Pharma Sep 2011

w w w. p h a r m a - m a g . c o m September/October 2011 ISSN 1746-174X Volume 7 Number 5

Filtration & Separation

Sterilizing-Grade Filtration

Biotechnology

The global magazine for the pharmaceutical and biopharmaceutical industry

Extracellular and Intracellular Actions of Albumin

Clinical Studies

Setting Up, Conducting and Reporting Oncology Studies

R&D

A Solution to the Antibiotic Conundrum?

INGREDIENTS & RAW MATERIALS International GMP Regulations and HPAPI Production

STRAP Quality Reliability Traceability Sustainability

Sustainability At DSM, our purpose is to create brighter lives for people today and generations to come. This mission is supported by sustainability as a core value and one of four pillars in our Quality for Life™ commitment.

Its philosophies and metrics are evident in everything we do, highlighted by a top ranking in the Dow Jones Sustainability Index in the global chemical industry for 10 consecutive years. Sustainabiity is also an increasingly valued criterion for vendor selection, so it’s not only a responsible approach, but a strategic business driver.

DSM Pharmaceutical Products 45 Waterview Boulevard, Parsippany, NJ 07054-1298 USA Tel: +1 973 257 8011 www.dsmpharmaceuticalproducts.com www.dsm.com

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September/October 2011

CONTENTS

SEPTEMBER/OCTOBER 2011

Contents FOCUS TOPIC

08

Ingredients & Raw Materials

Contributing Companies: Adhesives Research

Inc, Almac, blue inspection body GmbH, CARBOGEN AMCIS, Covance and Pfizer CentreSource.

Industry experts discuss a variety of themes and trends influencing the sector.

CPhI/ISCE Preview: Responding to Change

Haf Cennydd — UBM Live

The Brand Director of ICSE, P-MEC and BioPh at UBM Live explains how feedback from visitors of last year’s event has been used to shape this year’s show.

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Filtration & Separation: Sterile Filter Pre-Use/ Post-Sterilization Integrity Testing

Implications

Maik W Jornitz and Theodore H. Meltzer — Sartorius Stedim North America Inc. and Capitola Consulting Co.

The authors provide some clarification concerning paragraph 113 of EU Annex 1.

Outsourcing: Harnessing the Value of Outsourcing-Led Innovation

Sanjiv Gossain — Cognizant

Are you wasting money by investing in innovation initiatives that are failing to deliver tangible results?

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FEATURES

28

50

Clinical Studies: Challenges in Oncology Studies

Quanitcate Statistical Consultancy Team

Making a success of setting up, conducting and reporting oncology studies.

62

Cost Reduction: Getting More Out of Less

Keith Foster — Moorhouse

Using a programme management approach to strip out costs can seriously improve a company’s health.

66

R&D: Botanical Alternatives to Antibiotic Solutions

Paolo Pontoniere and Roberto Crea — CreAgri

Hydroxytyrosol from olives could provide a new, more effective and substantially safer approach to health management.

38

Compliance & GxPs: Comprehensive Sample Management: The Foundation of Drug Development Lori Ball — BioStorage Technologies, Inc.

Maximizing the potential of biospecimens for current and future drug development.

REGULARS

05

From the Editor: Fruits of Our Labour

Corrine Lawrence

Musings on the prospect of this year’s CPhI Worldwide and EOA.

42

Emerging Markets: The Time is Right to Invest

Kamal Biswas — Infosys Consulting, Inc.

Can the benefits of operating in emerging markets be the much‑wanted drop of rain in the severe R&D drought?

Biotechnology: Albumin: Multifunctional Benefits for Cell-Derived Applications

44

Luke Dimasi — Novozymes Biopharma

The author analyses the role of albumin’s interactions with ligands or bioactive factors that influence metabolic and

biosynthetic activity, cell proliferation and survival.

06

Comment: Making a Success of New Drug Development Lars‑Helge Strömquist — NDA Group

How does the industry improve its strategy in getting new drugs to market quicker?

70

Nostrapharmus: Building Emerging Markets BRIC by BRIC

Nostrapharmus

Nostrapharmus considers what the future holds for pharma companies operating in the BRIC (Brazil, Russia, India, China) nations.

For up-to-date news follow us on Twitter (PharmaMag) and join our Pharma group discussions on LinkedIn September/October 2011

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STAFF

Contributors Editor Corrine Lawrence +44 (0) 771 517 7767 corrine.lawrence@via-medialtd.com Editorial Director Kevin Robinson +44 (0) 1392 202 591 kevin.robinson@via-medialtd.com Art Director/Production Paul Andrews Tel. +44 (0) 1372 364 126 paul.andrews@via-medialtd.com Content/Marketing Manager Claire Day Tel. +44 (0) 1372 364 129 claire.day@via-medialtd.com Sales Manager Fred Winsor +44 (0) 1372 364 125 fred.winsor@via-medialtd.com Financial Officer Cherelle Saunders +44 (0) 1372 364 123

cherelle.saunders@via-medialtd.com

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

miranda.docherty@via-medialtd.com

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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 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

Gino Martini Director, Strategic Technologies GSK (UK)

Kurt Speckhals Senior Director, Supply Chain Pfizer Inc.

Jim McKiernan Chief Executive Officer McKiernan Associates GmbH

Geoff Tovey Visiting Professor Dept of Pharmacy King’s College

Maireadh Pedersen Head of Business Development Wes Wheeler President, Quay Pharma WPWheeler LLC Ray Rowe Chief Scientist/Prof of Industrial Pharmaceutics Intelligensys/Uni of Bradford Harald Stahl Senior Pharmaceutical Technologist GEA Pharma Systems

To subscribe

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.

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.

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September/October 2011

FROM THE EDITOR

Fruits of Our Labour

M

y hand-gathered collection of blackberries and Bramley apples signals the arrival of autumn and thus, the anticipation of CPhI Worldwide and the European Outsourcing Awards (EOA).

I have, however, been reliably informed that this year we’ll be doing more talking and less walking.

I truly hope so because last year’s event found me clomping up the Champs Elysses in a borrowed pair of brown brogues … it’s a long story. Does every CPhI have to be characterized by a saga? Anyway, I digress.

Once again, the Pharma team will be in full force, as will our Via Connect colleagues who have spent many months organizing two Outsourcing Roundtables and the EOA, which will be taking place alongside CPhI. The show marks the point at which many companies hope to realize the fruits of their labour; so much work, energy — and probably sleepless nights — have gone into

the new product and service launches that shape the show. Innovation is, after all, the name of the game.

But innovation isn’t always a tangible asset; instead, it can be a key ingredient of new business methods and successful company alliances, hence the Most Innovative Relationship category of the EOA. We are all now too familiar with the mantra of ‘doing more with less,’ but it is from this and the pressures of gaining market share that innovation is — to continue the autumn theme — sorting the wheat from the chaff.

Personally, I look forward to meeting some of you in Frankfurt (alas, 3 days just isn’t enough time for me to see you all) and learning more about what your company has to offer. Do feel free to drop by our stand, which is 41K14, to discover what we’re up to and how we can highlight your company’s achievements. With a bit of luck, I’ll manage to return from the event with a rich seam of content for 2012 … and my shoes.

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

COMMENT

MAKING A SUCCESS OF NEW DRUG DEVELOPMENT Wasting $60 billion on failed drug development programmes is unacceptable. But just how does the industry improve its strategy in getting new drugs to market quicker?

I

n 2009, the failure rate of new drug applications (NDAs) in the European centralized procedure peaked again at 40% — a trend that is showing no sign of declining.1 The cost for the industry of failed drug development programmes is estimated to be $60 billion worldwide.2 These combined failures of pharmaceutical companies, of all sizes, to get new drugs to market is placing a huge toll on society.

Is it acceptable that a large number of patients are put at risk in trial programmes that have no chance of ever delivering a product to market? Is it acceptable that investigators and their sites are involved in studies of limited medical value?

Is it acceptable that regulatory agencies are bogged down in assessing applications that cannot be approved? Finally, is $60 billion spent every year on drugs that fail to get approved really sound business?

The industry needs to change this trend, to reduce the failure rate and to get new drugs to market quicker. In addition, there is a need to generate solid facts to encourage the termination of inferior drugs that are in development as early as possible.

Lars‑Helge Strömquist

References

1. www.nature.com/nrd/journal/ v9/n5/full/nrd3169.html 2. http://online.wsj.com/article/ SB100014240527487048 28104576021760502330 204.html 3. www.ncbi.nlm.nih.gov/ pubmed/19936724

For more information Lars‑Helge Strömquist CEO NDA Group info@ndareg.com www.ndareg.com

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Why do so Many NDAs Fail?

The European Medicines Agency (EMA) is transparent with the reasons drug applications fail and statistics are presented regularly that show why. The majority of failures are not because of poor molecules or therapies; they are the result of suboptimal clinical programmes and the resulting data that fails to demonstrate whether the treatment’s benefits outweigh the risks to patients.

Usually, such deficiencies can be caught much earlier than is currently the case. Many of the programmes that have failed in late Phase III had sufficient signals to justify terminating the programme much earlier. Yet, because development was allowed to continue, patients were put at risk, agencies had to engage in activities that were predestined to result in refusals, and the companies in question spent huge amounts of money on trial programmes that would never succeed. In addition, the time spent on a failed programme could have been channeled into other scientific or business‑related activities to create true value to the organization, patients and society as a whole.

Solving the Puzzle

To get to grips with these issues it is important to understand that any company will first and foremost look to its own survival. Indications that a company’s single product is predestined to fail will not be appreciated by anyone with a vested interested. Expecting people within an organization

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to step up and deliver this bad news at such early stages is perhaps not entirely realistic. This fact is also reflected in the statistics from EMA where external scientific advice was primarily requested by the bigger companies, who understand that engaging with regulators early in development will provide a roadmap to approval and are prepared to take the consequences in those cases when the news is bad.

Successful drug development is all about ‘doing the right things right first time’ and, to ensure this, drug developing companies should seek qualified third‑party opinion before putting their plans into practice. Securing early third‑party input and second opinion on the drug development programme is the only way to ensure that it is in line with external requirements and avoids internal bias.

According to research by the EMA, “obtaining and complying with scientific advice appears to be a predictor of outcome” (for a successful marketing authorization application) and “obtaining scientific advice early in development and at major transition points, as well as compliance with the advice given by the CHMP are recommended.”3 Today, such impartial and qualified advice can be delivered through four main sources: FDA in the US; the EMA Scientific Advice Committee in Europe; the European National Competent Authorities; and through the NDA Advisory Board, an independent third party.

The earlier this external advice is sought, the more value it will deliver to the development process, by providing intelligence on, for instance, clinical end point selection, trial design and regulatory strategy.

The most natural stages of drug development optimal for third party assessment are • Non-clinical plan • Phase I plan • Phase II plan • Phase III plan.

At each of these stages, external advice can provide practical, strategic, economic and societal benefits. It is of outmost importance to secure health economic and reimbursement requirements are covered no later than in the Phase III plan.

This will ensure that the drug being developed is likely to be widely marketable once it obtains approval.

For the industry, as well as for society, the end goal has to be to get good medicines to patients faster. The pharmaceutical industry can, therefore, not afford to ignore the benefits of seeking external scientific and regulatory advice during their drug development programmes. Failing to do so risks them spending significant sums of money, resources and patients on studies that will not deliver regulatory success.

September/October 2011

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INGREDIENTS & RAW MATERIALS

COMPLIANCE OF APIs WITH INTERNATIONAL GMP REGULATIONS

APIs and excipients have evolved into globally traded goods. GMP regulations, however, still vary worldwide. Auditing API production, therefore, demands considerable knowledge in foreign GMP standards.

Bohong Meng of blue inspection body highlights the difficulties of auditing GMP compliance abroad.

I

ncompliance of APIs with specified quality standards can be fatal, as the Heparin scandal in 2008 has shown. In the quality control tests of the API, the deliberate adulteration with oversulfated chondroitine sulfate went unnoticed, which demonstrates that even extensive analyses cannot sufficiently address quality problems.

Put simply, analytical methods will detect only those quality defects and impurities one is actively searching for; hence the necessity of Good Manufacturing Practice (GMP).

European manufacturing authorization holders are obliged to ensure GMP compliance of the entire production chain of their medicinal products. This is laid down in Article 46f of Directive 2001/83/EC and the subsequent national legislation. The new revision of the ‘Production’ Chapter 5.26 of the EU GMP guideline, which is soon to come into effect, clarifies that GMP compliance of ingredients has to be verified at the place of production: “Suppliers of active substances […] should be periodically audited to confirm that they comply with current GMP requirements.”1 Such audits can be performed by the responsible qualified person (QP) of the purchasing company itself or by contracted and qualified third‑party auditors.

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GMP Does Not Equal GMP

During the past years, APIs and excipients have evolved into globally traded goods with main production sites in Asia. GMP regulations, however, vary worldwide. First, the World Health Organisation (WHO) has issued the compendium Quality Assurance of Pharmaceuticals.2 GMP requirements for ‘APIs (bulk drug substances)’ are described in Chapter 2.

Second, the US, Europe and Japan have adopted the ‘ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients,’ which substantiates and extends the WHO requirements.3 In the European Union, ICH Q7 carries the name ‘EU GMP Guideline Part II.’ To keep matters simple, we will use ICH Q7 as an umbrella term for these (virtually) identical regulations.

Third, India has laid down its GMP requirements in Schedule M of the ‘Drugs and Cosmetics Rules,’ which contains ‘Part 1‑F’ that covers API manufacturing, while China has its own ‘GMP for Pharmaceutical Products.’4,5 The current ‘revised edition 2010’ was published by the State Food and Drug Administration (SFDA) in February 2011 and discusses APIs in its Appendix 4. Most Chinese manufacturers are still operating according to

September/October 2011

INGREDIENTS & RAW MATERIALS

Table I: Chapters of the relevant GMP guidelines in the US, Europe, India and China.

September/October 2011

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INGREDIENTS & RAW MATERIALS Bohong Meng

References

1. http://ec.europa.eu/health/ files/gmp/chapter5_pc112010.pdf 2. www.who.int/medicines/ areas/quality_safety/quality_ assurance/QualityAssurance PharmVol2.pdf 3. www.ich.org/products/ guidelines/quality/ quality-single/article/goodmanufacturing-practice-guidefor-active-pharmaceuticalingredients.html 4. The Drugs and Cosmetics Rules (India), Schedule M. 5. Drug Administration Law of the People’s Republic of China (China), Article 9.

6. http://eng.sfda.gov.cn/ WS03/CL0757/62350.html

For more information

Bohong Meng blue inspection body GmbH Tel. +49 251 625 620 40 bohong.meng@ blue-inspection.com

Dr Stefan Kettelhoit blue inspection body GmbH Tel. +49 251 625 620 40 stefan.kettelhoit@ blue-inspection.com www.blue-inspecetion.com

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the ‘revised edition 1998’ of the SFDA GMP, because existing sites have been granted a transition period “of no more than five years” to meet new requirements.6 The 1998 SFDA GMP edition covers APIs in Appendix 2.

In all these cases, the complexity of the rules governing active substances is lower compared with ICH Q7, which exclusively deals with APIs.

Importing from Non-EU Countries

Pharmaceutical companies selling medicinal products within the ICH region are required to comply with ICH Q7. Hence, differences between the GMP standards of the supplying countries (for example, India, China) and the receiving countries (for example, France, Germany, UK, US) can result in ambiguities and difficulties concerning GMP compliance.

In the simplest case, different formal structures of ICH Q7, Schedule M or SFDA GMP can be the reason for difficulties (Table I). What is more, some ICH Q7 topics are not covered in the Indian and Chinese guidelines at all; for example, ICH Q7 Topic 1.3 suggests starting points when GMP requirements need to be fulfilled for different kinds of API starting materials. The SFDA GMP (1998), however, primarily focuses on the final manufacturing steps; for API manufacturing, batch records are required starting with the “refinement from crude” step (cf. SFDA GMP 1998, Appendix 2, Article 10). Hence, Chinese manufacturers may very well be non‑GMP‑compliant

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Dr Stefan Kettelhoit

judged by ICH standards, even if they adhere to SFDA GMP requirements by the letter.

Many Asian API manufacturers have aligned their quality management systems and manufacturing processes to national regulations and ICH‑Q7 simultaneously to comply with export requirements.

But the fundamental differences in form and content of the underlying GMP guidelines themselves (for example, SFDA GMP versus ICH Q7) continue to make auditing a laborious and difficult business.

Outlook

International GMP standards are beginning to converge — albeit very, very slowly. The new version of the EU GMP guideline, for example, will tighten regulation regarding the qualification of suppliers (chapters 5.25 and 5.26) and regarding supply chain traceability (chapters 5.26 and 5.27). The 2010 revision of the Chinese SFDA GMP, too, demands stricter qualification of suppliers and defines (basic) traceability requirements; but at the current pace, any meaningful steps towards harmonization seem to take 10–15 years at the least.

In the meantime, the auditing of API production in non‑ICH regions — which is explicitly required by the new Chapter 5.26 of the EU GMP Guideline — demands not only expertise in pharma production, but considerable knowledge in foreign GMP standards. Otherwise, neither the QP conducting the audit nor the manufacturer itself will be able to actually assess GMP (non-)compliance according to all relevant guidelines.

September/October 2011

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INGREDIENTS & RAW MATERIALS

KEYS TO HPAPI PRODUCTION

High potency active pharmaceutical ingredients (HPAPIs) are in high demand, particularly as key ingredients for anticancer therapies. The manufacture of HPAPIs requires stringent, risk‑based containment measures. CARBOGEN AMCIS shares best practices in HPAPI containment.

