Pharma Nov 2011 by Paul Howells

w w w. p h a r m a - m a g . c o m November/December 2011 ISSN 1746-174X Volume 7 Number 6

The global magazine for the pharmaceutical and biopharmaceutical industry

Biotechnology

Single-use bioreactors

Lyophilization

Advances in technology

Legislation

The SPC application process

Biosimilars

Approval pathways

Trends and emerging technologies

DRUG DEVELOPMENT

STRAP Quality Reliability Traceability Sustainability

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November/December 2011

CONTENTS

NOVEMBER/DECEMBER 2011

Contents FOCUS TOPIC

Drug Development

Contributing Companies: Quotient Bioresearch Ltd,

Accenture, Onyx Scientific and PRECOS.

Industry experts highlight a range of trends and new technologies, including drug transporters and using patient-relevant models to improve preclinical efficacy testing of cancer drugs.

FEATURES

Lyophilization: The Move from Art to Science Steven L. Nail, Gregory A. Sacha, Wendy

Saffell‑Clemmer, Lisa M. Hardwick and Michael J. Akers — Baxter International Inc.

The evolution of lyophilization science and technology, with a focus on three specific advances.

Personalized Medicine: Tailored Opportunities Jennifer Gordon — Baker Botts

Can personalized medicine offer a lifeline to specific patient populations, rescue ‘failed’ therapeutics and extend patent exclusivity?

Biotechnology: Reacting to Demand

James B. Schultz, PBS Biotech, Inc.

The author considers what is required for the broad adoption of single‑use bioreactors.

Legislation: Give and Take: There is No Compromise Paul Ranson, Sharmela Thevarajaha and

Antonina Nijran — Fasken Martineau LLP

Practical advice for pharmaceutical companies seeking to manage their risks regarding The Bribery Act 2010.

Manufacturing: A New Role Model

Hiroshi Sheraton and Robert Lundie‑Smith —

McDermott Will & Emery

The author discusses the impact that ‘uncertainties’ are having on patentees and the SPC application process.

Biosimilars: To BLA or Not to BLA?

David P. Halstead — Ropes & Gray

The risks and benefits of the different approval pathways for biologics.

November/December 2011

Validation: Understanding CE Marking and PUWER During Equipment Validation Peter Harvey — amtri veritas Ltd

Compliance with CE marking and requirements is in addition to, not instead of, validation.

PUWER

Industrial Vending: Ten Ways to Cut Costs with Industrial Vending

Tony Goodwin — Propeller GB Ltd

Semi‑automated, line‑side parts vending substantially reduce operating costs and boost productivity.

can

Legislation: The SPC Regime: A Minefield for the Patentee Monica McDonnell — Teradata

Looking beyond pharma to see how data can be used to improve the manufacturing process.

Generics: Painting by Numbers Kevin Robinson —Via Media UK ltd

The sobering reality of patent expiries and the progression of the generics industry.

REGULARS

From the Editor: Efficiently Inefficient

Corrine Lawrence

As many companies concentrate of becoming more efficient, some, it seems, don’t have a clue.

Comment: Pharma Adverse to Social Media?

Ban Bryant — Red Dog Communications

Regulation is needed, but pharma brands need to stop making excuses.

Nostrapharmus: The Complex Business of Simplification in Clinical Research Nostrapharmus

Nostrapharmus considers how the industry can continue effective global trials and align with a simpler future regulatory landscape.

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

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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

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

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

Patrick Crowley Vice President Product Line Extensions GSK (US)

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

Enric Jo Plant Director Reig Jofre Group

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

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

Financial Officer Cherelle Saunders +44 (0) 1372 364 123

cherelle.saunders@via-medialtd.com

Alan Lahaise Consultant Lahaise Consulting

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

miranda.docherty@via-medialtd.com

Carlos Lopez Relationship Director Healthcare & Pharmaceuticals Lloyds TSB Corporate Markets

Kurt Speckhals Senior Director, Supply Chain Pfizer Inc.

Gino Martini Geoff Tovey Director, Strategic Technologies Visiting Professor GSK (UK) Dept of Pharmacy King’s College Jim McKiernan Chief Executive Officer Wes Wheeler McKiernan Associates GmbH President, WPWheeler LLC Maireadh Pedersen Head of Business Development Quay Pharma Ray Rowe Chief Scientist/Prof of Industrial Pharmaceutics Intelligensys/Uni of Bradford Harald Stahl Senior Pharmaceutical Technologist GEA Pharma Systems

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The publisher endeavours to collect and include complete, correct and current information in Pharma but does not warrant that any or all such information is complete, correct or current. The publisher does not assume, and hereby disclaims, any liability to any person or entity for any loss or damage caused by errors or omissions of any kind, whether resulting from negligence, accident or any other cause. Pharma does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take any responsibility for any losses or other damages incurred by readers in reliance on such content. Copyright © 2011, Via Media UK Ltd All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording or information storage and retrieval system, without permission in writing from the publisher. Send permission request in writing to Permissions Department, Pharma, Fax +44 870 487 3469. Authorisation to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted for libraries and other users registered with the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK (ISSN: 1742-447X).

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September/October 2011

FROM THE EDITOR

Efficiently Inefficient

e continue to be deluged with reports of companies going out of business and work forces being made redundant, but just when I thought most businesses were reining in their purse strings and trying to streamline their operations in an attempt to weather the economic storm, I find myself regularly presented with stories that beggar belief. My source? Not the Internet, not press releases … but my husband. After being made redundant at the beginning of this year, my husband found employment in a 24/7 labelling factory. On his first day his supervisor advised him to check his machine before each shift in case the previous shift operator had sabotaged it (there’s a productivity rivalry between the two shifts). In instances of bullying by peers, he was encouraged to seek revenge with ‘interest’ to deter repeat performances. Operators ‘cherry-pick’ their work despite there being a priority list. Spelling mistakes and typos on the labels are ignored, because “they’ve always been like that.” During nightshifts, when management is absent, operators steal out (without ‘clocking off’) in their cars to purchase fast food. Recently, one (night shift) employee went missing for more than an hour (how come it took that long to register?); after the canteen, car park and washrooms were searched, he was discovered in another area of the factory catching up on some missed TV! Was he reprimanded? No.

Clocking on one morning, my husband discovered that most of the night shift had more or less done nothing because a machine — one that is instrumental to the continuity of the following processes — had gone down during the night and no one knew the password to reset it. Flabbergasted, my husband wondered why he, the new guy, knew it and no one else did. After punching in the code and cajoling the machine back to life, my husband approached the colleague, who’d told him the password, to question why no one else knew it. He was met with: “Shhhh, that’s our little secret.” The ethos of the workforce is to follow the path of least resistance. Yet, should the company decide to make redundancies, there will be uproar among employees. Last week, 16 employees were issued warnings for not wearing their ‘uniform’ baseball cap, which I hasten to add serves no health and safety purpose. Management had identified the culprits by going through the factory’s CCTV. If only they’d spend as much time enforcing other aspects of the business, perhaps their balance sheet would be a little healthier; did I mention that last year’s turnover was £20 million, yet the net profit was only £22,000? My point? The current economic difficulties have not removed complacency and incompetence. Counterproductive practices are not always identified. Before you scoff at the above examples, are you sure they’re not found in the pharma industry? Really sure?

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

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8833

COMMENT

PHARMA ADVERSE TO SOCIAL MEDIA?

Regulation is needed, but pharma brands need to stop making excuses.

References

1. www.msnbc.msn.com/ id/43009784/ns/healthhealth_care/t/nearlypercent-americans-getmedical-info-online 2. www.huffingtonpost. com/2011/08/26/ medtronic-insulin-pumphack_n_937648.html 3. http://adage.com/ article/news/facebookpolicy-spurs-bigpharma-rethink-socialmedia/227906/ 4. http://wave.wavemetrix. com/content/pharmassocial-media-challengesopen-facebook-wallsmay-not-risk-muchnegativity-00809 5. http://blog.nielsen.com/ nielsenwire/wp-content/ uploads/2009/11/NielsenOnline-Healthcare-Practice_ Social-Media-AdverseEvent-Reporting_nov09.pdf 6. www.gponline.com/News/ login/1090894/

For more information Dan Bryant Account Manager Red Dog Communications @DanBryantRD

Dan@reddogcommunications.co.uk www.reddogcommunications.co.uk

e’re nearly at the end of 2011 now, and we’re still waiting. Waiting on the likes of the MHRA and FDA to get their pens out and start writing us a set of regulations for this new‑fangled social media contraption that everyone’s been talking about since 2005. 2005 is probably a bit inaccurate, but the pharma industry has been kept waiting since at least 2009, when several pharma companies received warnings from FDA regarding their use of social media to falsely promote products, having made claims that were “misleading” or did not fully explain the risks of certain medications. If you throw in the potential for adverse events (AEs) with Facebook removing the ability of pharma brands to moderate walls and remove comments, social media is more of a minefield than ever. Yet, although on the surface it seems daunting, brands are glossing over the immense potential that social media offers. A recent survey found that 60% of Americans’ first port of call for medical and health‑related information was the Internet.1 That’s a staggering figure, but one that needs to be taken advantage of. Social media offers any brand — pharma included — the chance to engage with consumers on a unique level. It gives consumers a direct channel of communication to a brand, if they allow it, which can then be crafted into a community. This series of conversations provides brands with access to a torrent of rich, valuable customer data, which can be turned into a highly effective marketing strategy. By taking the opportunity to engage, reward and learn more about consumers, the benefits can be game‑changing. Of course, it’s important to handle social media in the same way as any other marketing strategy — strategically. Social media isn’t about setting up a Twitter account and letting the world know what’s on the lunch menu today down in the restaurant; it’s about refining a positive public image for the company and engaging with consumers to ultimately create brand advocates. The fear for pharma brands, however, isn’t helped by some particularly weak attempts to engage that we’ve seen. For example, acne remedy Aczone thought it was putting two and two together when it decided to draw upon the success of High School Musical and Twilight to appeal to teens. The result was ‘Aczone High’ featuring awful musicals, broken links and ‘Twilight’s’ Michael Welch, who was unrecognizable out of his vampire costume.

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You also may remember the storm Medtronic faced after it came to light that a hacker claimed it had found security holes in a popular electronic insulin pump product, which had the potential to remotely program and alter doses. This, of course, could have lethal effects, yet Medtronic’s response was that they would “evaluate the sources of the information and figure out what [to] do with it.”2 With an effective social media strategy, they could have focused on protecting the brand image and allaying the fears of their patients, rather than adopting a passive stance and allowing consumers to begin to communicate about the shortcomings of the company as a whole. One reason why brands are shying away from a proper social media strategy is the AE quandary, which is a myth I’d like to dispel. Although I have some sympathy for those cowering in fear of breaching regulations that haven’t yet been defined (namely those in the US) to shy away from Facebook as though the recent changes (removing pharma brands’ abilities to moderate and disable comments) would unleash a deluge of negativity is an overreaction.3 What constitutes an AE is specific, with all four criteria — an identifiable patient, an identifiable person reporting the event, an indentifiable suspect product and the actual adverse experience that occurred — needing to be clearly met. A report from WaveMetrix suggests that only a small percentage of consumer comments on US‑based pharma brand Facebook Walls are negative — and the number becomes miniscule if the page is less product‑focused and more brandand community‑focused.4 Meanwhile, the new Facebook rules do still allow product‑specific pages to be moderated, so there’s little that’s new to be feared. Furthermore, a Buzzmetrics/Nielsen study found just one message out of 500 to meet all four of the AE reporting requirements.5 It’s important to remember that communication through social media is often truncated; for example, Twitter only allows 140 characters. Pharma brands can overcome their wariness of using social media to interact with their customers by devoting time to understand how social media can be used for their gain and how to approach it strategically — rather than withdrawing and burying their heads in the sand. This, however, may soon be a moot point. Recently, MHRA has been reported to be investigating the use of smartphone apps and social channels by GPs for the reporting of pharmaceutical AEs.6 This seeming admission that social is a viable medium for pharma could be a step towards the regulations so many have been waiting for, but it will create a level playing field. It’s time to be bold and steal a march on competitors by leveraging social media to create some rich, effective and engaging campaigns.

November/December 2011

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Published 9/11

PATH0214R0

November/December 2011

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DRUG DEVELOPMENT

DRUG TRANSPORTERS EMERGING TECHNOLOGIES

Drug transporters are increasingly being implicated as a source of drug–drug interactions (DDIs) and potential organ‑specific toxicity in humans and interactions with these membrane bound proteins are becoming increasingly important to assess during drug development as recent regulatory draft guidance reflects. As a result, in vitro technology is rapidly advancing in the assessment of drug transporter interactions and some of the major approaches being adopted are discussed.

n the US, approximately 770,000 people are injured or die each year from adverse drug reactions (ADR) (in the UK the rate has recently been estimated at 50,000 people a year).1,2 A drug that is a victim of, or perpetrator of, clinically relevant DDIs in humans risks postmarket withdrawal. The DDI potential for a new drug, therefore, is a crucial parameter to assess during drug development. From a regulatory perspective (FDA and EMA), this assessment requires a full understanding of the clearance mechanism(s) for the drug, which includes both metabolic and transport‑mediated processes.3,4 From the metabolic perspective, our understanding of the major drug metabolizing enzymes (DMEs), such as cytochrome P450s (CYP450) and UGTs (UDP‑glucurononsyltransferases), allow us to make certain predictions from in vitro data regarding DDI potential in vivo, particularly with respect to CYP450 inhibition and induction. During the past 5–10 years, however, DDIs involving transporter proteins have been increasingly identified and the development of in vitro transporter assays is an area of active research for pharmaceutical DMPK/ADME (drug metabolism and pharmacokinetics/absorption, distribution, metabolism and excretion) groups.

Abbreviations

ATP

Adenosine Tri Phosphate

BSEP

Bile Salt Export Pump

MDCKII

Madin-Darby Canine Kidney Type II

OAT

Organic Anion Transporter

OATP

Organic Anion Transport Protein

OCT

Organic Cation Transporter

MRP

Multi Resistance Protein

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The wide distribution of drug transporters (across the body) may lead to them playing fundamental roles in ADME and organ‑specific toxicity. Drug transporter proteins can be embedded in the membranes of physiologically important organs and tissues, such as intestine, kidneys, blood brain barrier and liver. Their function is to either pump drugs out of cells (efflux) or to transport drugs into the cell (uptake).

