3: In vivo sensorial analysis of 250 N tablets.

Figure 4: Percentage of acceptance of the different poyols.

Figure 1

In Vitro Sensory Evaluation There is practically no fragmentation observed for NEOSORB P300 DC tablets. The curves are flattened in comparison with tablets made of SweetPearl P300DC and XYLISORB DC. This result was observed for both 100 N and 250 N tablets. Accordingly, the maximum force required to breakdown the tablet increased with the increase in tablet hardness (Table III). When we consider the maximum force required for disruption of XYLISORB DC tablets, this force is higher for both 100 N and 250 N tablets than for NEOSORB P300 DC tablets. We observe also that the number of peaks

Figure 4

March/April 2011

Figure 2

Figure 3

References

1. T .M. Michele, et al., “Safety of Chewable Tablets for Children,” J. Asthma 39(5), 391–403 (2002).

2. P. Van Arnum, “Pediatric Formulations: Technical and Regulatory Considerations,” Pharmaceut. Techn. 33(8) (Suppl.) s58–67 (2009).

3. H . Suzuki, et al., “Acetaminophen‑Containing Chewable Tablets with Suppressed Bitterness and Improved Oral Feeling,” Int. J. Pharm. 278(1), 51–61 (2004).

4. C . Dusautois, “Creative and Reliable DC Formulations with Roquette’s DC Polyols Portfolio,” Pharma & Healthcare News 11, 4 (2009).

5. P .M. Olinger and T. Pepper, “Xylitol,” in L.O. Nabors, Ed. Alternative Sweeteners (Marcel Dekker, New York, NY, USA, 2001), pp 335–365.

6. R. Wilson, Ingredients Handbook: Sweeteners, 3rd Edition (Blackwell Publishing, 2007), pp 251–270.

7. H . Mitchell, Sweeteners and Sugar Alternatives in Food Technology (Blackwell Publishing, 2006), pp 295–317.

www.pharma-mag.com

19

SOLID DOSAGE

Table II: Physical properties of tablets (mean ± SD).

SweetPearl

P300 DC

Table III: Maximum force applied and number of peaks recorded by the Instron Texturizer.

XYLISORB DC

NEOSORB

P300 DC

Compression force (kN) 10 20 30 10 20 30 4 9 10 20 30

Weight (mg) 1186 +/- 2.1 1235 +/- 4.5 1193 +/- 4.7 1198 +/- 1 .2 1198 +/- 1.6 1203 +/- 2.9 1209 +/- 1.7 1206 +/- 6.9 1210 +/- 9.1 1193+/- 1.6 1198+/- 2.5

Thickness (mm) 4.72 4.50 4.18 4.87 4.47 4.34 6.29 5.42 5.26 4.54 4.39

Hardness (N) 59.4 +/- 5.8 318.6 +/- 11.2 272.6 +/- 33.8 86.6 +/- 10.9 192.6 +/- 19.3 248.5 +/- 39.5 115 +/- 3.5 283.8 +/- 28.3 365.2 +/- 29.1 469.5 +/- 91.7 435.8 +/- 115.1

Table II

Tabet hardness 100 N

XYLISORB DC SweetPearl P300DC NEOSORB P300 DC

Maximum force (N) 179 +/- 61 53 +/- 10 82 +/- 9

Tablet hardness 250 N

Number of peaks 38 +/- 5,74 12 +/- 0,6 2 +/- 0,5

Maximum force (N) 359 +/- 21 265 +/- 27 278 +/- 82

Number of peaks 21 +/- 2,6 6 +/- 0,5 1 +/- 0,81

Table III

is multiplied approximately 20‑fold. These results highlight different behaviours for the two polyols and, therefore, would confirm differences in the perception of these two polyols upon chewing and dissolution in the mouth. The SweetPearl P300DC tablets exhibit an intermediate behaviour between NEOSORB P300 DC and XYLISORB DC tablets.

In Vivo Sensory Evaluation

For more information Yves Bourteel Mechanical and Sensorial Evaluation Expert José Lis Tabletting Team Expert Delphine Damour Pharmaceutical and Powder Technology Manager Sophie Chesnoy Pharmaceutical Project Development Manager Philippe Lefevre Pharmaceutical and Powder Technology Development Coordinator Roquette Frères www.roquette.com

20

In vivo, NEOSORB P300 DC tablets are characterized mainly by a sensation of melting and practically no crunchiness. In comparison, XYLISORB DC tablets exhibit both crunchiness and melting sensations (Figure 2). SweetPearl P300DC tablets are characterized by a dominant perception of crunchiness.

There is no statistical difference in the perception of crunchiness between SweetPearl P300DC and XYLISORB DC tablets. Conversely, XYLISORB DC and SweetPearl P300DC tablets are significantly crunchier than NEOSORB P300 DC tablets.

We observe similar profiles as for the 100 N tablets. For a tablet’s hardness of 250 N, however, XYLISORB DC tablets are significantly crunchier than SweetPearl P300DC tablets (Figure 3).

In Vivo Versus In Vitro Sensory Evaluation When we compare both in vitro and in vivo sensory evaluation testing, we can correlate the difference in behaviour of the tablet during fragmentation under pressure with differences in the crunchiness

www.pharma-mag.com

and melting attributes. NEOSORB P300 DC tablets are characterized by a predominance of melting sensation upon chewing probably as a result of the particular crystalline shape of the particles and high compressibility of the powder, which is in agreement with the rather flat fragmentation curve.

SweetPearl P300DC tablets exhibit more crunchiness.

XYLISORB DC tablets combine both melting and crunchiness attributes. Both SweetPearl P300DC and XYLISORB DC have the crunchiness anticipated from their fragmentation curves.

The overall acceptance from a palatability point of view between these three polyols was evaluated.

There is a clear preference for XYLISORB DC tablets with approximately 70% of the entire panel (Figure 4).

Conclusion

This study describes two different methodologies for sensory evaluation of two attributes — crunchiness and melting. The differences observed in both attributes can be directly linked to the compressibility behaviour and the crystal shape of the powder, and more specifically to the rearrangement and the brittleness of the different polyols under compression.

The in vivo study has revealed that the evaluation of both crunchiness and melting is a good combination for predicting a good taste and mouthfeel.

March/April 2011

SOLID DOSAGE

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21

ASEPTIC PROCESSES

THE CLEANING AND DISINFECTION CHALLENGE

References

1. T he Orange Guide: Rules and Guidance for Pharmaceutical Manufacturers and Distributors (Pharmaceutical Press, UK, 2007) .

2. S.J. Hiom, C. Lowe and M. Oldcorne, “Validation of Disinfection in Hospital, Pharmacy Aseptic Units,” Pharmaceut. J. 272, 611–614 (2004).

For more information Helapet Ltd sales@helepet.co.uk www.heleapet.co.uk

C

lean room and aseptic managers have a daily challenge of keeping aseptic areas for manufacturing pharmaceuticals as free as possible from microbial contamination.

Alcohols remain the disinfection of choice as they have rapid evaporation properties and leave no residues, thereby offering excellent control over the microbial contamination commonly found in clean room environments.

Before disinfection can take place, the area must be ‘cleaned’ with a good quality pH‑neutral detergent to remove debris and residues from prior cleaning agents, such as alcohols and biocide residues. Alcohols will not control fungal spores, but a good quality broad‑spectrum biocide may be used weekly/monthly as part of the clean room cleaning protocol to control this. Alcohols are also widely used for aseptic transfer — the specialist technique of transferring components for manufacture within an isolator cabinet or sterile

area, from storage through two aseptic transfers to the sterile zone, thereby minimizing contamination that is taken into the critical area.

Aseptic areas also require that both the cleaning product and the packaging are sterile prior to use and that spray products should have a closed system that prevents the ingress of potentially contaminated air into the sterile contents. Components from storage are liberally sprayed with alcohol and wiped with a nonlinting wipes to remove any endotoxins before being transferred to the clean room. This process is repeated a second time, before the items are admitted into the isolator environment. Care should be taken to ensure that all areas are covered and that the bottom of bottles and vials are not forgotten.

Aseptic techniques are performed using strict protocols and these can be undermined by poor technique. These techniques should be in line with The Orange Guide and can be validated using a validation method developed by NHS Wales.1,2

CHALLENGES AND TRENDS

M

For more information Neal Wesley Technical Director SCM Pharma www.scm-pharma.com

22

anufacturing medicines aseptically is, to say the least, challenging.

Some of the obstacles that have to be overcome include redundant equipment graveyards, because of totally dedicated equipment, and huge spend losses in vessels, isolators, pumps and other equipment being rendered unusable following dedicated production.

In addition, because traditional sanitization processes are not directly transferable/compatible with flexible disposable systems, this can lead to novel techniques requiring the development and redevelopment of established sanitization processes (cycle developments, etc.). As such, equipment dedication remains an issue, but there is a move towards disposable, less expensive equipment, such as flexible disposable isolators instead of hard walled stainless steel. And, as detecting highly potent products at increasingly lower limits of detection and quantification can be difficult, cleaning verification and validation has become of paramount importance — and more focused. If you can demonstrate that you can clean an item of equipment, then you can reuse it.

www.pharma-mag.com

Using presterilized primary closures may be a solution to these verification and validation challenges, which has contributed to their increased use. Vials and ampoules, for example, are purchased already sterilized, so their closures do not require steam sterilization, dry heat sterilization or irradiation prior to aseptic manufacturing.

Negating the requirement to develop bespoke cycles that end up costing significantly more than originally anticipated can offset the initial and apparently high costs of using such closures. Faster room clearances and less clean room downtime also offset the cost. By the time you develop a sterilization cycle, validate it and prove it, the cost is already quite high, as is the relative risk.

Unless the cycle is going to be reused many times, it’s often not worth the effort. This is frequently the case with clinical trial materials, which are only made once or twice.

The added costs of presterilized primary closures can, therefore, rapidly be offset unless you are manufacturing the same thing, many times over. At the same time, there is a general move towards cartridge fills from traditional ampoules and vials. This is in line with a trended shift toward self-administration IV medicines.

March/April 2011

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Two-day pharmaceutical conference & post-conference workshop 14-15th June 2011, Hotel Concorde, Berlin

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The industry is changing and so is forecasting excellence - get involved with new executive speakers and topics that provide answers to help make the unpredictable, predictable 12 weeks of in-depth research of the pharma forecasting industry with directors and senior managers from the top 50 pharma companies such as Novartis, AstraZeneca and Roche has ensured we know exactly what YOU need to know about forecast techniques and strategy for changing pharma climate We have confirmed senior forecasters from companies like Johnson and Johnson and Actelion to present riveting case-studies on the processes they use Stimulating debate: get involved in interactive discussions with forward-thinking forecasters in discussions, scheduled sessions and dedicated networking opportunities – this is the premier European pharma forecasting event so you can be sure the biggest names are there A tightly-focused and comprehensive agenda that deals with the biggest issues affecting global forecasting functions. We’ll be investigating challenging aspects of forecasting and getting answers on what value redesigning your processes will bring The best industry speakers- combining global and European forecasters to bring you a true representation of pharma as we know it Global Sponsors:

March/April 2011

Gold Sponsors:

Silver Sponsors:

Benchmark your strategies against our expert speakers Dr Eckhard Scheufler Director of Forecasting EMEA Janssen-Cilag

Prasad Saraph Supply Chain Excellence Project Manager Bayer Miriam Stache Sr. European Demand Forecasting Manager Eli Lilly Robert Siegmund Director of Commercial Analytics Actelion Nich Guthrie Head of Global Forecasting AstraZeneca

Matthias Keller Director of Finance and Business Planning Novartis

“Best forecasting conference for a Pharma forecaster to attend” Global Forecasting Director, Eli Lilly

Supporting Sponsors:

www.pharma-mag.com 23 www.eyeforpharma.com/forecasting/VIA

ASEPTIC PROCESSES

CLOSED VIAL TECHNOLOGY

A new solution to improve sterility assurance levels and to simplify the aseptic filling process.

T

he aseptic filling of injectable drugs has always been particularly challenging for the pharmaceutical industry.

Contamination accidents, despite being rare, are still recorded among the 25 billion injections and infusions made every year worldwide. It is estimated that contaminated drugs affect more than 200,000 people each year.1,2 Another challenge in recent years is the complexity of aseptic filling. As the risk of contamination is permanent, authorities are scrutinizing the processes in depth, resulting in expensive solutions, such as the use of isolators and an increase in validation requirements, with the addition of a significant risk of batch rejection. Closed vial technology addresses these two issues by using stoppered and ready‑to‑fill vials (Figure 1).

Overall Process

The process to produce the vials consists of two major steps: • The vial body, which is made of cyclo‑olefin co‑polymer (COC) and the stopper, which is made of thermoplastic elastomer (TPE) are molded in an ISO Class 5 clean room at the same time and assembled by robots, resulting in a closed vial with ISO Class 5 environment inside, hence the absence of the washing process.