H

PAPIs are the fastest growing segment in the API market. The appeal of HPAPIs lies in their ability to target diseased cells more precisely and in smaller doses than non-high potency APIs. Because of the ever‑strong demand for anticancer therapies, more than 25% of new compounds entering clinical development are focused on oncology and are HPAPIs.1

HPAPI Containment

An API is classified as an HPAPI if it has an occupational exposure limit at or below 10 µg per cubic metre of air.

This presents a number of challenges to manufacturers because conventional plants are usually inadequately equipped for the manufacture of HPAPIs. Before September 2010, when the International Society for Pharmaceutical Engineering issued the Risk‑Based Manufacture of Pharmaceutical Products Guide (Risk‑MaPP), no scientific risk‑based approach was publicly available to manage the risk of cross‑contamination in multiproduct facilities.2 The lack of expertise in containment chemistry led many HPAPI manufacturers to hire external consultants to handle containment issues. Only a small number of companies anticipated the need for a scientific risk‑based approach and gradually built a cross‑functional team of experts in toxicology, industrial hygiene and good manufacturing practices that focus on risk assessment and management.

Charlie Johnson

References

1. w ww.carbogen-amcis.com/ pdf/CA_whitepaper3.pdf 2. B aseline Guide: Risk‑Based Manufacture of Pharmaceutical Products, ISPE (September 2010).

For more information

Charlie Johnson High Potency Business Manager CARBOGEN AMCIS charlie.johnson@ carbogen-amcis.com www.carbogen-amcis.com

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Containment Levels

At CARBOGEN AMCIS, the required containment level is determined based on the substance’s pharmacological and toxicological activity, and the exposure potential of the anticipated unit operations, leading to a performance‑based exposure control limit or occupational exposure limit in cases where sufficient toxicological data exist. Cleaning limits are calculated by defining an acceptable daily exposure (ADE), maximum allowable carry over and cleaning limits for final rinse and surface contamination. The ADE (µg per day) is calculated based on the lowest clinical dose for the previously prepared API and the maximum recommended dose for the API to be manufactured. In the presence of genotoxic or reprotoxic impurities, the threshold of toxicological concern in line with the current European Medicine Agency’s guidelines further corrects these limits.

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Contamination Risks

Risks are assessed based on the amount of HPAPI handled, the type of operation performed (routine versus nonroutine), whether the substance is a dry powder or solution, how often steps are repeated and whether the processing happens in a closed or open environment. We apply a so-called ‘protection cascade’ for facility design to address these risks. To avoid direct contact between the substance and the operator, any process involving a high potency material is confined within specific manufacturing areas and contained within sealed processing equipment, such as reactors, filter dryers or self‑contained glow boxes and isolators. Air locks separate the high potency areas from the rest of the building following the ‘building within a building’ concept with relative positive pressure in clean zones and relative negative pressure in manufacturing zones. This ensures that no airborne contamination reaches the clean zones. The heating, ventilation, air‑conditioning system delivers clean air into and out of the facility, preventing the stagnation of any airborne contaminants within the manufacturing cells and eliminating the risk of exposure in the non-manufacturing area. Furthermore, single pass high‑efficiency air filtration obviates the need for routine use of personal protective equipment, which is available as backup in case of an emergency.

Emergency measures are ready in the event of accidental exposure and include personal protective equipment for operators and an ‘easy‑clean’ design for efficient decontamination. Standard operating procedures, constant training and a well‑defined health‑monitoring programme are key measures that further enhance workers’ safety and awareness.

Handling Dry Powders

An increasingly important aspect of API manufacturing is particle size distribution because finely ground powders increase a drug’s bioavailability. To limit the higher exposure risks associated with handling dry powders, CARBOGEN AMCIS adopted in‑line wet milling as a core particle sizing technology during the past 2 years and uses it as the preferred approach for particle reduction where technically feasible. Experience shows that a scientific risk assessment and management approach, combined with modifications to facility design and equipment, the use of risk‑minimizing technologies and well‑defined operational containment guidelines make the production of HPAPIs safe and protect the health of patients and employees.

September/October 2011

September/October 2011

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INGREDIENTS & RAW MATERIALS

OPTIMAL API DEVELOPMENT STR ATEGY FOR FIH

API development is critical to achieving the first‑in‑human (FIH) milestone. This article provides thoughts on how to overcome the major API challenges and come up with the optimal chemistry, manufacture and control (CMC) development strategy to FIH and beyond.

A

PI development is critical to achieving the FIH milestone for your molecule.

The goal is to supply an API for preclinical and clinical studies with high quality documentation to ensure a successful submission. Achieving this goal requires a broad range of complementary scientific skills such as synthetic chemistry, analytical sciences, process safety, sourcing, crystallization, and API preformulation and cGMP manufacturing, from a multidisciplinary team that can tackle the major API challenges occurring on the road leading to the FIH milestone.

The Recommended Workflow

When a new drug candidate is selected for entry into development, the synthetic chemistry team will assess the discovery synthesis route for the investigational new drug (IND). The aim is to deliver safe, scalable, reproducible and robust protocols for API manufacturing at cGMP pilot‑plant scale. The nature and quality of the technologies, and ability of the scientists to interpret the data are critical to the quality of the API and to successful time‑savings in the development process.

During process development the chemists will work on increasing the yield and on minimizing the costs by replacing the expensive reagents and by reducing the waste. The chemists are used to removing the toxic reagents and to selecting appropriate reagents and solvents. In most cases, the laboratory reference

Figure 1: FIH/Phase I API development considerations focus on three key areas in obtaining the desired and appropriate API properties.

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procedure is tested at about 1‑kg scale during the API manufacture for toxicology study supplies. The feedback on the production of this batch enables the chemists to make adjustments to the chemical processes for cGMP API manufacturing. From a safety perspective, a process safety team will provide all calorimetric data needed to validate the laboratory reference procedure before its implementation at pilot‑plant scale.

The pilot plant should be involved early on in process development to ensure optimal implementation of the chemical processes in the pilot facilities. The pilot plant delivers the cGMP API (ICH Q7A as reference) and the documentation, including a batch record for each step, risk assessment and API batch report, for dossier and for API release.

To expedite the development, the sourcing expert will propose scenarios to support early needs in raw materials. At the same time, the analytical sciences team will support the process development and manufacturing activities by developing and validating suitable analytical methods, performing relevant quality control activities for cGMP APIs manufacture.

Challenges and Considerations

A major challenge in API development is the design of the appropriate physicochemical properties for the API with regard to the administration route. The API composition (free molecule, salt or co‑crystal),

Figure 1

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September/October 2011

INGREDIENTS & RAW MATERIALS the crystal form (polymorph, pseudo‑polymorph or amorphous), crystal morphology (needle, platelet, cube, sphere, rod), crystal size distribution and crystal quality will all affect its solubility, dissolution profile, bioavailability, and drug product and API processability.

All along the development process such properties are refined based on the formulation needs. A dedicated team specializing in crystallization and preformulation is recommended for this role.

For FIH/Phase I, crystallization studies are focused on the API composition and polymorph screening and selection, and development of a purification and scalable process leading to the desired and appropriate API crystal properties (Figure 1). Robust knowledge of a variety of technologies is also essential to the design of physicochemical properties of an API. Only a small amount of API is available at the beginning of the development and the use of miniaturization tools allows an increase in the number of tests during salt and polymorph screenings. Methods such as X‑ray powder diffraction and thermal analysis can provide evidence of polymorphism or characterize specific polymorphic forms.

A highly skilled technical team is invaluable in API development. Their experience can ensure the effective management of the genotoxic impurities (GTI) issues in the API development, which allows you to maintain a shorter timeline. Experience in emerging chromatography technologies, such as UPLC, can reduce the method development time and provide smart separation solutions. Moreover, the use of hyphenated techniques enables successful management of GTI issues by providing a methodology to track a GTI at the ppm level.

The Benefits of a Centre of Excellence

It would be beneficial to have all activities involved in API development located at a centre of excellence (COE). When a single site manages all the required processes, there is a huge time saving in technical transfer and information sharing at all stages and cost saving as a result of equipment coordination among teams. The scientific continuity achieved by a collaborative approach simplifies strategic planning and project management, which in turn will improve operational quality, efficiency and flexibility.

Seenu Srinivasan

For more information

Laurent Lafferrère, PhD Director, CMC Pharmaceutical Development Services Covance Laurent.lafferrere@covance.com

Seenu Srinivasan, PhD Global Vice President and Chief Scientific Officer CMC Pharmaceutical Development Services Covance Seenu.srinivasan@covance.com www.covance.com

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INGREDIENTS & RAW MATERIALS

ADDRESSING THE GROWING NEEDS OF TR ANSDERMAL DRUG DELIVERY APPLICATIONS

Pressure-sensitive adhesives (PSAs) are critical components that affect the functionality of transdermal drug delivery systems (TDDS). Pharmaceutical‑grade PSAs perform multiple functional purposes in a patch design such as reliably attaching the patch to a patient’s skin for dosing, as well as bonding component and protective overlays. As more patch formats become available for new and existing drugs and diverse patient populations, the challenges of developing high‑performing and stable pharmaceutical‑grade adhesives are equally as diverse. This article will discuss how evolving patch designs from reservoir to drug‑in‑adhesive formats impact adhesive formulation, as well as the key design challenges adhesive manufacturers must overcome when formulating adhesives for TDDS.

T

ransdermal drug delivery systems (TDDS) offer many pharmacological advantages compared with oral forms whilst also improving patient acceptability and compliance. With the wide acceptance of the patch format, following the introduction of the nicotine patch in the early 1990s, TDDS remain an ongoing area of research because they enable drug manufacturers to deliver new and existing molecules in an alternative drug delivery format. Often when a drug is transitioned from an oral solid dose to transdermal format patient compliance improves because TDDS avoid issues related to first pass metabolism by the liver, deliver a controlled dosage with time requiring less daily dosing, and result in fewer side effects as peak plasma levels of the drug are reduced.

The Role of Adhesives in TDDS

Brecon_75x210_flash

Today, drug manufacturers are seeking the latest technologies in component materials to enhance 1/8/11 15:55 Page 1 existing transdermal drug delivery products whilst

ICSE 2011

Stand: 41D67

further improving compliance and convenience with diverse patient populations. Increased healthcare costs and a wider availability of transdermal patch treatments are enabling more patients to self‑dose for serious conditions that previously required treatment in a professional healthcare office or hospital setting.

Examples can be seen in the current availability of self‑dosing transdermal osteoporosis treatments, which eliminate the need for daily injections (Figure 1).

With the exception of microneedle applications, the active ingredient used in a transdermal patch is contained either in a reservoir system or in a drug‑in‑adhesive matrix construction. A reservoir patch holds the drug in a gel or solution with delivery determined by a rate‑controlling membrane between the drug reservoir and the skin. The drug reservoir system was introduced in first‑generation nicotine, hormone and pain patches.

Matrix patches feature the homogeneous distribution of a drug throughout the adhesive polymer matrix, which bonds the patch to the skin whilst also controlling the drug delivery rate. Because the construction requires

Serving the pharmaceutical industry with confidence With over 30 years’ experience of providing the highest quality in commercial packaging and clinical trials services, Brecon is acknowledged as one of the leading outsource service providers in the global pharmaceutical industry.

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September/October 2011

INGREDIENTS & RAW MATERIALS

fewer components related to a reservoir, matrix patches can be cheaper to manufacture. Adhesive manufacturers are adding increased sophistication to their formulation techniques to enable a wider range of available drugs suitable for matrix product designs. Although the majority of matrix patches available today are based upon drug‑in‑adhesive solutions, adhesive manufacturers with the sophistication to also formulate emulsions and dispersions bring increased formulation capability and flexibility to patch developers (Figure 2).

The adhesives used in any TDDS play a critical role of reliably bonding a device to a patient’s skin to enable treatment and are also often used to bond layers of membranes or other components within a patch construction. The majority of patch products currently available are intended for daily wear, but extended wear applications of up to 7 days are gaining interest. Longer wear times are challenging adhesive manufacturers to develop formulations that demonstrate high levels of reliable adhesion over time whilst also providing a gentle removal experience for skin of varying ages and conditions.

Formulating Through a Compatibility Obstacle Course

The science of formulating adhesives for TDDS is a careful balance of delivering functionality and stability through a robust product design that incorporates components compatible to other materials used in a device. Two key obstacles to overcome are maintaining compatibility between the active drug and the adhesive chemistry whilst assuring biocompatibility of the adhesive to skin.

Adhesive formulations may include additives or excipients such as antioxidants, plasticizers and tackifiers to improve specific aspects of an adhesive’s functionality; however, the use of these must be balanced as they1/8/11 can interfere withPage a drug’s Brecon_75x210_flash 15:55 2 chemistry or affect drug delivery. For example, the addition of a

■ ■ ■ ■

Commercial contract packaging Clinical trial services Stability packaging & testing Storage & distribution

Figure 1: Reservoir and matrix patches.

plasticizer to control an adhesive’s wear properties can affect the therapeutic properties and effective delivery of certain drugs. Adhesive polymers containing moieties with reactive functionality such as hydroxyl groups, can affect the delivery of some hormones.

Any leachable and most extractable materials, such as residual solvents and monomers related to the adhesive, must be removed to avoid reactions or interference that could affect the performance and the therapeutic properties of the patch. Some extractables, including plasticizers and enhancers, are essential for enhancing the wear or performance of the patch and, therefore, are not removed.

Formulators must also consider how compatibility can potentially change during extended wear times and as the device ages with time. Accelerated and real‑time ageing studies ensure the adhesive properties and drug bioavailability are maintained throughout the product’s shelf life. Because some transdermal devices, such as those that incorporate microneedles for porating skin, require sterilization, measures must be taken to ensure the adhesive will withstand the sterilization dosage and procedures, whilst maintaining its adhesive properties and compatibility with the drug (Figure 3).

■ Analytical services ■ QP release of non-EU products ■ Encapsulation & Powder Filling

growth through excellence

Brecon Pharmaceuticals Ltd, Wye Valley Business Park, Hay-on-Wye, Hereford, HR3 5PG, UK ■ T:+44 (0) 1497 820829 ■ E sales@breconpharm.com September/October 2011 www.pharma-mag.com

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INGREDIENTS & RAW MATERIALS

Figure 2: Adhesive coating manufacturing.

the adhesives industry has experienced an increase in product discontinuations or product consolidation from raw material suppliers.

Responding to Outside Influences

Mary Lawson

For more information

Mary Lawson Pharmaceutical Business Manager Adhesives Research, Inc. Tel +1 717 227 3407 mlawson@arglobal.com www.adhesivesresearch.com

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Once the ideal adhesive formulation is identified for compatibility and performance, ongoing influences continue to challenge formulators. It is not unusual for unexpected changes in industry regulations or performance requirements to dictate a change to an existing adhesive formulation that has been performing as expected and required. Recently, FDA released a draft guidance, “Residual Drug in Transdermal and Related Drug Delivery Systems” that suggests reducing the amount of residual drug remaining in a transdermal patch after treatment by modifying a product’s formulation, design or system components through the use of permeation enhancers, self‑depleting solvent systems and appropriate adhesives. As drug manufacturers evaluate existing and new product constructions to reduce residual drug levels, adhesive manufacturers will respond by developing new formulations to withstand sophisticated enhancers, and work closely with clients to determine optimum adhesive coat weights and compatible component materials.

In recent years, the adhesives industry has experienced an increase in product discontinuations or product consolidation from raw material suppliers. Although alternative raw material product choices are available, replacing a material or excipient in an adhesive formulation

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requires significant research and change control testing to ensure bioequivalence for any new materials. An example of this can be seen in the use of polyisobutylenes (PIBs), which are a common polymer used in pharmaceutical‑grade adhesives. A modification or replacement of a PIB polymer would likely result in the new material having a different molecular weight from the original. Proving bioequivalence for each pharmaceutical adhesive formulation utilizing the new PIB polymer requires a detailed study on behalf of the adhesives manufacturer.

Conclusion

Adhesive manufacturers adept in the art of formulating and casting adhesives, particularly as it pertains to drug‑in‑adhesive systems, are well‑positioned to provide drug manufacturers with the increased formulation flexibility they are seeking for their transdermal product designs. Formulating adhesives for transdermals requires custom chemistries for each product application to balance adhesive performance with a plethora of compatibility challenges to ensure a safe, therapeutic dose. As drug manufacturers push the boundaries of known capabilities of this drug delivery format, adhesives manufacturers will answer the challenges with constantly evolving adhesive and coating technologies to advance the performance of TDDS.

September/October 2011

Your Drug Development Processes – from a Single Source Think about it: a single source connecting no fewer than seven key drug development areas.

One source that combines the latest technology with the best of human expertise.

That source is Almac. And it’s that unique combination that puts us at the leading edge – and enables you to grow.

Talk to us about integrated solutions today.

FOR FURTHER INFORMATION VISIT OUR WEBSITE OR CONTACT ALMAC: Europe: USA:

T: +44(0)28 3833 2200 T: +1(215) 660 8500 E: info@almacgroup.com

INGREDIENTS & RAW MATERIALS

ACCELERATING CHEMICAL DEVELOPMENT AND MINIMIZING COST FOR FINE CHEMICAL/API MANUFACTURE AND METABOLITE SYNTHESIS

There is a growing acceptance and use of biocatalysis in industry, not only as an alternative to conventional chemistry optimization and scale‑up but as the preferential technique. The authors evaluate the developments of the last 10 years that have predicated this systemic change in approach. In addition, recent innovations are continuing to drive forward biocatalysis as a maturing technology in the delivery of chiral intermediates, fine chemicals and APIs.