Regulatory Landscape

In 2007, the International Transporter Consortium (ITC) was formed to collate and clarify current knowledge and key opinion of the role of drug transporters in therapeutic and adverse drug response. The ITC consists of scientists from all sectors of drug discovery, development and regulatory approval, academia, industry and FDA. The ITC met periodically from 2007 to 2009 and held an open Critical Path Transporter Workshop in October 2008, which resulted in a white paper that proposed that interactions be assessed using in vitro methods for seven specific transporters. 5 The ITC recommendations were subsequently endorsed by FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee and were largely included in last year’s draft guideline on The Investigation of Drug Interactions issued by EMA (their second ITC meeting is schedules for March 2012). 4 The transporters recommended for initial assessment generally included those for which a clinical relevance to drug disposition has been identified, namely, the efflux transporters P‑glycoprotein (P‑gp) and Breast Cancer Resistance

November/December 2011

DRUG DEVELOPMENT

we now have at our disposal a variety of sophisticated in vitro models to help assay for transporter‑related interactions. Protein (BCRP), and the uptake transporters OCT2, OAT1, OAT3, OATP1B1 and OATP1B3. There was, however, no ITC recommendation for BSEP and OCT1, although they have been included in the EMA 2010 draft guideline on drug interactions.4 For each transporter, it is recommended that in vitro testing is conducted to assess whether a new drug is either a substrate or an inhibitor of these transporter proteins. The ITC suggests decision trees for each of the recommended transporters outlining how in vitro data should be viewed and the possible consequences for clinical assessment in vivo.

the test compound under test, as this will determine the appropriate in vitro model to use (generally, only sufficiently permeable molecules will be subject to efflux unless they undergo active uptake into the cell). Furthermore, compounds that undergo a degree of nonspecific binding may also be unsuitable for testing in cellular systems. A variety of models, therefore, have been developed and are currently used to test for interactions with drug transporters in vitro, which typically involve cellular and/or membrane‑based assays. The approaches outlined below focus on the major human efflux transporters.

In Vitro Models

Cell-Based Model Systems

An accurate assessment of transporter interactions must take into account the cellular permeability of

Monolayer Efflux Assay Polarized cells, either differentiated (for example,

Figure 1: Inhibition of P‑gpmediated transport of digoxin by commonly encountered diagnostic chemical inhibitors of P‑gp activity in vitro.

November/December 2011

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DRUG DEVELOPMENT

Figure 2: Inhibition of P‑gpmediated transport of NMQ by PSC‑833 and LY335979 in P‑gp over‑expressed vesicles.

References

1. D.C. Classen, et al., “Adverse Drug Events in Hospitalized Patients,” JAMA 277(4), 301–306 (1997). 2. T ai-Yin Wu, et al., “Ten-Year trends in Hospital Admissions for Adverse Drug Reactions in England 1999–2009,” J. R. Soc. Med. 103, 239–250 (2010). 3. C enter for Drug Evaluation and Research, Food and Drug Administration (Rockville, MD, USA), Drug Interaction Studies — Study Design, Data Analysis, and Implications for Dosing and Labeling (September 2006). 4. G uideline on the Investigation of Drug Interactions, Committee for Human Medicinal Products (CHMP) CPMP/EWP/560/95/Rev. 1 – Corr.* European Medicines Agency, 22 April 2010. 5. K .M. Giacomini, et al., “Membrane Transporters in Drug Development,” Nat. Rev. Drug Disc. 9, 215–236 (March 2010). 6. W .J. Hua, W.X. Hua and H.J. Fang, “The Role of OATP1B1 and BCRP in Pharmacokinetics and DDI of Novel Statins,” Cardiovascular Therapeutics (2011). doi: 10.1111/j.17555922.2011.00290 7. M .L. Reitman and E.E. Schadt, “Pharmacogenetics of MetforminResponse:AStepin the Path Toward Personalized Medicine,” J. Clin. Invest. 117(5), 1226–1229 (2007).

Caco‑2 cells) or transfected with the transporters of interest (such as MDCKII, HEK293, LLCPK cells) are often used to characterize efflux drug transporter interactions. Usually, in these models, the cells are cultured as a monolayer and the vectorial transport of the drug is measured (the drug flux is measured in two directions, namely, apical‑to‑basolateral [AB] and vice versa [BA]). The net flux ratio is then calculated (flux BA/AB) and if >2 (and if it can be reduced in the presence of chemical inhibitors) then this is generally regarded as positive for active efflux of the test compound. By measuring the flux of probe substrates in the presence of various concentrations of the test drug, inhibitory interactions can also be assessed. The major issues with these monolayer models are that the physicochemical properties of the compound can affect the results (for example, permeability and nonspecific binding of the test compound) and it is necessary to fully understand the behaviour of the drug in a cellular system to interpret the data meaningfully. The availability of monolayers in a variety of well formats (for example, 12, 48 and 96), however, makes them highly flexible and amenable to automation, which can assist throughput. Furthermore, monolayer models consisting of a double (and triple) transfect are now commercially available; for example, MDCK11 cells transfected with both OATP and BCRP. These double/triple transfected models will help to improve predictions regarding efflux interactions with poorly permeable compounds. Figure 1 presents some of our recent results obtained using Caco‑2 cells in a novel 96‑well format using digoxin as the P‑gp substrate. The apparent permeability of digoxin is markedly reduced in the

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presence of P‑gp inhibitors indicating that digoxin is subject to P‑gp‑mediated efflux in Caco‑2 cells. Uptake Assays Drug uptake can also be measured using cell‑based models including the use of both primary cells (for example, hepatocytes and kidney cells) and transfected cell lines (for example CHO and HEK293 cells).

Non-Cell‑Based Models

Membrane‑Based/Preparations For membrane‑based assays, the transporters of interest are over‑expressed in cellular systems (usually eukaryotic, insect or mammalian cells) and then membrane fractions are prepared. Membrane‑based assays can be highly sensitive to detecting transporter‑mediated interactions because they provide ‘clean’ test conditions without potentially interfering drug metabolising enzymes or other cellular barriers. They also provide the opportunity to study drug transporters individually. Vesicular Transport Inverted plasma membrane vesicles (so called ‘inside‑out’ vesicles) are usually used to study the ATP‑dependent ABC efflux transporters such as P‑gp, BCRP and MRP‑2. With vesicle‑based assays drug concentrations present at the active regions of the transporter proteins can be measured/monitored and the permeability of the test drug is not a limiting factor to study interactions. For all the vesicle assays, rapid filtration of the membrane suspension through a filter retains the membrane vesicles containing the effluxed (trapped) probe substrate, which is then quantified. Generally, these assays are used to indicate that an interaction between the test compound and the transporter

November/December 2011

DRUG DEVELOPMENT has occurred and, in typical format, they cannot distinguish between interactions as a substrate or inhibitor because a probe substrate is used as marker of the interaction. Once an interaction has been identified, additional investigations (typically using polarized cell monolayers) would be undertaken to look specifically at the type of interaction occurring. Figure 2 presents some of our results obtained using P‑gp-containing vesicles using N-methyl quinidine (NMQ) as the P‑gp substrate. The potency of PSC‑833 and LY335979, two commonly used diagnostic inhibitors of P‑gp in vitro, can be clearly seen (complete inhibition of NMQ transport). ATPase Assays In ATPase assays, drug transporter interactions are detected via stimulation of ATPase activity (ATP consumption) in cellular membranes that have been over‑expressed with a particular transporter protein. Because ABC transporters are active transporters, they are able to operate against cellular concentration gradients and ATP hydrolysis is used as the energy source. Transported substrates enhance the ATPase activity of the transporter over‑expressed in the membranes and this is usually detected as an increase in inorganic phosphate measured by

colourimetric analysis. Unlike vesicle‑based assays, ATPase assays can be used to differentiate between substrates and inhibitors. Currently, ATPase assays are available for a broad range of human drug transporters including P‑gp, BCRP and MRPs. In addition to the membrane‑based methods outlined above, other noncell‑based models have been used, including nucleotide trapping and liposomal‑based approaches, but generally these assays are not widely used.

Summary

It is becoming evident that assessment of transport related DDIs will become an increasingly important part of safety assessment during drug development and will form part of the clinical development strategy. The potential for transporter‑mediated DDIs to occur is great, considering, for example, that the widely prescribed statins are substrates for the OATP uptake transporters and metformin (widely prescribed for type 2 diabetes) is a substrate for OCT‑mediated secretion in the kidney. 6,7 Fortunately, drug transporter technology is developing quickly and we now have at our disposal a variety of sophisticated in vitro models to help assay for transporter‑related interactions.

For more information Guy Webber, MSc Chief Scientist (In Vitro Sciences) Quotient Bioresearch Ltd

guy.webber@quotientbioresearch.com

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DRUG DEVELOPMENT

THE UNCERTAIN FUTURE OF PHARMACEUTICAL INNOVATIONS

R&D is facing an uncertain future as pharmaceutical companies try to find ways to close the widening innovation gap. An Accenture Life Sciences expert discusses the importance of a holistic approach to pharmaceutical R&D that maximizes strategy, processes and organization, and funding.

Roland Andersson

Reference

1. www.challengergray. com/press/PressRelease. aspx?PressUid=154

For more information Roland Andersson PhD Senior Executive Life Sciences Accenture

roland.andersson@accenture.com www.accenture.com/us-en/Pages/ service-life-sciences-researchdevelopment.aspx

Daniel Zweidler — external consultant to Accenture — contributed to this article.

s highlighted through a series of recent announcements by major pharmaceutical companies such as AstraZeneca, Pfizer and Sanofi, pharmaceutical R&D is facing serious challenges and is currently trying to address these mainly through restructuring initiatives. In 2010, more than 53,000 pharmaceutical jobs were lost in the pharmaceutical industry.1 Companies are seeking growth opportunities in emerging markets whilst focusing R&D spending. During this time of uncertainly, the life sciences industry has been experimenting with a variety of business and operating models to close the innovation gap. A number of performance indicators demonstrate the major problem for pharmaceutical R&D — a lack of productivity. The industry is developing fewer new molecular entities (NMEs) and the cost for each NME is increasing, whilst blockbuster drugs — the historical success recipe for the industry — are harder to identify and face significant reimbursement challenges. As a result, the industry is relying more on external molecules from smaller biotech companies as a source of new products. In addition, the increasing recognition of targeted therapies and ensuing patient subsegmentation leads to potentially lower approachable patient segments, but may offer predictive efficacy and potentially attractive pricing. Although accelerating, lack of R&D productivity is not an entirely new phenomenon and the industry has been trying to address this through a number of initiatives during the past two decades, including ‘silver bullet’ solutions, such as the omics, process re‑engineering, six‑sigma initiatives and adaptive trials, all of which have made an impact, but are insufficient to reverse the productivity trend. There is no single solution to address the current challenges; instead, a holistic approach is required to address the need for innovation. Specifically, companies must address all dimensions of pharmaceutical R&D productivity focusing on strategy, processes and organization, and funding for R&D.

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Strategy

Pharmaceutical companies need to develop more focused R&D portfolio strategies by targeting only those disease areas for which best‑in‑class or first‑in‑class assets can be developed. It is important for there to be less reliance on blockbuster drugs and business models that allow also for profitable smaller products. Innovation strategy must entail a willingness to go against the mainstream and avoid overly competitive areas.

Processes and Organization

The industry should abandon the fully integrated pharmaceutical company model. Instead, pharmaceutical companies need to embrace a model that manages their innovation processes through partnerships with clinical research organizations (CROs) for execution, and biotechs and venture capitalists for IP and innovative molecules.

Funding

Industry players should consider bringing in external investors, such as venture capitalists, to identify and co‑invest in the early pipeline, to increase the number of potentially available assets and share the risk. For large and risky late‑stage assets, the industry should consider co‑investing with venture capitalists, which increasingly need to develop a virtual and outsourced model of project finance, private equity and hedge fund investors. Another alternative would be to partner with some of the larger CROs that have developed investing initiatives to capture upside on their basic service model. This can help balance cash flow constraints for the late pipeline and minimize the impact of late‑stage failures on cash flow and stock price. In a period of uncertainty, the holistic approach may appear daunting. Yet, to remain competitive, pharmaceutical companies will be forced to evolve significantly or embrace new R&D models to address the current innovation dilemma.

November/December 2011

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November/December 2011

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DRUG DEVELOPMENT

PATHWAY TO EFFICIENT DRUG DEVELOPMENT

Despite efforts made in recent years to accelerate the drug‑discovery‑to‑commercialization process it still takes a considerable time. Meanwhile, the patent clock ticks inexorably away.

Dr Tony Flinn

For more information Dr Tony Flinn CEO Onyx Scientific

tonyflinn@onyx-scientific.com www.onyx-scientific.com

welve years or so to commercialize a new API leaves only 8 years to recoup the massive investment of $500 million per drug. The critical pathway throughout this process depends on different things depending on the stage a drug is at. Securing preclinical and clinical supplies of the API, however, should not be on the critical path; with good management it is possible to ensure that API supply is constant. It has been common to obtain early development quantities (grams to hundreds of grams) and later development quantities (kilos to tens of kilos) from different suppliers. Companies that are able to remain profitable through the smaller‑scale manufacture generally lack the ability to make the larger amounts of APIs. By contrast, those that specialize in, for example, Phase III supply and larger, have historically had no interest in the smaller‑scale supply. Why? First, the probability of a preclinical project reaching maturity and, therefore, being made in the larger supplier’s facilities is very low. Second, the larger‑scale supplier’s scientific staff has to support their plant work and projects close to commercialization. A downside of this is that both companies have to learn about the chemistry, to understand (in detail) and familiarize themselves with the the limits and parameters that the chemistry imposes. All this takes time — which might impinge on the critical path — and money. API synthesis of course doesn’t occur in isolation. The physical properties of the API — such as crystal and salt form, polymorph form — have to be optimized. Specialist equipment is usually required and scientific personnel are of different disciplines. This niche historically has also been the province of yet another company — one specializing in solid‑state work, not synthesis. The drug sponsor, therefore, has a major task simply co‑ordinating the activities of these two or three companies. When other suppliers, such as formulation development and drug product manufacturers, are taken into account, this becomes a major management headache. A fragmented supply side should not be unexpected. The different scientific disciplines that predominate in each service company will have separate origins. Expertise in a specific niche will naturally develop first. The decision to amalgamate different service offerings will have been the

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result of a deliberate decision. Consolidation of the fragmented pharmaceutical service industry into fewer players offering multiple services is a more recent development. Mergers and acquisitions are increasing among pharmaceutical supplier companies. Acquisitions in any industry are fraught with difficulties and frequently have a high failure rate. The same is true in the pharmaceutical supplier industry. There are examples where incorporation post acquisition has failed, such as Sigma Aldrich’s acquisition of Ultrafine, but happily there are significantly more successful examples to date, including Galapagos’s acquisition of Biofocus. Recently, Ipca Laboratories acquired Onyx Scientific to complement its contract manufacturing arm Covenance. By working in an integrated, unified and coherent manner, Onyx Scientific can now execute early‑stage programmes such as lead optimization, custom synthesis, process development and small‑scale GMP manufacturing before an internal tech transfer process to scale‑up, Phase II/III and commercial production. The concept of ensuring efficient and timely transfer from early development to manufacturing and remaining off the critical path of pharmaceutical development is very much about minimizing the amount of management time required by clients to drive the efficiency of the project. Merging service companies is fairly complex as the respective cultures of an R&D house are quite different from a large‑scale manufacturer. Drivers at the earlier stage include technology, speed and flexibility whereas at the larger‑scale they include quality and price. Thus the two sides operate to different motivators. Decisions at the R&D level can be made quickly and incorporated easily; decisions at the manufacturing level involve multiple specialists, working in committees to longer time‑scales, which are by comparison, relatively slow. Attempts to incorporate both cultures in both organizations are bound to fail. Those companies with successful solutions accept the differences that make each successful. Key to the successful incorporation of different services is good communication and effective project management. Good project management will ensure superior technology transfer processes and that the learning curve is traveled only once and that ultimately, a better and more efficient drug development pathway is provided.