• After final assembly and packaging, the vial is sterilized by gamma irradiation.

This process generates ready‑to‑fill vials; that is, they are clean and sterile with the stopper in place.

To perform the overall filling process, the filling line comprises three key steps: • Filling — done after piercing the stopper.

• Laser resealing — to restore the closure integrity.

• Capping — made by snap fit.

These three steps are made in an ISO Class 5 environment, according to the latest good manufacturing practice (GMP) requirements. The entire process is summarized in the Figure 2.

The Closed Vial Figure 1: Range of closed vials from 1 to 50 mL nominal volume.

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The closed vial is made of five elements: • The vial body — made of COC because of its excellent barrier and transparency properties.

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Figure 1

• The stopper — able to absorb laser energy and to melt, fuse and restore the closure integrity at the piercing trace.

• The top ring — secures the closure integrity of the vial container closure.

• The bottom ring — ensures superior stability of the vial and firm holding during piercing and needle withdrawal.

• The cap — made of polyethylene. It ensures a second closure integrity at the stopper surface level thanks to a rib pressing on the stopper surface, thus preventing stopper contamination until use by the practitioner.

The Closed Vial Filling Line

The filling of the vial is performed on a dedicated filling line equipped with specific technologies: • The filling — made by a 13‑G needle with a pencil point to pierce the stopper. The needle design has been made to avoid coring in the stopper, to dispense the liquid smoothly thanks to the exit angles and to eliminate by venting the overpressure generated during the filling.

• The laser resealing — to fully restore the closure integrity, the resealing of the pierced stopper is performed by a laser, which is absorbed by the stopper.

Its surface melts and fuses to restore the closure integrity during cooling.

• Capping — by using plastic caps with snap fit technology, capping is easily performed without need for crimping.

Key Advantages

Compared to the classical glass vial, closed vial technology exhibits three major groups of advantages.

March/April 2011

ASEPTIC PROCESSES Figure 2: Closed vial process from vial manufacturing until capping.

Figure 2

Better sterility assurance level and reduced particle presence The most important advantage is an increase of the quality (the sterility assurance level and particle presence) for the patient. The higher quality is obtained by keeping the vial permanently closed, unlike a glass vial, whose internal surface and stopper surface are exposed for long periods of time. The technology prevents entry of contaminants so well that already five media fills have been conducted in unclassified workshop areas without contamination. This illustrates the success of the concept of keeping the vial permanently closed; the risk of bringing bacteria inside the vial is extremely low, even in challenging situations.

Thanks to the cap design, a circular rib located on the inner face of the cap protects the entire stopper surface.

This creates additional closure integrity to prevent the external stopper surface becoming contaminated.

Simplified filling operations A second advantage is a simplified filling operation.

Closed vial technology removes the need for some ‘traditional’ glass‑filling equipment/processes, including washing, water for injection on the filling line, sterilization, a stoppering station and a crimping station using aluminum caps. The elimination of these unnecessary steps can significantly reduce the investment and operating costs of using closed vial technology. In addition, the limited process steps combined with on‑line checking of both weight and laser resealing, practically eliminates the risk of batch rejection.

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Secured supply chain and easier handling Finally, the design of the vial improves the supply chain up to the point at which the product is injected into the patient. COC is resistant to breakage, which avoids vial damage during filling, storage, transportation and handling by healthcare practitioners. In addition, the vial design makes handling, opening, piercing and liquid collection easier compared with glass vials, thus resulting in a clear preference as recorded during internal market research study, in which 250 healthcare professionals (doctors, nurses and hospital pharmacists) were interviewed: 87% declared their preference for closed vials whereas only 7% stated a preference for glass vials.

Looking Ahead

The future of closed vial technology looks promising, with several recent installations done in high value technologies. In particular, the technology is currently used for cell therapies, viral therapies, cytotoxics and biological drugs. Closed vials are primarily selected because of the reduced loss of product (because of adsorption on the vial walls) and because they safely store hazardous and/or expensive products in an unbreakable container. More recently, new lyophilization projects have been launched thanks to excellent results regarding cake quality, and the absence of both vial breakage and stoppers sticking to shelves.

Benoît Verjans

References

1. R .M. Klevens, et al., Public Health Rep. (Center for Disease Control, CDC) 122(2),160–166 (2007).

2. R.P. Vonberg and P. Gastmeier: J. Hosp.

Infect. 65(1), 15–23 (2007).

Fore more information Benoît Verjans Commercial Director Aseptic Technologies Tel. +32 81 409 410 benoit.verjans@aseptictech.com www.aseptictech.com

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ASEPTIC PROCESSES

THE NEED FOR CONTAINMENT AND ASEPTIC PROCESSES

Quality organizations are embracing good manufacturing practices for satisfactory containment processes on the production floor. Clean rooms have a significant role, although aseptic barrier systems to limit the air environment to the intermediate area around the processes are becoming a remarkable alternative. Furthermore, protective systems will in due course become automatic and not involve personnel — the main source of microbiological contamination and main receivers of potent compound effects.

P

otent compounds are currently playing an increasingly prominent role in fighting illness and disease, presenting great benefits to patients; but potential adverse effects to healthy individuals working with them are numerous. Quality organizations within companies are embracing good manufacturing practices (GMPs) for satisfactory containment processes on the production floor, thus reducing or eliminating the potential for cross‑contamination. Other goals are the business and environmental benefits related to reducing production costs and limiting the impact to the outdoor environment. Containment is, therefore, required to ensure protection to the operator and the environment from the product and vice versa. Containment is the retention of a material, substance, liquid or organism so as to ensure it is effectively prevented from dispersing

Table I: Operator Exposure Bands classification.

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into an environment or is released into that environment only at an acceptable level. This environment can either be natural or artificially created within an enclosure.

Organizations use operator exposure bands (OEBs) to split the substances being handled into one of five categories with each category equating to a range of operator exposure limits (OELs). This approach can simplify the evaluation of containment requirements as often there will be internal guidelines developed for the level of containment required depending on the OEB of a substance (Table I). Many substances being handled by pharmaceutical companies, however, are not hazardous, but do require protection from external influences to prevent contamination of the substance.

A significant amount of these products are handled in conventional clean rooms, which are designed to provide a desired air classification.

Table I

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March/April 2011

ASEPTIC PROCESSES

Table II: Room classification according to current standards.

Figure 1: Determinant factors on sterility assurance level.

Figure 2: Range of sterility conditions according to isolation system applied.

Table II Vial washing & depyrogenation

Surrounding environment (cleanroom/RABS/isolator)

Product path sterilization & filtration

Product SAL

Pressure balance response Stopper transfer method

Cleaning & sterilization process System & subsystem validation

Figure 1

Control and monitoring issues System reliability

Figure 2

Clean rooms have a significant role within the industry, but the capital and running costs of such facilities can be great. A more economic alternative is to create localized clean environments by using aseptic barrier systems so the clean air environment is limited to the immediate areas around the process.

The required classification for a certain area can be given by room classifications as per ISO‑14644-1, US FS 209D, EU GMP or BP 5295 (Table II). 1–3 The first work on the microbiological control and monitoring of aseptic processing environments began in the early 1990s. At that time, the Pharmacopeial Forum focused on the microbiological classification of clean rooms — a concept that became controversial and was opposed by industry, trade associations and those designing clean rooms professionally.

Since then, following revisions on the USP <1116> have focused on environmental monitoring, gradually removing aseptic validation information.

March/April 2011

Furthermore, alert and action levels have been replaced with incidence rates.

From a compliance perspective, it is believed that monitoring can prove a facility’s ability to achieve adequate “sterility assurance.” Scientifically, though, it is more reasonable to think that environmental monitoring can demonstrate that a clean room is operating within a consistent state of control, but it certainly cannot prove that an environment is “sterile” — monitoring a facility to measure its “sterility assurance” is scientifically impossible. Neither air sampling technologies nor current microbiological methods support the current microbiological requirements for in‑process environmental monitoring as reflected in FDA’s Aseptic Guidance and EU Annex 1.4,5 Furthermore, both the limits of detection and quantization of growth and recovery methods are unknown: zero does not mean absence of contamination, but rather that it is below the level of detection at that point in time. According to scientific literature, ±0.5 log is a reasonable assumption of variability.6 The sterility assurance level (SAL) quantifies the probability of a nonsterile unit to appear in a sterilization process. In life sciences, the best design leads to an expected probability of finding a nonsterile unit below a million (SAL ≤10-6). But this level is reliant on numerous factors, such as the surrounding environment (SAL is equivalent to PNSU: probability of nonsterile unit) (Figure 1).

Even within the best operational conditions, clean room operators may contribute 100–1000 of viable organisms/h to an environment, thus rendering it unacceptable for the aseptic assembly of sterile products, unless aseptic processing systems where direct operator interventions do not occur (that is, restricted access barrier systems [RABS]) are considered (Figure 2).

Using protective systems such as RABS or isolators ensure the highest operator protection from potent compounds, as well as product protection and sterility assurance. In due course, these systems will become automatic and will not involve personnel — the main source of microbiological contamination and the main receivers of potent compound effects.

References

1. www.iso.org/iso/iso_ catalogue/catalogue_tc/ catalogue_detail. htm?csnumber=25052 2. www.ema.europa. eu/ema/index. jsp?curl=pages/regulation/ document_listing/ document_listing_000154. jsp&murl=menus/ regulations/regulations.jsp &mid=WC0b01ac0580027 088&jsenabled=true 3. http://shop.bsigroup.com/ en/ProductDetail/?pid=000 000000000201397 4. www.fda.gov/downloads/ Drugs/GuidanceCompliance RegulatoryInformation/ Guidances/ucm070342.pdf 5. http://ec.europa.eu/health/ files/eudralex/vol-4/pdfsen/2008_02_12_gmp_ annex1_en.pdf 6. http://pharmtech. findpharma.com/ pharmtech/data/ articlestandard/ pharmtech/212004/ 95525/article.pdf

For more information

Marina Cazador Sterile Production Manager Reig Jofre Group www.reigjofre.com

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ASEPTIC PROCESSES

INTEGR ATING A SILICONE PART IN A PHARMACEUTICAL DEVICE The challenge is to make the silicone part compatible with other parts and materials used in medical devices, and industrially and economically efficient, all in accordance with aseptic processes.

Liquid Silicone Rubber process in a clean room.

C

ompared with other elastomers, silicone’s physical properties are far superior: higher elongation at break; excellent tear resistance and rebound resilience; heat stability; better performance in repeated temperature exchanges; low temperature flexibility down to −50 °C; high transparency; pigmentable with FDA‑approved pigments; constant mechanical properties across a wide temperature range; good ultra‑violet (UV) and ageing resistance; and excellent environmental compatibility. Furthermore, new medical grades of silicone outperform in high purity, do not contain organic plasticizers, are tested and certified for biocompatibility according to ISO 10993‑1 and USP Class VI (selected tests), are vapour permeable and easy to sterilize.1,2 Although these features make silicones particularly suitable for use in medical devices, the wide variety on offer can make it difficult to choose the right one, to design the part according to its characteristics and to establish the appropriate production process with the best efficiency. A proper feasibility analysis and excellent engineering are instrumental to success. The variables to consider during the conception stage are: • The part design — to optimize the critical mechanical issues of the part.

• The choice of the correct compound (medical grades).

• The yearly production volumes.

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• The target price: a balance between the complexity of the mould and the required level of productivity.

• The effective specification for the application required; for example, clean room classification, type of packaging and automation.

Once the compound has been chosen, the silicone type must be considered: liquid silicone rubber (LSR), high consistency rubber (HCR) or high temperature vulcanizing (HTV). For use in medical devices, LSR is the best choice, because it affords clean and automated production and fast cycle times. Some LSR grades are specifically certified for medical applications, including standard medical grades, grades for self‑bonding to plastic or metal substrates, low friction grades for automatic assembling purposes and UV‑resistant grades. Having the expertise and knowing exactly the final application are important to making the correct choice.

Part Design

The design of the medical device part must take into account the performance of LSR; for example, the compound must avoid sharp corners and friction areas in contact with abrasive components of the medical device. Tooling (in this case, mould engineering, mould making) is a solution’s masterpiece — using the proper tool can account for at least 50% of the project’s success.

March/April 2011

ASEPTIC PROCESSES Silicone parts for medical devices.

Injection systems for LSR can be ‘traditional’ — hot runner or cold runner systems and direct injection into the cavities with open gate or shut off nozzles. To mould parts for use in medical devices, this choice is limited to cold runner systems, as the parts must be compliant with medical cleanness certification. With traditional hot runner systems, manual or die cutting separation and handling of runners are required, thus making the process unstable and subject to contamination. For most medical applications, therefore, shut‑off nozzle technology is advisable.