T

he wealth of information regarding enzyme technology and development is growing exponentially, and biocatalysis technology has now become one of the first choice methods in the fine chemical and pharmaceutical industry. Given the severe pressure to lower costs, minimize waste and shorten existing syntheses, the industry is in need of economic, robust, scaleable and reliable processes for manufacturing chiral APIs and intermediates. This need has resulted in process chemists utilizing their skills at the interface of chemistry and biology, and embracing biocatalysts and biocatalytic processes in organic synthesis. This paradigm shift has resulted in biocatalysis becoming the work‑horse of the chemists’ tool‑box for chiral chemistry.

Why has there been this surge in the application of this technology? The answer is simple: success breeds success. The key difference between biocatalysis today compared with 10 years ago is the availability of all the supporting technologies, such as bioinformatics, enzyme evolution and high‑throughput screening, which make a real difference in enzyme development.

Processes can now commence within weeks, and enzymes evolved in months.

The rapid implementation, economic benefits and ‘green’ reputation of biocatalysis provide superior

solutions for solving complex chemistry problems.

Enzymes have numerous advantages in this field, particularly their ability to discriminate between subtle differences in shape and functionality, either within a given molecule or in a mixture of compounds. This allows selective chemistry, for example, regio‑selectively transforming a single functionality (out of several) in a single molecule or, more importantly, effecting the biotransformation of one isomer in a racemic mixture, facilitating its separation into the component isomers. Furthermore, enzymes have been used successfully in the scale‑up of asymmetric processes, particularly in chiral alcohol and amine production, and for accessing difficult‑to‑synthesize metabolites.

Biocatalysts are unsurpassable when it comes to selectivity and distinguishing between subtle differences within a molecule. It has been shown repeatedly that speed of enzyme identification and scale‑up is critical in demonstrating to customers that biocatalysis will compete with other technologies in respect to the cost of goods and development. At Almac, for example, the selectAZyme platform for enzyme identification is used. Typical timelines required from selection of a selectAZyme catalyst to actual manufacture of product is similar to that of conventional chemistry optimization and scale‑up (Figure 1).

Figure 1: Timelines for using the selectAZyme platform.

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INGREDIENTS & RAW MATERIALS

Figure 2: CYP450 mediated bio-oxidation using Almac’s proprietary selectAZyme technology.

The marriage of microbial and recombinant enzymes is a real powerhouse in accessing difficult‑ to‑ synthesize metabolites.

For more information Dr Tom Moody Head of Biocatalysis Almac

tom.moody@almacgroup.com

Dr Stefan Mix Biocatalysis Technical Leader Almac stefan.mix@almacgroup.com www.almacgroup.com

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Hydrolases and carbonyl reductases continue to dominate the press and application stream. Enzymes such as transaminase and oxidative enzymes are growing in influence, because they become more tolerant to extreme conditions; that is, have higher substrate affinities translating to high activities, compatibility with organic co‑solvents, tolerance of increased temperatures, and the availability of practically applicable and economical cofactor recycle systems.

In many cases, the development and scale‑up of bioresolution and bioreduction have become routine, accessing hundreds of kilos of product in timelines comparable, if not shorter, to that of alternative chemical routes. The next milestone is in bio‑oxidation. Increasingly, it is being applied to metabolite syntheses and has been proven to be the superior solution in accessing those metabolite that are difficult‑to‑make via conventional chemistry.

Metabolite synthesis is another tool within selectAZyme’s service offering that provides access to both oxidative and glycosylated products.

Almac has implemented state‑of‑the‑art biocatalytic technology for rapid metabolite synthesis, isolation and structural identification. In addition, the company

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has also developed recombinant P450 technology for accessing metabolites at levels from a few milligrams to hundreds of grams. These enzymes, which mimic human P450 systems, are powerful tools for accessing metabolites rapidly. The marriage of microbial and recombinant enzymes is a real powerhouse in accessing difficult‑to‑synthesize metabolites. The scale‑up capability allows the company to rapidly take ‘hits’ from conception to gram delivery as and when the customer requires the products. In addition, radiolabelled versions of these metabolites can also be supplied, utilizing the in‑house isotope chemistry facility.

A typical project for a bio‑oxidation is shown in Figure 2 and was initiated with selectAZyme platform screening. Following a successful screening project, which identified an active P450 enzyme (AL‑103) for the transformation, Almac was contracted to generate 15 g of the API metabolite. Expression of the desired P450 in E. coli enabled the growth of the required biomass in a 150‑L fermentation vessel after brief optimization at shake flask scale. A finding of particular note was the large beneficial effect of supplementing the growth medium with Fe(III)Cl3 during the expression phase. Process development studies indicated that the dissolved oxygen level and the substrate addition rate were key parameters to control the accumulation of acceptable product concentrations. Specifically, it was found that dissolved oxygen levels needed to be maintained above 70%, whilst an addition rate of 25 mL/h of a 0.5 g/L solution of substrate in dimethylsulfoxide could not be exceeded. Higher addition rates resulted in the formation of an insoluble polymorph that was completely incompatible with the biocatalyst.

Overall yield for this process following purification by filtration through a silica pad was 61%.

There has been a paradigm shift in the acceptance of biocatalysis as a powerful tool at the forefront of process research within the industry. This is being driven by market needs and stresses, and key for future success are flexibility and rapid response to change.

Biocatalysis is a maturing technology and will play an increasingly pivotal role in future success with the rapid supply and delivery of chiral intermediates, fine chemicals and APIs.

September/October 2011

Meet us at CPhI stand 30G40

New Kilo Lab and Pilot Plant for Fine Chemicals Production Alfa Aesar Synmax production plant in Yantai, China is now open for your custom chemical production needs, with kilo scale production and pilot plant capacity up to 2,000L. • Mulitple Scale Manufacturing Capabilities • Seamless Progression from Laboratory to Pilot Plant Production • 8 Fully Adaptable Flexible Reactor Vessels up to 2,000L • Flexible Array of Glass and Stainless Steel Reactors • Site Operating Temperatures -70oC to 180oC • Full Complement of Analytical Capabilities and Equipment • Cost Effective Manufacturing

Let Alfa Aesar experts help you today with a Custom Synthesis.

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September/October 2011

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23

BIOPHARMACEUTICALS

From DNA to Harvest: A Platform Approach to Improved Bio-Production

Biologic drug revenues now represent around $90–100 billion of the $825 billion global pharmaceutical market and are growing at a rate of 11–12% annually, compared with 3–5% for small molecules. Biopharmaceutical companies are continuing to focus on more cost‑effective processes to address the technical, regulatory and supply chain management issues related to the development of these biologics and, as a result, platform processes have emerged as a means through which the industry can effectively address these issues. By following a platform development and manufacturing strategy, a company can limit the number of variables, essentially using the platform as a ‘plug and play’ system that allows better control of technical, regulatory and supply chain management systems across multiple new molecule projects.

E

ngaging in the development of a platform process reduces the need for optimization. This means that less development effort is required, resulting in shorter timelines, cost‑of‑goods savings, simplified technical transfer and greater predictability upon scale‑up. Early adopters of this strategy, such as Amgen and Genentech (Roche), have successfully demonstrated the essential values of the platform process as a development model: speed, cost, predictability and consistency.

SAFC is working to bring platform concepts and materials to those biopharmaceutical industry organizations that do not possess the infrastructure or resources to develop platforms for themselves.

Using their expertise in cell line, medium and feed development, raw material characterization, vendor qualification and supply chain management, the company is working to improve Chinese hamster ovary (CHO) monoclonal platform cell lines

Zinc Finger Nucleases (ZFNs) are site‑specific DNA nucleases that result in double‑stranded DNA breaks within the genome, providing scientists with the ability to modify genes of interest. Although classical methods for gene disruption or modification are

Superior transfection efficiency

DG44

CHOZN dhfr-/X

Shorter doubling time

X

X

X

X

X

X

X

X

Does not clump in suspension DHFR selection and gene amplification Easy to adapt to CD formulations

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A New Approach to Biopharmaceutical Cell Line Engineering

CHO K1 X

Higher cell densities

Table I: Differential characteristics of CHOZN® dhfr-/-.

and to redesign the way the platform processes are conceived and executed, and the company’s off‑the‑shelf platform will include parental CHO cells genetically engineered for enhanced bioproduction, and chemically defined media and feeds designed to work in harmony with the cell lines. In addition, a comprehensive set of protocols — from transfection through lab‑scale bioreactor production — will be assembled into an easy‑to‑follow manual, enabling users to execute a complete platform process — from DNA to product harvest.

Cells mutagenized

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X

X

X September/October 2011

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BIOPHARMACEUTICALS

limited by their efficiency and the extended timeline needed to isolate a desired mutant, ZFN‑mediated genetic modifications are very efficient and specific, resulting in significantly decreased cell line development timelines. By modifying specific genes, SAFC now has the ability to engineer bioproduction cell lines with novel selection markers, extended bioreactor longevity and increased productivity.

In addition, genes involved in post‑translational modifications of recombinant proteins can be altered, resulting in increased protein quality and enhanced clinical efficacy. Improvements in drug yield and efficacy translate into real economic benefits for the biopharmaceutical producer.

Exclusive access to ZFN technology will allow SAFC to create multiple novel cell lines to plug into the platform process. The starting point for the platform cell line development programme is a proprietary CHO cell line. This cell line was developed by adapting CHO K1 to serum‑free (SF) growth, suspension culture and bioreactor robustness in EX‑CELL CD CHO Fusion media. All SAFC platform cell lines will be engineered from this SF, suspension‑adapted CHO K1 and will be called SAFC CHOZN cell lines.

In a recent study, SAFC used ZFNs to knockout the dihydrofolate reductase (dhfr) gene in the parental CHO K1 and compared with CHO DG44. DG44, a dhfr null cell line, is the most commonly used cell line for biotherapeutic manufacturing today. 1 DG44

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cells are routinely clumpy in suspension cultures and can be difficult to adapt into CD media formulations.

SAFC, therefore, sought to create an improved dhfr-/- cell line that retained the robust properties of a CHO K1 cell line while adding the metabolic selection and amplification properties of DG44.

After treating CHO K1 cells with CHO dhfr ZFNs designed by Santiago, et al. , biallelic gene disruption was observed in approximately 1% of the cells examined. 2 Five new dhfr-/- cell lines were isolated and evaluated for their cell growth, stability, metabolic profiles, transfection efficiency and transient protein production capability compared to DG44 and CHO K1. These five dhfr-/- cell lines possessed selection properties very similar to the original DG44 cell line, but maintained the growth and transfection characteristics of the original CHO K1 cell line (Table I). This data suggests that ZFNs can be used to rapidly engineer CHO cell lines with desirable characteristics.

The specificity and efficiency of the ZFN technology allows alteration of multiple genes simultaneously, a process referred to as ‘trait stacking.’ By applying trait stacking to CHO K1, SAFC can engineer multiple desirable characteristics in a single CHO line. This ideal cell line, would exhibit such desirable traits as increased selectivity, increased cell culture longevity and productivity, and enhanced monoclonal antibody (mAb) protein quality.

September/October 2011

BIOPHARMACEUTICALS Additional Benefits

During the development of CHOZN cell lines, SAFC will also formulate optimized medium and feed from a very early stage. Both the medium and feed will be simplified and chemically defined. Furthermore, SAFC will develop an optimized scale‑up process from transfection through the bioreactor stage using industry‑relevant model mAbs. The final product offering will be a true platform — one in which all components were designed and optimized together as a working system. Extensive application data and technical support will accompany the package.

To further enhance the platform, SAFC will apply its raw material characterization (RMC) findings to the CHOZN platform. The objective of the RMC programme is to characterize key raw materials used in SAFC cell culture formulations.

These raw materials will be evaluated by biological and analytical assays for parameters critical to the control of cell culture performance, in addition to vendor qualification and supply chain evaluation.

SAFC will develop the media and feeds for the platform using the characterized raw materials.

September/October 2011

Consistency will be ensured by design of platform components and through control of the raw materials and supply chain that underpins the platform. Thus, the company will offer a complete solution that can be licensed for use in commercial manufacturing of approved biopharmaceuticals.

Summary

By creating a dedicated platform that pulls together numerous characteristics and benefits into a single CHO line through leveraging Sigma‑Aldrich’s proprietary ZFN technology, SAFC is able to support its customers in establishing optimized production systems that will enable the development of drugs with greater speed, higher quality and which potentially have greater efficacy. Through using this platform to increase efficiencies in manufacturing processes and improving yield and productivity, SAFC is positively affecting operational excellence and lean manufacturing. Through linking this platform approach to its RMC programme, SAFC will soon offer a complete solution that can be licensed for use in the commercial manufacturing of approved biopharmaceuticals.

References

1. w ww.ncbi.nlm.nih.gov/ pmc/articles/PMC393004/ 2. w ww.pnas.org/ content/105/15/5809

For more information Bruce Lehr Director of Development SAFC Kevin Kayser Associate Director of Cell Engineering SAFC

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CPhI/ICSE PREVIEW

Enabling Technologies and Services

Roquette is a longestablished supplier of actives and excipients to the pharmaceutical and cosmetics industries.

Our new slogan, Simply formulate your wishes, emphasizes our service offerings and the strength of our underlying support. Whatever your requirements and aims, we are committed to providing the guidance you need to make the best possible use of our excipients, throughout the development process, from the creation of prototypes to scale‑up, in areas such as injectables, solid dosage forms, film forming and coating, syrups, suspensions, granules and sachets, orodispersibles, nutraceuticals, toothpastes and mouthwashes. Direct formulation scale‑up offers a new way to reduce the time and cost of drug development. To further strengthen this drive, Roquette and the Institut de la Garonne have pooled their expertise to provide a new compression modelling service. On‑site assistance is now available for LYCOAT and Readi LYCOAT, our new natural, inert polymer and ready‑to‑use coating system for fast aqueous film coating. In addition to the Kleptose cyclodextrin range, Roquette now offers a new tastemasking technology: KLEPTOSE Linecaps, a pea maltodextrin is capable of masking the bitter taste of drugs by decreasing the overall amount of drug particles that are exposed to the taste buds. Roquette looks forward to welcoming you to CPhI (Stand 42G24), where our specialists will be ready to answer any of your questions about our enabling technologies and services (www.readilycoat.com/ www.roquettepharma.com).

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RESPONDING TO CHANGE

Additional zones, expanded features and a new standalone event will enhance visitors’ experience of this year’s event, explains Haf Cennydd, Brand Director ICSE, P-MEC and BioPh at UBM Live.

This year, ICSE has three new zones — New Exhibitors, USA zone and Logistics & Supply Chain; P-MEC will now include a LABworld pavilion; and InnoPack makes its debut. Why have all these been added and why now?

As a large‑scale events organizer, it is imperative to our success that we consistently research the markets we are operating in and obtain feedback from our visitors.

These new and expanded features are the direct result of guest input and current industry trends.

Zoning debuted in Paris in 2010 with exceptional feedback. The logic of ‘more talking, less walking’ proved positive for guests who found it easier to locate providers of products and services they were looking for in each zone. For 2011, the General Floor and CRO — Clinical Trials Zones will return to ICSE, and will be joined by new zones to highlight New Exhibitors, USA Exhibitors, and Logistics and Supply Chain.

The introduction of the LABWorld pavilion within P‑MEC Europe originated from the changing demographics in exhibitors and attendees of the global P‑MEC events. The event offered resources for pharmaceutical machinery, equipment and technology for large‑scale laboratory applications. We recognized, however, that there was an unanswered need for a wide range of high technology such as instrumental analysis, measuring and testing technologies, materials testing, quality control and laboratory equipment resources for smaller‑scale applications. The LABWorld pavilion will address these needs.

Perhaps the most exciting introduction this year is the new standalone event, InnoPack. During the past few years, concerns regarding quality, validity, security and sustainability of pharmaceutical ingredients and products have been a hot topic for both manufacturing companies and the consumers that use them. InnoPack will address these concerns

Haf Cennydd

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September/October 2011

Direct measurement of air or gas volumes Perfect flow measurement for cleanrooms and similar demanding processes

Simply a question of

better measurement SCHMIDT速 Flow Sensors

The high requirements of modern control technology in ventilation systems require an accurate measurement of volumetric flows in air or gases. Its documentation is essential in areas in which people or products are subject to safety requirements or the air conditions must meet certain hygienic requirements.

A perfect method of measuring volumetric flows is offered by thermal flow sensors from SCHMIDT Technology. The particular advantage of this technology is its wide measurement range, completely covering all relevant air and gas flows in air-conditioning technology for cleanrooms. This includes minimum air velocities, such as the ones observed during idle periods, and maximum flows at full load. The striking feature of the so-called thermal anemometry is that it allows easy, accurate and direct measurement and ultimately simple evaluation of the detected data.

Selectively designed for demanding applications The newly developed thermal flow sensors SS 20.250 from SCHMIDT Technology present a minimum resistance in the air flow and are easy to mount, due to the little space required. The patented dumbbell technology can be positioned safely and quickly in the gas flow. In addition to that, the completely seamless design of the sensor head inhibits the adhesion of dirt particles, thus making it easy to clean. If required, the sensors can be delivered with a protective coating that makes them resistant to aggressive media and to reagents present in disinfectants.

The sensors are an adequate solution for applications such as the continuous monitoring of filter units, the control of volumetric flow in extractors or the monitoring of laminar flows in cleanrooms.

SCHMIDT Technology GmbH Feldbergstr. 1 D-78112 St. Georgen Phone +49 (0) 7724/899-0 Fax +49 (0) 7724/899-101 E-mail: info@schmidttechnology.de Internet: www.schmidttechnology.de

Just to make sure!

SCHMIDT速 Flow Sensors surpass the reliable detection of pre-defined flow velocities and precisely measure the energy efficiencies from clean room to clean room environments.

This is of high importance for individual safety and quality management.

Perfectly suitable for users and manufacturers of cleanrooms and pharmaceutical equipment with high quality demands.