November/December 2011

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November/December 2011

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DEVELOPMENT

DELIVERY

SUPPLY

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DRUG DEVELOPMENT

IMPROVING PRECLINICAL EFFICACY TESTING OF CANCER DRUGS USING PATIENT‑RELEVANT MODELS

Using new technologies and models, including 3‑dimensional multicellular systems, to increase development efficiency and reduce attrition rates.

etween 1995 and 2007, 77% of 800 cancer drugs that entered into Phase I clinical trials failed to reach the market as a result of inaccurate predictions of efficacy and/or toxicity.1 This high attrition rate amongst the cancer drugs calls for more advanced and challenging preclinical modelling for drug development. It is fundamental for cancer drugs entering clinical trials to demonstrate high levels of medical capacity and safety, whilst at the same time being cost effective.

The Limitations of Conventional Models

Animal cells or tissue have traditionally been used in the majority of the large pharmaceutical and biotech companies in the development of anti‑cancer medications. The majority of animal models, however, are not human‑relevant and, therefore, do not provide an accurate prediction of the true human pathophysiology. Methods that use nonhuman models are vulnerable to flaws, as they present no real semblance to disease progression in humans. In addition to the lack of constant response measurement using these current models, the biology of the cancer and/ or the target cannot be optimally simulated, meaning that new cancer drugs aren’t sufficiently challenged. As a result, false‑positive drugs can enter into clinical trials. To prevent irrelevant drug development results, new technology and models in both in vitro‑ and in vivo‑based systems are being created to obtain reliable preclinical efficacy assessment, which will, in turn, increase development efficiency and reduce attrition rates.

New Alternative Dr Rajendra Kumari

Reference

1. J. Fricker, et al., “Time for Reform in the Drug Development Process,” Lancet Oncology 9(12), 1125–1126 (2008).

For more information

Dr Rajendra Kumari Chief Operations Officer PRECOS enquiries@precos.co.uk www.precos.co.uk

Innovative approaches to assess efficacy optimally in patient‑relevant cancer models is urgently needed. An established approach is the development of cancer models derived from patients’ tumour tissue. Further development being made with this approach by modelling the human tumour micro‑environment in 3‑dimensional multicellular systems, which more intensely challenge the new therapeutic entity by incorporating relevant human cell types, including those associated with the tumour stroma. Unlike the current standards practised within the pharma and biotech industries, which provide analysis using monolayer single cell culture, this approach can provide more accurate predictions of clinical efficacy. The 3‑dimensional models produced using this approach, demonstrating human stromal epithelial interactions, can then be transplanted in vivo.

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Improved efficiency is offered via real‑time imaging through the utility of reporter systems, enabling continuous temporal information from a single experimental model. In addition, more robust statistical analysis can be gained from fewer experimental repetitions meaning that lower costs are incurred. The approach offers the potential for a more robust drug development process with micro‑environmental signal measurement, limited need for post‑test procedures and the use of medium throughout 3‑dimensional in vitro model screens, thus reducing the necessity for larger scale in vivo models in line with the 3Rs (replacement, refinement, reduction). This cutting‑edge approach, developed within an academic setting, offers the unique advantage of reducing the need for additional monitoring and post‑test procedures, and the use of expensive supporting technology whilst also having the capacity to ensure maximum data over a short time frame with the associated cost benefits.

The Advantages of Outsourcing

Based on IMS Health global sales forecasts for 2012, approximately 25% of the estimated $1.75 billion devoted to preclinical R&D is outsourced. It is becoming common practice for companies to outsource the development of patient‑relevant models to specialized service providers because of the numerous advantages they offer. Outsourcing provides time and cost efficiencies, as well as a stronger preclinical package for regulatory submission by pharma and biotech organizations. Furthermore, specialist providers can apply innovative technologies across all cancer types, benefiting the wider scientific community and, essentially, enabling new cancer drugs to reach patients sooner.

Conclusion

High cancer drug attrition rates, ever‑increasing R&D costs, and higher demand for regulatory and scientific accuracy are all elements of the current drug discovery landscape that call for patient‑relevant models. The new technologies that focus on the use of patient‑relevant models, designed to fast‑track new agents into the clinic, provide superior analysis to traditional preclinical models and reflect more closely the patient’s situation for each aspect of cancer progression. Outsourcing is increasingly used to provide time and cost efficiencies, and to facilitate regulatory approval of new drug candidates through effective and accurate predictions of drug behaviour in clinical trials.

November/December 2011

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LYOPHILIZATION

THE MOVE FROM ART TO SCIENCE The authors consider the evolution of lyophilization science and technology, with a special focus on three advances — tunable diode laser absorption spectroscopy (TDLAS), controlled nucleation and Quality by Design (QbD) development.

yophilization technology continues to advance as academicians, industry scientists and manufacturers of lyophilization equipment and analytical instrumentation discover and develop new approaches and methodologies. It was not too long ago that freeze drying involved cycles developed without the use of thermal analyses and freeze‑dry microscopy to optimize the formulation and cycle parameters. The advantages of cryo- and lyoprotectants were unappreciated. Product vials were loaded manually into the dryer chambers and the cycles monitored with thermocouples. Today, state-of-the-art technology involves automated loading and unloading systems without thermocouple monitoring. Much greater understanding now exists of phenomena such as heat and mass transfer, thermal history, microcollapse, relaxation enthalpy, amorphous‑crystalline transitions, dry layer

Figure 1: Schematic and photograph of TDLAS (courtesy of Mr William Kessler, Physical Sciences, Inc.).

resistance, choked flow, effect of cooling rate on ice crystal size and resultant dry product stability and reconstitution time. Development of lyophilization process cycles has definitely moved from an art to a more exact science. Improved technology and understanding continues to lead to advances in lyophilization science and technology, such as the three described below.

TDLAS

TDLAS is a new analytical tool for monitoring the mass flow and velocity of water vapour from the lyophilization chamber to the condenser.1–3 It uses optical methods to detect trace concentrations of water subliming during the primary drying cycle. Figure 1 shows a schematic of the instrument. TDLAS gives the instantaneous mass flow rate of water vapour moving from the chamber to the condenser of the freeze dryer, as well as the cumulative

Figure 1

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November/December 2011

LYOPHILIZATION

Figure 2: Typical product temperature profiles during cooling for uncontrolled (conventional) nucleation. Note the variability of nucleation (temperature quickly increases as a result of the release of heat during nucleation). Figure 3: Typical product temperature profiles during cooling for controlled nucleation.

Figure 2

Figure 3

mass of ice sublimed. TDLAS can provide accurate batch average product temperature data during primary drying, which replaces the monitoring of individual vials using thermocouple probes. TDLAS can also assist with a QbD approach to freeze‑dry cycle development and optimization, including measurement of vial heat transfer coefficient, resistance of the dried product layer to flow of water vapour and equipment capability. From this information, design space for primary drying can be established. TDLAS applies to both laboratory‑size and production‑size freeze dryers to facilitate cycle development and scale‑up. Other potential advantages of TDLAS monitoring of lyophilization cycles include

November/December 2011

• R educing uncertainty in cycle end point determination, thus reducing the need for overly cautious lengthening of primary drying times. • Q ualifying and comparing freeze dryers, to facilitate the establishment of freeze‑dryer equivalency. • Lyophilization cycle scale‑up and technology transfer if TDLAS monitoring is used both on laboratory‑scale dryers and production‑scale dryers.

Controlled Nucleation

Ice crystal nucleation is a stochastic process — it occurs randomly and high degrees of supercooling are common (Figure 2). Random ice nucleation contributes to process variability and inefficiency.

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LYOPHILIZATION Figure 4: Stepwise procedure of the QbD process.6

References

1. W.Y. Kuu, S.L. Nail and G. Sacha, “Rapid Determination of Vial Heat Transfer Parameters Using Tunable Diode Laser Absorption Spectroscopy (TDLAS) in Response to Step Changes in Pressure Set‑Point During Freeze‑Drying,” J. Pharm. Sci. 98(3), 1136–1154(2008). 2. S.C. Schneid, et al., “Non-Invasive Product Temperature Determination During Primary Drying Using Tunable Diode Laser Absorption Spectroscopy,” J. Pharm. Sci., 98(9), 3406–3418 (2009). 3. W.Y. Kuu and S.L. Nail, “Rapid Freeze‑Drying Cycle Optimization Using Computer Programs Developed Based on Heat and Mass Transfer Models and Facilitated by Tunable Diode Laser Absorption Spectroscopy (TDLAS),” J. Pharm. Sci. 98(9), 3469–3482 (2009). 4. A.K. Konstantinidis, et al., “Controlled Nucleation in Freeze‑Drying: Effects on Pore Size in the Dried Product Layer, Mass Transfer Resistance and Primary Drying Rates,” J. Pharm. Sci., 100(8), 3453–3470 (2011). 5. S.L. Nail and J.A. Searles, “Elements of Quality by Design in Development and Scale‑Up of Freeze‑Dried Parenterals,” BioPharm International 21(1), January 2008. 6. L. Mockus, et al., “Quality by Design in Formulation and Process Development for a Freeze‑Dried, Small Molecule Parenteral Product: A Case Study,” Pharm. Dev. Technol. 16(6), 549–576 (2011).

Ice crystals are smaller in vials that freeze rapidly once ice nucleates, as compared with those in vials that freeze more slowly. Smaller ice crystals mean smaller pores in the partially dried layer when the ice sublimes. Smaller pores mean higher resistance to flow of water vapour. Higher resistance to flow of water vapour means longer drying times. As the slowest vials to dry must govern cycle times, the variability caused by the stochastic process of ice nucleation leads to a cycle design that is suboptimal compared with what could be designed if all vials were to nucleate and freeze at the same time. Conventional lyophilization cycles freeze vials using a controlled cooling rate without pressure or vacuum. Control of nucleation is obtained by applying a pressure to vials that are cooled to a temperature below 0 °C and rapidly releasing the pressure to initiate nucleation. Rapid release of the pressure initiates nucleation in all of the vials at the same time (Figure 3). 4 Using sucrose as a model formulation, we have observed approximately 40% reduction in primary drying time when using controlled nucleation versus conventional freezing. Studies are currently being conducted to determine whether controlled nucleation can be a viable alternative to annealing by initiating nucleation of crystallizing components in the formulation.

QbD Development

The principles underlying QbD are not new. QbD involves the following components:5 • A formalized risk assessment process to identify the most important formulation and processing factors affecting product quality. • U tilization of prior relevant knowledge wherever possible. • A systematic experimental approach intended to place appropriate limits on key formulation and process variables. • D eveloping an understanding of equipment capability. • I dentification of appropriate formulation and process design spaces. Mockus, et al . published a case study to illustrate a QbD approach to developing a freeze‑dried parenteral product using actual development data, whereby an existing small molecule product (formulation and process) has been redeveloped by applying QbD principles.6 Their work now gives pharmaceutical development scientists a concrete example of the work process and the experimental approach employed. An overview of the work process is illustrated in Figure 4. A key feature of this approach is that it combines prior knowledge, preliminary experiments, and a formalized risk assessment process. Use of prior knowledge makes experimentation much more

Figure 4

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November/December 2011

LYOPHILIZATION

we have observed approximately 40% reduction in primary drying time when using controlled nucleation versus conventional freezing.

efficient than the blind application of design of experiments (DOE), for example. This is particularly important in freeze drying, as there is a wealth of published information within the past 30 years on such topics as the physical chemistry of freezing, materials characterization, heat and mass transfer operations, and process monitoring and control that apply to all formulations and container systems. This means that construction of the process design space can be largely a process of calculation, using key measured parameters such as the maximum resistance of the dried product layer, the vial heat transfer coefficient and the maximum allowable product temperature during primary drying. These three advances, plus others not discussed in this brief article (for example, new one‑step liquid to powder transfer devices; dual‑chambered devices; lyophilization cycles performed above product collapse temperatures; and new analytical methods for headspace analysis, collapse temperature determinations and protein–excipient interactions) exemplify the continual evolution of lyophilization technologies in the development, manufacturing and improved quality of freeze‑dried medicines.

For more information Steven L. Nail Principal Scientist

Gregory A. Sacha Senior Research Scientist Wendy Saffell-Clemmer Director Lisa M. Hardwick Research Scientist I Michael J. Akers Senior Director BioPharma Solutions Baxter International Inc. www.baxterbiopharmasolutions.com

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PERSONALIZED MEDICINE

TAILORED OPPORTUNITIES

The future of personalized medicine offers a lifeline not only to specific patient populations, but also to companies looking to rescue ‘failed’ therapeutics and extend patent exclusivity.

he prospect of personalized medicine offers significant benefits to patients and to companies that develop and market therapeutics. The term ‘personalized medicine’ is commonly used to describe a particular therapeutic or its dosage that has been individually tailored for specific patient populations based on shared genetic characteristics. Detection of such characteristics, often referred to as ‘biomarkers,’ enables doctors to more effectively assess the suitability of a particular therapeutic intervention. Equally important, drugs that have been removed from the market as a result of safety or efficacy concerns may be rescued by identifying patient subpopulations, defined by particular biomarkers, that exhibit desirable safety and efficacy profiles. Personalized medicine also offers opportunities for additional patent exclusivity relating to the identification and use of novel biomarkers, although recent legal developments have created uncertainties concerning such exclusivities.

New Products

Many companies are already taking advantage of the potential of personalized medicine when developing

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new products and new methods of treatment. To date, a number of medicines have been developed to treat specific populations identified by one or more biomarkers; for example, Gleevec (imatinib), a treatment for chronic myeloid leukemia (CML). Gleevec specifically inhibits the BCR‑ABL tyrosine kinase generated by a particular chromosomal fusion and thus, is only indicated for patients who carry that particular chromosomal fusion. Novartis, the company that markets Gleevec, is further refining the CML patient subpopulation that is capable of responding to Gleevec by developing tests that identify specific mutations in the BCR‑ABL kinase that render the medication ineffective. Another example of a therapeutic developed for a particular patient population is Herceptin (trastuzumab) — a humanized monoclonal antibody that specifically binds to the tumour cell surface receptor HER2. Herceptin is only indicated for patients with breast cancer that over-expresses HER2, as others would fail to gain any therapeutic benefit from the administration of Herceptin.