At the stage of prototyping, validating and integrating the part in the device, there are still two important steps to take. First, the production process needs to be set up, with the installation qualification, operational qualification and performance qualification certification phases. The tool (mould) that has been engineered and produced so far requires a top quality clean room, machines for LSR (injection systems) and auxiliary equipment, such as pumps, vacuum devices and ovens to guarantee the best performance and production reliability.

Second, an accurate quality control (QC) procedure, including part and material traceability, is critical to avoid any defect that can affect the functionality of the final medical device and to guarantee the absolute consistency of the process. A QC process for a part can include measuring its dimensional characteristics and verifying the cosmetic aspects, such as the absence of flashes.

The difficulties associated with measuring LSR medical parts are the high precision required by dimensional tolerances and the low hardness (usually 10–80 Shore A) of the LSR used. The methods using contact have an important influence on the measurements of dimensions with tolerances usually around the 0.01 mm. The state of

March/April 2011

Optical quality control in a clean room.

the art is to dispose of 3D‑optical control equipment to realize the dimensional measurements with an accuracy of 4 µ. For medical devices, the parts must be post‑cured to eliminate the volatile materials. According to the European Pharmacopoeia, the post‑curing should succeed with a 4‑h process at 200 °C. The QC process consists of weighing the parts before and after the post‑curing, and verifying that the weight loss is constant at a fixed percentage depending on part thickness and on the grade of compound.

Summary

The demand for LSR (or 2K) parts in medical devices is fast growing. These functional parts require sophisticated development and production for its final integration into a more complex device. By carefully following the feasibility analysis and engineering procedure above, and the necessary prototype, approval and integration steps, completed by an efficient production set up and quality management, this outstanding material offers the best efficiency for use in the medical devices of the future.

References

1. w ww.iso.org/iso/iso_ catalogue/catalogue_tc/ catalogue_detail. htm?csnumber=44908 2. w ww.usp.org/ referenceStandards

For more information Andrea Tomayer Business Development Manager Top Clean Packaging Dominique Dupard General Manager Top Clean Silicone www.topcleanpackaging.com

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VACCINES

TAP: NOVEL TARGETS FOR CANCER VACCINE DEVELOPMENT r Pee ed iew rev ticle ar

Reduced expression of TAP (transporters associated with antigen presentation) correlates with poor immune responses in cancer. The restoration of this pathway through expression or up‑regulation of TAP in TAP‑deficient cancer cells can enhance the functioning of the major histocompatibility complex (MHC) Class 1 antigen‑presenting pathway and increase the production of tumour‑infiltrating cytotoxic T‑cells. Accordingly it provides a promising approach for the development of cancer vaccines.

T

he immune system can target tumour cells for destruction by recognizing tumour‑associated or tumour‑specific antigens displayed on their surface.

In principle, immunosurveillance is a fundamental defense mechanism that can recognize and destroy malignant cells before they develop into tumours.

Advances in our understanding of tumour‑associated antigens have stimulated the clinical development of immunotherapies for the treatment of cancer. The clinical appeal of immunotherapy is the potential to control disseminated metastatic disease with a minimum of toxic side effects because of the immune system’s exquisite specificity. Many of the therapies involve vaccination with protein/peptide antigens, plasmids, or recombinant virus-encoding genes for antigens, or whole cell vaccines that consist of autologous or allogeneic tumour cells, or autologous dendritic cells with a variety of modifications.1 These diverse approaches aim to stimulate a T cell‑mediated antitumour immune response.

Although conceptually appealing, the success of cancer vaccines and immunotherapies in humans is variable.

Figure 1

Figure 1: Role of TAP (TAP1/ TAP2) and associated proteins in loading peptides to MHC Class I molecules and presentation to cytotoxic T-cells.

Figure 2: AdhTAP1 treatment leads to fewer and smaller tumours in mice bearing B16F10 tumours.

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In most cases, the vaccines are very well tolerated and specific immune responses to particular antigens can be achieved, but the response rate of the disease to the therapy is low. The reasons for the low response rates are thought to be because of several factors, which include low immunogenicity and tolerance to tumour‑associated antigens, immunosuppressive microenvironments and defects in the cellular machinery for antigen processing and recognition.2 If the cellular machinery for antigen processing is defective or fails, cancer cells can escape immunosurveillance. The correlation between increased tumourigenicity and a decrease in major histocompatibility complex (MHC) Class I expression has been well established. A decrease in cell surface expression of MHC Class I can be the result of a defect in the MHC Class I biosynthetic pathway.3–10 One central component of this pathway is a group proteins called transporters associated with antigen processing (TAP). Reduced expression or loss of TAP represents a central mechanism correlating with poor immune responses in cancer. The restoration of this pathway by expression (or up‑regulation) of TAP genes provides a promising approach for the development of new cancer vaccines.

TAP

TAP plays a central role in immunosurveillance as it functions to shuttle peptides from inside the cell (proteosome) to MHC Class I, which are transported to the cell surface where they can be recognized as foreign by cytotoxic T lymphocytes. Activated cytotoxic T cells can infiltrate tumours and destroy tumour cells. TAP is a member of the ATP‑bindingcassette (ABC) transporter family. It delivers cytosolic peptides into the endoplasmic reticulum where they bind to newly synthesized MHC Class I molecules.11

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VACCINES

300

40 30 20 10 0

References

350 Tumour mass (mg)

% Mice tumour free

50

250 200 150 100 50

Adh TAP1

(A)

5

0

PBS

Treatment

n=10

(B)

n=11 ANOVA: p=0.003 n=7 Adh TAP1

5

PBS

Treatment

Figure 2

The TAP structure is formed of two proteins: TAP1 and TAP2, which assemble into a heterodimer. TAP is found in the lumen of the endoplasmic reticulum associated with the peptide‑loading complex. This complex of β2 microglobulin, calreticulin, ERp57, TAP, tapasin and MHC Class I functions to hold MHC molecules until they have been fully loaded with peptides.12 The intracellular components of this pathway and the presentation of MHC Class I antigens to T‑cells are shown diagrammatically in Figure 1.

There is abundant evidence that a variety of solid tumours (for example, melanoma, ovarian, breast, lung) have deficiencies in TAP levels. In a study evaluating human melanoma tissues levels of TAP1 and TAP2 were greatly reduced in metastatic lesions and the reduction in TAP levels in primary lesions correlated with lesion thickness, disease stage, faster disease progression and lower survival rates.13 Loss of the TAP complex is highly correlated with loss of human leucocyte antigen (HLA) expression in cervical carcinoma.14 In addition, a higher frequency of down‑regulation of this complex has been observed for metastatic lesions than for primary lesions.5 The TAP complex has been particularly strongly implicated in tumourigenicity of several cancers such as melanomas, cervical carcinomas and renal cell carcinomas.5,15 Thus, these findings suggest that TAP down‑regulation may represent an important and widespread mechanism for immune escape of malignant cells in a variety of tumours, and raised the question whether genetic transfer of TAP genes could restore immune recognition of tumours and provide the basis for a new approach to the development of therapeutic cancer vaccines.

Restoration of TAP as a Strategy for Cancer Vaccine Development

Whereas the correlation between the down‑regulation of TAP and increased tumourigenesis had been widely established the research of Dr Wilfred Jeffries and colleagues at the University of British Columbia, Vancouver BC provided the first critical demonstration that TAP1 gene transfer into tumour cells and cancer

March/April 2011

bearing animals could significantly improve the immune recognition of tumour‑associated antigens. Details of these studies were published in a series of landmark publications, which also demonstrated that TAP1 and TAP2 gene transfer could also improve the potency of vaccines for the treatment of viral diseases.16–20 In a study evaluating TAP levels in tissues from nine cases of human small cell lung cancer and 10 cases of non‑small cell lung cancer, 59% of tumour lesions were negative for TAP expression as determined by immunoperoxidase staining of the tissues for this protein. Using this methodology only one of 19 tumours tested strongly positive for TAP.18 The researchers demonstrated that a nonreplicating adenovirus encoding the gene for TAP1 (AdhTAP1) could restore TAP1 expression in the mouse lung carcinoma cell line CMT.64, and increased tumour‑specific immune responses. This cell line was derived from an aggressive metastatic small cell lung cancer and is defective in TAP. The ability of TAP to restore an immune response has also been demonstrated in a series of animal studies. In a mouse model of small cell lung cancer animals receiving the TAP1 gene administered via a vaccinia virus vector demonstrated improved immunogenicity and increased survival. Up to 60% of cancerous mice that had restored expression of TAP1 were still alive after 100 days and metastasis was reduced. In contrast, 50% of untreated mice died of multiple tumours after 40 days.16 In a separate series of studies, AdhTAP1 produced effective immune responses in a mouse model of melanoma.20 This model, which uses the B16F10 cell line, is widely used to evaluate T‑cell‑based vaccine strategies, as it is a highly metastatic and poorly immunogenic cell line and is defective in levels of TAP1 and TAP2.

These studies determined that melanoma‑bearing mice that were administered AdhTAP1 were less likely to develop tumours, had a 10‑fold slower tumour growth rate and improved survival time. In contrast to 100% of animals that died by week 3, more than 40% of the AdhTAP1‑treated animals were tumour‑free at this time (Figure 2). In addition, the treated animals also showed

1. J.A. Berzofsky, et al., J. Clin. Invest. 113(11), 1515–1525 (2004).

2. E. Gilboa, Nat. Rev. Cancer 4(5), 401–411 (2004).

3. K. Tanaka, et al., Science 228(4695), 26–30 (1985).

4. R. Wallid, et al., Nature 315(6017), 301–305 (1985).

5. B. Seliger, et al., Immunol.

Today 18(6), 292–295 (1997).

6. F. Garrido, et al., Immunol.

Today 18(2), 89–95 (1997).

7. G. Hammerling, et al., Biochim. Biophys. Acta.

907(3), 245–259 (1987).

8. D.P. Singal, M. Ye and X. Qiu, Int. J. Cancer 68(5), 629–636 (1996).

9. H.G. Rammensee, Int. Arch. Allergy Immunol.

110(4), 299–307 (1996).

10. J.J. Neefjes, et al., Curr.

Opin. Cell Biol. 3(4), 601–609 (1991).

11. W.K. Suh, et al., Science 264(5163), 1322–1326 (1994).

12. A.N. Antoniou, S.J. Powis and T. Elliott, Curr. Opin.

Immunol. 15(1), 75–81 (2003).

13. K.N. Kageshita, et al., Am. J. Pathol. 154(3), 745–754 (1999).

14. F.V. Cromme, et al., J. Exp. Med. 179(1), 335–340 (1994).

15. M.J. Maeurer, et al., J. Clin. Invest. 98(7), 1633 (1996).

16. J. Alimonte, et al., Nat. Biotechnol. 18(5), 515–520 (2000).

17. A.F. Setiadi, et al., Cancer Res. 65(16), 7485–7492 (2005).

18. Y. Lou, et al., Cancer Res. 65(17), 7926–7933 (2005).

19. T.Z. Vitalis, et al., PLoS Pathogens 1(December), 289–298 (2005).

20. Y. Lou, et al., Vaccine 25(12), 2331–2339 (2007).

21. L. Karyampudi, et al., Clin. Cancer Res. 16(3), 825–833 (2010).

22. M.J.E. Havenga, et al., Biotechnol. Bioeng. 100(2), 273–283 (2008).

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VACCINES

Glynn Wilson

For more information Glynn Wilson, PhD Chairman and CEO TapImmune Inc. www.tapimmune.com

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increased levels of tumour‑infiltrating lymphocytes and memory cells further validating restoration of immune function. It is particularly significant that the B16F10 model is deficient in many antigen processing components (including tapasin, LMP‑2, LMP‑7, LMP10, and PA28α/β) yet expression of TAP1 function alone could lead to significant restoration of MHC Class I surface expression.

Collectively, these studies show that TAP1 gene transfer and expression of small amounts of TAP results in several critical effects: • It restores the MHC Class 1 antigen‑presenting pathway.

• It increases the number of tumour-infiltrating cytotoxic T‑cells and dendritic cells.

• It enhances memory T‑cell subpopulations.

• It improves animal survival.

As these immune effects are central to the development of a successful cancer vaccine the potential importance of using TAP expression in the immunotherapy of cancer was recognized. Moreover, studies on TAP expression also demonstrated a number of potential advantages for the development of a therapeutic product: • It allows the immune system to recognize all tumour antigens presented on tumour cells.

• Only a small proportion of tumour cells need to be treated.

• It is independent of genetic variability of MHC Class 1 proteins.

• It has application to many solid tumours.

• It is relevant to immuno-compromised individuals.

• It can be administered by simple injection.

Collectively these animal studies have provided the basis for evaluating the up‑regulation of TAP in human clinical studies.