SCHMIDT Technology GmbH 78112 St. Georgen/Germany Phone +49(0) 77 24 / 89 90 sensors@schmidttechnology.com www.schmidttechnology.com

CPhI/ICSE PREVIEW Zones and Pavilions at ICSE

• CRO — Clinical Trials Zone: This exhibition area, formerly known as the Clinical Trials Zone, will now cover Clinical Trials, Pre‑Clinical, Clinical Research, Phase 1–4 Clinical trials and Contract Research Organizations.

• New Exhibitor Zone: New companies exhibiting at ICSE. • USA Zone: Companies from the US exhibiting at ICSE 2011 wishing to be placed in a dedicated zone.

• Logistics & Supply Chain Zone: Exhibiting companies offering logistics, distribution and supply chain management solutions to the pharmaceutical industry will be placed in a dedicated zone at ICSE 2011.

• General Floor: The general floor showcases companies that offer a range of outsourcing and contract services, which are thus not to be divided into the zones.

• BioPh Pavilion: BioPh offers a natural business platform to the world of pharma, focusing on biopharmaceutical development and services, both face‑to‑face and online.

Zones and Pavilions at InnoPack 2011

InnoPack brings together buyers and specifiers from the packaging and pharmaceutical industries, creating business opportunities through a dedicated worldwide forum.

• Labelling: The Labelling Zone is for companies in the labeling industry, providing anticounterfeiting and track‑and‑trace solutions to the pharmaceutical industry.

Zones and Pavilions at P-MEC Europe 2011

P -MEC delivers innovative pharmaceutical machinery, equipment and technology to a worldwide forum of decision makers through face‑to‑face networking and education.

• LABWorld Pavilion: LABWorld connects the pharmaceutical community active in laboratory, analytical and biotechnology instrumentation, offering a forum for business development, networking and education.

by offering global resources for pharmaceutical packaging and delivery methods.

How has the global economic climate affected the number of exhibitors and/or their stand designs this year?

We are very pleased to say that numbers are up across all sectors. We have seen many new exhibitors and many returning exhibitors have chosen to expand their presence at the show. This promises to be a very exciting year in Frankfurt. The market has been showing a continuing trend towards outsourcing and partnering, which our events will be able to effectively cater to.

For more information

Haf Cennydd Brand Director ICSE, P-MEC and BioPh UBM Live www.icsexpo.com www.p-mec.com

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What are you looking forward to most at this year’s event?

Frankfurt has always been a popular location for the events and for our clients. Beyond that, we have a fabulous programme this year and have been able to introduce some attractive new features that we feel our customers will greatly enjoy, but more importantly, benefit from on a large scale.

This year, we are offering pre‑show conferences for attendees to benefit from great content and networking before the events are even underway. There will also

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be new educational lunch sessions where attendees can have a catered lunch and listen to high‑level industry players discuss innovations, developments, trends and solutions for the current market. The concentration of CMOs and CROs in Germany is also exciting.

These companies will offer new tools and resources to attendees who are operating in an outsource‑driven global market What can you tell us about ICSE/P-MEC/ Innopack visitors?

The synergy between the brands successfully creates a lot of crossover of exhibitors and visitors throughout the brands. Our visitor profile echoes this with a comprehensive and globally diverse group of exhibitors and attendees with reasons for attending that vary from sourcing new products and services to recruiting new talent to finding research partners.

What trends have you seen since last year’s event in Paris?

2010 was a record year for us. Moving into the 2011 events, we are seeing that the demographics of visitors are similar to last year, but their motivating needs and goals for the events have become more defined. As the market changes, our client base is seeing a need for more outsourcing and strategic partnership building.

At the same time, the drive towards R&D of generics has opened up more demand and innovation within the packaging and drug delivery sectors.

Overall, the trend is on a continuous upswing with innovation and collaboration being key drivers.

Registration for 2011 is up and we feel that we are ready to cater to this diverse group.

the drive towards R&D of generics has opened up more demand and innovation within the packaging and drug delivery sectors.

September/October 2011

INNOVATIVE PACKAGING SOLUTIONS. SHORT-RUN CAPABILITIES.

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For more information, contact us at +353 184 183 00, email us at info@millmount.com, or visit www.millmounthealthcare.com © Millmount Healthcare Ltd.

FILTRATION & SEPARATION

STERILE FILTER PRE-USE/POSTSTERILIZATION INTEGRITY TESTING IMPLICATIONS

EU Annex 1, paragraph 113 recommends a pre‑use/poststerilization integrity test of sterilizing‑grade filters. The word “should” in this paragraph — regarding the degree of enforcement of such test — may be confusing. A risk assessment approach to determine whether or not such test may be performed would be far more appropriate to maintain drug safety.

W

ith the rise of large molecule drug products, sterilizing‑grade filtration has become a necessary step in aseptic processing. To customarily verify that the sterilizing‑grade filter is flawless, nondestructive filter integrity tests, such as bubble point, diffusive flow or pressure decay are used.

Integrity tests can be performed pre‑use/presterilization, pre‑use/poststerilization and post‑use, whereby use is the actual filtration activity. Post‑use testing is obligatory, whereas pre‑use tests are most commonly an end‑user choice. In addition to routine integrity testing, sterilizing‑grade filters undergo qualification and process validation tests before they are installed into the processes.1–3 An important element of qualification and validation is the sterilization of the filter, which must be

checked for effectiveness and for any potential stress that these sterilization processes could subject the filter to.

Typical filter sterilization methods are steam sterilization, either in‑line or in an autoclave, gamma irradiation and, very rarely, by gases such as ethylene oxide.

The integrity test of a sterilizing‑grade filter has to be and is most commonly done after the filtration process (post‑use). Few sterile filter users test the integrity before the sterilization and filtration process. Very rarely, integrity tests are performed pre‑use/poststerilization, as such tests require downstream filtrate manipulation and, therefore, are thought to be precarious.

Regulatory authorities request the integrity test of a sterilizing‑grade filter after the filtration, post‑use, and recommend integrity testing pre‑use, without specifying whether pre- or poststerilization.2–6 EU

Figure 1: Integrity test and downstream design examples using pre-use/post-sterilization integrity testing.

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FILTRATION & SEPARATION Annex 1, paragraph 113, however, states: “The integrity of the sterilized filter should be verified before use and should be confirmed immediately after use by an appropriate method such as bubble point, diffusive flow or pressure hold test.”7 The paragraph, in its first sentence, recommends the uncommon and potentially hazardous pre‑use/poststerilization integrity test. This in itself is not new, as this statement has been made in earlier versions of Annex 1. In addition, it has to be pointed out that “should” is considered to be a strong recommendation. Yet, there have been many instances of misinterpretation of this recommendation and European inspectors have enforced pre‑use/poststerilization integrity testing. These enforcement incidences caused major problems within the industry — in both new and existing applications. Established validated processes are subjected to undesirable changes, as the enforcement would mean new downstream designs, equipment installations and revalidation.

Reasons Given for Pre-Use/PostSterilization Integrity Testing

The reasons for a pre-use/post‑sterilization integrity test were given in an Integrity Testing Q&A in 2007.8 In answer to the question: “How should the integrity of sterilizing filters be verified?” the following statements were made: “Annex 1, paragraph 85 states: “The integrity of the sterilized filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test.” The filter sterilization process may be physically stressful for the filter; for example, high temperatures during the process may cause the filter to distort, potentially leading to fluid pathways that allow the passage of particles greater than 0.2 µm. The performance of a filter can improve with use, as particles begin to block individual pathways and remove larger pathways that smaller particles could successfully navigate. For these reasons, filters should be tested before use, after sterilization and again after use. Furthermore, testing should be performed in situ in to verify the integrity of the filter complete with its housing.”

The second paragraph of the answer can be broken down into two main reasons: 1. The sterilization process is stressful to the filter device and, therefore, could cause damage to the filter or cause pore size increases.

2. A possibly damaged filter may become integral during the filtration process because of blockage.

Evaluation of the Reasons Given

Regarding sterilization damage, one has to consider that all sterilizing processes require stringent qualification — the effectiveness of the sterilization process is not only subject to evaluation, but also whether it adversely

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Tributes to Theodore H. Meltzer

On 30 July, Theodore H. Meltzer sadly passed away. Many within the industry who have benefited and learnt from his many years of experience in membrane separations have expressed their regret at losing such a great friend, colleague and industry expert. It is only fitting that we share some of their epitaphs with you here in dedication and memory of Ted for his countless contributions to the industry: “Ted has been a mentor, adviser and friend. Most of all he has been the most influential expert in the field of filtration and water preparation, having served the industry in this capacity for 60 years. He will be dearly missed.” Maik W. Jornitz, Sartorius “Bad news for this beginning of August. The science of filtration has now moved to the sky.” Didier Meyer, Getinge “I have wonderful memories of Ted as a true icon of our business.

His sense of humour and ability to get women to surround him will always be a dear reflection of a wonderful friend.”

Jim Fernandez “A loss for all of us. He taught us so much — about filters, water, service, humour, friendship and life. We will all feel his absence.”

Jim Agalloco, Consultant “He was truly a unique and wonderful person. I will remember him as being incredibly knowledgeable about all aspects associated with water, as well as having a quick wit and wry sense of humour. He will be missed.”

Sue Schniepp, Consultant “He was truly an expert in his field, but also a wonderful friend, raconteur, and gentleman. He is perhaps the last of his breed, certainly was one of the best. We will miss him.”

Daniel Gold, Consultant “I have known Ted for more than 40 years and appreciated his sense of humour, his technical expertise and his friendship. He will be sorely missed by all. In the past few years, he has been my mentor and lunch companion. He had sense of integrity that I recognize in few people. His unique expertise in filtration in the pharmaceutical industry is, however, well served in the numerous books he authored and co‑authored and is a testament to his legacy.” Roger Dabbah, Consultant

September/October 2011

FILTRATION & SEPARATION effects the equipment. This means that the end‑user will verify whether the sterilization qualification process exceeds the maximum operating parameters. If so, the threat of filter damage is elevated and the sterilization process requires adjustment, in which case a pre‑use/ poststerilization test is unnecessary; it does not add to process safety because the assurance of such has to be qualified before the filters are used.

In addition, one has to distinguish between the different sterilization methods, as the stress applied to the filter is higher in an inline steam sterilization process compared with gamma irradiation. This does not mean that any of the stresses should be neglected, but the likelihood of filter damage is substantially higher in a steam sterilization process because of gradual temperature and pressure increases, temperature/pressure ratio specifications, condensation vacuum, superheated steam, inappropriate valve settings and so on. Gamma irradiation has its own problems — primarily the degradation process continues after the irradiation. That said, suppliers qualify the effectiveness of gamma irradiation and the maximum shelf-life of an irradiated filter, extractable/leachable profiles, particulate shedding and any possible damage.

Experience of gamma irradiation indicates that this sterilization process has a low stress cycle and does not usually damage filters.

With regard to 2), a damaged filter can become integral during the filtration process and the damage might not be discovered during the post‑use integrity test; it has to be verified whether or not this is possible. Data from hundreds of Bacteria Challenge Test results, even with filters that failed a pre‑use integrity test, showed that these filters did not block during filtration to a degree that the post‑use test could not detect these. The challenge level of 107/cm2 is rather substantial and not usually found in the industry. Yet, even with this elevated contamination burden, filters that failed pre‑use also failed post‑use.

The filters used in such tests were pleated, process-scale devices, not flat filters. This might be of importance; pleated filter flow dynamics are different from those of flat filter discs. In addition, preliminary test runs with 10” polyethersulfon (0.45/0.2 µm) and cellulose acetate (0.45/0.2 µm) blocked to different degrees — 25–95% showed that pre‑use failed filters also failed post‑use (publication is forthcoming). The data and experience available have, so far, not shown the likelihood of filter “healing” within the filtration process.

The Problem with Pre-Use/ Poststerilization

The major risk factor with pre‑use/poststerilization integrity testing is downstream manipulation. Any integrity test requires downstream manipulation, as the filter needs to be wetted with a wetting agent.

Furthermore, when the integrity test is performed, the

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downstream, filtrate side must be under atmospheric pressure. Both wetting and venting manipulations should be avoided after the filter and filtrate side have been sterilized, either in situ by steam or as a single‑use assembly by gamma irradiation. In a filling process, manipulating the sterile, filtrate side of a filter is as severe as human intervention. Engineering options are available that divert the wetting fluid into a fluid receiver, which can also be used for venting purposes (Figure 1). Any extra equipment supplementation, however, requires an increase in connections, risk and potential oversight.

More importantly, sterilized filtrate systems are usually kept over pressure after steam sterilization or, in the case of single‑use systems, are preassembled containment systems. The introduction of a vent filter and/or atmospheric pressures on the sterilized downstream side can cause an undetected breach of the sterile filtrate side.

Overcoming Generic Enforcement

The word “should” in paragraph 113 is a recommendation and should not be used as a generic mode of enforcement.

To overcome generic enforcement and show that the process is under control, risk assessments should be done. It is important to determine the risk involved to or not to perform a pre‑use/poststerilization integrity test.

Within this analysis, filter sterilization processes can be assessed, as well as filtrate side convolution, connection risks, potential bacterial ingress and its possibility of detection. The severity within pharmaceutical processes are inherently “high risk,” with or without a pre‑use integrity test, although the frequency and detection of an adverse event will vary greatly. Previous risk assessments, for example, showed that the use of a pre‑use/poststerilization test seems to be associated with a higher risk; failures may occur more frequently as a result of over‑complicated filtrate design and the lack of bacterial ingress detection.

Conclusion

The word “should” in paragraph 113 of the guidance documents is meant as a ‘strong’ recommendation.

This means the total enforcement of a pre‑use/ poststerilization integrity test ought not to be common practice, but only required when there is a compelling reason for such tests. Conscientious process risk assessment, with or without a pre‑use/poststerilization test, will result in an appropriate evaluation of the value of such tests. Doing a proper risk assessment, by the end-user, creates a risk review platform for the inspector to work with and from. Regulators and drug manufacturers alike ultimately strive for drug safety.

When risks increase, drug safety decreases; therefore, any risk elevation needs to be avoided. As stated on numerous occasions: “You cannot test quality into your product, you have to produce it.”

Maik W Jornitz

References

1. PDA Technical Report 26, Liquid Sterilizing Filtration (2008).

2. FDA, Guideline on Sterile Drug Products Produced by Aseptic Processing (2004).

3. ISO 13408‑2:2003(E), Aseptic Processing of Health Care Products — Part 2: Filtration (2003).

4. Ministry of Health, Labour and Welfare, Sterile Drug Products Produced by Aseptic Processing (2005).

5. Pharmaceutical Inspection Convention (PIC/S), Recommendation on the Validation Of Aseptic Processes, PI 007-2 (2004).

6. World Health Organization (WHO), WHO Good Manufacturing Practices For Sterile Pharmaceutical Products, QAS/09.925 Rev1 (2009).

7. EudraLex Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products (2008).

8. EU GMP Guide Annexes — Supplementary Requirements: Annex 1 Manufacture of Sterile Medicinal Products 1, How should the integrity of sterilizing filters be verified?

(H+V June 2007).

For more information Maik W Jornitz Senior Vice President Marketing Bioprocess Sartorius Stedim North America Inc. Maik.Jornitz@ Sartorius-Stedim.com

Theodore H. Meltzer, PhD † Principle Capitola Consulting Co.

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37

COMPLIANCE & GxPs

COMPREHENSIVE SAMPLE MANAGEMENT THE FOUNDATION OF DRUG DEVELOPMENT

Maximizing the potential of biospecimens for current and future drug development by ensuring their long‑term integrity through best practices, regulatory mandates and preparation techniques.

G

iven the significant role of biospecimens in drug development, it has become essential for pharmaceutical and biotech companies to develop a comprehensive strategy for the preservation of collected biological samples. The value of these materials (tissue, DNA, RNA, plasma and so on) is rapidly increasing because of discoveries that can be made from both prospective studies and retrospective analyses. These invaluable and sometimes irreplaceable materials represent assets that can bring significant long‑term commercial and scientific to an organization.

Companies are, therefore, collecting a growing amount of patient samples during clinical research; in fact, there are currently more than a billion samples stored in research labs and biorepositories worldwide.1 These samples are used to spearhead various initiatives, including a variety of testing, auditing, validation and qualification processes on collected specimens to • Detect new biomarkers.

• Identify biological and genetic factors responsible for different drug responses across individuals or populations.

• Reduce the time it takes to bring new drugs to market, thus maintaining a competitive advantage.

• Expedite R&D processes for new pharmaceuticals and therapeutics.

Because of the intrinsic value of these materials, preserving clinical specimens to the highest of standards has become a critical component of the drug development process.

Biospecimen Sample Collection and Preparation

Pre-analytical variables introduced during clinical sample collection and processing can significantly affect the molecular integrity of specimens and bias the results of assays and/or biomarker studies. An essential component of any sample management strategy, therefore, requires standardized protocols for sample collection and preparation techniques.

Biospecimen collection involves three components: collection of the sample, processing of the sample and recording of information about the sample. Information about the sample is of three types: its source (study subject), its characteristics (skin tissue plug biopsy) and its post‑collection processing and storage (for example,

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placement in freezer 10 min after collection).2 For example, the time elapsed in each step from collection through storage should be recorded and tracked to ensure a consistent process and to possibly explain anomalies.

Unrecorded information could be unrecoverable, which could exclude usage of a valuable time point, data point and/or disease state. This omission could inhibit discovery, as future uses of a sample often cannot be anticipated.

Sample preparation methods may also affect the results or interpretation of biological studies. Inexact sample preparation can lead to sample loss, reprocessing or complicated data interpretation. This bottleneck can delay studies, which ultimately delays a potential drug candidate from going to market.