Companion Diagnostics

Diagnostic biomarker tests, or ‘companion diagnostics,’ are often used in tandem with personalized medications to identify the patients who should receive these medications. For example, FDA recently approved Zelboraf (vemurafenib), a drug to treat patients with metastatic or unresectable melanoma, along with its own companion diagnostic. The drug was only tested, and is only approved, for the treatment of patients with melanoma whose tumours express the BRAF V600E gene mutation, as Zelboraf functions by inhibiting the protein produced by this mutation. Along with the drug, FDA approved the cobas 4800 BRAF V600 Mutation Test, which determines whether a patient’s melanoma cells have the BRAF V600E mutation. Another example is Ziagen (abacavir), an HIV treatment, which although is effective, can cause severe and potentially life‑threatening reactions in some patients. To address this, a companion diagnostic has been developed to test for the antigen allele HLA‑B*5701, which correlates with the adverse reactions. The companion diagnostic effectively increases the safety of the medication, as the population that receives it is prescreened to remove those who are likely to suffer adverse effects.

November/December 2011

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PERSONALIZED MEDICINE pursue a new clinical trial for treatment of metastatic breast cancer on patients with high levels of VEGF‑A in their blood. If this trial is successful, Genentech may be able to re‑introduce the drug for breast cancer in the defined subpopulation.

Additional Patent Exclusivity

Jennifer Gordon

Rescuing Therapeutics

For more information Jennifer Gordon Partner Baker Botts

Personalized medicine may also be a way for companies to rescue therapeutics that are failing to meet required safety and efficacy endpoints during early clinical trials. In the past, if a therapeutic was shown to be unsafe or ineffective in a clinical trial, a company would often have little choice but to abandon it. Today, that company can identify those patients within a trial that respond well to the therapeutic and continue its development by focusing on patients having biomarkers that correlate with responsiveness. Similarly, a drug that had previously been approved, but was subsequently removed from the market for safety or efficacy concerns, could be re‑evaluated and re‑introduced by identifying a subset of patients that respond to a medicine even if that medicine ultimately failed to prove effective for the general patient population. A recent example of this approach is Avastin (bevacizumab). Avastin is a humanized monoclonal antibody that had been FDA approved for the treatment of certain types of cancer, including breast cancer. On 30 June 2011, an FDA panel unanimously voted to revoke the approval of Avastin for breast cancer, noting that postapproval studies found that the drug was ineffective for this indication. FDA revocation means that Avastin can no longer be marketed for this indication, insurance will no longer pay for Avastin for breast cancer patients and most doctors will likely stop prescribing it for this purpose. Genentech, which markets Avastin, subsequently announced that it would

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Personalized medicine can have a significant impact on patent life cycle management. Because companies may be able to take a therapeutic indicated for a general population and demonstrate that it works for a subpopulation with a particular genotype, they may be able to file for patents concerning the treatment of the subpopulation. For example, in some instances, the methods and biomarkers may be unexpected, which may support a patent filing on the new method or biomarker. As these patents are typically filed after the underlying therapeutic product has been patented, they will likely expire later and thereby lengthen the period of time that a company has patent protection associated with a particular therapeutic. There have been several recent legal developments concerning the availability of patent protection for isolated nucleic acids, which are often used as proxies for biomarkers and diagnostic methods that make use of biomarkers. The Federal Circuit, which is the court of appeals for patent cases, held that isolated nucleic acids are patentable in Ass’n for Molecular Pathology v. US Patent and Trademark Office (commonly referred to as ‘Myriad’). The Supreme Court has agreed to review an earlier Federal Circuit case finding that diagnostic methods were patentable, Prometheus Labs., Inc. v Mayo Collaborative Servs. The Supreme Court’s decision in Prometheus will likely provide additional clarity on whether and what types of diagnostic methods may be patented. In addition, it is possible that the plaintiffs in Myriad will ultimately file a petition for the Supreme Court to review the case. Thus, although the Federal Circuit cases are currently favorable to diagnostic methods and techniques, it may be several years before the law in this area is settled.

Conclusion

Personalized medicine holds great promise for patient care. It can allow doctors to prescribe therapies to which patients are more likely to respond, and doctors can avoid wasting valuable time with therapies that are likely to offer little or no benefit. In addition, personalized medicine will almost certainly allow for more informed decisions by our drug approval agencies as to the therapeutic value of certain medicines. Yet, given uncertainties in the legal environment for biomarkers and diagnostic techniques, biotechnology and pharmaceutical companies will have to carefully consider their patent filing strategies to obtain robust protection for inventions in this context.

November/December 2011

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BIOTECHNOLOGY

REACTING TO DEMAND Broad adoption of single‑use bioreactors awaits fully scalable GMP systems, improved and less costly disposables, better analytics, greater process automation and low shear mixing.

lobal biopharmas are embracing single‑use bioreactors for use in R&D to good manufacturing practices (GMP) production to gain operational flexibility, to create rapid capacity gains, bioprocess efficiency, to drive out operational costs and accelerate time‑to‑market for a wide range of biologics. Today, cell cultures for both mainstream and pipeline drugs, and vaccines are being rocked, stirred, mixed, perfused and harvested with increasing regularity at all stages of the bioprocess using single‑use systems, which are taking market share daily from traditional glass and stainless steel bioreactor systems. Competition is now heated and aggressive across continents for accelerating new pharmaceutical products, including biosimilars, to market globally. Innovative modular and easier‑to‑use platforms and technology are emerging that will offer better tools and performance for biopharmas, and an economical approach to meeting production needs. “Compared with conventional bioreactors, single‑use bioreactors are relatively easy to manufacture, as well as disassemble,” said Krishna Venkataramani, research

analyst at Frost & Sullivan. Single‑use bioreactors “are set to revolutionize the biotechnology industry and represent its future,” he added.1 Integration of single-use bioreactors — which use hardware and software control systems similar to their predecessors, and single‑use or disposable bags, vessels and containers — is providing innovative and early adopter firms with these new levels of value. Even so, the technology has yet to be fully exploited, as it needs to cross the technology chasm into fully mainstream user application. Many single-use bioreactors are throwbacks to traditional stainless units with limitations in efficiency, usability, mixing performance, maintenance and scalability. Moreover, costly and less than robust disposable bags, expensive tubing and filters, large and multicomponent products, complex control systems, fluctuating operating performance, few quality disposable sensors and erratic postsales technical support are stifling faster and broader acceptance. At this early stage of the industry’s history no one firm dominates the market. Although single-use bioreactors systems are starting to force out T‑flasks and glass systems at the upstream

Figure 1: Industry adoption of large volume single-use bioreactors up to 2000 L for production will signal mainstream use and accelerate sales to global biopharma firms. This graph shows projected revenue for lab, seed train and cGMP production subsegments. Source: PBS Biotech

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November/December 2011

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

Simply a question of

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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.

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BIOTECHNOLOGY

Figure 2: The past three decades have seen pharma advancements in process tools and automation including single-use bioreactors that help to improve product quality whilst reducing cost of manufacturing per gram of product.

screening and lab‑level bioprocess stages they face potential premature commoditization by the lack of differentiation and price pressures. This year, several new single‑use bioreactors below the 50‑L scale entered the market with various agitation systems ranging from traditional motor‑driven stirred tank units, paddle‑based mixing, a mixing cube, a shaker device and a fully integrated and novel Air Wheel mixing system offering low shear and fully scalable products from lab to production. Laboratory, process development and preclinical‑stage users have many choices in single‑use bioreactors. Conversely, there’s a dearth of suppliers, as well as reliable, fully scalable systems and technology, for above 50‑L volume levels. The barrier to entry at this level is higher given the design size challenges for both bioreactors and disposables, and the need for rapid homogeneous mixing, bioreactor design limitations, external impeller mixing systems, robust operation and high mean time before failure (MTBF) levels, and complex Performance Qualification (PQ) and GMP certifications. Only a handful of single-use bioreactor firms can support the complete lab to production linear scale‑up. This is an emerging market segment, which has pent up demand, but which is currently underserved. Only Thermo Fisher, Xcellerex, Sartorius Stedim and PBS Biotech offer large‑scale systems with 500‑L (or higher) working volume. It is this segment of the market that holds the most promise for rapid adoption and growth, which occur when larger biopharmas make the shift from embedded stainless to single‑use in both new and retrofit production sites.

Major Growth Industry

Even with the noted limitations, the market for these single‑use bioreactors is expected to grow at rate of 21%

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per year or as high as 40% annually for the next decade and topping $1 billion in annual sales by 2017.2 Inherent advantages, including mitigation of cross‑contamination, faster campaign turnovers, huge cost savings in capital equipment and recurring costs (such as utilities and labour), compared with stainless bioreactors are accelerating product trials and adoption at the lab to clinical level (Figure 1). FDA is a single-use champion. At the BioProcess Systems Alliance (BPSA) conference in Washington last July, David Doleski (acting branch chief, New Drug Manufacturing Assessment Branch Office, Office of Compliance of FDA), indicated his agency would not be providing formal guidance on single‑use; but he underscored the value gained through mitigation of cross‑contamination and industry cost savings.3 He cited the advantages as • Reduced need for cleaning and sterilization systems and validation. • Reduced risk of cross-contamination. • Improved containment. • May allow greater control of aseptic operations. Doleski urged industry suppliers to thoroughly test their systems following 21 CFR § 211 and 21 CFR § 600, particularly disposable bags and containers to ensure high quality, and predictable and repeatable performance. He also said it was the supply chain’s challenge to educate the user community on single‑use quality metrics and processes to forge industry/vendor partnerships to include vendor/material qualification considerations, manufacturing agreements, vendor audit, notification of product changes, certificate of analysis for endotoxin, particulates and bioburden. The 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production reports 36% of

November/December 2011

BIOTECHNOLOGY respondents said single‑use bioreactor adoption as seed reactors was top choice for them in the past year followed by nearly 33% saying single‑use production bioreactors were purchased during the past 12 months.2 In 2011, the report indicates the average contract manufacturing organization (CMO) will spend more than $160,000 per facility on single‑use bioreactors and innovator firms will spend approximately $150,000 per facility.2 The survey also indicated customers were focused on using single‑use in rank order for 1) productivity gains, 2) cost cutting, 3) production quality, 4) and to improve employee performance. Single-use vendors were graded high for providing customer satisfaction for quality of product and strength of product, yet received low marks on ability or willingness to provide custom design of systems. This trend toward single-use is increasing as the biopharma world shifts to non‑blockbuster drug development requiring smaller and more cost‑effective runs. The capital costs of a 500–2500‑L stainless system is approximately 3–5 times that of a single‑use alternative and the 10‑year annualized operating cost is 50% less per year using a single‑use bioreactor platform. Customer adoption of single-use bioreactors at large scale is all about saving money, curbing cross‑contamination whilst producing high‑quality products. There is every reason to believe that the commercial bioprocessing facility of the future will be primarily single‑use. Just a few years ago, 1 g/L was the benchmark titer for monoclonal antibody production. Today, titers of 7 g/L in fed‑batch are routine and cell culture titers of >10 g/L are being achieved . . . and potential exists to double that number soon (Figure 2). As such, a 2000‑L single‑use bioreactor becomes very cost effective, producing 7 g/L or 200 kg of purified drug substance per year compared with 1 g/L from a 10,000 L stainless system.4

Both established biopharmas and those in emerging markets consider single‑use bioreactors as a way to design and commission factories and labs quickly, reduce out‑of‑pocket costs, and get new drugs and vaccines, orphan products and even biosimilars requiring lower volume production runs to market quicker and cheaper. The savings go to the bottom line. CMOs, contract research organizations (CROs) and biotech start‑ups are major single‑use bioreactor advocates, as the systems help them to become more flexible and efficient, reduce machine dependency, attract and serve more customers as they accelerate product development, save on both fixed and variable costs, and gain competitive benefit. Estimates suggest that more than 35% of the total addressable market (TAM) currently uses one or more single‑use bioreactor systems and in excess of 70% of current global labs and research centres, including academia, use at least one single‑use bioreactor. As noted the majority are R&D, seed and clinical systems, with large numbers of scientists, techs and engineers using a rocking type mixing system to complement a wide range of ageing glass and stainless steel units. A canvassing of typical laboratories today will see a patchwork quilt of units with every brand represented yet limited interoperability, scalability or cost benefit. Hence tier 1s (the top 100 pharmas and biotechs in the world), small and medium enterprises (SMEs), as well as CMOs, CROs and biotech start‑ups, are looking to employ a more flexible, scalable and generally better suite of bioreactor tools.

Single-Use Bioreactor Solution

Companies keen to adopt single‑use bioreactors need to be discerning and have a good understanding of how to migrate to gain maximum benefit and mitigate risks. Typically, biopharmas using single‑use pursue one of two routes. One is discrete solutions at the lab and other

Figure 3: Low profile, fully scalable single-use bioreactors permit rapid design and commissioning of lab, seed train and production facilities, thereby saving millions in CapEx and operating expenses.

November/December 2011

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BIOTECHNOLOGY

Figure 4: A handful of single-use bioreactor makers provides a broad range of bioreactors for a fully scalable solution for a wide range of applications.

nonGMP levels. In this case, the installation of single‑use bioreactors overhauls an existing facility that has older bioreactors of typically every type, make and model (Figure 3). With time, a company procures a variety of equipment, but new applications, processes and product development demands indicate the configuration can no longer meet the efficiency, flexibility, scalability and reduced operating budgets of the business unit. Tier 1 reagent facilities, labs and process development (PD) sites are making the transition to single‑use and are selecting one or two vendors with systems ranging from nanobioreactors for screening to bench‑top 3‑L up to 200‑L systems to create a state‑of‑the‑art, modular and scalable facility to meet internal and external customer needs. They must work with many sensors, biomass systems, perfusion devices, probes and cell density units. Fully automated, remote monitoring and configuration, legacy OPC (OLE [Object Linking and Embedding] for Process Control: a programming interface for controlling multi units or systems from a central software system) for compatibility and modular systems are preferred. Conversely, for clinical development to production, larger volume units between 200 L and 2500 L are needed. These systems must be fully cGMP ready. The best solution for process development, scale‑up and production is a holistic approach, which uses a common mixing mechanism — preferably low shear — from lab to production to create high cell culture growth and viability performance (Figure 4). Each route has its advantages and challenges, and in the US and Europe, for example, either solution is created by means of moving steadily from a legacy position to a hybrid and then a fully single‑use environment. Many firms, particularly CMOs, biotech start‑ups and early adopter tier 1 and tier 2 firms, are now choosing single‑use in new facilities, bypassing costly traditional glass and stainless systems. This is especially true in emerging

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markets where legacy equipment is limited, and cost savings and time‑to‑market are critical. In a numerous cases, biotechs have chosen and integrated single‑use bioreactors from lab to seed, pilot to production, particularly where manufacturing runs are smaller and require GMP bioreactor sizes <2000 L working volume.