As a prerequisite for entry into the clinic the reproducible manufacturing and safety of TAP1 constructs needs to be established. Particular focus is on the use of a commercial cell‑based manufacturing system for adenoviral‑based vaccines that greatly reduces or eliminates the production of live virus through recombination events.21 In addition, safety studies in animals and Phase I/II studies in man will need to establish an immunostimulatory dose of TAP1 without the induction of widespread autoimmunity to self‑antigens. Clinical development strategies include the up‑regulaton of TAP expression alone or in conjunction with other tumour‑associated antigens as a therapeutic cancer vaccine or in combination with other immunotherapies. Initial clinical trials, starting this year, will target the treatment of HER2/ neu breast cancer. This approach will evaluate the use of AdhTAP1 in concert with a set of novel HER2/neu antigens.22 The overall strategy of this approach is to target both MHC Class I (TAP‑dependent stimulation

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Although a number of vaccine and cellular immunotherapies have progressed to late‑stage clinical trials, immunotherapy for the treatment of cancer is still in its infancy. of cytotoxic T‑cells) and MHC Class II pathways (TAP‑independent stimulation of T‑helper cells) to achieve activation of different T‑cell populations for a robust and prolonged immune response. Patients selected for these trials will be those who have low to moderate expression of the HER2/neu antigen and are not prime candidates for monoclonal antibody therapy using Herceptin (trastuzumab). The ability to measure TAP levels in tumour tissue biopsies will provide an additional selection tool for selecting patients that could best benefit from the combined treatment. This will be the first clinical trial to test the combined effect of a tumour‑associated antigen and restoration of TAP expression. The wide variety of solid tumours that have reduced levels of TAP suggest that this approach will have widespread application in the treatment of cancer.

Although a number of vaccine and cellular immunotherapies have progressed to late‑stage clinical trials, immunotherapy for the treatment of cancer is still in its infancy. The US approval, in 2010, of Provenge (sipucel‑T), the first marketed autologous cellular immunotherapy for the treatment of late‑stage prostate cancer, has drawn attention to the emergence of this field and the opportunities for development of improved, simpler and more cost effective therapeutic vaccine products. Currently, Gardasil, used for the prevention of cervical cancer caused by the human papilloma virus, remains the only preventative cancer vaccine on the market. While the results of TAP1 expression in experimental animals look extremely promising the results of the clinical studies will determine if this approach can provide a safe and effective platform for the development of a range of novel cancer therapeutics that are HLA‑specific and tumour‑specific.

March/April 2011

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EXHIBITION & SYMPOSIUM | MAY 3–5 2011 PENNSYLVANIA CONVENTION CENTER | PHILADELPHIA | USA

DELIVERING THE RIGHT FORMULA Chemspec USA was created and is being launched because the market thought that there should be another choice in North America for a chemical event. As with all other successful Chemspec Events, CSUSA aims to draw in a diverse audience of exhibitors and visitors from such industries as fine chemicals, pharmaceuticals, crop science, biotechnology, cosmetics and personal care, water treatment, dyes and colorants and general specialty chemicals. We believe that Chemspec USA is the most significant new event in this global arena.

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Seifi Ghasemi Chairman & CEO, Rockwood Holdings

Peter Young President, Young & Partners

Craig Rogerson CEO, Chemtura Corporation

Guy Villax, CEO, Hovione

Dr. Magid AbouGharbia Former Senior VP at Wyeth and now Dean for Research, School of Pharmacy, Temple University

Dr. Joe Carleone CEO, AMPAC

Dr. Tom Connelly Executive VP & Chief Innovation Officer, DuPont

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Philadelphia is at the heart of the US custom chemicals industry (Pennsylvania, New Jersey and adjacent states) and is also a major hub of the whole life science sector. Over 60% of SOCMA members are within 100 miles and over 27% of ACS members are within the same distance of the city. Philadelphia is one of the top three centers for biotechnology in the US.

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PLANT/FACILITY DESIGN

BLACK TO THE FUTURE PLANTS WITH AGILITY

A two-floor facility that incorporates the ‘black to white’ concept may provide oral solid dosage manufacturers with an effective solution for future demands.

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hoosing between a single-floor and multifloor plant design for a new oral solid dosage (OSD) facility is a major decision. When land is expensive it is usually more economical to consider the latter option because of its smaller footprint. The new facility should be laid out for ‘future needs,’ but without the initial high investment cost and without high modification costs later. A single‑floor design simply won’t fit such a flexible scenario and a multistorey building might be excessive. A two‑floor facility, however, may be an effective compromise, particularly when the second floor can do without good manufacturing practice (GMP) classification: this is the ‘black to white’ concept for ‘agile’ solid dosage facilities.

Prepare for the Future

With the capacity planning insecurities involved in a new drug application, the best approach for designing a new OSD facility is to make it suitable for multiproduct manufacturing. A plant designed for flexibility can handle last‑minute retractions, new life generics or a sudden increase in sales of certain products. Agility helps with ‘future proofing.’

In a multiproduct facility, the quickest product changeover is achieved when the discrete unit operations can work in parallel and independent from one another.

This automatically leads to the use of intermediate bulk containers (IBCs) for the transfer of batches, or lots, from one step to the next. Unlike vacuum transfer systems, their discharge capacity, although depending on the model, is medium to very high, which reduces the nonvalue add and cycle times for the operation.

The IBCs are cleaned offline and so do not negatively influence changeover times: in Lean terms, better overall equipment effectiveness is achieved.

Figure 1: A traditional single-floor facility.

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Capacity Boost

Let’s assume that the plant has gone through Lean exercises and ‘flow’ has been created with minimal waste — as far as the highly regulated pharmaceutical processes allow it — and the incentive to reduce inventory and ‘make what has been sold’ has reached its boundaries and batch sizes have matched customers’ orders. Assuming a further increase in demand for the product, now the time has come to lift the whole production chain to a higher capacity level and bigger batches. This means, however, that the overall stack up of equipment will become higher.

How could the original facility design have anticipated that development? Both the building cost and utility consumption make ‘white’ (clean room) pharmaceutical production areas very expensive. Creating extra volume in the process cells for future use is an expensive option.

The solution can be found in the materials handling floor concept (addressed later).

Single‑Floor Operation

Analysing the typical OSD operations that require a clean room environment (dispensing, granulation, drying, blending, compressing, coating and primary packing) it can be concluded that machine height does not largely increase with higher capacities: a 10,000‑tablets/min press is not significantly higher than one of half the capacity; if you double the capacity of a coating machine, the height only increases to a limited extent. It is the need to increase the batch size that presents a problem. Single‑floor facilities are usually limited to 250‑kg batches — if you want to use gravity to feed and empty the various processes. There is insufficient headroom to load a bigger IBC above the processes.

This restriction usually explains why drums and vacuum systems are selected for the transfer of batches from process to process. In traditional set ups (Figure 1)

Figure 1

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March/April 2011

PLANT/FACILITY DESIGN particularly, where the use of large stationary blenders is common practice, there is not enough room to fit a good‑sized IBC above or below such machines. This compromises equipment utilization and plant output (blending time is 20 min, but the overall cycle time can be a few hours). Furthermore, all the manual operations, as well as the many ‘open’ transfers, dramatically increase the risks of error and cross-contamination.

The Non-Lean Way Forward

The existing wet granulation equipment is a difficult factor to consider when batches need to be increased. Allowing these expensive systems to become redundant because of batch capacity is not easily justifiable. A common solution is to collect multiple granulated lots into one (bigger) IBC, which increases the average output of the granulation process, provided the feed and discharge methods are fast (such as when gravity is used). This could be called ‘isolated campaigning’ in an otherwise synchronized and flowing production line.

A single‑floor plant layout that can accommodate future bigger batch size requirements must be designed to include high ceilings. Investing in this option is costly and the overall downtime required for cleaning is significant.

Furthermore, in a typical GMP‑classified room, the extra air volume needs to be replaced many times per hour. The capital and maintenance costs associated with the many pillar lift‑handling units (needed for each gravity discharge point) are not to be neglected either.

The Material Handling Floor

A simple and flexible solution for making the plant fit for larger batches of the future — without investing in high ceilings (costly clean rooms) or dusty equipment that slows down the plant flow (vacuum transfers or manual drum handling) — is the construction of dedicated materials handling floor. Above the process cells, an open area is

created where the only ‘obstacles’ are batch‑discharge positions, which are placed directly above the applicable unit operation; for example, granulation, compressing and coating. Using a centrally positioned elevator to, the batches are transported up and brought to the applicable discharge position (Figure 2).

Using a positive pressure in the rooms below and, moreover, implementing state‑of‑the‑art IBC techniques such as ‘cone valve’ technology or ‘split butterfly valve’ principles avoids the risk of contamination between discharge positions. The ground‑floor suites can now be realized using standard clean room heights without restricting any potential growth in batch sizes. Dispensing also would occur from a second‑floor suite down to the receiving area on the ground floor. If wet granulation is used, solutions exist to get the dried product back into the IBC within the same room. There is also proven technology available for cleaning, sampling and venting, as well as for the crucial prevention of segregation (during the powder drop through the floor). Powder blocking phenomena, typically occurring prior to granulation or in direct compression applications, should be fully dealt with by the IBC system.

With regard to blending there is an additional aspect to consider. A prime benefit of an IBC blender compared with a stationary blender (such as a V‑blender) is the intrinsic containment of the batch inside the blender chamber, which is in fact the IBC itself. There is no transfer of powder into or from the blender, which assures the absence of blender‑room contamination. An IBC blender, therefore, does not have to be placed inside a suite, which in itself saves costs — it can be positioned on the material handling floor (Figure 3) if logistically more beneficial and if the overall ceiling height of the ground floor doesn’t allow a bigger IBC blender, such as one of 3 m3, to be installed.

Many two-floor facilities have been built with a materials handling floor, but only recently have Lean and agile aspects

Figure 2: Materials handling floor (GMP).

Figure 3: Blender at a materials handling floor (GMP).

Figure 4: Materials handling in a technical area.

Figure 2

Figure 3

Figure 4

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PLANT/FACILITY DESIGN Figure 5: A Lean and agile two-floor OSD facility using a technical area.

Figure 5

of the concept become major factors during plant design evaluation. Yet, the materials handling floor is still tends to be classified as a GMP area, Class 100,000. Why?

Technical ‘Black’ Area

Wim J. Spook

For more information Wim J. Spook Director Pharmaceutical Business Development Matcon Ltd www.matconibc.com

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In compact building designs it is logical and sensible to position utility services directly above — and isolated from — the ‘white’ GMP process rooms, in a ‘technical’ or ‘black’ space. Frequently, these spaces are true floors (as opposed to a space with ducting going through) and are fully accessible. Usually, the total footprint of the technical floor equals the total area of the GMP processes taking place below; yet, the area is often underutilized and so it makes sense to use the free space for the materials handling activity as described above.

The cost benefits of not having to build and operate the second‑floor area as a Class 100,000 clean room are obvious; but to be able to use such an area in a proper GMP way, the following points need to be considered: • IBCs travel between black and white areas. In the direction of black to white, the outer surface of the IBC will need to be cleaned using a dedusting cabinet, similar to that used for cleaning raw material bags and drums coming from outside the facility into the GMP area.

This is unnecessary if the IBC is undergoing a full clean because of a product changeover.

• The discharge positions will need to be of a closed design to minimize spillage of positively pressurized clean air into the technical area, which potentially carries dust. This is done with proven, currently available IBC technology.

• To avoid expensive and automated clean‑in‑place (CIP) systems, the discharge positions will need to be removed

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for cleaning, but without creating direct contact between the GMP area below and the technical area above.

Solutions are available to help with this.

• Powders can never block in the IBC. Opening up the IBC and breaking the containment to assist in the discharge is not an option in a technical area. Cone valve IBC technology will guard against this.

• Further detailed techniques must be applied to create self‑venting, mass flow, controlled discharge and proper deceleration to avoid segregation — or demixing — of the blended batches. Also this is available technology.

Summary

A two‑floor OSD facility design with a materials handling floor above, has the following main benefits compared with a single‑floor plant: • It is fit for future capacity requirements with limited extra cost, particularly when a technical floor is used; the black to white concept.

• Further investment reduction in the number of pillar lifts and sizes of clean room suites.

• Operational cost savings in cleaning time and HVAC utility consumption of the now smaller clean rooms.

If the floor is defined as ‘technical’ or ‘black,’ then additional technology will have to be installed for isolated discharge point cleaning and the dedusting of IBCs travelling from black to white. Extra attention also needs to be given to contained venting, as well as sampling, if required: these techniques are available. The concept of the materials handling floor, particularly when using the black to white concept, places high demands on the IBC system to ensure no blocking, no segregation and containment. A modern cone valve‑based IBC system can provide for that.