Logistical Challenges in Specimen Management

With the globalization of clinical research, the safe, punctual and compliant transport of biospecimens for testing and analysis is ever increasing in complexity and critical to the sample management process. The strict temperature constraints placed on these materials makes their timely distribution particularly important.

Cold chain management defines how specimens, such as tissue, blood and DNA, are packaged and transported throughout the research and development process.

Weakness or failure at any point in the chain of custody can compromise product integrity, breach security, delay shipments and ultimately result in financial loss or liability. Common issues that can affect biospecimen integrity during transport include • Prolonged delivery delays caused by transportation glitches, security inspections or customs scrutiny.

• Temperature fluctuations whilst in transit inside shipping vehicles.

• Seasonal or climatic differences between origination site and destination To mitigate risk of material degradation and ensure regulatory standards are upheld, personnel should understand the intricacies involved in transporting biospecimens on a global scale. The US Department of Transportation and the International Air Transport Association (IATA) require organizations and individuals who ship or receive biological materials to undergo formal training to meet their standards in packaging, labeling, documentation, declaration,

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COMPLIANCE & GxPs Section

Details

A.200 — SPECIMEN ACQUISITION, ACCESS AND CULLING

Policies should be established for the acquisition of new specimens, access to specimens for research purposes, for culling of collections when specimen resources have fulfilled their original purpose or are no longer suitable for their intended purpose, or if participants request the withdrawal of their specimens.

B4.000 — RECORD RETENTION

Unless otherwise specified by contract, corporate or government policy or other agreement, each repository should establish a period of time during which all records are retained. A policy should be in place for the destruction or return of records that no longer need to be retained.

E2.000 — QUALITY ASSURANCE PROGRAMME

Each repository should have a Quality Assurance Programme/Quality Management System (QA/QMS) or adhere to the QA programme of the organization with which the repository is associated. The programme should describe the repository’s commitment to its QA and QC programmes and describe approaches for ensuring that the requirements of the QA and QC programmes are met.

H2.000 — LABELS

Each specimen container should receive a computer‑printed label that tightly adheres under all projected storage conditions. Information encoded on labels should be resistant to all common laboratory solvents. Labels should include readable indications as to what is stored in the container.

I3.200 — VERIFICATION OF PACKAGING

Packaging should be tested prior to use with specimens. Tests should include measuring all parameters that could influence specimen integrity (that is, temperature, humidity, light sensitivity, structural quality and spill containment).

J4.100 — FREEZE/THAW CYCLES

Freeze/thaw cycles can be deleterious to the macromolecules intended for analysis.

Therefore, it is important to select aliquot sizes that are appropriate for the intended uses for the specimens to minimize the number of times a sample is thawed and frozen before it is used.

J9.200 — SPECIMEN RETRIEVAL

Specimens should be located and pulled from storage as documented on specimen requisition forms. If specimens are frozen, speed is necessary during the retrieval process. Such speed may require that at least two individuals carry out the retrieval process. If possible, specimens being retrieved should be maintained at the storage temperature throughout the process (for example, specimens stored at −80 °C should be kept on dry ice during the retrieval process).

K2.200 — INFORMED CONSENT

Consent may be obtained for a specific research project, such that the details of the project can be specifically outlined; alternatively consent may be obtained for unspecified future research, in which case general information about the possible future research uses is provided, in accordance with applicable national or local regulations and policies.

Mechanisms should be in place to assure that future research uses of identifiable specimens are consistent with the original consent (e.g., through an IRB, ethics committee review or other mechanisms consistent with applicable regulations and guidelines).

K2.600 — TERMINATION OF SPECIMEN RESOURCES

Specimen resources should develop plans at the time of their establishment for the disposition of specimens and/or data should the resource be terminated for any reason.

The disposition, including any transfer of specimens and/or data to third parties, should be consistent with the informed consent under which specimens and/or data were obtained.

Table I: ISBER best practices for the collection, storage, retrieval and distribution of biological materials for research.

Source: 2008 Best Practices for Repositories: Collection, Storage, Retrieval and Distribution of Biological Materials for Research

hazard assessment and emergency response. Aside from the regulations, improper packaging and handling are common causes of temperature deviations. Proper training and qualification of all cold chain partners minimizes such problems.

Regulations and Customs Agencies

The US Department of Transportation Hazardous Materials Regulations (HMR) and IATA Dangerous Goods Regulations (DGR), along with other country‑specific regulations, develop requirements for the safe transportation of hazardous materials by railway carriage, aircraft, shipping vessel and motor vehicles.3,4 These regulations dictate specifications for classification, packaging, hazard communication, shipping papers, incident reporting,

September/October 2011

handling, loading, unloading, segregation and movement of hazardous materials. Fines and shipping delays often result from lack of compliance with these regulations.

Customs regulations in emerging regions are also complex and strictly followed by informed local Customs agents.

Any issues with the shipment itself, or the accompanying paperwork, can result in material being held by various government authorities for prolonged periods. With the current growth in temperature‑sensitive products and time‑sensitive shipments, developing a strategy, including contingency plans, to avoid these issues is essential. For example, when materials face possible delays during the clearance process at Customs, consigning shipments with a courier who is capable of replenishing refrigerant, such as dry ice, whilst awaiting clearance may be difficult.

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COMPLIANCE & GxPs Rigorous demands from authorities and industry associations worldwide necessitate that standard operating procedures (SOPs) be set in place not only for shipping, but also for labeling and documentation. Any controlled transport storage conditions, as well as warning statements or content identification, should be clearly stated on the label applied to shipping containers. Labeling and packaging must comply with IATA guidelines, be securely attached and clearly state that materials are to be transferred to a specified storage temperature upon receipt.

Specimen Storage: Good Storage Practices

Lori Ball

References

1. www.labmanager. com/?articles.view/ articleNo/3455/ 2. http://firstclinical.com/ journal/2011/1101_ Biostorage.pdf 3. www.phmsa.dot.gov/ staticfiles/PHMSA/ DownloadableFiles/Files/ Overview%20of%20 HMR.pdf 4. www.iata.org/Site CollectionDocuments/ 51NoticeUN3373Dec09.pdf 5. www.isber.org/bp/ BestPractices2008.pdf 6. www.biomedcentral. com/1471-2407/9/409

For more information

Lori Ball Chief Operating Officer BioStorage Technologies, Inc. Tel. +1 866 697 2675 +49 6155 898 1011 www.biostorage.com

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The specifics of a sample management strategy may vary, depending on the nature and intended use of the biospecimen, as well as the size and complexity of the collection. To ensure biospecimens are properly handled, transported and stored, companies should be aware of and follow Good Storage Practices (GSPs) guidelines. Although GSP is not a regulatory mandated requirement, the International Society of Biological and Environmental Repositories (ISBER) and governmental organizations such as the US National Cancer Institute have established specific GSP. In 2008, ISBER drafted guidance of best practices for the collection, storage, retrieval and distribution of biological materials for research (Table I). Industry experts expect these guidelines to evolve into regulations such as those that exist in other GxP environments (for example, GTP, GCP, GLP, and GMP). Today, the guiding principles of GSP mandates the standardization of sample handling and management processes to ensure samples are prepared and stored in consistent conditions.5 Because it may take years before specimen samples are needed for future research, testing, or audits, samples must be stored in highly specialized and consistent conditions, often for decades. To maintain sample integrity for such long periods of time, standardized, secure and compliant storage is crucial. A sample that has maintained the appropriate storage temperature will yield better results than a sample that has undergone fluctuations in temperature because of poor handling or storage practices.6 In addition, proof of sample conditions, temperature history and chain of custody must be proven if samples are to be viable for inclusion. Examples of the various components of GSP include • Secure facilities and robust quality assurance measures to ensure specimens are stored in compliant conditions at all times.

• Qualified staff that has been trained and certified in global sample transportation procedures, including regulatory and customs issues.

• Temperature monitoring and recording of samples around the clock with a comprehensive, uneditable audit trail and automatic notification system.

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• Business continuity plans, back‑up power and redundant systems to protect sample integrity during emergencies.

Information Systems for Specimen Management

Although proper storage and transportation are critical, specimens are useless unless they can be located with their associated data, in a timely fashion. In the past, researchers applied ad hoc tracking systems, such as spreadsheets, to track and plot information associated with biospecimens. Today, the complexity of clinical trial research has rendered these outdated and archaic systems inefficient to handle expanding biospecimen inventories. The ideal system should offer tracking and reporting processes through all stages of a sample’s shipping, handling and storage life cycle.

Often, critical information about a sample is “missing” or “inaccurate,” which can lead to costly study‑specific errors. To this end, a solid informatics approach includes integration of sample preregistration, cataloging of qualitative and quantitative information at the time of accessioning, as well as defined SOPs regarding sample discrepancies.

Because pharmaceutical and biotech labs typically implement a wide range of information systems, specimen management systems should seamlessly interface with other systems, provide global data integration and access and be highly configurable to easily integrate with a variety of laboratory workflow models.

Recent innovations have even expanded information management systems to include mobile and web‑based solutions. The integration of sample storage, consent authorization and clinical result data is another area of expansion occurring as a result of the advent of new technology systems. Connecting information on sample storage location, temperature and pretesting evaluation with the resulting data from a clinical study can enable researchers to improve their selection of samples for biomarker testing and shorten personalized medicine research timelines.

Conclusion

Whether samples are outsourced and stored offsite at a global biorepository or managed onsite by an insourced service provider, a robust infrastructure for biospecimen tracking and distribution will be required to support a successful comprehensive sample management strategy.

This combination of GSP and innovative technology streamlines the process of sample management; ensuring samples and information are readily available for today and tomorrow’s research initiatives. Now is the time for organizations to establish a comprehensive management strategy that incorporates and dictates how samples are handled, stored, transported and documented throughout their entire life cycle.

September/October 2011

September/October 2011

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EMERGING MARKETS

THE TIME IS RIGHT TO INVEST

Emerging markets are offering a lifeline to many traditional pharmaceutical brands, as government investment and growth in education creates a wealth of innovation partners and a brand new customer opportunity.

T

he term ‘emerging market’ is used to describe developing nations, such as India, Brazil and China, which are in the process of rapidly growing or becoming industrialized.

In many ways, it is a misleading term that fails to represent the importance and influence that many of these countries already hold in the global economy.

In reality, emerging markets have already ‘emerged’ and pharmaceutical companies in particular have already taken confident steps towards engaging with them; for example, pharmaceutical brands in established countries, such as Novartis and Pfizer, have already invested in outsourcing R&D facilities, sales forces, and administrative operations to India and China. Such investment in new markets have a two‑fold benefit of helping pharmaceutical companies become more culturally aligned with their emerging market partners, and helping them to better understand a new and potentially lucrative customer base.

The move towards emerging markets is no surprise; prescription spend in established economies has been rapidly declining in recent years, whereas medicine spend in emerging markets is doubling every 2 years, which indicates that the future security of many pharmaceutical brands is in these new territories.1 In particular, regulatory constraints, higher manufacturing cost and changes in consumer demand, have made drug discovery and development difficult in the western world.

It is not just the pharmaceutical ecosystem, however, that makes emerging markets appealing, but also the culture and infrastructure of the countries themselves. Recently, many emerging market countries have made a concerted push to improve their work culture, education system, regulatory policies and infrastructures, to allow them to take advantage of these significant growth opportunities.

These burgeoning economies are primed with a rich supply of talent and resources, making them prime targets for western companies.

Targeting an Additional Two Billion Customers

The potential for pharmaceutical growth in emerging market is momentous, because of an ageing population, GDP growth, increased focus on wellness and modernization of healthcare systems. A report from IMS Health, Pharmerging 17, demonstrates the significant revenue growth opportunities for pharmaceutical brands (Figure 1) by suggesting that the combined sales revenue for the top 15 pharmaceutical companies in emerging markets is likely to grow from less than 1% in 2009 to 30% by 2012.2 Emerging markets offer potential benefits beyond just revenue growth — they can also maximize the past investments that pharmaceutical companies have made in drug discovery by increasing the long‑term revenue from the most common drugs. Although these may be considered

Figure 1: Emerging market growth potential.3

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September/October 2011

STRAP outdated to western customers, they often represent vast improvements on current offering in emerging markets. In countries such as India and China, modernization and a move away from tradition medicines, has created new customer segments that are looking for ‘newer’ drugs that can fulfil their unmet needs. This is giving a second life to many medicines that are on the verge of dying out in the western world.

In addition, there is also the long-term opportunity for pharmaceutical companies to establish links with local health authorities and help them to redefine countries’ healthcare system. Pharmaceutical companies that enter early into a country’s healthcare system can benefit the most; for example, late last year, Novartis announced its commitment to invest $500 million in Russia to expand its R&D collaborations.4 This move cemented the pharmaceutical giants’ long‑term intentions within the country by aligning itself with the Russian government’s plans to strengthen healthcare system and improve health outcomes.

Emerging Market Success Still Requires Investment

Furthermore, emerging markets are growing in wealth and global power. In Brazil, for example, 32 million people have moved into the ‘middle’ and ‘high’ income brackets during the last 5 years, and that figure is expected to double during the next 5.5 Pharmaceutical companies must, therefore, act now to establish themselves in these new markets, making the most of their experience, before local brands can grow and dominate the industry. Yet, to make the most of the opportunities on offer in emerging markets, pharmaceutical companies need to address a number of issues, including customer centricity, patient programmes and local infrastructure integration

Customer Centric Models

The boom in mobile and internet technology during the past 5 years in emerging markets means that pharmaceutical customers, even in remote areas, are better informed about their disease conditions and treatment options.

Pharmaceutical companies must ensure that their strategies align with this growth in customer awareness. This is even more important in the emerging market as the healthcare decisions that patients make are hugely dependent on cost, as these are normally borne by the patients themselves.

This kind of approach can be hugely successful, as shown

by Novartis, which reported a 2% growth in sales in Brazil after it implemented its “Customers First” strategy in the country.6 The approach was a targeted campaign that was designed to better meet customer needs and increase service quality, whilst at the same time driving top‑line growth and reducing back‑office savings

One Size Fits All May Not Work

For a pharmaceutical company to effectively establish itself in an emerging market, they have to take a country-specific

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approach. In the first instance, despite countries such as India, Russia and China all sitting under the umbrella term of ‘emerging markets,’ they all have different cultures and consumers, which require very different, targeted sales approaches. Pharmaceutical brands, therefore, need to base their pricing strategies on local market condition and socio‑economic trends to best understand how to work with, and sell to, emerging markets

Friendship Model

The majority of western pharmaceutical companies would struggle to compete with local, specialist businesses as they lack the ‘home advantage’ of understanding the intricacies of the market. That aside, they do have the strengths of being able to provide financial investment and global expertises that can’t be rivalled by the smaller competitors. Rather than competing for the same patch, western pharmaceutical companies should build local business relationships and make themselves part of a country’s core healthcare ecosystem. A well‑defined, local, empowered and integrated key account management structure can help streamline this ecosystem and be more effective. This needs strong focus on building the right local team with long‑term focus

Patient Value-Add Programmes

Driven by diseases, in particular the rising occurrence of chronic disease in Asia, a patient relationship management programme can benefit pharmaceutical companies significantly by improving patient commitment and adherence to treatments. The programmes help improve patient education by careful monitoring of a patient’s medication regime.

This approach has already been successfully adopted by brands such as Pfizer, GSK and Novartis, who are trying to develop a closer relationship with the patients in emerging markets

Conclusion

The increasing focus on emerging markets doesn’t mean that pharmaceutical companies are done with their customers in established economies. In fact, the two‑fold benefit of operating in countries such as India and China is that not only will it increase revenue by targeting a much larger market, but this growth in patients will mean that these key learnings — be they R&D or customer tactics — can be replicated in the western world. Who knows, this may be the much‑wanted drop of rain in the severe R&D drought.

Pharma companies need to look beyond selling products or using third‑party manufacturers in emerging markets; they need to be part of the local healthcare system to be able to make their business model work. A long‑term strategy with high commitment to the country growth can only make the strategy successful.

Kamal Biswas

References

1. A ccording to the IMS Institute, spending on medicines in ‘pharmerging markets’ will double to $285–$315 billion in the next 5 years from $151 billion in 2010.

This will catapult pharmerging markets to the second position where spending on medicines is concerned.

2. www.imshealth.com/

portal/site/imshealth/ menuitem.a46c6d4df3db4 b3d88f611019418c22a/?v gnextoid=01624605b5367 210VgnVCM100000ed152c a2RCRD&vgnextchannel=4 1a67900b55a5110VgnVCM 10000071812ca2RCRD&vg nextfmt=default 3. Infosys interpretation of data from IMS Institute on spending trends on medicines in ‘pharmerging markets.’

4. As announced by Novartis on 20 December 2010 — www.novartis.com/ newsroom/media-releases/ en/2010/1474003.shtml 5. www.globalmarkets

advisor.com/2011/06/ bric-countries-are-youready-for-the-new-bricconsumer/ 6. Referenced at the Novartis Strategy and Innovation Forum on 17 November 2010.

For more information

Kamal Biswas Global Consulting Lead Life Sciences Practice Infosys Consulting, Inc. kamal_biswas@infosys.com www.infosys.com

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43

BIOTECHNOLOGY

ALBUMIN: MULTIFUNCTIONAL BENEFITS FOR CELL-DERIVED APPLICATIONS

The application of albumin to improve cell performance in manufacturing biotechnology and in the emerging areas of vaccine production, tissue engineering and stem‑cell‑derived therapies is an important prospect. The author analyses the extracellular and intracellular actions of albumin, most importantly the role of its interactions with ligands or bioactive factors that influence metabolic and biosynthetic activity, cell proliferation and survival.