Meeting Industry Needs

Pharmas planning to implement single‑use systems or expand existing operations should consider the following platform requirements — regardless of volume — from their suppliers before conducting a product trial or making a procurement decision: • State‑of‑the‑art electronics, controllers and software, modular and upgradeable. Don’t compromise by selecting antiquated control systems and complex, labour‑intensive software packages. • Fully integrated system with controller, displays, bags, vessels and software housed in a single low‑profile unit. Mobile on wheels and casters for easy movement between lab and production suites. Total unit heights for large‑scale units of <12 ft (3.6 m). • Capable of working with a wide range of reusable and disposable sensors, probes and analytics. It’s not cost effective to extend the life of aged equipment by adding new sensors. • Lowest shear possible mixing mechanism, which promotes the broadest range of applications across mammalian cells and for adherent cells on micro carriers. Many traditional mixing mechanisms deliver lower cell growth and viability performance, as cell lines and media need to be made more shear tolerant to accommodate pressure vessel style impellers and geometries. • Minimum mechanical parts and motors, which add costs, weight and create reliability issues.

November/December 2011

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BIOTECHNOLOGY

Figure 5: Disposable bags and vessels for single-use bioreactors meeting USP Class VI requirements. They are robust, easy to handle and provide high cell density growth and viability performance, which are key to broad industry use. Photo courtesy of PBS Biotech

James B. Schultz

References

1. www.frost.com/prod/ servlet/press-release. pag?Src=RSS&docid =243015623 2. BioPlan Associates, 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (April 2001). 3. D. Doleski, “Regulatory Perspective on the Adoption of Single‑Use Technologies,” BPSA International Single‑Use Summit (Washington, DC, USA, 28 July 2011). 4. www.pharmpro.com/ articles/2010/03/ biopharmaceuticalprocessing-Single-UseTechnology-Where-has-itbeen-where-is-it-now-andwhere-is-it-going

For more information James B. Schultz Vice President Sales & Marketing PBS Biotech, Inc. www.pbsbiotech.com

• Intuitive operation and easy to set up and operate regardless of volume or application. • Remote internet/intranet connectivity for monitoring, alarm management and configuration. • Capable of running batch, fed batch, perfusion and transient transfection processes. • Backed by solid postsales service and support. • USP Class VI plastic materials and fully tested, improving the strength and reliability of bags (Figure 5). • Leachable and extractable (L&E) data and supplier ‘ownership’ of the materials, and disposable construction to ensure high performance, lot build and supply chain traceability. • Documented with installation qualification/operational qualification (IQ/OQ) and Validation Guides, and the supplier must support the customer’s PQ, factory acceptance test and site acceptance test requirements. For L&E studies and supplier documentation, FDA suggests the following: • Extractable data from vendors. • Testing with model solvents. • Cumulative effect of all manufacturing equipment. • Manufacturing process parameters (for example, temperature, pH, pressure, time). • Risk assessment. • Leachable study. • Product compatibility. The concern of sole source is also escalating as customers invest heavily in one supplier to provide both unique bioreactors, and custom disposable bags and containers. This challenge is well known and managed in other

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industries with mission critical equipment, and solved by ensuring the supplier–buyer agreement is not an arm’s length contract, but a partnership. A product development arrangement is often created with the single‑use bioreactor firm providing extensive design and post‑integration engineering and bioprocess support to the customer. Many options also exist to escrow technology in case of default and to develop long‑term strategic alliances that mitigate risk, and promote innovation and risk management. In addition, pharma companies want single‑use bioreactor suppliers to improve the overall performance, reduce the costs of disposable bags and vessels, and provide for quick turnaround and custom designs of disposables to meet new applications. This requires rapid configuration of ports, connectors, probes and sensors, product acceptance, disposable production, test and delivery. Single-use bioreactors are the way of the future in lab to production for biopharma applications for mAbs, therapeutic proteins, vaccines, viral expansion, stem cells, personalized medicines and biosimilars. New and more innovative designs, mixing, and ease of use and fully scalable systems from lab to production will accelerate adoption. Regulatory agencies such as FDA support single‑use as a game changer to reduce contamination hazard, promote faster campaign times and reduce costs. Within the next 5 years, single‑use bioreactors will permeate the biopharma landscape as material standards are developed, new mixing technologies emerge and become common place, and both disposable and bioreactor systems prove robust and efficient tools in the full range of the bioprocess.

November/December 2011

STRAP

November/December 2011

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LEGISLATION

GIVE AND TAKE THERE IS NO COMPROMISE The pharma industry is not immune to the recently enforced Bribery Act 2010. The authors provide some practical advice for pharmaceutical companies seeking to manage their risks in relation to the corporate offence with the legislation.

he Bribery Act 2010 (the “Act”) came into force in July 2011 and brought with it wide‑ranging powers to enable UK prosecutors to combat bribery and corruption. Significantly for companies, the Act also introduces a new corporate offence, which will only be defensible if adequate procedures to prevent bribery and corruption have been put in place. The corporate offence targets companies that fail to counter the culture and practice of bribery by making them strictly liable for the actions of their officers, employees, agents and any other associated person (someone who performs services on behalf of the company). Whether such a person is ‘associated’ is to be determined by “reference to all the relevant circumstances and not merely by reference to the nature of the relationship” so that the strictly legal capacity under which an individual performs the services does not matter.1 The bribe that gives rise to such criminal

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liability can occur in the UK or anywhere in the world where the person concerned has a ‘close connection’ with the UK, thus significantly extending the reach of the Act. The Act covers both the private and public sector, and creates a criminal offence that goes in some ways beyond the US’s Foreign Corrupt Practices Act (FCPA) in its scope. For instance, unlike the FCPA, the Act does not provide an exemption for anything akin to a “facilitating payment” for “routine government action.” The penalties for bribing another person, being bribed and bribing a foreign public official are punishable either by unlimited fine, imprisonment of up to 10 years or both.

Bribery and Corruption in the Pharmaceutical Industry

Allegations of corrupt practices are not uncommon in the pharmaceutical industry. The World Health Organisation (WHO) estimated that fraud and abuse

November/December 2011

LEGISLATION in healthcare costs individual governments as much as $23 billion per year.2 WHO observes that alleged unethical practices in the medicines supply chain can take many forms, such a falsification of evidence, mismanagement of conflict of interest or bribery. Examples of such allegations include conducting clinical trials without regulatory approval, selecting a nonessential medicine for the essential medicines list and promoting the excessive use of medicine to increase profits. In relation to bribery, WHO states that there are risks — corruption occurs throughout all stages of the supply chain, from R&D to dispensing and promotion, and results in the loss of enormous amounts of public health resources. WHO estimates that 10–25% of public procurement spending, including on pharmaceuticals, is lost to corruption each year. The fact sheet comments that in developing countries such loss of procurement and operational costs can be as much as 89%. WHO believes that to reduce corruption, thorough checks are required at each step of the supply chain. It further states: “ … good governance, transparency, accountability, promoting institutional integrity and moral leadership are also essential.”

Memorandum of Understanding

In the light of the particular uncertainty created by the Act in relation to hospitality, gifts and other inducements to healthcare professionals, the pharmaceutical industry welcomed the Memorandum of Understanding (MOU) agreed between the Association of the British Pharmaceuticals Industry (ABPI), the Prescription Medicines Code of Practice Authority (PMCPA) and the Serious Fraud Office (SFO). The MOU highlights how SFO intends to act in relation to breaches of the ABPI’s code of conduct. In it, there is a general acceptance that although sensible proportionate promotional expenditure is valid and not prohibited by the Act, and that SFO “will not routinely intervene in matters covered by the code,” it “reserves the right to take action if the issue is deemed serious enough to merit SFO investigation.” The MOU makes it clear that SFO is supportive of pharmaceutical companies’ self‑regulation approach and that SFO will not routinely intervene in matters covered by the Code or seek to prosecute unless it considers that this is in the public interest to do so.

Managing the Risks — Practical Measures

Practical advice on bribery risk management was provided in the guidance on the Act issued by the Ministry of Justice, which summarizes the measures that should be considered to ensure compliance with the Act.3 These include polices, hospitality, contractual safeguards, due diligence procedures, accounts and audits, monitoring and review, and whistle blowing procedures.

November/December 2011

Policies

It is important to maintain bribery prevention policies that are proportionate to the scale and complexity of the company’s activities. Such bribery prevention policies should have detailed procedures and controls for dealing with political contributions, charitable donations, sponsorships, facilitation payments, gifts, hospitality and travel expenses. Companies should be obliged to ensure that such policies are communicated to all their employees, business partners and other associated persons, and embedded within all training activity. Theses policies should be communicated through the staff intranet, through direct written communication or at trade fairs. Senior management should support such policies and help to establish an organization‑wide culture in which any form of bribe and/or behaviour may be construed as unacceptable.

Paul Ranson

Hospitality

The guidance states that bona fide hospitality, promotional or other business expenditure is acceptable, as it is an important part of doing business. Such expenditure, however, must be reasonable and proportionate. Companies should, therefore, consider what kind of hospitality, promotional and other expenditure would be proportionate and reasonable when it is offered by and to their employees, and the companies’ stance on such expenditure should also be recorded in a written policy.

Sharmela Thevarajaha

Contractual Safeguards

Companies are recommended to ensure their contracts, whether these are with employees, distributors, suppliers or other business associates, have antibribery provisions prohibiting any form of bribery. Such antibribery provisions would, for example, • Require the other party to comply with the Act. • Specify to not do any acts or omissions in contravention of the company’s antibribery policy. • Require the other party to provide an indemnity to the company in the event of its breaching the antibribery clause. • Permit the company and its third‑party representatives, access to and take copies of the party’s records and any other information, and to meet with the party’s personnel to audit the party’s compliance with its obligations under the antibribery clause. • Ensure that any subcontracts entered into by the party with a third party reflects the antibribery clause as set out in the agreement and that the company is provided a copy of such subcontract.

Antonina Nijran

Due Diligence Procedures

Due diligence procedures are also crucial to minimizing risk and accordingly, new employees, new business associates, new acquisitions and any overseas

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LEGISLATION

European pharmaceutical companies might be required to adapt also to the US model sooner rather than later.

References

1. www.legislation.gov.uk/ ukpga/2010/23/contents 2. www.who.int/mediacentre/ factsheets/fs335/en/index.html 3. www.justice.gov.uk/ guidance/docs/bribery-act2010-guidance.pdf 4. Cegedim Relationship Management, “2010 European Trends in Aggregate Spend, Transparency, and Disclosure,” November 2010.

For more information

Paul Ranson Partner Fasken Martineau DuMoulin LLP and Fasken Martineau Tel. +44 207 917 8624 pranson@fasken.co.uk Sharmela Thevarajaha Associate Fasken Martineau LLP Tel. +44 207 917 8675 sthevarajaha@fasken.co.uk Antonina Nijran Associate Fasken Martineau LLP Tel. +44 207 917 8587 anijran@fasken.co.uk www.fasken.com

jurisdictions in which business is to be transacted should be thoroughly reviewed for any risk of bribery. Companies could use a number of measures to review the bribery risk level including • Assessing the reputation of the other party and uncovering any previous allegations or reports of bribery. It is important to discuss with the other party its general approach for reducing bribery, and review copies of any compliance policy or materials and the procedures they have in place to combat bribery. • Undertaking a country risk review to assess how prevalent bribery is in that country, if a company’s services are to be provided or goods are to be supplied in a particular country. • Ensuring that the transaction is reviewed thoroughly to ensure that the transaction avoids potential bribery situations. • Evaluating business opportunities and determining whether they appear unusually profitable or unusually low in value, or lack a clear objective, as these factors may increase a transaction’s bribery risk profile.

Accounts and Audits

Companies should establish checks on accounting and record‑keeping practices to ensure that no improper payments are made to third parties. Financial audits may reveal fraud or corruption — examining financial records provides assurance that the financial statements are not misleading and present fairly the economic transactions of the company in accordance with an accounting framework.

Monitoring and Review

Companies are encouraged to undertake internal and external risk management reviews on a periodic,

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informed and documented basis. In relation to internal risk, companies should consider whether any internal structures present a risk, such as a bonus culture that rewards excessive risk taking, failure to implement the components of an effective compliance programme or failure to provide training particularly to employees who might operate in high risk areas of the business such as sales force and procurement personnel. In relation to external risk, companies should review the risk of bribery in the countries in which they operate, such as whether facilitation payments are accepted practice in that country and whether they have adequately vetted any agents and intermediaries that the companies use in those countries.

Whistle Blowing Procedures

Companies are recommended to establish a contact point for employees to obtain advice or raise concerns without the risk of reprisal. There should also be a whistle blowing procedure that employees can use to report bribery. Bribery investigations procedures should be established such that a suitably qualified and impartial person can investigate any incident of alleged bribery.

Conclusions

The initiatives recommended by the Ministry of Justice should go some way in helping pharmaceutical companies to establish mechanisms to help prevent bribery and corruption in their business. The regulatory activity in this area suggests that the obligations and duties on pharmaceutical companies to prevent bribery and corruption will increase in the coming years. Interestingly, the developments in the UK emerge at a time when the US is preparing for even stricter transparency legislation in the form of the Sunshine Act, which is due to come into force in the US in 2013. This requires US companies to proactively disclose a large amount of information regarding every aspect of healthcare practitioner and organization spend. Some recent changes brought in by the new ABPI Code, which will come into effect from 2013, suggest the UK is already moving in the same direction as the US. Pharmaceutical companies will be required to collect and declare, annually, total amounts paid to health professionals and others for services, such as speaker fees and participation on advisory boards. Companies will also be required to declare sponsorship for attendance at meetings organized by third parties. A Cegedim survey of regulatory compliance trends observed that European pharmaceutical companies might be required to adapt also to the US model sooner rather than later.4 If, as it is suggested in the survey, Europe is 3–5 years behind the US on compliance issues, then the UK’s new bribery laws could just signal the beginning of an increasingly stringent and tough era.