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HEALTH AND SAFETY

MAINTAINING A GLASS-FREE PRODUCTION ENVIRONMENT

With so much emphasis on hygiene and safety, lighting is an important consideration in the pharmaceutical industry. Much thought goes into designing light fittings, ceilings, walls and equipment to minimize dust and contamination as well as providing smooth, easy‑to‑clean surfaces, but what about the actual lamps fitted? Choosing fragment retention lamps, coupled with new regulations, can help to ensure you get measurable performance.

F

ragment retention lamps, also known as shatterproof lamps, have applications in a variety of industries, particularly pharmaceutical production and packaging.

Good quality fragment retention lamps offer protection from glass contamination in all areas of manufacturing and production, which in turn protects products, profits and personnel. Fluorescent lamps are notoriously fragile and are prone to accidental breakage during routine maintenance and cleaning — processes undertaken with great regularity to ensure a clean and hygienic manufacturing and testing environment for pharmaceuticals. A broken fluorescent lamp (Figure 1) can send thousands of shards of glass into the production chain, causing immediate disruption, product loss and clean up costs, and injure personnel.

Although pharmaceutical production facilities already take precautions against broken glass by using fully enclosed diffusers, these in themselves can be problematic — the lamps can break when changed, and diffusers can harbour dirt and bacteria. To remove these risks, manufacturing facilities should use fragment retention lamps, which eliminate the need for diffusers and dramatically reduces the risk of glass contamination in the pharmaceutical chain.

Raising Standards

Fragment retention lamp coatings have been available for a number of years now, but it was only in 2010 that strict regulations came into force defining lamp life, coating protection and lamp performance. Every pharmaceutical manufacturing facility should be aware of the new BS EN61549 standard, which requires that all fluorescent lamps should meet a 4‑m impact test and successfully retain all fragments. It also requires that the safety coating must remain active for a minimum of 8000‑h lamp life and withstand a 650 °C glow wire test. With a number of different shatterproof lamps available on the market, this standard represents an important step to improving safety and reassurance that glass contamination will no longer be a worry.

Figure 1

Packaging Production and Clean Rooms

Pharmaceutical packaging is covered by strict guidelines so it is important that every part of the production environment complies. When considering your lamp choices, it is important to choose a brand that complies with PS 9000, as well as with standard HACCP (see sidebar “Compliance”).

Clean rooms also benefit from fragment retention lamps. With control of micro‑organisms a real priority here, lamps coated with a hygienic fluoro polymer material provide a nonadherent surface that can easily be steam and chemical cleaned. The most hygienic option to prevent cross‑contamination is to eliminate old‑fashioned lamp guards by easily fitting fragment retention lamps into modern recessed light fittings.

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Compliance

PS 9000 focuses on the development and implementation, by suppliers, of a quality management system designed to provide assurance of the quality of their products and to enhance customer satisfaction. Product security and the avoidance of cross contamination underpins all pharmaceutical quality, and this is not just between raw materials, but also contamination from outside sources that should be controlled; for instance, dust, insects, hair or broken glass. As contamination can take many forms and be introduced anywhere, preventive measures, such as good facility design, standard operating procedures, training, area clearance and segregation controls must be applied throughout the facility.

HACCP is another good practice method to plan out potential risks, by conducting hazard analysis and identifying critical control points, such as fluorescent lamps. The use of fragment retention lamps provides a convenient way of implementing a quality management system and removing the risk of glass contamination.

March/April 2011

HEALTH AND SAFETY Figure 2

Figure 1: Glass shards from noncompliant lamps are a contamination risk at any stage of the pharmaceutical manufacturing and packaging process.

Figure 2: The BlackBand marking denotes a compliant lamp that provides full protection on impact and full glass containment.

Figure 3: Effects of heat on noncompliant and compliant lamps (left to right).

Figure 3

Raising Standards

Fragment retention lamp coatings have been available for a number of years now, but it was only in 2010 that strict regulations came into force defining lamp life, coating protection and lamp performance. Every pharmaceutical manufacturing facility should be aware of the new BS EN61549 standard, which requires that all fluorescent lamps should meet a 4m impact test and successfully retain all fragments. It also requires that the safety coating must remain active for a minimum of 8000h lamp life and withstand a 650 °C glow wire test. With a number of different shatterproof lamps available on the market, this standard represents an important

March/April 2011

step to improving safety and reassurance that glass contamination will no longer be a worry.

When sourcing shatterproof fluorescent lamps for a pharmaceutical facility it is important to only use those that reach or exceed BS EN61549.

Noncompliant shatterproof lamps that do not meet certain industry specifications offer far less in terms of life and performance and do not contain 100% glass on impact. Problems are experienced with the plastic coating becoming brittle, because of the heat and small amounts of UV emitted from the lamps, well before end of service life. High quality fluoropolymer‑coated lamps are shown to reach the standard required with a simple BlackBand marking at one end (Figure 2). These lamps will last for 20,000 h, when most other alternatives yellow and crack before 10,000 h of operation (Figure 3).

Compliant lamps also contain 100% glass fragments from the drop test and provide peace of mind, as well as a high‑quality light output. Shatterproof fluorescent lamps with the BlackBand ring can also be operated in enclosed high temperature fixtures as the coating can withstand up to 200 °C at continuous service.

Not all fragment retention lamps reach the new standards that are now enforced, so it pays to check with your supplier. When so much control is required in all areas of pharmaceutical manufacturing, the simple use of the right sort of compliant fluorescent lamp can go along way to raising standards and maintaining a safe working environment.

Chris Payne

For more information Chris Payne Sales Director Fotolec Technologies Ltd (GlassGuard) www.glassguard.co.uk

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ANALYTICAL METHODS

DEVELOPING AND VALIDATING ANALYTICAL METHODS FOR CLEANING VERIFICATION

In an operation where equipment is used for multiple products, the prevention of cross-contamination is critical. The selection, development and validation of analytical methods to verify that equipment has been adequately cleaned are important elements of the overall cleaning strategy.

A

nalysing samples to confirm the effectiveness of equipment cleaning is an important aspect of the cleaning process in the pharmaceutical industry. In many operations, it is not economically feasible to dedicate equipment to the processing of individual products. Analytical evaluation against prescribed limits ensures that product carryover does not occur and minimizes the risk of cross‑contamination. Even in those operations where equipment can be dedicated, the assessment of cleaning effectiveness mitigates the potential for build-up of impurities, which can jeopardize product quality.

Selecting an Analytical Technique

Prior to beginning the method development process, we need to consider what the method needs to achieve.

Questions that need to be asked include • Which materials are to be analysed for?

• What levels will we need to detect?

• Will we need a method that is specific to the materials in question (for example, an HPLC method) or will a nonspecific method (for example, a pH determination) be adequate to meet our needs?

• How long will the testing take and how much will it cost?

Materials Frequently, the materials to be tested for provide a good indicator of the appropriate methods to be used.

The removal of the API can be evaluated by using ultraviolet (UV) scans or by high performance liquid chromatography (HPLC). Using a chemical spot‑test or inductively coupled plasma (ICP) can ensure that all residual metal catalysts are removed. The removal of organic solvents could be demonstrated with gas chromatography (GC). The absence of residual cleaning agents — in particular, detergents — could be demonstrated with chromatography or a total solids test. In certain operations, when residual water cannot be tolerated, Karl Fischer may be used. For techniques used during drug product operations, it may be necessary to demonstrate the absence of inactive excipients to ensure

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that the next product is unaffected. We may also consider the reduction of bioburden or endotoxin load and the possible need to sterilize the equipment.

Levels It is also important to consider detection and quantitation limits, as well as the level of tolerated residue. Certain chromatographic techniques may be adequate for limits in the part‑per‑million range whereas total organic carbon (TOC) can be used in the part‑per‑billion range.

Method The choice of specific methods versus nonspecific methods should be taken into consideration. In practice, both methods have their advantages; but if we are trying to demonstrate that the equipment is free of acid, either from processing or from the cleaning procedure, the nonspecific method pH is the appropriate technique.

For APIs and their precursors, we have developed specific methods usually using HPLC. Fortunately, many active compounds have chromophores that can be detected

by UV. When the compound of interest does not lend itself to UV, mass spectroscopy, refractive index or evaporative light scattering detection may be necessary. It may also be possible to form a derivative of the active compound to produce a new compound that can be detected by UV. Occasionally, we have developed methods to quantitate the active compound and its precursors using the same HPLC conditions. Such methods provide a wealth of valuable information in relatively little time.

Time and Cost Finally, some thought needs to be given to the duration of the analysis and the cost of conducting it. Although we regard this as subordinate to the science, we do not want to develop methods that use exotic HPLC columns or expensive reagents, or take an extraordinarily long time to complete. A 60‑min run‑time to release the drug may be appropriate; in practice, we try to test cleaning samples with injections that run for no longer than 15 min, if possible.

More than one technique may be applied in a given cleaning campaign; for example, a reactor used in chemical synthesis. HPLC can be used to confirm the absence of

March/April 2011

ANALYTICAL METHODS

Material to test for Active pharmaceuticals Metal catalysts Solvents Acids, bases Water

Method to use HPLC, UV, TOC, LCMS ICP, AA, Spot-test GC, GC/MS, TOC pH Karl Fisher

Table I

active chemicals and TOC can be employed to confirm the absence of undesirable residual solvents. The recording of a pH can demonstrate that residual acids or bases have been neutralized or washed out. Finally, Karl Fischer can confirm that the equipment is dry.

Method Development

In practice, the development of analytical methods for drug release testing is often completed before scientists develop methods to evaluate cleaning samples, so this is usually a good place to start. There is one particularly important difference, however; the method for drug testing will be demonstrated to be valid in a range around the nominal test sample concentration, usually on the order of mg/mL. A cleaning method, on the other hand, will need to be sufficiently sensitive to detect and quantitate levels on the order of mg/L or three orders of magnitude more sensitive.

Furthermore, the method used for the drug release testing may use reagents or have testing conditions that are appropriate for drug release, but less so for the testing of cleaning samples. For example, many HPLC methods use acetonitrile in relatively small volumes. Cleaning and sampling of cleaned equipment would use substantially larger volumes that would be quite undesirable if there were a worldwide shortage of acetonitrile, as was the case 2 years ago.

In developing methods and the cleaning procedure itself, it is useful to evaluate the solubility of the materials to be tested for. If the compound is insufficiently soluble, the method will be difficult to validate because the results will be inconsistent. Be sure that the method is appropriate for the solvent used to collect the sample; for example, TOC would be inappropriate for the detection of API in an acetone rinse wherein acetone is more than 60% carbon. A good and experienced analyst can work with process development or operations to develop methods appropriate for evaluation of cleaning samples.

Some suggestions are listed in Table I.

Method Validation

There are two excellent and widely referenced guides for Validation of Analytical Methods: USP General Chapter <1225>, “Validation of Compendial Procedures,” and The International Conference on Harmonization (ICH) Guidance Q2.1,2 These references provide useful direction for characteristics to be evaluated and for a methodology to conduct these evaluations. Both provide direction

March/April 2011

for the evaluation of specificity, range and linearity, accuracy, precision, detection limit, quantitation limit and “robustness.”

These are extremely useful references, but they address method validation for drugs and drug substances, not for cleaning samples. Furthermore, while the ICH document is “guidance,” other approaches may be acceptable if they are scientifically rational and appropriately justified. In practice, we follow the ICH Guidance when validating cleaning methods. It is easier to defend this approach to regulatory inspectors and auditors than it is to defend a novel approach to validation.

In light of the fact that these references are for drugs and drug substances, there is one aspect of cleaning method validation that must also be addressed: cleaning swab recovery. A rigorous cleaning policy will include equipment sampling using swabs. Swabs are a necessity in areas that are “hard to clean” and/or “hard to see.” An important aspect of the development and validation process is the determination of the amount of material a swab will remove and release into the sample test medium. We take a known amount of compound and place it on a coupon of similar material as the equipment to be cleaned, such as glass or stainless steel.

We then swab the coupon, soak the swab in the testing medium and conduct the analysis. To calculate the average, we calculate the percent detected relative to the known amount placed on the coupon and replicate this experiment at least three times with a low and a high concentration.

Achieving as high a recovery as possible provides more accurate cleaning calculations. Sometimes, however, the compounds are not co-operative and we accept a recovery as low as 30%. Once the methods have been developed and validated and the swab recovery has been determined, cleaning verification and validation can proceed.

Cleaning Verification and Validation

Regulatory bodies (and client auditors) expect cleaning procedures to be validated to “establish documented evidence that provides a high degree of assurance that a specific process will consistently meet its pre-determined specifications.”

Prior to a pre-approval inspection, we conduct the cleaning process and subsequent testing, and prepare a report to meet this obligation. After validation and the processing campaign are complete, we perform analytical verification that the cleaning process continues to perform as expected, even if the cleaning process has been validated.

Conclusion

Cleaning and analytical verification to confirm the success of the cleaning process are critical steps in the manufacturing cycle for pharmaceutical products. We have provided a framework and suggested points to consider in the design of an effective programme to ensure patient safety and regulatory compliance in a multi-use pharmaceutical facility.