T

he production benefits of mammalian cell culture are no longer confined to monoclonal antibodies, but are providing new strategies for vaccine production, tissue engineering and stem cell therapies.1 Historically, serum was a key component in cell culture, as a provider of molecules such as hormones, growth factors, attachment factors and low molecular weight nutrients.

The emergence of industrial‑scale mammalian cell culture for the production of protein pharmaceuticals presented a new challenge for cell culture media design, as quality control issues arose from the use of foetal bovine serum (FBS). Reliability of supply, consistency and the risk of

contaminants (mycoplasmas, viruses and prions), created serious safety concerns for regulatory agencies and led to an increased demand for defined non‑animal‑derived media components.2 As the major protein in FBS, bovine serum albumin (BSA) was seen as the essential factor associated with successful growth of many cell types and cell lines in the absence of serum.

Albumin is the major protein in serum and is present typically at around 50 mg/mL, where it makes up around 60% of the total protein; approximately 60% of which is in the extravascular space.3 The main functions of albumin have been summarized to include maintenance of blood oncotic pressure and pH; binding and transport

Figure 1: Crystal structure of recombinant HSA. Figure modified from Curry, et al. (1998).

44

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September/October 2011

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GE Healthcare Bio-Sciences AB, Björkgatan 30, 751 84 Uppsala, Sweden K11074. First published May 2011.

imagination at work September/October 2011

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45

BIOTECHNOLOGY References

1. O .W. Merten, Cytotechnology 50(1–3), 1–7 (2006).

2. O .W. Merten, Dev. Biol. (Basel) 111, 233–257 (2002).

3. M . Ellmerer, et al., Am. J. Physiol. Endocl. M. 278(2), E352–356 (2000).

4. X .M. He and D.C. Carter, Nature 358(6383), 209–215 (1992).

5. B . Halliwell and M. Whiteman, Br. J. Pharmacol. 142(2), 231–255 (2004).

6. K . Oettl and R.E. Stauber, Br. J. Pharmacol. 151(5), 580–590 (2007).

7. G .J. Quinlan, et al., Hepatology 41(6), 1211–1219 (2005).

8. M . Al‑Rubeai, et al., Biotechnol. Bioeng. 45(6), 463–472 (1995).

9. N . Ma, K.W. Koelling and J.J. Chalmers, Biotechnol. Bioeng. 80(4), 428–437 (2002).

10. M . Hülscher, J. Pauli and U. Onken, Food Biotechnol.

4(1), 157–166 (1990).

11. K .T. Kunas and E.T. Papoutsakis, Biotechnol. Bioeng. 36(5), 476–483 (1990).

12. C.G. Smith and P.F. Greenfield, Biotechnol Bioeng. 40(9), 1045–1055 (1992).

13. Z. Zhang, Y. Chisti and M.J. Moo‑Young, Biotechnol.

43(1), 33–40 (1995).

14. Y. Chisti, Crit. Rev. Biotechnol.

21(2), 67–110 (2001).

15. F. Hesse, et al., Biotechnol.

Prog. 19(3), 833–843 (2003).

16. H. Yamazoe, T. Uemura and T. Tanabe, Langmuir 24(16), 8402–8404 (2008).

17. H. Yamazoe and T. Tanabe, J. Biomed. Mater. Res. A. 86(1), 228–234 (2008).

18. T. Peters Jr., All about Albumin: Biochemistry, Genetics, and Medical Applications (Academic Press, San Diego, CA, USA, 1996).

19. I. Petitpas, et al., J. Mol. Biol.

314(5), 955–960 (2001).

20. M. Schiller, et al., Apoptosis 13(2), 319–328 (2008).

21. J.S. Ha, et al., Biochim. Biophys. Acta 1640(2–3), 119–128 (2003).

22. www.plosone.org/article/ info%3Adoi%2F10.1371% 2Fjournal.pone.0001384 23. M. Arici, et al., J. Am. Soc. Nephrol. 14(1), 17–27 (2003).

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of physiologically important ligands, including lipids, metal ions, amino acids and other factors; and antioxidant functions.

This article discusses the properties of albumin and its potential as a cell culture supplement including albumin structure; actions of albumin in the culture medium; ligand binding and transport properties; and benefits in emerging technologies such as vaccine production and stem‑cell therapies.

Albumin Structure

The potential application for albumin in cell culture is primarily because of the unique physicochemical properties of the molecule. The crystal structure of human serum albumin (HSA) reveals a heart‑shaped molecule with 585 amino acids in a single chain with the dominant feature being the three homologous domains (I, II and III) each made up of two subdomains (A and B), with each of these composed of six and four helices, respectively, each helix being connected by flexible loops (Figure 1).4 The unique structure of albumin plays a major role in both the redox properties of the molecule, and its binding and transport ability of a variety of ligands.

Action of Albumin in the Culture Medium Albumin as an antioxidant

An important function of albumin both in the extracellular environment and intracellular compartment of the cell is as an antioxidant. In the culture vessel oxidative stress is created by reactive oxygen species (ROS) generated by high oxygen tension, various media components and general cell metabolism.5 The antioxidant potential of albumin is generally associated with the sulfur‑containing amino acids cysteine (Cys) and methionine (Met). There are 35 cysteine residues in albumin with all but one involved in disulfide linkages, leaving Cys‑34 as a free reduced thiol.

Although albumin is the major source of free thiols in plasma the antioxidant capacity of albumin relates largely to its ability to bind metal ions and to scavenge free radicals as a substitute substrate. The role of Cys‑34 and the surface‑exposed Met residues have been examined and the antioxidant effect of Cys‑34 was as a scavenger of free radicals, whereas Met acted mainly as a metal chelator to reduce subsequent generation of ROS. Albumin also provides protection against lipid peroxidation propagated by ROS generated by aerobic metabolism, both in vivo and in vitro where thiol oxidation at Cys‑34 occurs.6 Bioreactors in large‑scale mammalian cell culture are a potential environment for the generation of oxidative damage to cells, particularly at the cell surface interface with the external culture medium. The presence of dissolved oxygen or of sparged air bubbles together with media components,

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such as transition metal ions including cuprous (Cu+1) or ferrous (Fe+2) ions, can give rise to damaging ROS. When bound to albumin these metals are much less able to participate in the catalytic generation of ROS leading to cell damage. As a component in culture medium albumin would provide the capability of protecting against detrimental actions of free Cu to potentially facilitate its transport into cells. In a similar manner albumin has the potential to limit cell damage caused by redox‑active metal ion contaminants in media such as vanadium, cobalt and nickel.7

A Protective Function of Albumin

The physical environment of the industrial‑scale bioreactor in terms of hydrodynamic shear forces and the possible detrimental impact on mammalian cell survival or productivity has been widely studied.8,9 Evidence for a protective role for albumin against physical damage in airlift or sparged bioreactors has been shown, although the exact mechanism of action is still unclear.10–12 Mammalian cells differ markedly in their susceptibility to the hydrodynamic stress in the bioreactor environment and the ability of albumin and other additives to provide a protective effect.13,14 Although evidence exists that protein additives provide protection to animal cells in sparged culture systems, the exact mechanism by which these additives protect cells is unclear; for example, a well‑characterized production process using recombinant BHK‑21 cells, in both a 2.5‑L bubble‑free membrane‑aerated bioreactor and a 30‑L pilot airlift bioreactor, the addition of 1 g/L albumin (along with 10 mg/L transferrin and insulin) compared with protein‑free medium, lead to a significant reduction of cell lysis.15

Surface Binding Properties

One aspect of an extracellular role for albumin requires direct binding of albumin to the cell surface.

At the macroscopic level this has been studied in the biomaterials field for medical device applications where the cell adhesion properties of albumin are of interest.

The switching between nonadhesion and adhesion of fibroblasts could be achieved by ultraviolet (UV) exposure of the albumin coated surface.16,17

Ligand Binding and Transport Properties

Albumin has the potential to influence a wide range of cell processes because of its unique capability to bind a wide range of endogenous and exogenous ligands, such as fatty acids, metal ions, steroids, amino acids and a variety of drugs.3,18 The addition of these ligands to the culture media or prebound to added albumin highlights an important a role for albumin in bioreactor performance of industrial cell lines.

September/October 2011

September/October 2011

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BIOTECHNOLOGY 24. D .C. Carter and J.X. Ho, Adv. Protein Chem. 45, 153–203 (1994).

25. V .V. Wong, et al., Biotechnol. Bioeng. 93(3), 553–563 (2006).

26. D .A. Roess, et al., Chem. Biodivers 5(8), 1558–15570 (2008).

27. B.D. Liboiron, et al., J. Am. Chem. Soc. 127(14), 5104–5115 (2005).

28. M. Haratake, et al., Inorg. Chem. 47(14), 6273–6280 (2008).

29. E. Erkan, P. Devarajan and G.J. Schwartz, Am. J. Nephrol. 25(2), 121–131 (2005).

30. O. Takase, et al., Kidney Int. 73(5), 567–577 (2008).

31. C. Bolitho, et al., J. Vasc.

Res. 44(4), 313–324 (2007).

32. B. Barbaro, et al., Artif. Cells Blood Substit.

Immobil. Biotechnol. 36(1), 74–81 (2008).

33. W.S. Zawalich and K.C. Zawalich, Metabolism 57(2), 290–298 (2008).

34. J . Yang, et al., J. Neurosci.

Res. 87(2), 495–502 (2009).

35. K .J. Manton, et al., Stem Cells Dev. 19(9), 1297–1305 (2010).

36. S. Mujaj, et al., Tissue Eng. Part A 16(4), 1407–1420 (2010).

Lipid Binding to Albumin

Albumin is the main carrier in the circulation for delivery of unesterified fatty acids (FA) into and from tissues. Albumin possesses multiple binding sites and a total of seven binding sites in HSA for medium‑chain FA, and saturated, monounsaturated or polyunsaturated long‑chain FA molecules, have been mapped by crystallographic studies.19 The function of albumin in cholesterol transfer is an important function in many cell types particularly for cholesterol‑dependent cell lines such as NS0 myeloma and derivative hybridoma cells. The evidence for albumin‑bound lipids as modulators of cell physiology is widely available and the importance of this for industrial cell culture in the development of serum‑free media has been long recognized.2 Depending on the cell type, a differential response in cell growth may be observed with media containing either recombinant HSA, serum‑derived fraction V or fatty‑acid free serum‑derived HSA. Examples of cell responses to albumin with bound lipid include promotes cellular survival after apoptosis induction; mediates cholesterol efflux from cultured endothelial cells; regulates human embryonic stem cell self-renewal; and stimulation of kidney cell apoptosis by albumin-bound fatty acids.20–23 Albumin has enormous potential to modulate the functioning of cells via its capacity to bind lipids and facilitate entry into the cell. These examples highlight the applications using the lipid‑binding characteristics of albumin in the industrial bioreactor, tissue engineering and stem‑cell production processes.

Metal Ion Binding

Luke Dimasi

Metal ions can have contrasting functions within cell systems where they can be essential co‑factors for optimal performance or alternatively act as toxic compounds in certain biological process. Albumin has two high affinity metal‑binding sites, providing a potential role for albumin in these two situations.24 Metal ions such as Cu, zinc, venadium and selenium have been shown to be effective in promoting growth of a variety of industrially relevant cell lines including CHO, hybridoma and myeloma NS0.25–28 The ability of albumin to bind and transport metal ions, facilitating uptake into cells and enhancing cell performance, demonstrates an additional role for albumin in industrial cell culture.

Benefits of Albumin in Emerging Technologies For more information

Luke Dimasi Product Manager, Cell Culture Novozymes Biopharma

48

Cell culture models to examine the role of albumin in human health conditions such as the kidney‑derived cells MDCK, Vero, HEK‑293 and BHK‑21 cells have been used extensively for vaccine or recombinant protein expression.29 Studies where albumin was incubated with the kidney cell HKC‑8 induced marked cytotoxicity, which

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was found to be closely related to the fatty acid content of the albumin.30 In endothelial cells of vascular origin however, albumin has been shown to be anti‑apoptotic in its effect, independent of its ROS scavenging properties or bound lipid.31 Studies on both kidney and vascular endothelial cells show as little as one glycyl moiety per molecule was sufficient to dramatically increase the toxicity of albumin; therefore, for industrial and biomedical cell culture applications the presence of carbohydrate adducts appears to be undesirable.

The beneficial effects of albumin also translate to primary and stem‑cell culture. Improved performance of cultured mouse and human pancreatic islets was observed when incubated with bovine or HSA, respectively.32,33 The interaction of albumin with other biological factors such as insulin, epidermal growth factor (EGF) or as a carrier of the intracellular signalling molecule nitric oxide has also shown to be beneficial in commercial cell lines such as PER.C6TM.34 In stem‑cell applications albumin is a crucial media component to support differentiation of human embryonic stem cells (hESC) in the presence of added growth factor.

The use of recombinant HSA in the culture of hESCs in serum‑free, feeder‑cell‑free meets both the functional and regulatory requirements.35 Similarly, there is an increasing interest in albumin for use in culture media in tissue repair and engineering applications — particularly for recombinant HSA, which can provide the platform for serum‑free media, such as in the development of keratinocyte and fibroblast co‑culture in skin equivalent strategies.36 For stem‑cell therapies to become widespread in the clinic the availability of reliable sources of high quality recombinant albumin is an important requirement for achieving these goals.

Conclusion

Albumin has been widely used in cell culture during the last few decades as a component in serum‑free media, mainly because of its role as an important carrier of ‘serum‑derived’ substances that support mammalian cell growth. These include lipids, amino acids, hormones, peptides, metals and other undefined low molecular weight molecules. The use of albumin as a carrier of bioactive small molecules, or co‑factors, including metal ions in improving cell growth and performance has shown that albumin contributes to the efficacy of many of these molecules in improving cell performance. At industrial scale, where cells are producing large quantities of recombinant protein, they are under most physical and metabolic stress and it is here where there is a beneficial role of albumin.

The inclusion of recombinant albumin as an important component is also encouraging for cell‑based vaccine production, the production of cells for tissue engineering and in stem‑cell therapy.

September/October 2011

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49

OUTSOURCING

HARNESSING THE VALUE OF OUTSOURCING-LED INNOVATION Sanjiv Gossain, SVP and head of UK, Ireland, Cognizant, emphasizes the need to measure the return on investment (ROI) of outsourcing to recognize innovation.

I

n this age of globalization, outsourcing has become an integral part of the way large, multinational pharmaceutical companies are run.

From managing large‑scale R&D projects — testing product safety, monitoring reports, clinical data management and clinical development activities — and supply chain networks, to even leading on customer service, the majority of large businesses are spending more on outsourcing now than at any point during the last few years. Research from IDC shows that almost two thirds of pharmaceutical companies are increasingly using third‑party outsourcing firms to augment or replace varying aspects of their IT responsibilities.1 It is here that innovation is increasingly becoming a vital element of outsourcers’ offering, and pharmaceutical organizations are relying more heavily on their outsourcers to deliver innovation capabilities. Research we recently conducted with Warwick Business School among 250 CIOs and CFOs across six regions (the UK, Germany, Switzerland, Benelux, France and the Nordics), reveals just how important this innovation is: 70% of European C‑level executives believe the innovation achieved through outsourcing contributes to their organizations’ financial performance. But, worryingly, the research also suggests that businesses are failing to get the most of outsourcers’ innovation capabilities.2 If only 35% are actually quantifying the financial value that innovation adds to their business, how can they prove its worth and make the case for future investment?

Outsourcing-driven innovation

As companies navigate the reset economy, they need to be investing in processes that will be cost‑effective and beneficial in the long term. As both outsourcers and clients can attest, modern outsourcing relationships now offer and deliver far more than just cost savings: they can transform the business, achieving greater efficiency and productivity, thereby helping a company to maintain a competitive edge.

The survey suggests that many businesses are now turning to outsourcers to offer innovation capabilities.2 As CIOs across the globe are constantly challenged by the board to deliver value by doing things differently, 67% of European CIOs look to their outsourcing partner to develop ideas into new and improved processes.

Enterprise innovation is no longer a spectator sport; it is now in everyone’s hands. But, importantly, not all innovation is about once in a decade breakthroughs. Both radical and incremental innovation are delivering major benefits to businesses.

50

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Sanjiv Gossain

The future of work depends on next-generation business models that enable globally distributed teams consisting of the best innovative talent to provide new perspectives and insights on a project or ongoing line of work. For example, we have been working with the Pistoia Alliance using the latest cloud technology to transform the way the world’s leading pharmaceutical companies conduct R&D projects. We teamed up with Eagle Genomics to develop a cloud‑based platform for streamlining sequence services.

The vision is to allow pharmaceutical companies to securely share their bioinformatics resources among simultaneous, registered users in a secure environment, whilst enabling the flexibility, scalability and cost‑efficiencies of cloud‑based software as a service (SaaS) platform.

For innovation to work, it should be an enterprise‑wide, collaborative initiative whereby vision and enablement are steered by senior leadership. The middle level owns and drives the initiative with the team implementing it. To deliver innovation to clients, we think it has to be embedded into the outsourcer’s make‑up in three key ways: • Culture. By making innovation part of employees’ everyday work, they can seek and identify challenges — to generate ideas and to collaborate effectively. Only in such a culture can every employee discover what it means to innovate and how to contribute using their own ‘innovator’s mindset.’

• Process. For each innovation initiative, and at every stage, a series of discussions between the outsourcer and the client is vital to ensure stakeholders remain involved.

This sets the tone for innovation efforts to be tightly aligned with client business strategy.

• Infrastructure. Outsourcers have to have the right infrastructure to enable the global roll‑out and scalability of an innovation framework with clients, whereby operations and outcomes are measured and monitored, including the evaluation of innovation scorecards by the leadership team.