November/December 2011

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November/December 2011

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LEGISLATION STRAP

THE SPC REGIME A MINEFIELD FOR THE PATENTEE After providing a brief background to the Supplementary Protection Certificate (SPC) Regulation and regime, the author considers the areas in which uncertainty has arisen, and the consequences that these uncertainties have had on the Regulation achieving the purposes that gave rise to its enactment and, more practically, the impact that these uncertainties are now having on patentees and the SPC application process.

lmost 20 years ago the EU introduced a regulation that provided for an extension to patent protection for pharmaceutical products placed on the European market (“the Regulation”). This extension was to compensate pharmaceutical patentees for the reduction in time they had to exploit their patents as a result of the completion of the complex clinical trials required before the patented pharmaceutical could be placed on the European market. In addition to restoring lost monopoly time, the Regulation was required to address an imbalance between Europe, Japan and the US in patent protection for pharmaceuticals, as the latter two territories already had patent ‘restoration’ legislation. When the Regulation was proposed there was a fear within the European Commission that this discrepancy was

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leading to a decline in R&D within Europe, and thus a decline in the European pharmaceutical industry. Thus was born the SPC. SPCs are intended to provide a patent term extension for patent-protected drugs, but only for a single patent per drug, only for a limited period and only to the extent that the patent protects the drug placed on the market; that is, the extension would not apply to analogues or other compounds that are also protected by the basic patent. The protection to be awarded under an SPC was thus seen as important for ensuring the continued success of the European pharmaceutical industry. The costs of R&D and clinical trials to bring a drug to market needed to be recovered to encourage continued investment and innovation. As reflected in the recitals to the Regulation, the concept was not just in the interests of the pharmaceutical industry,

November/December November/December 2011 2011

LEGISLATION but also in the interests of public health, as pharmaceutical companies may be encouraged to undertake further research if the high research costs could be properly recovered. Although one might expect such historical reasoning to be consigned to a footnote of modern legal interpretation, deficiencies in the drafting of the Regulation highlighted by a rush of recent cases before the Court of Justice of the European Union (CJEU) have brought the fundamental purposes of the Regulation back into focus. Under the terms of the Regulation, obtaining an SPC appeared to be quite straightforward: • The patentee had to hold a ‘basic patent,’ which protected an ‘active ingredient’ (or combination of active ingredients) of a ‘medicinal product.’ • The medicinal product must have been authorized to be placed on the market in accordance with relevant EU regulatory regime and the approval must be the first such authorization. • The application for supplementary protection was to be made on a territory-by-territory basis, and had to be made quickly — within 6 months of authorization or the grant of the relevant patent. • The period of the extension was to be determined by the date of filing of the relevant patent and the date of the first authorization to place the medicinal product on the market in the Community. It is equivalent to an

extension of the number of years between filing the patent and the grant of the marketing authorization, minus 5 years. The term was capped at 5 years. Thus, a 6‑year delay between patent filing and regulatory approval would result in a 1-year term of the SPC, whereas a 12-year delay would result in a 5-year term (not 7 years). • The scope of the prolonged protection was limited to the medicinal product and any authorized use of that product (rather than simply extending the patent itself). • For the patentee to be entitled to an SPC the active ingredient (or combination thereof) must not have already been the subject of a certificate. Reflecting the apparently simple regime set out in the Regulation is the application form for an SPC which consists of just a few pages, with boxes to be completed setting out the name of the applicant, the publication number of the basic patent relied on, name of the product approved and the authorization number of the marketing authorization. Unfortunately, the Regulation has not lived up to the high expectations that surrounded its enactment. The over-simplistic nature of the Regulation has led to significant uncertainty with various anomalies arising and certain classes of pharmaceutical innovation being seemingly excluded from protection.

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41 41

LEGISLATION STRAP Combination Products

Perhaps the greatest uncertainties of the Regulation have surrounded SPCs for combination products. This has questioned whether a product consisting of a combination of active ingredients is “protected by” a patent covering one of those ingredients. The different interpretations by different national courts have not been assisted by the guidance provided by the CJEU. Thus, the English Courts have firmly answered the question in the negative (that is, combination products are not protected by a patent

SOME NATIONAL PATENT OFFICES WILL GRANT SPC APPLICATIONS WITH LITTLE OR NO SCRUTINY OF THE FACTS THAT UNDERLIE THE APPLICATION. to the single product because the patent must protect the ‘combination’ of active substances, not just one of them), whereas others have answered the opposite way (a combination product would infringe a patent directed to a single ingredient, and therefore is protected by that patent). The CJEU decisions to date on this issue have not addressed this question head-on, stating instead that it should be a matter of national law. A very recent opinion issued by the Advocate General (AG) of the CJEU, however, suggests that this view might be changing. In a case concerning combination vaccine products, the AG suggested that SPCs ‘should’ be granted on patents to single active ingredients based on an authorization for a combination product. The reasoning behind this view is that the overall purposes of the Regulation (to promote innovation and so on) must be considered when ruling on its meaning. The CJEU Combination Product Reference is still pending.

Second Medical Uses

Second medical uses are another highlighted area of uncertainty. On the face of the Regulation, if a product has been placed on the market previously (that is, for a “first medical use”), then it can be subject only to a single SPC based on that first marketing authorization.

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An SPC cannot be based on a second medical use patent that post‑dates the first authorization, nor can it be based on a later marketing authorization approving the second medical use. The fact that development of second medical uses for known products often take place ‘after’ the product has been marketed for its first use and frequently leads to innovations and lengthy clinical trials remains (at least on the face of the Regulation) irrelevant. That would suggest that the purpose of encouraging innovation and compensating patent holders for delays incurred under the regulatory approval process is simply not being achieved. The English Court of Appeal recently referred another case to the CJEU explicitly criticising the SPC regime, stating: “…Pharmaceutical research is not confined to looking for new active compounds. New formulations of old active substances are often sought. Most are unpatentable but from time to time a real invention is made and patented. Moreover there is much endeavour to find new uses for known active ingredients. The European Patent Convention 2000 has indeed made the patenting of inventions in this area clearer. Its effect is that a patent for a known substance or composition for use in a method of treatment is not to be regarded as old (and hence unpatentable) unless use for that method is known. It would be most unfortunate if second medical use patents could not get the benefit of an SPC. If [SPCs are not available] the Regulation will not have achieved its key objects for large areas of pharmaceutical research: it will not be fit for purpose.”

Single Product Questions

Another apparently anomalous situation arises when considering how many and to whom SPCs may be granted in relation to a single product. On the face of the Regulation, only one SPC may be granted per marketing authorization. A change in the law (implemented by a separate regulation concerning plant protection), however, allowed for different patent owners each to make separate applications for SPCs covering the same drug product, which in turn has led to a lack of clarity as to how “different” the owners of different patents need to be. Perhaps more significant though is the practice of applying for an SPC based on a ‘competitor’s’ product that is permitted by this change. Arguably, such third parties will not have incurred extra expense or delay by virtue of the regulatory approval process, nor will their own product suffer from any reduced patent term. One could, therefore, question whether the purposes of the Regulation are satisfied by a regime that allows this practice.

Key Terms and Language

There are many more examples illustrating the lack of clarity in the Regulation and uncertainly has arisen in relation to numerous key terms of the Regulation;

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LEGISLATION STRAP

Hiroshi Sheraton

for example, what is considered to be a ‘product,’ what makes one product a ‘new’ product, and even what counts as a first marketing authorization for the product. Not only are the terms of the Regulation uncertain; recent indications suggest that the CJEU can choose to ignore the express wording if the purposes of the Regulation are not being achieved. This makes assessing the viability of any particular SPC application or strategy a complex task. The language of the Regulation might be seen as merely a guide (and not a very good one at that), with the purposes behind the Regulation taking precedence. Complexities in applying legislation covering a significant and valuable area of commerce are not unique to the pharmaceutical field, nor to SPCs in particular. Yet, the fact that fundamental issues of interpretation are still unclear and/or undecided some 20 years after implementation and the lack of confidence in the system expressed by Courts is unusual. Moreover, businesses operating in the pharmaceutical field and their advisers must do their best to navigate the uncertainties.

National Patent Offices

Robert Lundie‑Smith

For more information Hiroshi Sheraton Partner McDermott Will & Emery Tel: +44 207 577 6910 hsheraton@mwe.com

Robert Lundie‑Smith Associate McDermott Will & Emery Tel: +44 207 577 6941 rlundie-smith@mwe.com www.mwe.com

If the uncertainties in the Regulation and the CJEU rulings in relation to SPCs were not enough, there are two further aggravating factors. The first is that significantly different practices exist before national patent offices of the different member states. Some national patent offices will grant SPC applications with little or no scrutiny of the facts that underlie the application, whereas others (such as the UKIPO) will investigate and consider the validity of applications in much greater depth. A rejection of an SPC application is final and the application cannot be re-instated following a change in the law (for example, following a CJEU ruling). Although patent offices such as the UKIPO do their best to apply the law in a consistent and up‑to‑date manner, there are sufficient uncertainties in the law to suggest that an appeal can rarely be ruled out as unmeritorious. This places a heavy burden on applicants to appeal any rejections through the courts and, ultimately, to the CJEU.

Practical Level

The second issue relates to how applicants should deal with uncertainties in the law on a practical level. A recent decision of the European Commission (as upheld by the General Court of the CJEU) found that a patentee had misled national patent offices by filing SPC applications with reference to the latest one of a series of possible marketing authorizations that could be argued to be the correct “first authorization” for that product. Although it was later clarified, at the time of filing there was uncertainty in the law as to exactly what was required to satisfy the requirement. Nevertheless, the applicant did not bring this uncertainty to the attention

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of the national patent offices as part of the application process and the CJEU held that this action amounted to deceiving those patent offices with a view to obtaining SPC rights that would prevent generic competition. As a result, the company engaged in anticompetitive behaviour and was subjected to a significant fine. Where there is uncertainty concerning a point of law that may affect the validity of an SPC application the patentee now arguably has a duty of candour towards the national patent offices and is obliged to bring the possible arguments against its application to the attention of all of the patent offices where it makes applications. A prudent applicant might choose to do so in all jurisdictions (including in those countries where little examination is conducted) and at the time of any application (rather than waiting for an objection by the examiner). In effect, the patentee has to act as its own opponent and raise both the case for the grant and the possible reasons why the application should be denied. Although the application itself might be only a couple of pages, the consideration that must go into it and the correspondence that will accompany the application setting out such detail will be of considerable length.

Legal Advice

This interface between SPC protection and European competition law also raises a further issue in relation to privilege attaching to legal advice, and whether and to what extent communications with legal advisers must be handed over to investigating authorities. Under many legal systems, communications with in-house legal advisers and patent attorneys benefit from a legal professional privilege. The European competition authorities, however, take a very different view. The CJEU has confirmed explicitly that privilege does not attach to communications with in-house lawyers (and by extension, would not apply to in‑house patent attorneys). The CJEU also confirmed that communications with external lawyers are only privileged from disclosure to competition authorities if they relate to the client’s right of defence to the allegations under investigation (that is, a breach of competition law). The privilege of communications with external patent attorneys in this regard has not been tested in the Courts. Yet, it is at least arguable that external patent attorneys would not benefit from privilege.

Conclusion

As indicated by the above discussion, the Regulation as it currently stands suffers from great complexity and significant uncertainty. Navigating the uncertainty is likely to involve significant and complex analysis of the latest case-law and, in many cases, important strategic decisions on how to proceed. A co-ordinated and consistent approach throughout Europe and regard to potential competition law concerns would also be advisable.

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STRAP

November/December 2011

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BIOSIMILARS

TO BLA OR NOT TO BLA?

An approval pathway for biosimilars has existed in the US for nearly 2 years, but the practical implications of this new option are still difficult to ascertain. Although analogy to the generic pathway for small molecule drugs is attractive, unique characteristics of biologics defy such straightforward logic. Further FDA guidance on several points is needed to accurately assess the risks and benefits of the different approval pathways for biologics.

ollowing in Europe’s footsteps, the US now has an alternative approval pathway for biologic therapies, intended to reduce some of the hurdles associated with a full Biologics License Application (BLA). Small molecule drugs have had an alternative approval pathway for years, ever since the passage of the Hatch‑Waxman Act in 1984. Now, for the first time, companies can choose between two regulatory approval pathways for marketing biologics in the US. For small molecules governed by Hatch-Waxman, the choice is clear: The first company to get a new drug approved must conduct extensive testing for safety and efficacy of the drug, but in return receives a set of protections against competitors who also want to market that drug. A competitor must await the end of these protections, but then can largely rely on the originator’s safety and efficacy data, avoiding much of the expense the originator incurred in gaining approval for its product. It is a system that is widely viewed as fairly respecting the needs of innovator companies whilst fostering the introduction of safe and inexpensive generic medications. In part, the system works because small molecule drugs can be reliably purified and characterized, making it easy to compare the content of a generic product to the originator’s approved drug product and predict its effects on patients. For biologic agents, this premise simply fails. Biologics are comparatively enormous and intractable molecules and are made not by carefully controlled chemical reactions, but by living cells. Techniques that are routinely used to understand the structure and purity of small molecule drugs are confounded by the size and complexity of biologics. A chemical reactor can be trusted to churn out the same molecule from the same reagents time and time again. Not so a cell, whose delicate machinery can be affected by minor variations in temperature, pH and other environmental conditions. In fact, biologics are rarely, if ever, limited to a single defined entity; typically, biologics contain a range of discrete molecular entities, differing in post‑translational modifications or other minor structural

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features. Unfortunately, minor structural features can have significant effects on the way a biologic interacts with a patient’s body. In short, nothing about biologics will ever be as simple as small molecule drugs. So the process for approving biosimilars simply can’t be as straightforward as the Hatch‑Waxman regime. In the wake of Biologics Price Competition and Innovation Act of 2009 (BPCIA), FDA faces the unenviable challenge of deciding how much testing of a biosimilar is necessary to be confident that it is as safe, pure and potent as the originator biologic. This decision is key to the success of biosimilars in the US. Too much testing, and the cost of biosimilar clinical trials threatens the fundamental economic incentive of the biosimilar pathway. Too little testing, and high‑profile adverse events could forever ruin the market for biosimilar products. And not all biologics are alike. Peptide therapeutics, antibodies, gene therapies and stem cells each have their own idiosyncracies and potential risks; a one‑size‑fits‑all approach is unlikely and unwarranted. Indeed, FDA has already signalled that biosimilar applications will be evaluated individually on a fact‑specific, case‑by‑case basis, looking to the totality of the evidence. So far, there is little clarity as to exactly how much testing FDA will require of those who pursue the biosimilar pathway.

Legal Pathways

The legal barriers a biosimilar applicant faces are, however, more clear. A biosimilar application can’t be filed for 4 years after the referenced originator biologic is approved, and the biosimilar product can’t be approved for 12 years after that approval. The follow‑on applicant who chooses the traditional BLA pathway instead can file — and be approved — at any time, lengthening the product’s market lifetime. If an approved product attracts multiple biosimilar follow‑ons, the lure of the traditional BLA pathway increases, because the expiry of the originator’s 12‑year market exclusivity could open the floodgates to an onslaught of “me‑too” biosimilars. A follow‑on manufacturer that opts for the traditional BLA pathway can beat these biosimilars

November/December 2011

BIOSIMILARS

to the market, command a higher price point, achieve greater market share and gain a brand recognition and differentiation edge compared with biosimilars. The follow-on manufacturer who obtains regular BLA approval receives the same 4- and 12‑year protections against biosimilar applicants as the originator. This protection, however, may not be particularly meaningful if competitive products can enter as biosimilars of the originator product at the earlier expiry of its exclusivities. Conversely, a regular BLA applicant — but not a biosimilar applicant — can put forward a product that meaningfully differs from an approved biologic in terms of structure, safety or efficacy. An improved product can obviously outcompete an originator product — and its biosimilars — on therapeutic merits.