Table I: Suggested analytical methods.

References

1. T he United States Pharmacopeia, 34th Revision, General Chapter <1225>, The US Pharmacopeial Convention (Rockville, MD, USA) 2011.

2. The International Conference on Harmonisation Tripartite Guideline, “Validation of Analytical Procedures: Text and Methodology Q2(R1),” Adopted July 1995 (Part A) and October 1997 (Part B).

Fore more information

Gary A. Baker Vice President, Quality Assurance/Regulatory Affairs James Hamby Vice President, Business Development Brian Spencer Director, Analytical Services Stephen A. Munk President and CEO Ash Stevens www.ashstevens.com

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INVENTORY MANAGEMENT

TRACK , TRACE AND REPLENISH Implementing an automated inventory management system can reward pharma companies with enhanced accuracy, compliance, efficiency… and ultimately… a successful business.

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harmaceutical warehousing and distribution companies face some unique challenges in inventory management. Similar to any other warehousing and distribution company, pharmaceutical companies strive to achieve optimal inventory levels whilst maintaining high service levels and the ability to move products quickly; but because they handle controlled substances, there is no room for error.

Furthermore, it is imperative that they react to ever‑changing regulatory standards and legislative requirements from federal, state and local levels. In addition, very low profit margins make speed and accuracy of delivery imperative.

So, how can pharma companies hope to achieve this delicate balancing act? The answer is to implement an automated inventory management system as part of their corporate enterprise resource planning (ERP) solution.

These systems can track, replenish and locate inventory, thus enhancing inventory accuracy, ensuring regulatory compliance, increasing efficiency and improving customer service.

Accuracy

Maintaining near-perfect inventory accuracy is a significant challenge for a pharmaceutical company. When dealing with controlled substances, specifically Schedule 2–5, there can be no discrepancies.1 This requires meticulous attention to detail — a time‑consuming task considering the high volume of orders received. Manual data entry also impedes the replenishment process because of time constraints and human error, making it difficult for users to determine exact quantities of product in the warehouse.

Adding to the regulatory requirements that demand inventory accuracy is the low level of inventory that is kept on fast‑moving, high‑demand product. Inventory Management Agreements (IMAs) with prime vendors limit the amount of inventory that pharmaceutical wholesalers can have on hand at any given time. For example, IMAs require a maximum of 15 days on hand with a minimum of 98.5% service level.2 The way to increase accuracy, which also has the most direct impact on inventory, is to implement a quality inventory management system. This system can automate replenishment, which ensures product is available for shipping, thus reducing customer shortages. Furthermore, if an error is made during manual purchase order receiving

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or product ‘putaways,’ the system will discover the error and alert employees of it, resulting in potential maintained accuracies of at least 99.8%.

The system can also track inventory movement more closely to better determine exact inventory quantities and locations within the warehouse. Some systems have the unique ability to maintain infinite locations for one particular item in the same warehouse facility, which is important to help gain more accurate inventory numbers.

Pharmaceutical companies can easily check received item quantities during the put away process and check return quantities processed through its restock programme.

Automated processes within the system can also be used to check quantities and determine inaccuracies. More accurate inventory numbers enable warehouses to always satisfy demand without having increased expenses from holding excess product for undetermined amounts of time.

Compliance

Regulatory compliance is particularly important to a pharmaceutical company. In the US, not only are there federal regulations through the Prescription Drug Marketing Act (PDMA), FDA and the Drug Enforcement Administration (DEA), there are also state regulations such as the Florida Pedigree Law and local pharmacy board regulations. It is nearly impossible to ensure that a pharmaceutical company is following every rule for every customer without automation.

Automated inventory management systems interface with third‑party services to not only notify the pharmaceutical company of current regulations that apply to each customer and product, but also to regularly update databases to include new or changed regulations. This allows the system to alert users of these changes as they apply to new orders or customers.

Efficiency

If one industry is in need of efficiency, it is the pharma industry. The high volume, low margin environment requires an enormous amount of efficiency to appropriately cycle products through the sales process whilst still maintaining a profit. By streamlining distribution operations, improving information availability and increasing inventory accuracy, pharma companies can all but remove human error — or at least catch these errors

March/April 2011

much sooner. This results in more accurate counts at bin locations, more accurate shipping and faster movement of products through the warehouse.

Customer Service

Conducting business is about relationships and customer relationship management (CRM) is vital to a business’s success. The way in which a telephone call coming into a company’s call centre is handled may determine the future relationship with that customer.

The best way to ensure quality customer service is to provide tools and information to customer service representatives so that they can quickly and easily answer enquiries and solve issues.

The accessibility of information, such as customer and shipping data, enables representatives to pull up a specific customer’s account and tell them exactly what they need to know. With a quality inventory management system, this can be done through a user‑friendly interface, where employees can quickly create reports, and retrieve customer and order information. This facilitates a better use of time and allows personnel to focus on providing exceptional customer service and accurate inventory management. Ultimately, the accessibility of information reduces the number of complaints received from customers who were given incorrect information and makes for a better relationship.

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There are a variety of functionalities to consider when looking to implement an automated inventory management system. The solution needs to provide a robust suite of software that can be customized to a company’s specific needs. Voice picking software, and automated and semi‑automated picking machines can help to increase efficiency; an intelligent warehouse control system (WCS) makes for better accuracy and tracking of product within a warehouse; and third‑party interfacing can ensure compliance with regulatory organizations.

Above all, it is important to pick the right partner to implement the solution. This partner should have both the expertise in the solutions it provides and experience with clients in the pharma industry. The final outcome should be an end‑to‑end, integrated solution designed specifically to improve pharmaceutical supply chain management, customer relations and inventory control whilst improving the accuracy, efficiency and success of a company.

Notes

1. The Drug Enforcement Agency (DEA) categorizes drugs according to this schedule.

The lower the schedule number, the higher the need for tracking. Distributors must account for and report on these drugs.

2. Service level refers to a distributor’s report card on being able to fill customer orders.

Vendors expect this to be a high number, ensuring the end‑consumer will get their product when needed; otherwise, they will limit the amount of product the distributor can move.

For more information Claudio Gallina Project Director Vormittag Associates, Inc. cgallina@vai.net www.vai.net

March/April 2011

Isaac Rogers Vice President, Operations Smith Drug Company www.smithdrug.com

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45 3

GENERICS

GENERICS ARE DEAD! LONG LIVE GENERICS! Generic companies are equally feeling the same pressures as large pharmaceutical companies; yet, by embracingthe emerging payment‑by‑results model and new technologies, generics companies stand to reap the rewards of the drive to do more with less.

T

he current period represents a lucrative harvest for the generics industry, with a flood of valuable, mainly small‑molecule, drug patent expiries.

Lipitor (Pfizer Inc.), for example, is rapidly heading for genericization and currently generates approximately $10 billion a year in sales.

Moreover, governments actively encourage the generics industry; for example, in the US, the Hatch‑Waxman Act can give a company 180‑days’ exclusivity for a generic drug; it also partially mitigates the risk of litigation from the patent owner during the drug development.

In future, with economic pressure and armed with much better knowledge of how an individual tolerates a drug and how amenable their condition is to a particular therapeutic regimen, targeted generics will form the first‑line mainstay treatments in the majority of patients. This favourable climate has put Teva, the largest generics company, in the top 15 of all pharmaceutical companies by sales and it is considered to be the largest pharmaceutical company by the number of prescriptions filled.1

Crucially, however, although drugs continue to be approved those approvals are consisting of a larger proportion of biopharmaceuticals — six biologics were approved in 2010.

Biopharmaceuticals do not offer the same market opportunities for genericization as small‑molecule drugs, which have traditionally formed the life‑blood of the industry offering • Low‑cost development.

• Low‑cost manufacturing.

• Huge‑volume markets — they are being taken by millions of patients everyday for same price as a daily newspaper.

These critical factors associated with small‑molecule drugs enable the generics companies to thrive by aggressive marketing tactics and greatly undercutting prices. The market dominance, however, is turning from small‑molecule blockbuster drugs taken by millions of people to large‑molecule ‘niche-busters,’ which cost thousands of dollars per dose and are taken by considerably fewer patients. The opportunities and business models that have served the generics industry so well are in upheaval.

Generics are Dead

In the same way that restaurants say they make all their money from selling alcoholic drinks and pubs claim to make all their money from selling food the generics industry is moving towards patented products whilst the world’s “big beast” proprietary pharmaceutical companies move towards generics and biosimilars. Teva’s pipeline includes several patented developments covering

Despite the opportunity, the classic branded generics industry has a serious problem looming. Proprietary small‑molecule pharmaceutical pipelines are drying up; the food on which the generics companies have traditionally feasted is disappearing.

FDA approved 21 drugs in 2010: a drop from the previous few years and a continuation of the general downward trend.

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GENERICS Table I: Examples of new reimbursement models.

neurological, auto‑immune and oncological diseases. The company also has a strong franchise in Copaxone, which it is fiercely defending from generic competition, poacher turned gamekeeper style.

Meanwhile, Novartis has its Sandoz arm; GSK has a deal with Dr Reddies; Daiichi Sankyo is in alliance with Ranbaxy; Pfizer tried to acquire Ratiopharm and Ranbaxy before it got its hands on King Pharmaceuticals; and AstraZeneca has a deal with Torrent Pharmaceuticals.

In dealing with their own problems proprietary pharmaceutical companies are pursuing strategies to reduce risk. By diversifying both into markets that are outside the generic drug field and pushing deep into generic pharma’s own territory these strategies provide further threat to classic generics businesses.

Long Live Generics

The future for the generics industry is, however, rosy and can be realized by virtue of those very threats to the proprietary industry. Whilst economics and markets have been studied and predict growth for the generic companies, many of the opportunities are rooted in advances in technology and the changing face of how drugs are prescribed, taken and their effectiveness measured.

We see three tiers of healthcare emerging, driven by economic constraints, deeper regulation and technological opportunity: • Proprietary personalized medicine, which is costly and the onus of its success will be placed firmly with the pharmaceutical or medical device company.

• Generic personalized regimens, using low‑cost generics targeted to provide optimum care with close monitoring of outcomes.

• Individual responsibility for wellness — education and stimulus to live healthily.

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A far better understanding of patients’ reaction to drugs and the diseases from which they are suffering will enable this three‑tiered healthcare model. Currently, we are just at the start of this revolution of understanding: • The individual response of a particular patient to a particular therapy (or lack of therapy); for example, the patient’s genotype, such as their genetic predisposition to drug metabolic pathways and cytochrome P450 status.

• The response of a particular disease condition or injury to a particular therapy, information drawn from biomarkers associated with the disease.

• Economics and life issues of a particular treatment in the context of the particular patient.

The rise of biomarkers and genetics to define responders and nonresponders to pharmaceuticals is enabling this new model.

This does not just apply to new drugs — as our understanding of the genetic responses to drugs improves we can raise the effectiveness of generics to their full potential.

For example, warfarin costs pennies a day and is widely given to patients at risk of blood clotting. It is, however, the second most common drug implicated in adverse drug reaction‑linked emergency room visits. One‑third of thrombosis patients metabolize their warfarin dose differently from that expected primarily because of variations of two genes: VKORC1 and CYP2C9. Since 2007, FDA has recommended that doctors consider lower initiation doses for patients with variations in these genes.

In January 2011, FDA updated the labelling referring doctors to a table containing stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 variants. The newly updated warfarin label also notes that the dosing ranges in the table account for clinical factors, such as age, race, body weight, sex, concomitant medications and co‑morbidities, along with genotype.

March/April 2011

GENERICS As a new model of stratified medicine emerges, suppliers of high‑value proprietary drugs will feel the squeeze as payers seek to minimize cost using high‑cost drugs as the treatment of last resort. A major factor impeding the success of new molecular entities is the economic case that must be made for the prescription and reimbursement of drugs. The pressure from payers is increasingly on pharmaceutical companies to link payment to successful results in the patient. This is exemplified by a number of new reimbursement models (Table I).

The current system of prescribing drugs to patients is an open loop system. The point at which the patient picks up the prescription generally marks the end of the control the healthcare system has regarding the outcome in the patient.

Patients may choose not to take drugs at all, take them wrongly because they don’t understand the instructions, or make a conscious decision to take the drugs in a different regimen from what’s prescribed because they find that works better for them. Whereas some patients may not understand how to take their medication others recognize that the prescribed regimen does not work for them and so adapt it to their personal responses. Adherence, or concordance, has long been recognized as an issue. There are variously published figures on the subject, but the World Health Organization (WHO) figure of 50% is representative.2 As the understanding of the importance of adherence monitoring increases technologies have abounded to assist both patients and clinicians in adherence.