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51

OUTSOURCING Framework

References

1. www.computing.co.uk/ctg/

news/1821648/two-thirdspharmaceutical-companiesoutsourcing 2. www.valueofinnovation.com/

resources 3. www.cio.co.uk/

news/3256901/it-headsadmit-they-are-notspending-enough-oninnovation

For more information

Sanjiv Gossain SVP and head of UK, Ireland Cognizant Tel. +44 207 297 7600 www.cognizant.com

A key barrier to firms’ ability to build an innovation capability is in the management. From measuring the ROI to proving that all processes have tangible benefits, management must be integral to any outsourcing engagement. A recent study by SAP among 500 senior IT staff in eight countries across Europe, the Middle East and Africa, showed that they feel restricted in their investments as they have to divide expenditure between operations, maintenance and innovation.3 One third said the current IT strategy focuses on ‘keeping the lights on’ in the day‑to‑day running of existing IT systems and two thirds claimed this strategy ‘held them back’ from investing in innovation.

If innovation achieved through outsourcing is boosting a company’s financial revenues, this needs to be properly appraised and communicated. A modern outsourcing relationship, therefore, should help a business to innovate and be able to quantify its success by setting out measurable performance metrics from the start.

To drive repeatable innovation, companies need to establish a framework with their outsourcing partners to

determine their objectives and formalize the innovation achieved. Developing metrics will also help the C‑level share the results and prove the worth of outsourcing‑led innovation. This benefits both parties — the CIOs in terms of the innovation and expert knowledge they can work with, and the CFOs with regard to their balance sheets and to increase profit margins.

Our research demonstrates that CFOs and C‑level IT executives are aware of the financial benefits of outsourcing‑led innovation. Whilst businesses are clearly turning to outsourcers to aid and deliver innovation within their organizations, many are missing a major opportunity to demonstrate its success by failing to measure the benefits achieved or communicating these effectively. This can only mean that money is being wasted by investment into innovation initiatives that are not delivering tangible results.

The next steps must be to harness this innovation, by measuring it, communicating the effect it has on a company’s bottom line and growing it. Only by doing so can those in the pharmaceuticals sector remain at the top of their game.

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53

CLINICAL STUDIES

CHALLENGES IN ONCOLOGY STUDIES

Oncology clinical programmes represent a significant investment in costs, resource and time. Understanding the challenges at all stages is vital to a programme’s success.

The Quanticate Statistical Consultancy Team provides an overview of some of these challenges (and associated recommendations) in setting up, conducting and reporting oncology studies.

I

n the UK and US, approximately 1 in 4 people die from a cancer or cancer‑related disease, making it the second most likely cause of death (after cardiac‑related diseases). There is a major focus on developing new treatments to improve the survival of patients with cancer. Oncology studies in just one specific cancer, non‑small cell lung cancer (NCLC), account for >22,000 patients being recruited worldwide in Phase III clinical trials today leading to intense competition for patient recruitment.

With so many studies ongoing, it is important to select clinical research organizations (CROs) with the appropriate expertise to ensure that the myriad complexities associated with oncology studies are considered. CROs will often have expertise in specific cancers. Specialist biometric organizations are likely to have a broad range of experience across many types of cancer. Multiple suppliers with their areas of specialty may be involved in the reporting of a full clinical programme.

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Study Design

There are several study designs in the early development phase specifically tailored for oncology studies. These include dose escalation designs based on safety and efficacy considerations, and incorporation of overlapping dose groups. Phase I studies are usually based on patients because of the anticipated toxicities. It is rare even in Phase I to be able to include a placebo as a comparator because of ethical considerations; although some Phase I cohort designs can incorporate random placebo insertion. The challenge for all phases is to keep the length of recruitment to a minimum — particularly challenging for rare cancers.

This is compounded in the later phases, when larger numbers of patients are required — and there is a need to balance both the recruitment and the length of follow‑up with large numbers of sites and countries. Discussions with investigators to identify realistic recruitment rates (adjusting for competing studies where appropriate) will help in these planning aspects.

September/October 2011

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CLINICAL STUDIES The gold standard for oncology studies from the regulatory perspective would be the endpoint of overall survival (OS) in a randomized double‑blind study or studies demonstrating the required clinical superiority compared with the current standard therapy in the chosen indication.1 Overall survival can take years to collect and surrogate or alternative endpoints such as progression‑free survival (PFS) or quality of life (QOL) data may be accepted as interim approval endpoints. Double‑blind studies are difficult to achieve: treatment regimens differ in length, delivery and complexity making single‑blind studies more common. Use of double‑dummy is rare, so if it is the only means to blind the patient from the treatment allocation, then open label studies may be the only option. Open‑label studies can be subject to intense scrutiny by the regulatory bodies as it is difficult to achieve unbiased assessments.

A high proportion of patients are likely to experience a serious adverse event (SAE) and these cases are often complex.

The sponsor is responsible for providing and blinding any comparators used, along with funding the standard of care treatment at each of the sites. To allow for effective usage of study and comparator medication, an interactive voice (or Web) randomization system (IVRS/IWRS) is strongly recommended. Although these systems are efficient in managing the investigational product, it is important to allocate additional time to the setup phase to establish the system.

Consideration of follow-up for overall survival should be built into all studies as part of the informed consent (IC) to enable easy access to patient records for 1, 2 or more years’ follow‑up for the restricted information pertinent to the key endpoints of interest. This requires considerable forethought in the planning processes and will generate more complete follow up at the later stages of the programme, compared with post‑hoc data collection that can be both costly and only partially successful.

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Patient Recruitment and Retention

Treatment-naïve patients are rare. Competition for patients in most areas is intense and many patients (although suitable for inclusion in the trial) are often exhausted from previous chemotherapy or radiotherapy and are subsequently unwilling to consent. Study‑related tests that are additional to their current care may also deter participation. To maximize recruitment within each centre, it is recommended to discuss with as many sites as possible prior to finalizing the protocol, to balance the minimum number of invasive/ additional tests against recruitment targets.

Eligibility for the study will be affected based on previously failing treatment with the selected comparator, thus reducing the recruitment pool further. Recruitment of 1 or 2 patients per year is not uncommon and this will have a significant effect not only on the quality of the data, the duration of recruitment, but also on treatment by centre analyses.

Study Setup and Conduct

Oncology studies are resource-intensive both at site and for the sponsor with all the setup and monitoring aspects that such studies entail. Some of the major challenges are listed below and these range from site setup, protocol approval with the appropriate authorities, data collection (verification of source data, samples, follow up, serious adverse events) and independent committees.

Ethics committees (ECs) often raise issues regarding patient recruitment, comparator usage (as these may have different labels in various countries), and the privacy and legal requirements for anonymization of scans and samples. This may drive long EC approval timelines (affecting study start up timelines) and may lead to subtle protocol differences across countries. It is recommended to assume at least another two EC review cycles per site (for a 10‑site study) and four EC review cycles (for a 100‑site study) in the planning phase before 100% of sites are recruiting.

Source data verification (SDV) is more difficult for some indications as the patient notes are complex and voluminous and, therefore, require more time to conduct. Clinical research associates (CRAs) will be able to monitor only 3 or 4 sites at any one time because of the high workload and will need to be familiar with the RECIST criteria as part of the patient’s evaluability assessment.2 A high proportion of patients are likely to experience a serious adverse event (SAE) and these cases are often complex. The assessment of causality and distinguishing from underlying disease and concomitant therapies can be particularly challenging, which emphasizes the need for high quality and complete SAE reports. Many oncology trials will be conducted in high morbidity and high mortality diseases, and may have efficacy endpoints that could also be reportable adverse reactions.

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CLINICAL STUDIES

Figure 1: Plot of Kaplan-Meier estimates for Treatments A and B.

The systematic breaking of the blind for such cases (as required for expedited reporting to EU competent authorities) could compromise the integrity of the clinical trial: under such circumstances it may, therefore, be appropriate to reach agreement with competent authorities in advance concerning SAEs that would be considered disease related and not subject to systematic unblinding and expedited reporting.

Differences between regulatory authorities currently exist on this particular aspect, but the most comprehensive reporting requirements need to be considered. For blinded trials with agreement not to undertake systematic unblinding and expedited reporting, the appointment of an independent Data Monitoring Committee to review safety data on a regular basis is also recommended. Robust procedures for SAE collection, assessment, follow‑up and ongoing evaluation is imperative. The volume of SAEs, follow‑up, regulatory requirements and tracking will be time consuming and requires significant pharmacovigilance and medical expertise, in addition to input and support from the CRAs. Early involvement of pharmacovigilance experts in the protocol will ensure these aspects are adequately covered, both in the protocol and any regulatory interactions prior to the study start.

There will be potentially a large amount of data/ samples to collect/track for the study. These can include (but not be limited to): biopsy samples, images/scans, blood samples (including pharmacokinetics [PK] and biomarkers). Collection and shipping may require

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multiple approvals from multiple countries, potentially creating delays and degradation of samples rendering them unusable, so this aspect needs to be considered as part of the site assessment. Some of these samples/scans may be required for central (blinded) reading leading to dummy patient numbering to protect the identity of patients and sites. All these data will be eventually required to be analysed, so storage in a central place is helpful for the end of study reporting.

Given the potential toxicity of such treatment(s) under investigation, it is likely that the study will have a Data Safety Monitoring Board (DSMB) overseeing the overall patient safety. This will necessarily require continuous monitoring and data collection to ensure all appropriate data available at the required time points for the DSMB. Reflective of the disease complexity with multiple treatment regimens and endpoints, the Case Record Forms (CRFs) need to be clear, concise and unambiguous to enable accurate completion. With electronic capture becoming more prevalent, this is enabling on‑line validation as data are entered allowing immediate corrections (as needed) to be completed by site personnel. This is increasing the accuracy of entry and enabling queries to be restricted to more complex cross‑page checks. This is particularly helpful for interim database locks (for example, for a DSMB) to reduce the time required for answering any outstanding queries. SDV can be recorded on the e‑CRF by the monitors, providing an easy way of tracking the SDV required/performed.

September/October 2011

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CLINICAL STUDIES Tumour assessment pages continue to be the CRF section that generates the most queries. This is not that surprising given that tumour shrinkage is likely to be a key secondary endpoint, and it is important to track the right lesions and ensure they are consistently assessed, recorded and collected at the appropriate time intervals.

The volume of adverse events and concomitant therapies require a significant amount of review to ensure data accuracy and co‑correspondence with the safety (SAE) database and ability to report in a consistent format. The number of therapies ongoing will be high and indicative of the seriousness of the patient’s condition.

Structuring the (electronic) CRF for ease of entry at site will support the study nurse and investigator in the entry of data, and help the CRA with the monitoring aspects. It is important, however, to consider the data management and analysis requirements to ensure that the study can be reported as planned. Consideration should also be given for all the external sources of data upfront and how they will be incorporated both into the database and the analysis. In particular, survival follow‑up that may continue for many years following study reporting needs to be linked to the original study for ease of reporting.

Analysis Considerations

References

1. FDA Guidance Document, “Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics,” May 2007.

2. Revised RECIST Guideline (version 1.1), “New Response Evaluation Criteria in Solid Tumours,” 2009.

For more information

Quanitcate Statistical Consultancy Team enquiries@quanticate.com www.quanticate.com

60

Several of the key endpoints in oncology use survival methodology, such as overall survival or progression‑free survival, which can account for patients that fail to achieve the endpoint and can be censored at the point of no further information available. With time, these can be illustrated using Kaplan-Meier plots and analysed using the Log Rank test, with summary statistics for median survival and associated 95% confidence intervals.

Adjustment for covariates of interest can be applied in proportional hazards modelling or accelerated failure time modelling depending on the underlying model distributions with appropriate treatment comparisons described using hazard ratios. More complex models to adjust for interval censoring, competing risks and multiple states are available for use as sensitivity models or the main analysis.

Even for the more simple analyses, the data collection and understanding of the data available are important in the interpretations drawn from the data. Considerable care needs to be taken for patients censored prior to time point of interest — the reason for lack of information needs to be scrutinized to ensure that the patient does not represent a patient with ‘informative censoring.’

This can easily be demonstrated with an example: 100 patients recruited on two treatments A and B using 1:1 allocation; the number of deaths in treatment A is higher (74%) than B (54%) and the median survival time is 12 and 19 months, respectively during a 36‑month time period (Figure 1). For treatment A, all patients have either died prior to the time point or censored/

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alive after 24 months. For treatment B, 46% of patients were censored prior to 36 months (20% of patients prior to 19 months) as a result of lost to follow‑up and withdrawal of consent. Further investigation indicated that the lost to follow‑up were because the patients were so unwell that their care was transferred to a hospice and the withdrawal of consent was to enable the patient to take additional treatments because of poor prognosis. In all cases, the censoring would be considered informative with the potential to bias the results of the analysis.

If the 20% of patients censored prior to 19 months in Treatment B had died within the confines of the time period (36 months), the results would be very different.

This extreme example demonstrates how important the data collection of follow‑up, and the care and attention of censoring applied in survival methodology. It is possible that the difference observed between treatments A and B of 7 months in median survival is much smaller, and that the indication of treatment effect provided by the Log Rank (p=0.0989) is inflated.

Progression-free survival can give rise to other challenges: progression can be identified by predetermined criteria, but will be generally assessed at intervals. When did the progression actually occur? If considered at the day of visit, then this is a potential over‑estimation of time to progression. Bias can also be introduced by a visit schedule that is scheduled to the treatment needs — visits need to be frequent and spacing of visits identical for each treatment. By understanding the importance of how the data are collected and minimizing the bias as much as possible with appropriate data collection in place, the data can be appropriately analysed and the analysis plan appropriately set up to take these aspects into account.

Concluding Remarks

As a sponsor conducting oncology trials, a fine balance is required between the requirement for accurate, appropriate and timely information versus the complexity, cost and quality of such trials. It is important to allocate enough time in the set‑up phase to ensure the scientific expertise is built into the study, with all the design considerations thoroughly scrutinized to maximize the likelihood of a successful study with appropriate sites, endpoints, analyses and reporting.

Similar to many other indications, the relationship between sponsor and clinical partner(s) will be critical to successful recruitment and retention of patients.

Follow‑up of patients is essential and success is governed by early identification of requirements and building in survival follow‑up at the earliest stages of clinical development. Understanding of the best ways to collect and ultimately report the data will be critical to any successful submission and ability to register new treatments.

September/October 2011

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www.pharma-mag.com biotechnica.de 61

COST REDUCTION

GETTING MORE OUT OF LESS Reducing costs in the pharma industry is no mean feat. Using a programme management approach though can seriously improve a company’s health.

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uccessfully stripping out cost from a business is notoriously difficult; for example, is it possible to release staff or cut training and yet still retain the skills needed to drive the business forward? In pharma, the challenge is made even more so because the industry has, until recently, been focused on growth.

Companies and employees now need to embrace a cultural change to help them face the new reality of reducing costs in a strategic, disciplined and sustainable manner, delivered at pace.

Cutting costs is a demanding, high-risk activity, which, executed badly, can fail to deliver or significantly undermine an organization’s business goals and service integrity. It should be more than a loose aggregation of individual, local activities and should go beyond finance or operational tasks — two common mistakes many organizations make. It is also important to avoid indiscriminate, arbitrary reductions, typically in headcount and high-visibility projects, just to be seen to be doing something. Concentrate instead on activities that don’t contribute to achieving strategic goals. Cutting costs requires a programme management approach, managed in full alignment with the corporate strategy, across all areas of the business.

For the programme to be successful there must be sufficient input, involvement and buy-in from staff

September/October 2011

COST REDUCTION throughout the organization that are best placed to identify savings and who will certainly be required to deliver them. Many companies have successfully used working groups or task forces comprising staff from across the organization with different skills and experience, or company‑wide consultation exercises to identify significant cost savings and build commitment to the programme. When setting up a cost reduction programme, there are five essential areas that an organization needs to get right: designing the cost reduction programme, agreeing the desired outcomes, the approach, ensuring realism and facing the new reality.

Designing the Cost Reduction Programme

Getting the right balance of initiatives is important when designing the cost reduction programme: too few creates a high risk of failure or obsolescence; too many promotes a danger of mixed messages, which lead to poor delivery or a significant detrimental impact on business‑as‑usual activities. The temptation to over analyse the opportunities, however, should also be avoided; analysis should be advanced to the point where the decision is clear, rather than to the point where further analysis cannot be done.

Agreeing the Desired Outcomes

Care must be taken to specify the programme’s appropriate outcome. The reductions should not threaten the organization’s core capabilities and, therefore, put the delivery of the business strategy at risk. Equally, the reductions should not be so loosely defined that a lack of clarity means that the net reductions realized are less than the sum of reductions promised by the programme.

The Approach

Delivering sustainable, strategic cost reduction requires controlled and managed change delivered through a central team working to a clear process. The central team must have the authority, independence and experience to drive the programme. It should be primarily an internal team supported by external expertise to bring in good practice from other organizations, and to test the thinking and ensure it is sufficiently challenging.

It should also have a good functional spread to ensure an integrated approach across the organization. The process must encompass the entire delivery of cost savings from establishing the links into those elements of the corporate strategy that are relevant to the cost reduction programme to ensuring that the benefits have been delivered and are seen to be sustainable.

It is important for the longer term benefit to the organization that the cost reductions are sustained; this

September/October 2011

means that the organization needs to learn from the cost reduction programme and adjust its future behaviours to maintain the lower cost base. The programme should also facilitate training that offers staff the opportunity to continually improve.

Ensuring Realism

By working with a reliable, detailed cost dataset and associated metrics derived from the cost drivers for the company, insightful analysis can deliver meaningful and realistic targets. Supporting this analysis with internal debate, external benchmarking and identification of best practice will deliver a list of the current and potential initiatives that could be included in the programme.