Patent Protection

Another complicating factor is patent protection for the originator product. The patent landscape will differ for each product and will remain relevant whether an applicant chooses a traditional BLA or the biosimilar pathway. Unlike the world of generic small molecules, where patent litigation can trigger an automatic 30‑month stay of the generic’s approval, patents have no role in the biosimilar approval process. Still, patents can present a barrier to biosimilar market entry. In some cases, the long market exclusivity for biologics may mean that biosimilar applicants face few or no patents after approval; but strong patents in effect during that 12‑year period may diminish the incentives for early approval via a traditional BLA. Occasionally, the originator’s life‑cycle management strategies may provide patent protection that outlasts the 12‑year statutory market exclusivity. The resulting patent disputes regarding biosimilars will be governed by the

November/December 2011

byzantine system of rules established by the BPCIA. In some circumstances, an applicant might seek to force the innovator down this dark alley; otherwise, choosing the regular BLA route completely bypasses this complex and arcane system in favour of ordinary patent litigation. Overall though, the BPCIA does little to substantively affect the role of patents in the biologics marketplace, so would‑be biosimilar applicants can assess the patent landscape protecting their target products of choice and understand the role of patents in their approval and marketing strategies regardless of their route of approval.

Nomenclature

One more murky area of biosimilar regulation is nomenclature. Will biosimilar products have the same generic name as the originator product? If not, will the names be similar? Will products approved through a regular BLA have more dissimilar names, even if the products are similar enough to an existing product to use the biosimilar pathway? Follow‑on manufacturers that intend to devote few resources to sales and marketing may desire names that benefit from association with the name of the originator product; those that plan to invest in aggressive sales and marketing efforts may want the market differentiation that comes from having a dissimilar name.

David P. Halstead

Conclusion

For now, only further guidance from FDA — either in the form of regulations or guidelines, or in the treatment of early biosimilar applicants — can allow companies to meaningfully project the potential savings of the biosimilar pathway or the value of a traditional BLA. Until then, the biotech world watches — anxiously — and waits.

For more information David P. Halstead Partner Ropes & Gray www.ropesgray.com

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VALIDATION

UNDERSTANDING CE MARKING AND PUWER DURING EQUIPMENT VALIDATION

Is your pharma company guilty of overlooking CE marking and PUWER regulations in the assumption that they are covered by validation? If so, you had best read on!

alidation is a lengthy and detailed process used to document and demonstrate evidence for the suitability of use and application of various pieces of equipment, plant and processes. Compliance is essential to meet the strict requirements of the ‘Orange Guide’ and to provide confidence both internally and externally in a company’s ability for reproducible quality.1 But how often during the validation process, for equipment and plant in particular, are the CE requirements and ongoing PUWER (Provision and Use of Work Equipment Regulations) 1998 compliance overlooked under the mistaken impression that they are covered by the validation package?

The CE Mark for Machinery

Under UK and European law, namely, the Supply of Machinery (Safety) Regulations 2008 (UK), more commonly known as the Machinery Directive 2006/42/EC (the ‘Directive’) in Europe, any machine (a powered device with at least one moving part, a lifting attachment or a safety component) must be CE marked when built, entered or used for the first time in any country inside the European Economic Area (EEA) since 1995. This includes one‑off, bespoke manufactured items for use internally in many pharmaceutical firms and significant modifications to existing equipment (such as a new control system, alteration of guards or a change to the original design characteristics). The requirements also include the integration of machinery to make a process line, even if the individual components used to make the line are themselves CE marked.

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PUWER 1998

Under UK law, namely the Health and Safety at Work etc Act 1974, employers have duties placed under them detailed in section 2, to provide a safe working environment for everyone under their control. This manifests itself into various Regulations. For the provision and use of all work equipment, these duties and the specific requirements for compliance are laid out in the PUWER 1998. Use is defined as cleaning, programming, operating, maintaining, adjusting and transporting. Work equipment is defined as any machinery, apparatus, tool or installation used at work. All work equipment must be assessed against PUWER 1998 on a regular basis to ensure compliance is maintained. This satisfies the requirements of part 3(3) of the Management of Health and Safety at Work Regulations 1999 and guidelines laid out in HSG65/ILO‑OSH 2001/ OHSAS 18001.

Where these Requirements Get Overlooked

CE Marking Let’s concentrate first on the validation process. An often neglected part of the validation process is the Design Qualification (DQ). This should be the point at which items such as CE marking are stipulated, but often get transferred in to the Installation Qualification (IQ), where inevitably, once the machine is on site — when purchased from a supplier or manufacturer — it is too late. Why? Because it

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VALIDATION

Peter Harvey

Abbreviations HSG65: Health and Safety Guidance ILO‑OSH 2001: International Labour Organization‑Occupational Safety and Health Management Systems OHSAS 18001: Occupational Health and Safety Advisory Services EN 12100: 2010: Safety of Machinery — Basic Concepts, General Principles for Design

Reference

1. MHRA, Rules and Guidance for Pharmaceutical Manufacturers and Distributors (Pharmaceutical Press, UK, 2007).

For more information

Peter Harvey Compliance Engineer amtri veritas Ltd www.amtriveritas.com harvey@amtriveritas.com

is the responsibility of the supplier to ensure compliance to any relevant Directives associated with the equipment at the point of sale. Once on site, that responsibility can, in some circumstances, transfer to the purchaser, as they have effectively become the importing agent. This is less of an issue when designing a machine in‑house, but the CE mark cannot be applied without following the correct procedures as laid out in the Machinery Directive. In some instances, certain machines require a Notified Body to issue a Certificate of Conformity before the machine can be legally used inside the EEA. More often than not, the desired functional requirements of the equipment, in terms of performance and compliance with the ‘Orange Guide,’ take precedence over additional requirements laid out in National Law. If CE marking does become part of the validation process, it tends to get relegated into a tick box exercise for the IQ, consequently missing the legal obligations. Probably the largest area in which the requirements of CE marking are overlooked is in the integration of process lines. If one or more machines are arranged to function as an integral whole, then even though the individual machines that make up that process line are CE marked, the entire assembly falls into the parameters of the Directive as a new function. PUWER 1998 Any assessment or compliance check, if done, usually becomes an initial tick box activity when a piece of equipment arrives on site or has just been purchased. This usually omits the relevant mechanisms to close out any nonconformances found during the inspection, and certainly does not introduce a re‑assessment date. The PUWER 1998 check is an assessment of the equipment’s condition at a given point in time. It is not an assessment on the manufacture or design of that equipment — they are captured in CE marking. During revalidation of equipment, whether that is Operational Qualification (OQ) or Performance Qualification (PQ), this process is often assumed to cover all aspects of the machines suitability. In reality, it just repeats the steps taken in the initial OQ or PQ, without covering the detailed aspects of PUWER 1998. Aspects such as an assessment of the risks specific to that machine that should be detailed in the rarely seen Equipment Risk Assessment (RA). The Process RA does not deal with certain risks relating to the machine, such as handling, cleaning and maintaining. Other aspects include an assessment of the training that has accompanied the use of the equipment and, rather ironically, Regulation 10 of PUWER 1998 requires an assessment of the equipment’s compliance with Community Directives; that is, CE marking. Regulation 10 asks for an assessment on the suitability of the CE mark — does the user have full confidence in the validity of that CE mark and the machine’s ability to meet all the relevant essential health and safety requirements? If yes, the PUWER assessment is reduced. If the user is not confident that the machine has met the requirements of a given Directive, then a full PUWER assessment is required. This must be

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repeated, however, to determine the ongoing compliance of the equipment both to the applicable Directive and to PUWER 1998. To ensure Regulation 10 is understood and applied properly, along with a thorough PUWER 1998 check, experts — such as Notified Bodies — can provide peace of mind and confidence that all your machinery meets current legislation.

What is Required?

For CE marking, the requirements for the machine to meet the Directive must be clearly laid out in the DQ and must be agreed when discussing purchasing arrangements with the supplier/designer/manufacturer. The ability of the machine to meet these requirements should be assessed during the factory acceptance test, from which, a large part of the necessary documentation for the CE mark can be reproduced for inclusion in the DQ and part of the IQ. To ensure the process is followed to the letter of the law, employing a Notified Body from the outset can reduce expensive retrospective procedures and any noncompliance issues. For bespoke items that are built in‑house or via a third party, it is essential that the CE marking procedures are followed to allow the machine to be declared and marked accordingly. This procedure must start on the design board and should begin with a risk assessment in accordance with EN 12100: 2010. In some cases, certain types of machinery cannot be declared compliant with the Directive without the use of a Notified Body, unless it is in full compliance with a C‑type standard — a standard that deals directly with a single machine or a group of machines. This is a rare occurrence, largely because the reason for designing/build of the machine in the first place is for a specific task not attempted before. Where most companies fail, however, is in the compilation of a machine’s Technical File. This is essentially a similar process to the validation package and is documented evidence of a machine’s compliance with a given directive. This can be a time‑consuming exercise and is best outsourced to ensure that the guidelines are followed correctly, either in terms of assistance in constructing and compiling the Technical File or in its complete compilation. Existing machines without the CE mark are not exempt from this exercise, even if they have been used for some years, and must be assessed for CE compliance. Does this level of knowledge exist in most companies? Does your company have staff suitably trained and experienced to understand the requirements of PUWER 1998 and, in particular, Regulation 10? Most companies tend to prioritize resources elsewhere; but as with most safety legislation, the added value is only realized long term. Once any machinery or work equipment has been correctly certified and all legislative requirements have been met, continued compliance with PUWER 1998 must be implemented in addition to, not instead of, any other quality and safety systems used. Does your company comply with all CE marking and PUWER requirements? If not, it is worth exploring which areas are noncompliant.

November/December 2011

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INDUSTRIAL VENDING

TEN WAYS TO CUT COSTS WITH INDUSTRIAL VENDING

Tony Goodwin of Propeller explores how semi‑automated, line‑side parts vending will substantially reduce operating costs and boost productivity.

nventory, stock, parts or MRO (maintenance, repair and operations) consumables provide the ‘oil for the engine’ in manufacturing and processing plants. They can represent up to 20% of total enterprise spend and account for more than half of all indirect purchasing transactions; yet many organizations do not have the systems in place to restrict access to inventory, and monitor the usage of spares and consumables down the line. Too often, storerooms are free‑for‑all facilities, where users take parts on autopilot, squirrelling stock away in lockers and, worse still, pilfering company property as a perk of the job. As a result, inventory costs run out of control, storeroom data are totally inaccurate and the inevitable stockouts of critical spares lead to costly downtime, lost production and cancelled orders. Emerging from much the same technology as coin‑operated snacks and drinks machines, industrial vending equipment dispenses MRO consumables, personal protection equipment (PPE), tooling or whatever in a similar semi‑automated manner, except that instead of payment transactions, access is normally by means of time and attendance swipe cards, biometrics or personal identification codes. Known as ‘point‑of‑use’ or ‘line‑side’ vending machines, because they are located close to the production line or work area, they are now advanced inventory management systems, enabling strict control of stock access, monitoring of usage down to user level and automatic re‑ordering of out‑of‑stock items. Although previously designed around an engineering footprint for handling mainly tools and parts, the latest generation of industrial vending technology, such as Pro‑Vyda equipment, is configured to be genuinely usable by a whole range of industry sectors, including pharmaceuticals, and can accommodate a variety of shapes and sizes of stock items. For those new to the technology, semi‑automated parts vending offers a secure environment in which to store and dispose a whole range of items and an effective method of driving down inventory spend. In fact, here are 10 ways that point‑of‑use vending will help you to cut costs, typically by as much as 30–40%. • Reduces inventory holding — As much as 70% of inventory items are never used or obsolete, so

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an initial data cleansing exercise and plant‑wide amnesty on parts in lockers and toolboxes, as part of a vending machine implementation programme, will bring about immediate stock reductions; add to that subsequent opportunities for weeding out low turnover items and eliminating duplication across the whole enterprise. • Frees up valuable floor space — new lines mean storing spares to meet service and maintenance needs, which puts pressure on storerooms already overstocked with excessive inventory; by utilizing vertical space and high density storage technology, modern vending machines are designed to hold a vast array of products within a highly compact footprint, freeing up manufacturing floor space — a commodity usually in short supply. • I mproves staff productivity — a major cause of downtime is when staff have to spend time collecting spares from a central storeroom, building cumulatively into hours of lost production. Point‑of‑use vending machines serve the location where they’re installed, thereby dramatically cutting the times taken to travel, locate and retrieve parts, whereas touch‑screen interfaces with ‘shopping basket’ functions speed transaction times. • Drives down inventory spend — the most powerful way to reduce spend is to restrict access to inventory, with a complete lock‑down ensuring that only authorized users can remove items. A full audit trail and subsequent monitoring of usage down to user level will identify wasteful employees or departments and indicate excessive maintenance activities, in turn highlighting issues of asset reliability. • Optimizes costly parts usage — modern machines can allocate a unique status to each compartment, so that refurbished or reconditioned parts can be dispensed instead of new items, saving on routine costs. The machine will also deliver the exact amount of parts required, rather than automatically dispensing standard packs of 10 or 20 — again optimizing usage. • Eliminates staff pilfering — as economic pressures mount, workplace theft tends to increase,

November/December 2011

INDUSTRIAL VENDING whilst at particular times of the year certain items are consumed at greater levels than normal, such as gloves around bank holidays, paint pens and markers during school vacations and batteries at Christmas. Locking down access and making staff fully accountable for what they are consuming, has a remedial impact on such behaviour. • R educes employer liability — as all transactions are logged against a user, an employer can identify precisely what an individual has received, providing vital evidence of access to essential PPE in the event of a health and safety incident, and helping to avoid expensive litigation. Real‑time access to vending machine data also enables supervisors to immediately question why incorrect items are being removed. • Provides 24/7 parts availability — management has to balance the cost of either paying stockroom staff to support shift workers or allow unmanned stores access out of hours. Vending machines eliminate that problem by providing 24/7 controlled access and monitoring, whilst a feature such as Pro‑Vyda’s reservation facility enables off‑site staff to prebook parts for planned maintenance whenever they arrive.

• Minimizes costly downtime — with manual storerooms where there are no routine stock checks, there are often discrepancies between inventory records and physical items on the shelves, leading to stockouts at critical points and consequent downtime. Vending machines ensure accurate data and user‑defined depth of stock on vital parts, as well as incorporating expiration and calibration dates against any part. • Improves budget control — as well as avoiding bloated inventories and restricting access to parts, vending machines can allocate budget ceilings to individuals, cells and departments, thereby ensuring budget compliance. Given strict control of parts distribution and automatic restocking, stockholdings can be kept below 1 or 2 months in hand and complete stock checks can be done within hours, rather than days. Finally, contrary to the view that workers might object to point‑of‑use vending machines, we find that hardworking staff respond positively to the idea of having the right parts in the right place at the right time, rather than wasting energy tracking down items themselves. Furthermore, they appreciate facilities for reserving MRO consumables for upcoming maintenance and repair jobs, instead of finding much‑needed parts out of stock at the last moment.