Existing approaches to improving concordance range from the simple, such as assistance programmes and reminder systems, to the complex, involving direct monitoring of the preparation, administration or efficacy of treatment. Highly sophisticated approaches, such as Proteus Biomedical’s Ingestible Event Markers, allow the identification of the type and source of the drug and enable measurement of certain vital signs.

The benefit of integrating technologies into clinical testing and as part of a regulatory submission offers an additional degree of protection or options for life-cycle management. This may represent a significant opportunity for generics companies who can build added‑value propositions attractive to payers by demonstrating increased compliance savings across the care pathway. The issue is to understand how a given technological approach enhances concordance and by how much to remove cost at the population level, making broad adoption of added‑value generics an attractive proposition (Figure 1).

There are also many drug delivery technologies that assist the user in taking medicines. An example is rheumatoid arthritis (RA) drugs. The modern RA drugs are biologics given by injection. The nature of the condition, however, means that it is difficult for patients to self‑inject. Consequently, the proprietary RA drugs are presented in an auto‑injector and the follow‑on biosimilars will be forced to do the same. A generic drug enhanced, for example, by an innovative delivery system or more convenient packaging, is looking increasingly to be a better deal than the latest, best‑in‑class and still patented drug: better in terms of clinical outcomes because the recent increments being made by best‑in‑class drugs are small relative to the many issues that still exist regarding proper and compliant use of the drug; and better for the payer because the cost of the generic drug combined with the innovative device or enhanced packaging is likely to be much cheaper than the patented drug.

The emergence of diagnostic, monitoring and drug delivery technologies together provide a huge opportunity for generic medicines. Providing that generics companies can embrace the emerging payment‑by‑results model and integrate new technologies then they stand to reap the rewards of the drive to do more with less.

Figure 1: The value that a diagnostic (Dx) can provide to a proprietary drug (Rx) and a generic drug (Gx).

Gregory Berman Sarah Wren

References

1. www.nytimes. com/2010/05/09/ business/09teva.html?_r=3 2. WHO report: Adherence to Long-Term Therapies: Evidence for Action (2003).

For more information Gregory Berman Healthcare Expert PA Consulting Group Sarah Wren Healthcare Expert PA Consulting Group healthcare@paconsulting.com

Figure 1

March/April 2011

www.paconsulting.com/healthcare

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SOFTWARE/IT

RHYTHMS OF LIFE

T

Using genetic algorithms to inspire evolutionary progress in pharmaceutical R&D. he pharmaceutical industry appreciates that an understanding of human biology can aid the development of systematic scientific approaches and research techniques: in the 1950s it was geneticists, not technologists, who first began exploring the possibilities of simulating the natural selection of evolution and the artificial selection of intentional breeding to inform problem solving and streamline industrial processes. Today, genetic algorithms routinely inspire professionals across many industries to find practical solutions to business problems that help to optimize productivity. But it is in sectors such as the pharmaceutical industry, which rely so heavily upon inspired innovation, discovery, informed selection and rational R&D, that genetic algorithms can deliver the most significant practical and economic benefits.

How Does it Work?

Is it a great leap to suggest applying trusted Darwinian‑age principles — such as survival of the fittest and progressive evolvement of species — to the problems of optimizing and streamlining a large portfolio of projects across a business? Not in concept, perhaps, but in its basic application, such ideas can quickly present difficulties.

Without a mature, sophisticated approach, we would simply have to attribute each project a large number of distinguishing characteristics, including costs and levels of resources required, as well as predicted benefits or estimated returns on investment.

Although this might seem a good start towards determining which projects to include in a portfolio or not, the sheer variety of information that could be applied to each project would make the process cumbersome at the least. A modest portfolio containing about 100 candidate projects would result in combinations of characteristics of enormous orders of magnitude. Even powerful supercomputers would take many years to sequentially crunch through every possible combination involved; but genetic algorithms offer a more practical and human solution.

In general terms, genetic algorithms are mathematical simulations of biological evolution, applied to industrial optimization problems — such as which collection of projects is most deserving of continued funding and resourcing. It is a method of trying to evolve an optimum portfolio even when starting with a random collection of projects — a mixed population if you will — and then ‘scoring’ each depending on how well they are matched to their ‘environment,’ or business goals. In this world, we assess a broad population of alternative

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portfolio combinations according to overall cost, sales and other factors. A formula can then be applied that judges how ‘good’ a portfolio is in fulfilling targets and goals within defined constraints. Using a software platform, ‘generations’ of portfolios may be paired and ‘mated’ together. During successive generations, the strongest candidates within a portfolio become paired more frequently to produce ‘children’ in a process commonly called generation sequencing. In time, the strongest combinations show through, as portfolios are shaped and reformed, converging into optimum portfolios in 1000 generations or so…and all within a matter of seconds.

Why is this Progress?

Genetic algorithms represent a fundamentally different approach that provides highly sophisticated functionality for portfolio analysis, visualization and optimization that cannot be achieved with mechanical testing alone.

It has been accepted as the future of project portfolio management — despite the complexity involved in its development — simply because it is an extremely efficiently solution to a long‑felt problem. In the real world away from solutions development, companies have fixed objectives that they attempt to maximize to make their businesses more successful; for example, maximizing the future sales value for a pipeline of new products, constrained by budgets and resources.

Hands‑on managers will have some intuitive judgment that gives them a good jump start as compared with mere David Munt

March/April 2011

SOFTWARE/IT

mechanical number grinding; but more sophisticated decision support is still desirable to get ever more accurate combinations of ‘best’ products. Anything that helps a company to deliver better future value of sales for the same resources represents a distinct advantage.

Of course, other approaches do exist; for example, Microsoft Excel. It still features an ‘add‑in’ called Solver that can be used to make basic business forecasts based on ratios. It enables quick calculations of ratios of sales against project costs, for instance, which can be a useful guide for companies with a single consistent restraint or just a few constraints. But constraints are far more varied in project portfolio management. Budgets and resource constraints must be segmented, for example, by skill type or job function, resulting in numerous constraints attributed per skill area, ultimately resulting in many hundreds of discrete areas of constraint. Simple approaches such as Solver don’t adequately address the multi‑criteria issues of portfolio management.

Another technique is the ‘efficient frontier’ method of optimizing portfolios. This is a straightforward approach that goes back to financial portfolio management of the 1950s. The theory is to maximize investment portfolio returns and minimize risks.

Again, this approach is ratio‑based, although typically depicted graphically. Efficient frontier is a particularly useful method of weighing up reward versus risk; it is now also sometimes touted as a project portfolio management solution. Yet, a shortfall again arises from a lack of constraint handling capacity: efficient frontier just doesn’t have the scalability to deal with a huge number of dimensions. This isn’t surprising, because financial portfolio management solutions such as this were developed on the basis that managers would be able to easily switch in and out of investments, incurring negligible costs to alter their positions. Of course, it’s not quite so easy to re‑allocate resources between different pharmaceutical R&D projects without incurring considerable switching costs as a result of the diversity of R&D skills involved.

March/April 2011

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SOFTWARE/IT

Pharmaceutical portfolios frequently run into many hundreds of projects, so efficient software tools are all the more appreciated.

A Good Fit for Pharma

The superior insight of the genetic algorithm approach is relevant to almost any industrial sector in which the problem of choosing portfolio projects exists; but what makes it particularly attractive in the pharmaceutical industry is the relatively long average lifetime of projects. This means that there is a longer time commitment and potentially bigger rewards on offer in return for putting greater effort into the decision‑making process that selects which projects to have in the portfolio. In shorter life‑cycle industries, managers might choose to shoot from the hip and an entrepreneurial approach may be more acceptable. But in pharmaceuticals where project life cycles frequently have 5-, 10- or 15‑year outlooks, there is a more protracted period during which accurate and sustainable decisions must be made. The stakes and rewards are bigger so the decision process must be more thoughtful, conscious and deliberate.

In addition, although genetic algorithms can contribute to any form of portfolio management, optimizing fewer than 10 projects probably doesn’t make much sense as results could usually be achieved in those cases using simple judgment, analytics or even trial and error. Pharmaceutical portfolios frequently run into many hundreds of projects, so efficient software tools are all the more appreciated.

Visibility and Control

For more information

David Munt Managing Director and Co-Founder of Project Portfolio Management Specialist The GenSight Group Tel. +44 208 939 5800 info@gensight.com www.gensight.com

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The representation of projects in genetic algorithm software may be loosely compared to biological chromosomes. Human cells have 23 pairs of large linear nuclear chromosomes. A fruit fly has just eight whereas an adders‑tongue fern has 1260. Similarly, each list or string representing projects that are in or out of a particular portfolio will have a different identity. In maths, we represent the alternative portfolios as strings, we identify patterns then the evolution process takes two strings and combines them, taking elements from the parents. We join them together, introduce a little mutation to simulate random occurrences and then model possibilities across candidate portfolios.

www.pharma-mag.com

The portfolio recommendation produced by genetic algorithm software will have a graphical element — usually visualized by bubble combinations on charts. Most parameters can be controlled if desired, with the main concerns of most portfolios being goals and constraints.

Of course, managers ultimately have full control regarding which projects are selected or prioritized for their business in any given portfolio. Although genetic algorithm software will propose a solution, there are still major decisions to be made based on real‑world implications and human considerations. Managers have to do this — a machine simply proposes mathematically sound and interesting candidate solutions to think about.

Getting Started

If you want to explore adopting a genetic algorithm‑based approach to tackle your own project selection/resource allocation requirements, then what are the first steps?

There’s certainly a level of base information that is required before any business can contemplate gaining any benefit from genetic algorithms. That base information concerns robust forecasts on the potential benefits of every project across the portfolio, coupled with accurate forecasts of expected costs of each project and the types of resource requirements demanded. This is a fair bit of entry‑level information, and isn’t a feasible approach for every business; but if a company has weak forecasts, there is no point putting these into a sophisticated algorithm — if you put garbage in, expect garbage out.

Find a company experienced in delivering genetic algorithm technology. If your business does have all the base information in place, then it is a relatively immediate step up in the sophistication curve. Do you know your goals to be optimized and what constraints you must consider? Is there general clarity of thought across the business? Then you are ready to embark on a pilot phase of genetic algorithm project portfolio management.

Ultimately, it’s about getting the best bang for your buck, albeit that in this context the ‘bang’ has multiple perspectives and the ‘buck’ has multifaceted constraints. I have witnessed many scenarios in which the management team has stepped up to use genetic algorithms and has been able to reshape their portfolio dramatically — in some case producing many millions of dollars of increase in value within the same constraints of budgets and resources.

A willingness to inform business decisions with recommendation from genetic algorithms can provide incremental benefits that often prove significant. Because the duration of projects and product life cycles in the pharmaceutical industry are so long, any improvement, even quite small benefits in optimizing a portfolio, can be reaped during the longer term. Shifting the dial of effectiveness just a little can have enormous consequences — when portfolio longevity and scales are this big, often so are rewards.

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53

MARKETING

A PICTURE CAN PAINT A THOUSAND WORDS

A look at how images are used in pharmaceutical communications and the importance of breaking down the barriers to medicine by using imagery to create a human connection with consumers and patients.

Figure 1a

Figure 1b

I

mages are a hugely powerful tool in communicating with consumers, and building a relationship between brands and the public. The most successful kinds of imagery used in marketing capture the zeitgeist and show a true understanding of what the target audience is feeling at that moment. Central to all communications for the pharmaceutical industry in particular, is the ability to convey peace of mind and contentment to reassure patients and ultimately, instil faith in a course of treatment. The healthcare industry has always been particularly savvy about how it can use visuals to talk to its audience. A great photograph can often comfort by expressing empathy in a way a page of heavy text and details cannot; it can reassure by underlining expertise and compassion, or encourage consumers to momentarily forget their health worries and anxieties.

Shifts in Visual Trends

Getty Images’ recent research into visual trends in the pharmaceutical industry demonstrates that companies have changed the imagery they use to communicate with customers and other stakeholders.1 Most obviously, this is connected to the recession and a global shift in perceptions, particularly concerning what defines success. Rather than Figure 1

Figure 1: NHS baby, teen and mid-life checks campaign.

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monetary and business success there is now a much greater focus on personal happiness. Some 83% of pharmaceutical visuals focus on enjoying life, living it to the fullest and nurturing personal relationships.1 This is coupled with a decline in the use of business and sports imagery, indicating a shift in global priorities. Through its research, Getty Images has also noted a 10% rise of the use of images in pharmaceutical brand communications that don’t include people. Within the pharmaceutical industry the move has leaned towards animals, plants and nature with plenty of green imagery, reflecting a wider visual trend around the rising concern with environmental issues.

Health is a very personal subject and one that is only on people’s minds when they lack it. With more people focusing on their own personal happiness as an indication of success, it is increasingly important that the pharmaceutical industry is able to speak to its audience on a more personal level.