This list can then be filtered, refined and prioritized based on value, timescale and delivery risk to establish an optimized cost reduction programme that meets the requirements for cost reduction, is feasible with reference to the actual cost base of the organization and can be realistically managed by the organization.

Facing the New Reality

Changing culture is a particularly difficult challenge for a management team to achieve. To help employees face the new reality they need to understand why change is necessary and then be motivated to help make the change. Sometimes this means encouraging them to accept the harsh realities of business; for example, seeing a comparison between drug development pipelines today and 10 years ago. It is also important to recognize that the entire organization cannot be changed in a single go. Forward thinking organizations, however, will identify individuals with a disproportionate influence in the organization, highlight their achievements and use them as ‘champions’ for the change. This approach really helps the change gather momentum. Reinforcing achievements and early successes with publicity will also help accelerate the new ways of working and deliver the cost reductions required.

Is your Cost Reduction programme designed to deliver?

Ask yourself the following: • Is the programme aligned to the organization’s business strategy?

• Is it driven by an analysis of reliable data and balanced between quick wins to generate momentum, changes to improve organizational efficiency and radical longer term measures?

• Does the programme have the full commitment and involvement of senior management?

If the answer is ‘no’ to more than one of the above, your programme may not deliver what you need it to.

Keith Foster

Conclusion

A poorly thought through or incoherent programme can take the organization backwards. A programmatic approach to cost reduction that includes the right approach and lifecycle management is essential and will ensure your cost reduction programme generates permanent improvements in operating efficiency, rather than damaging your business. Adherence to a disciplined approach will enable pharmaceutical companies to position themselves to meet the imperative of near‑term cost reduction and to emerge as more efficient, responsive organizations ready to meet the future challenges of a rapidly changing healthcare industry.

For more information Keith Foster Consultant Moorhouse

keithfoster@ moorhouseconsulting.com www.moorhouseconsulting.com

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63

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65

R&D

BOTANICAL ALTERNATIVES TO ANTIBIOTIC SOLUTIONS

The world is mired into a deadly and expensive arms race. But rather than being a military endeavour, this race is of medical nature — healthcare providers versus a growing number of superbugs, and, for now, the superbugs are winning.1

F

for the treatment

of C. difficile infection occurring annually in the US; up from 150,000 cases in 2001.3 With an annual death toll exceeding 15,000, C. difficile is now the most common cause of infectious diarrhea in US hospitals and long‑term care settings.4 According to Science 2.0, MDR‑TB is a growing problem in India, whereas in the US a report revealed that MDR‑TB is greatly increasing the risk of contracting TB among the African– American population.5,6 Furthermore, the emergence of Plasmid-encoding Carbapenemase‑resistant Metallo‑ß‑Lactamase (PCM or NDM‑1), an enzyme that renders bacteria resistant to a broad range of ß‑lactam antibiotics (including the antibiotics of the carbapenem family, the preferred treatment for antibiotic‑resistant bacterial infections) has scientists worldwide calling for urgent action to stop the spread of this plasmid.

Bacteria that produce carbapenemases are often referred as ‘superbugs’ because they cause difficult‑to‑treat infections.7 Antibiotic resistance has become such a widespread phenomenon that the US CDC has named it as “one of the world’s most pressing public health problems.”8 Writing in the The Lancet Infectious Diseases, Dr Tim Walsh, a leading authority in multidrug‑resistant Enterobactericeae infections — which include E. coli and salmonella — warned that the spread of drug‑resistant bacteria genes could herald the end of the antibiotics age.9

of human

The Paradox

or decades, following Fleming’s discovery of penicillin, scientists considered antibiotics a safe and effective method of eradicating infectious diseases. Until 20 years ago this notion may have held true; however, the world has been experiencing a resurgence of old contagions and the birth of new ones.2

The Offence

Today, methicillin-resistant Staphylococcus aureus (MRSA), multidrug‑resistant Mycobacterium (MDR‑TB), vancomicin-resitant tuberculosis enterococci, cephalosporin-resistant Neisseria gonorrhea, carbapenem-resistant and Klebsiella pneumonia, antibiotic-resistant Clostridium difficile (C. difficile) — to name just a few — are a great source of morbidity and cause thousands of deaths every year worldwide. The Centers for Disease Control (CDC) reports that there may be as many as 500,000 cases

Hydroxytyrosol could exert therapeutic effects

respiratory tract and intestinal infections.

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‘The Antibiotic Paradox’ is a problem that has been created by overusing these life‑saving drugs for managing conditions that could be easily addressed just by strengthening our immune system or avoiding, more absurdly, treating virus‑induced illnesses, such as influenza — which is insensitive to antibiotics —

September/October 2011

R&D References

with the latest class of antibacterial remedies.10 Also, the widespread use of antimicrobial agents, such as wipes, hand‑sanitizers and nebulizers, as well as the creation of antibacterial coated surfaces, including tabletops and antimicrobial tools, have compounded the problem. Whenever a chemically synthesized agent is used against micro‑organisms a few of the organisms survive the application and some random mutations will produce bacteria resistance to the drug. Discontinuity of treatment — patients failing to complete their course of antibiotics — or an incorrect prophylaxis may produce a failed cure and help the emergence of a more resistant strain of the bacteria we intended to eradicate.

Drug-Resistant Bacteria Environments

And the rise of drug‑resistant bacteria is not long fostered just by direct use, or misuse, of antibiotics in hospitals or for individual therapy; nowadays, bacteria mutate also in animal environments through the widespread practice of adding penicillin and tetracyclin into animal feed to improve the growth rate of healthy animals, to reduce the amount of feed used in their diet, for animal treatment during illness, and to curb recurrent infectious outbreaks caused by livestock living in cramped and unsanitary living situations. Reports by the Natural Resources Defense Council, Inc. have

September/October 2011

found that approximately 80% of all antibiotics used in the US are utilized in animal environments to promote faster growth and less feed.11 According to the Organic Consumers Association, the use of antibiotics on farms has led to an increase in antibiotic‑resistant cases of campylobacter and salmonella food poisoning in humans.12 In particular, virginiamycin‑resistant bacteria — which can be found in almost 50% of supermarket‑sold chicken, turkey and pork — are directly responsible for the at the least 5000 case of grave food poisoning annually.

Furthermore, virginiamycin‑resistant bacteria in chicken are believed to be the causative agent for the rise of synercid‑resistant bacteria in humans.

The US’ National Academy of Sciences claims: “The specter of untreatable infections — a regression to the prebiotic era — is looming just around the corner.”13 In a recently published study, the Cook County Hospital (IL, USA) and the Alliance for the Prudent Use of Antibiotics reported that the use of antibiotics from all animal sources costs Americans $16.6–26 billion annually.13

A New Defence Strategy

The Achilles’ heel of the pharmaceutical approach to prevention and therapy for bacterial epidemics has shown its limits during Europe and America’s

1. S .R. Palumbi, The Evolution Explosion: How Humans Cause Rapid Evolutionary Change (W.W. Norton & Company, New York, NY, USA, May 2001).

2. S.B. Levy, The Antibiotic Paradox: How Miracle Drugs Are Destroying the Miracle (Plenum, New York, NY, USA, 1992) p 279.

3. www.cdc.gov/washington/ testimony/2008/ t20080624.htm 4. http://integrisok.com/cdiff 5. www.science20.

com/news/mutated_ tuberculosis_a_growing_ problem_in_india 6. www.bcm.edu/news/item.

cfm?newsID=3498 7. http://thewatchers.

adorraeli.com/2011/04/27/ scientists-are-calling-forurgent-action-by-healthauthorities-worldwide-totackle-the-new-superbugstrains 8. www.cdc.gov/features/ worldhealthday 9. www.shirleys-wellness cafe.com/superbug.htm 10. P.R. Lee and C. Lin, “The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers (Review),” Perspect. Biol. Med. 46(4) 603–604 (2003).

11. http://blogs. desmoinesregister.com/dmr/ index.php/2011/02/25/80percent-of-antibiotics-goto-animals 12. www.organicconsumers.

org/Toxic/animalfeed.efm 13. http://www.huffingtonpost.

com/2011/05/25/ antibiotics-in-animalfee_n_867123.html?

14. www.webmd.com/food recipes/news/20110711/ can-hot-coffee-or-tea-cutmrsa-risk 15. www.hindawi.com/ journals/btri/2011/917505 16. www.savewithgreen. com/green-tips/herbs/ herbalantibiotics.htm 17. P.M. Furneri, et al., “Antimicoplasmal Activity of Hydroxytyrosol,” Antimicrob. Agents Chemother. 48(12), 4892–4894 (2004).

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18. E. Medina, et al., “Comparison of the Concentrations of Phenolic Compounds Olive Oils and Other Plant Oils: Correlation with Antimicrobial Activity,” J. Agric. Food Chem.

54(14), 4954–4961 (2006).

19. A. Tafesh, et al., “Synergistic Antibacterial Effects of Polyphenolic Compounds from Olive Mill Wastewater,” Evid. Base.

Compl. Alternative Med. 2011, article ID 431021 (2011).

20. G. Bisignano, et al., “On the In-Vitro Antimicrobial Activity of Oleuropein and Hydroxytyrosol,” J. Pharm. Pharmacol. 51(8), 971–974 (1999).

21. F. Mendel, et al., “The Olive Compound 4‑Hydroxytyrosol Inactivates Staphyloccoccus Aureus Bacteria and Staphylococcal Enterotoxin A (SEA), J. Food Sci. (2011).

22. www.nature.com/ ejcn/journal/v58/n6/ full/1601917a.html?iframe =true&width=80%25&heig ht=80%25%23aff1 23. www.scipharm.at/

download.asp?id=629 24. C. Manna, et al., “Biological Effects of Hydroxytyrosol, a Polyphenol Form Olive Oil Endowed With Antioxidant Activity,” in V. Zappia, Ed, Advances in Experimental Medicine and Biology, Vol. 472: Advances in Nutrition and Cancer 2 (Kluwer Academic/Plenum Publishers, New York, NY, USA, 2010).

For more information

Paolo Pontoniere Director of Communications CreAgri Inc. Tel. +1 510 732 6478 ext. 107 ppontoniere@creagri.com www.creagri.com Roberto Crea, PhD Founder and Chief Scientist CreAgri Inc. rcrea@creagri.com Tel. +1 510 732 6478

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Hydroxytyrosol

Roberto Crea

Paolo Pontoniere

latest food‑borne epidemics. There is an opportunity, however, to revisit our traditional approach to antimicrobial and pathogens’ control, whether it may be human diseases, food safety control and/or decontamination as in the case of an outbreak, and to expand our scientific and medical interest into natural active compounds that may provide new and more general defence against bacteria and viruses as well. Of all the natural compounds being tested in the nutraceutical and biopharmaceutical field for their antibiotic and antimicrobial properties, phytomolecules hold the greatest promise for a solution to the antibiotic paradox.

Phytomolecules, a class of plant-based biogenic substances (which includes flavonoids, carotenoids, terpenoids and polyphenols), are derived from fruit and vegetables, and are credited with having healthy and restorative properties, and for being a good source for many of the bioactives used to produce some of the newest biopharmaceuticals.

Recently, a Medical University of South Carolina’s study reported that thanks to catechins (a specific class of flavanoids found in plants ranging from grape to cocoa), coffee and tea drinkers run a 50% lower risk of contracting MRSA. 14 The study estimates also that, had it not been for coffee and tea catechins, the number of MRSA carriers — now standing at 2.5 million in the US — would be much higher. Processed and raw honey have been recently reported to be an effective antimicrobial agent against the proliferation of both gram‑negative and gram‑positive bacteria. 15 Furthermore, the list of plants and plant extracts, including echinacea, goldenseal, sage, garlic, ginseng, peppermint and thyme, exhibiting (either proven or suspected) antimicrobial and antibiotic properties grows longer by the day.16 But of all the natural/novel compounds being investigated by the nutraceutical, pharma and food industries, olive polyphenols and specifically hydroxytyrosol (HT) — which have been shown to have a potent antibacterial activity against E. coli 107:H57, salmonella and listeria — hold the most promise.17

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A recent study assessed the antimicrobial effects of HT and other phenolic compounds against gram‑positive and gram‑negative bacteria (Streptococcus pyogenes, Staphylococcus aureus [S. aureus], E. coli and Klebsiella pneumonia).18 Although the majority of the compounds tested exerted only minimal antimicrobial actions, HT induced powerful inhibition of four bacterial strains that were examined.19 One of the first complete reports of HT’s potential effects against human pathogens demonstrated that this natural product exerted inhibitory actions against 49 strains of clinically relevant bacteria, including haemophilus influenzae, salmonella and S. aureus.20 HT, at minimum inhibitory concentrations ranging from 0.24– 31 µg/mL, had broad‑range effects against the bacterial strains studied.20 On the basis of these findings, the authors proposed that HT could exert therapeutic effects for the treatment of human respiratory tract and intestinal infections.

HT efficacy as antimicrobials applies also to its unique activity against S. aureus’ enterotoxin A (SEA). Laboratory experiments, conducted at US Department of Agriculture in California, using Creagri Inc.’s proprietary formulation of HT with Hidrox 12%, demonstrate that the use of HT and olive polyphenols are natural, safe antimicrobials against food‑borne pathogens and some of their virulent toxins, particularly Shiga toxin, produced by E. coli and S. aureus in meats, poultry and humans.21 Similar to E. coli’s toxin, SEA is a super antigen that contributes to human emesis, diarrhea, arthritis and toxic shock. Multiple evidence that HT may easily penetrate tissues and cells as a result of its unique bioavailablity, together with the discovery of new processes to mass produce large, safe and effective quantities of olive polyphenols and HT for medical and industrial applications, may provide a viable alternative management to bacterial outbreak and deliver some therapeutic effects not easily obtainable with traditional synthetic antibiotics.21 The beneficial effect of HT and olive polyphenols on the immune system and the enhancement of the phagocitic activity of white cells/lymphocytes indicate that the benefits provided by the HT and olive polyphenols may be two fold: a direct antimicrobial activity against the pathogens and their toxins as result of its direct protein‑modifying activity mechanism; the potentiating and enhancing of innate immune defence that helps the human body to fight the toxic effects of bacteria infection.22–24 In addition, their strong safety profile and ready availability as dietary supplements (Olivenol Plus) would justify their study as alternative natural ailment in bacteria epidemic outbreaks affecting humans. HT from olives could provide a new, more effective and substantially safer approach to health management and food safety.

September/October 2011

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NOSTRAPHARMUS

BUILDING EMERGING MARKETS BRIC BY BRIc With India predicted to be among the top 10 drug producers by 2020 and China well on its way to becoming the third largest pharmaceutical market, just what does the future hold for the BRIC (Brazil, Russia, India, China) nations?

A

References

1. www.adb.org/documents/ reports/asia-2050/ asia-2050.pdf 2. www.businesswire.com/ news/home/ 20110125006249/ en/Research-MarketsAsia-Pacific-PharmaSector-Analysis 3. http://pvnet.wcigroup.com

For more information

nostrapharmus@wcigroup.com

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sia, the world’s largest continent, is home to some 4.1 billion people, representing almost 60% of the world’s estimated total population.

It is unsurprising, therefore, that Asia is expected to double its share of global gross domestic product from 27% in 2010 to 51% in 2050.1 As the wealth of the BRIC nations improves and the ageing population increases, the demand for quality drugs is also boosted. The Asia Pacific pharmaceutical market is predicted to grow at a compound annual growth rate of more than 12% during 2011–2013. 2 Pharmacovigilance in Asia is still in something of a development phase and, to a large extent, still varies from one country to another. Yet, drug safety and pharmacovigilance are now very much on the national agenda and are viewed as key components on the journey to become a First World nation.

China’s State Food and Drug Administration (SFDA) recently overhauled adverse drug reaction reporting and monitoring procedures, placing more emphasis on data analysis and evaluation, and putting additional responsibilities on manufacturers.

Nostrapharmus believes that further regulations inspired by ICH will be established as SFDA consults with First World regulators, including EMA and FDA. There are already stirrings of a China risk management plan.

As economic growth in advanced economies remains uncertain, businesses are looking to mitigate risk and diversify revenue streams by entering into emerging markets, particularly Asia.

More clinical trials are being conducted in the region and as more products are brought to market, occurrences of adverse events will continuously increase. It is believed that only a fraction, if any, of these adverse events are being reported. As healthcare professional and consumer awareness of adverse events in the market increases, it will only be natural to expect the volume of reported cases to increase. And once regulations move toward

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holding the manufacturing authorization holders accountable for reporting, case volumes will rapidly increase. A recent analysis of a top 25 pharmaceutical company shows that they expect their case volume to nearly triple by the end of 2014, with Asia accounting for 43% of total case volume.3 In gazing further into the crystal ball, Nostrapharmus sees SFDA as an agency with a higher capacity than First World regulators to review drug applications, including new APIs, allowing for products to be launched in China first.

SFDA has the benefit of First World hindsight, and Nostrapharmus believes that SFDA knows it is essential to have a robust regulatory framework for monitoring product safety in their market during clinical trials and postmarketing to assume a leading global position in bringing health options and solutions to their people. Significant changes in pharmacovigilance are certainly happening in the world, BRIC by BRIC. Nostrapharmus predicts: “In the coming years Asia will become a significant source of workload for pharmacovigilance organizations. As regional acquisitions are explored and expansion into these markets continues, pharmacos must be ready to support pharmacovigilance due diligences with local regulations in mind. Awareness of approval and marketing plans will be needed to anticipate the increases in pharmacovigilance staffing requirements to support the region, and these local offices should be considered as part of the integrated pharmacovigilance system, not just a growing affiliate. This will enable global resource flexibility, leveraging of time differences and global consistency of data for effective signal detection with the ultimate aim of continuously ensuring the safety of products across the globe.”

September/October 2011

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