Real People

Photography is the simplest entry point for any communication regarding medicine — usually, a portrait of another human enables people to make a connection that is reassuring and removes some of the barriers to medicine that can make it seem ‘alien.’ In addition, it allows people to find empathy and understanding in another human who appears to be in the same situation as them. Getty Images’ research highlights an increase in the use of real people in advertising. Featuring testimonials instead of models in communication adds a new level of authenticity and helps to increase confidence.

The idea of ‘Me,’ of identifying with human feelings, is also about human beings as a collective, being able to support each other. The concept of community is a hugely powerful idea for the pharmaceutical industry to tap in to, both online and offline.

Because of legal restrictions in the UK on consumer advertising in the pharmaceutical industry there are far fewer examples of marketing having a great impact than in the US. A recent campaign from the NHS, however, to promote baby, teen and mid‑life checks highlights the shift to using testimonial photography. The campaign features close‑up portraits of real people of all ages and ethnic backgrounds, and embraces the consumers’ desire to identify with the subject (Figure 1).

This ‘slice of life’ imagery has helped the NHS to connect with the consumer and make them feel that they are understood. In addition, the imagery reinforces the message behind the campaign that good health is vital to

March/April 2011

MARKETING your wellbeing, playing on the consumers’ shift in attitude towards personal happiness as an indication of success.

This trend towards authentic imagery of real people is taken one step further with a noted rise in the use of regional‑specific imagery. The central theme of real people is still very much at the heart of the image, but the regional setting adds another layer of authenticity (Figure 2). Furthermore, the rural settings of many of these images increase the feeling of wellbeing, which speaks to the new consumer, who has moved away from a monetary‑based evaluation of success.

Creating a human connection is the key, but the pharmaceutical industry also needs to radiate the feeling of authority and confidence. There is an aura of mystery around medicine because people don’t necessarily understand it; yet they still need confidence and trust in the success of their medication or treatment. Today, patients have access to information through the Internet and can research illnesses, medications and alternative treatment options, but self‑diagnosis can only go so far; people will always want the confirmation of a medical professional, the assurance of authority embodied in the images of experts at work.

Pharma’s audience has become savvier and the industry needs to move towards collaboration between doctors, medical staff, researchers and their patients. This shift needs to be reflected in pharmaceutical companies’ brand communications. Showing the doctor–patient relationship as a combination of expertise and warm bedside manner reassures patients that their wellbeing is at the centre of healthcare.

Figure 3

Figure 4

March/April 2011

Figure 2

Novartis has been using documentary black‑and‑white photography in its annual reports, showing patients, doctors and nurses in their everyday lives, focusing on the relationships and emotions, and telling stories of support and care with their imagery (Figures 3 and 4). By stripping out colour, Novartis highlights the human qualities of medical professionals.

Underpinning our beliefs and knowledge of medicine is the fundamental understanding that medicine exists to improve our quality of life. In a complicated and hectic world our health needs are still very simple: ‘I need to be well.’

Quality of life is about the choices people make, balancing work and home life. The value of being healthy isn’t simply the absence of illness, but rather the positive value of health as a precondition of all the activities that define us — this is central to the pharmaceutical industry.

Pharmaceuticaladvertisementsneedtobeabletocutthrough the noise of a busy life and appeal to our basic requirement to be healthy. Advertisements that connect most efficiently and directly are often those that communicate through strong photography; that is, images that are well composed, evocative and memorable. The most effective campaigns are those that use imagery that clearly relates to each other, whether through tone, style or model choice. The feeling of continuity expresses reliability and reassurance.

Photography can have a huge impact if used effectively in brand communications. In the pharmaceutical arena, this is an image that immediately connects with the onlooker by reflecting their personal experiences or emulating a scene from their life. The pharmaceutical industry must constantly connect with people in a profound way around important, and often complex and difficult, human issues. They must show that they understand people’s fears, hopes and emotions, and prove they have the expertise to help. Ultimately, putting real people in the centre of communication helps gain trust and builds confidence.

Figure 2: Real people and rural settings increase the feeling of wellbeing in consumers.

Figure 3: Novartis’s annual report uses black and white photography.

Figure 4: The use of real people creates a human connection.

Micha Schwing

Reference

1. http://apacimagery. gettyimages.com/pharma/ gbr/?isource=gbr_ trendslanding_ Pharmaceutical

For more information

Micha Schwing Creative Planning Manager Getty Images www.gettyimages.com

www.pharma-mag.com

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LITIGATION

MINIMIZING LITIGATION PAIN

In the wake of the reports of the negative effects of the Avandia litigation on GSK’s profits, now is a good time to reflect on the role of lawyers and litigation.

B

usiness people are often wary of dealing with lawyers, particularly litigators. The situation is akin to that of drugs; that is, most people prefer to avoid having to take them. Happily, both lawyers and pharmaceutical companies can take comfort in the fact that they are rarely the cause of problems and that, in any event, they remain indispensable.

Indeed, people shun lawyers and drugs at their own peril, as most illness and litigation are unavoidable and must be dealt with should they materialize. So the question is: what can be done to minimize litigation pain? Pending further research by pharmaceutical companies, drugs are not yet the solution.

As with illness, litigation comes in many guises and there is no one‑cures‑all solution. The company in question can initiate it or be at the receiving end of a suit brought by others. Litigation can relate to an individual transaction (for example, a licence or distribution agreement, a joint venture) or to multiple claims (such as the Avandia litigation). It can involve different types of issues, claims and consequences.

Litigation, similar to illness, is better avoided, as it is inevitably painful, disruptive, a source of bad publicity, expensive and uncertain in its outcome. Lawyers can, however, play an important pre‑emptive role, either in making litigation less likely or in better positioning the company should litigation occur. To do so, they should be consulted at the earliest possible stage, just as a physician is best consulted at the onset of illness before it sets in or becomes more serious. Lawyers can be precious when negotiating and drafting contracts, and in setting up intellectual property

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(IP) rights or in planning strategically for litigation, where possible; for example, by deciding between arbitration and litigation in court, introducing appropriate choice of law clauses and so on. All this can be decisive in some types of litigation. There are, of course, situations when lawyers can do little or nothing to forestall litigation, such as when it is the result of claims that products are unsafe, cause side‑effects or are unsuitable in certain situations. In these cases, the burden is entirely on the company to ensure that the products are adequately tested before they are marketed.

The role of lawyers is even more important when a disease (that is, a dispute) manifests itself. Even at this stage they can help to avoid litigation. Well‑versed and pro‑active lawyers can promote sensible solutions through mediation or other alternative dispute resolution mechanisms.

Regrettably, there are occasions when litigation cannot be avoided; that is, when claims are excessive or unreasonable; third parties or insurers are involved; questions of principle, personalities or idiosyncrasies come into play; or when, for whatever reason, there is a desire to defer the appearance of problems or responsibilities. During these circumstances, lawyers show their worth. It is up to them to advise whether to wait for a claim to be brought or to make the first move and where to bring the suit, and to decide every subsequent strategic issue, including whether there are opportunities for settlement in the course of the proceedings. Identifying the right court (and country), a technique known as forum shopping, is key. Among the matters that depend on which court is seized are the rules that will be applied, the nature of

March/April 2011

LITIGATION evidence that can be used and the availability of discovery, punitive damages and class actions, and the role of juries.

All these issues may be crucial to tipping the balance of the decision in favour or against one party or the other.

Although most decisions require sophisticated technical expertise, it is essential that the client always remains directly engaged at every stage of the litigation, through its in‑house counsel and, where warranted, the management. This ensures that the company maintains a clear understanding of what happens and close control on the strategy and of costs. It also helps to reduce surprises regarding the outcome of the litigation.

The choice of lawyers is of paramount importance for the prospective litigant. Choosing a top quality law firm, and one with the right expertise and experience for the dispute at hand, is the equivalent of visiting the right doctor and taking the right tablet. Similar to drugs and doctors, lawyers and law firms differ. Of course, each company will usually have a preferential relationship with a law firm. When it comes to big‑ticket litigation, however, special attention must be given to picking the best firm for the particular dispute. Frequently, the dispute may have a transnational dimension; that is, the same dispute, or different facets, may be litigated in different countries or may involve different legal systems. In these cases, the choice of law firm must factor in its ability to deal with these issues. Despite appearances, the so‑called global

law firms are not necessarily the ones capable of providing the best possible assistance in all relevant jurisdictions.

There exist networks of firms comprising some of the best firms in the main jurisdictions, which are able to provide the same type of seamless service as global firms, whilst simultaneously drawing on the expertise and contacts of the top local firms.

Costs are a fundamental factor in the equation, but should not be the prime driver when the stakes are high.

Again, the analogy with the choice of a doctor or a medicine is evident: cheap advice may come at a price further down the road. The concern that costs may get out of hand, however, is understandable. The matter must, therefore, be negotiated in advance with great attention.

Law firms and professional rules are becoming more creative with regard to fee arrangements. Hourly rates are losing their attractiveness in favour of solutions based on different forms of risk sharing and insurance. The solutions necessarily vary depending on the type of litigation and on the jurisdiction. The aim is always to take at least some of the financial pain out of litigation.

Litigation — and illness — will never be eliminated and will never be painless. Nevertheless, just as good doctors and effective drugs can help to successfully treat patients, top quality lawyers and a pro‑active and a professional approach by the prospective litigants can work wonders.

Luca G. Radicati di Brozolo

For more information

Luca G. Radicati di Brozolo Partner Bonelli Erede Pappalardo Luca.Radicati@beplex.com www.beplex.com

Park Hotel Bremen, Germany www.ciosummiteurope.com

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NOSTRAPHARMUS

NAVIGATING THE PERFECT STORM Nostrapharmus explores how life science organizations are going to have to navigate the perfect storm to shape the future of patient safety.

T

Reference

1. W.G. Mcbride, “Thalidomide and Congenital Abnormalities,” The Lancet, 278(7516), 1358 (1961).

For more information

nostrapharmus@wcigroup.com

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he origin of our current pharmacovigilance systems can be traced back to the teratogenic effects of thalidomide, first reported as a series of three cases in The Lancet in 1961.1 Recognition of thalidomide’s association with a variety of birth defects and, in particular, limb defects known as phocomelia, led to the drug’s withdrawal from the market. Up until this time, the only way of reporting adverse drug reactions was through publication in medical literature. The lessons of thalidomide, 50 years ago, led to the creation of systems to detect, assess and report suspected adverse reactions.

Early systems for drug safety reporting relied upon a medically qualified person, suspecting a causal association between the event and the medication to report a suspected adverse reaction. Today’s pharmacovigilance systems are still built upon adverse event reporting, with more than 50% of the resources in a typical drug safety organization being dedicated to this activity alone. When the requirements to report summaries of the same data in aggregate form are considered, then close to 80% of resources are consumed in performing routine and reactive safety processes.

This routine safety workload has been increasing by 15–20% per annum during the past 10 years and shows no signs of slowing down. In fact, with greater public awareness, regulatory efforts to increase reporting rates from health practitioners and patients, coupled with the impact of electronic and social media, it is easy to imagine that suspected adverse reaction report volumes will increase at an even greater rate.

Simultaneously, newer regulations have required a greater emphasis on proactive safety via risk management planning and again this will increase as practice and regulation moves forward towards consideration of benefit–risk balance. In Europe, the new legislation that comes into force in July 2012 will require market authorization holders to manage more robust safety risk management systems, to be able

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to demonstrate the effectiveness of those systems, and to report on post-market safety and efficacy studies. The identification, analysis and management of safety signals are increasingly being conducted in the public domain, thanks to the combined effects of regulator watch lists, media campaigns and litigators.

The business environment in life sciences is changing rapidly, reflecting major trends seen across society. There is an explosion of data that is now available to practitioners and to patients from both reputable and, sometimes, less informed sources. Emerging markets are bringing new patient groups and new demands, the potential divergence of regulation and an increased risk of counterfeiting. Individual patients expect to receive far more personalized care and freedom to choose treatment and help manage their own conditions, whilst still expecting the highest standards of efficacy and protection. Never before have pharmacovigilance professionals been required to communicate so clearly or to act so promptly in questions of patient safety and the balance of benefit and risk.

In this rapidly changing environment the traditionally and necessarily conservative and heavily regulated pharmacovigilance functions are at the heart of a perfect storm.

These issues clearly extend beyond the safety function and across the entire medical, legal and business organizations.

Nostrapharmus says: “In these uncertain times for patient safety, change can come from within. Now is the time for pharmacovigilance professionals to become more vocal, to advise and to provide leadership and direction to help not only healthcare professionals, not just the regulators or industry, but society as a whole, in placing the patient at the centre of our future pharmacovigilance systems. In 10 years’ time, we should see pharmacovigilance systems that are more focused on improving the benefit–risk balance for patients than they are on the compliance of individual case safety reports. Such a revolution in safety will require an integrated approach to be taken by all interested parties.”

March/April 2011

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