For more information

Tony Goodwin CEO Propeller GB Ltd Tel. +44 0191 569 1690 sales@propellergb.co.uk www.propellergb.co.uk

MANUFACTURING STRAP

A NEW ROLE MODEL? Pharma companies would do well to look beyond their own industry to see how data can be used to improve the manufacturing process, says Monica McDonnell, manufacturing industry consultant for Teradata.

t had to happen. The continual rise of the pharmaceutical industry just couldn’t go on for ever. So now, despite global revenues of more than $700 billion, there are definite signs of burnout.

Thin Pipelines

The challenge of expiring patents and the subsequent rise in the production of generic drugs has been well documented and discussed. Currently, more than half of all medicines supplied are generic and represent just 18% of production in value terms. It is, therefore, clear that inevitable further rises in demand could put a significant dent in profits of brand label drugs in the future. Consequently there is a consensus that the glory days are over. “Something is wrong in today’s pharmaceutical industry,” Jonathan Anscombe, joint head of European pharmaceuticals and healthcare at A T Kearney told Management Today last year. “An unprecedented number of blockbuster products are going off patent and despite record investment in R&D, the pipeline of new drugs to replace them is decidedly thin. The industry’s current model may become irrelevant in the context of the 21st century’s global healthcare needs,” he added.

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Fresh Thinking

Everything points to the need for fresh thinking — and, of course, change never comes easy. Because the past decade has been so profitable, many big pharmas have seen little point in even tweaking their model or workflow, which means that, unlike some manufacturers who have pared processes down to the bone, pharmas still have areas of business where improvements can be made. Particularly pertinent to this argument are data management and the optimization of data as a business asset, particularly in relation to quality control and FDA’s push towards Quality by Design (QbD). Up until now, pharmas have looked to each other for direction and inspiration. Failing this, the next stop has often been the chemical industry. But, they could do well to look even further afield at, for example, aviation, automotive or the semiconductor industry, considering how these industries use their data to fully understand their manufacturing process.

The Data Warehouse Solution

The use of a data warehouse (DW) is not unknown in the pharmaceutical industry. Many finance or sales and marketing departments use the business intelligence provided by an enterprise data warehouse (EDW) combined with analytics tools for reporting, pricing analysis, forecasting and other purposes.

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MANUFACTURING Now there are DWs available with the processing power to integrate large volumes of manufacturing data from multiple sources, combining information about different products from various production sites to create a single version of ‘the truth.’ Ultimately, this data can also be combined with other operational and business information. A DW’s flexibility allows a company to start small — with, for example, capturing all the data on the testing of an emerging product on one site — and then build on this at a pace that suits the business. The pooling of a company’s knowledge in one accessible store, where data integrity is assured, is desirable best practice. These data can be interrogated easily and relied upon to provide a timely response. This is far more effective than keeping random memory sticks or spreadsheets about individual projects and products at multiple locations as it avoids duplication of effort and a confusing mismatch of vital statistics. The key to being first to market in the future will be the ability to gain an accelerated, but thorough, understanding of a new product. This requires the integration of data about a company’s equipment on the manufacturing line, quality systems and the corporate enterprise resource planning (ERP) system. Some pharmas may have linked these before for a single product, but few, if any, will have total integration to give the holistic view required. For validation, quality control teams need to create a design space based on input to a product, settings and other variables and set parameters accordingly. Having the right data at their disposal will allow them to know the process so well that within a certain window they are guaranteed a quality product, thereby minimizing the need for testing or inspections. At the heart of this QbD approach is the need for a flexible data management platform that gives pharmas the freedom to analyse and understand their manufacturing process for each product. Without the right technology, it could take days, if not weeks or months, to gather all the information related to a particular drug, making it almost impossible to control a batch and perform real-time release. When batches can be released this way (real-time release), based on this thorough understanding of the manufacturing process, they can be shipped without further testing, so eliminating the need for excess inventory. When these data can be blended with sales data, a company can track where a drug goes and whether it was ever returned with a quality issue. The right DW will support any query and can be easily rolled from one site to another, or from one department to another, without the need to duplicate information and effort … it’s a case of build once, use many times. Nobody currently knows which direction the industry is heading or what data will be needed to comply with future legislation. Getting the data management right, however, will halt a major change becoming a crisis.

November/December 2011

Taking a Lead from Other Industries

Returning to the semiconductor industry mentioned earlier, when the large US embedded semiconductor firm Freescale initiated what it called the Diamond Project, the bringing together of all manufacturing data from each of its facilities together with an enterprise data model in a new EDW, it very quickly logged a 1% yield improvement. This equated to around $100 million in gross margin contributions. It also reduced the cycle time of customer incidents from 25 to 14 days and reporting — which once took days — is now done in minutes. Semiconductors are, of course, a totally different product from drugs; they are neither life saving nor life threatening. Yet, the precision and expert knowledge

THERE IS OFTEN MORE INTELLIGENCE SURROUNDING THE PRODUCTION OF A POTATO CRISP THAN IS HELD ABOUT SOME DRUGS. needed for manufacture is similar … and the industry’s optimization of data for manufacturing happens to be ahead of the game. At one stage, Freescale made the decision to transform its workforce from being task-based to knowledge workers — a clear indication of the change of mindset required. An industry commentator once pointed out that if a paint manufacturer can deliver a product of exactly the right shade every time, why does the pharmaceutical industry find consistency such a problem? It may surprise some that there is often more intelligence surrounding the production of a potato crisp than is held about some drugs. But the industry shouldn’t allow itself to be beaten down by its prophets of doom. For those in the pharma industry that aren’t capturing and analysing their production to make timely decisions on product quality, they should talk with those in other sectors such as high tech or semiconductor who are, as they will be far more willing than competitors to share ideas and experiences. Perhaps it’s time to regain the entrepreneurial spirit and see this watershed as a real opportunity.

For more information Monica McDonnell Manufacturing Industry Consultant Teradata

monica.mcdonnell@teradata.com www.teradata.com

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GENERICS

Painting by Numbers

Adding numbers, be they Dollars or percentages, to the debate on patent expiries and the progression of generics, paints a sobering reality.

Kevin Robinson

For more information Kevin Robinson Editorial Director Via Media UK Ltd

kevin.robinson@via-medialtd.com www.via-medialtd.com

he immediate future is not looking particularly rosy for the brand-name drug industry. Patent protection is about to expire for some of Big Pharma’s bestsellers, including Lipitor, Plavix and Singulair. In the US alone, 5.7 million people take Lipitor, which generates $11 billion a year in sales, and Plavix, both of which are set to expire in the next few weeks. And when you consider that the total amount that drug companies could lose between now and 2015 as popular patents expire could reach the heady heights of $250 million, it’s no wonder that key players such as AstraZeneca are already announcing redundancies. The decision to cut jobs comes as the company faces increasing pressure from generics and approaches the so-called 2016 patent cliff. Britain’s second-largest drug maker intends to cut 400 jobs in the company’s US base in Delaware, US. It has been planned that 70 of the 400 cuts will come from existing vacancies, and employees will be allowed to apply for voluntary redundancy, with decisions to be finalized by early December. AstraZeneca’s North America head, Rich Fante, said: “These changes are necessary to build a leaner, more efficient company.” And, no doubt, there’s more to come; an undisclosed source suggested that up to 53,000 jobs in the industry were culled in 2010, and that the figure was set to rise! Looking at the American system, the writing is quite clearly on the wall, and it’s obvious to see what Big Pharma has done … and why. Given that pharmaceutical companies spent approximately $4.7 billion in 2010 to advertise brand-name drugs, and that the average copay for a generic drug is $6, compared with $24–35 for a brand-name version, extra revenue had to be generated from somewhere. The result? To prepare for patent expirations, some organizations have raised their prices during the last few years by as much as 20%. Some might argue the case for basic commerce … but the practice doesn’t always deliver the desired endpoint. In the UK, for example, the National Institute for Health and Clinical Excellence (NICE) recently rejected BMS’s skin cancer drug, Yervoy, stating that it did not measure up to cost-effectiveness and benefit parameters in its initial review. Basically, NICE found in its analysis that Yervoy did not offer sufficient evidence through its clinical trial data to justify its high cost. Furthermore, NICE believes that its cost estimates could be “significantly higher.” Gustav Ando, Director, Healthcare, IHS Global Insight, commented: “Yervoy, the first new treatment against deadly skin cancer for decades, has been rejected for use on the NHS by its health cost

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regulator, NICE. The news comes as little surprise to IHS Global Insight, who had long questioned whether a drug with such a high initial price point could feasibly reach the cost-effectiveness threshold that guides NICE’s decision. Still, it is a major setback for cancer patients, who had been hoping that the highly innovative therapy could give some respite to the lack of treatment options.” Also from IHS Global Insight, Analyst Anne‑Charlotte put the spotlight on the French market. The years 2011–2012 will see the patent expiry of France’s top-selling reimbursed drugs, Tahor and Inexium, with consequent savings expected as a result. Respective savings of between €130 and €170 million are foreseen with the market entry of generic versions to Inexium and Tahor. Overall, the generic market has progressed during 2010 in France, unlocking savings of about €1.3 billion during the period. The patent expiry of Plavix — now the bestselling generic in France — triggered savings of €200 million during 2010. Overall, one reimbursable medicine out of four sold in the outpatient sector is a generic version. The progression of the generic market is derived from the progress made in terms of substitution rate and to the expansion of the official list of substitutable generics — known as the Répertoire des Génériques. The slowdown seen in the pharmaceutical market in France is attributable to a rise in the use of generics, to the decline in volume dispensed, and to price and reimbursement cuts applied during 2010. Last year, price cuts of about €500 million were applied to reimbursable medicines and medical devices. Meanwhile, the reimbursement rate of drugs with a low/insufficient SMR rating was decreased by 20 percentage points to 15% in April 2011. Overall, cost‑containment measures adopted by the government have been successful in containing drug spending, especially in the reimbursable drug market — which only grew 0.3% year-on-year during 2010. Progenerics measures and cuts will further restrain growth in the pharmaceutical market during 2011–2012 in France. During 2012, price cuts of about €670 million are planned, whereas reimbursement cuts will concern a total of 64 drugs during the period. Watch out for more merger and acquisition activity in the sector and, let’s make no bones about it, whether you’re in the biotech, nutraceutical, cosmeceutical, biofuel industry, Big Pharma is watching you, scrutinizing and studying you, perhaps almost as narrowly as a man with a microscope might scrutinize the transient creatures that swarm and multiply in a drop of water.

November/December 2011

NOSTRAPHARMUS

THE COMPLEX BUSINESS OF SIMPLIFICATION Nostrapharmus considers how the industry can continue effective global trials and align with a simpler future regulatory landscape.

lobalization of clinical research has presented both opportunities and challenges to the pharmaceutical industry. The logistical challenges of global operations have driven the industry to advocate for consistency and for a reduction in bureaucracy for conducting multinational trials. New initiatives in EU, US and BRIC (Brazil, Russia, India and China) countries indicate a move towards simplification, harmonization and transparency; but despite the best intentions of these initiatives, the immediate future remains complex. So, Nostrapharmus asks: “How can we continue effective global trials and align with a (hopefully) simpler future regulatory landscape?”

European Clinical Trials Directive

As Europe continues to struggle with escalating costs, slow recruitment into trials and the threat from the emerging market competitors, a pragmatic update to the EU legislation is much needed. The proposed revision of the Clinical Trials Directive 2001/20/EC aims to harmonize the application for authorization, with all member states indicating a strong trend towards a single submission process with a co‑ordinated assessment procedure. The Commission states that to achieve greater harmonization and risk‑adaptation on the content of the application dossier, “sufficiently detailed provisions could be included in the Annexes to the basic legal act.”1 Although some form of harmonization is expected, the elements that would be required by the “harmonized” clinical trial authorization application remain unclear. The ‘revision’ is also set to address the classification of investigational and noninvestigational medicinal products, sponsorship of clinical trials across EU, emergency clinical trials and clinical trials performed in third countries. The Commission received 143 responses from stakeholders across the board — there is general consensus with finding a solution to the impediments caused by the EU legislations. It will be interesting to see whether the Commission will hold any further consultations ahead of the proposed legislative changes in 2012.

Reference

1. http://ec.europa.eu/health/ files/clinicaltrials/concept_ paper_02-2011.pdf

For more information

nostrapharmus@wcigroup.com

Phamacovigilance in Europe

Other developments in Europe include the European Commission’s consultation paper “Better Regulation of Veterinary Pharmaceuticals,” which outlines the potential introduction of good clinical practice (GCP) legislation for veterinary clinical trials, harmonization across the EU and the introduction of ethical standards for third‑country activities. On submissions and variations, expected developments

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are set out in the recent pharmacovigilance (PV)‑related amendments to the Medicinal Products Directive, which establish an obligation to provide a risk management plan and to clarify the information required for the consolidated version of the file in renewal dossiers. Regarding veterinary medicinal products, the current expectation is that marketing authorization procedures will be simplified. Yet, the operational impact remains unclear. The key trends are the centralization and simplification of adverse event reporting procedures, increased requirements for studies regarding the safety and efficacy of medicines, increased requirements for the documenting of marketing authorization holders’ PV processes, and increased transparency. All these point to significant burden on PV operations.

Change in the US and BRIC Countries

The situation in the US is similar, with updates to pharmacovigilance requirements, the Prescription Drug User Fee Act, new safety reporting requirements for veterinary medicinal products, medical device regulations 510(k) reform and regulation of laboratory‑developed tests. In BRIC countries, the increase in research and manufacturing activities are leading to more regulatory infrastructure developments in food and medicinal product safety, medical device manufacturing requirements and changes to submission requirements. An increasing emphasis on GCP across human, veterinary and medical devices will lead to increasing regulatory burden and complexity of development activities. A statement of GCP standards for third‑country clinical trials activities will increase the scope of the operational and compliance burden for companies, but may also offer an opportunity for convergence of GCP across human, veterinary and medical device areas. The increasing transparency initiatives, such as registration of trials activity in third countries and regulators sharing benefit–risk data with the public, will lead to increased business risk via public exposure. The industry will need to adapt agile medical and regulatory governance processes to accommodate future regulations. Identifying areas for convergence and areas requiring operational flexibilities are necessary to accommodate the transition periods in the constant regulatory flux in the coming years. The increasing burden in third‑world activities requires closer oversight and compliance management, as well as appropriate resource provision. Nostrapharmus says: “It is essential then that we improve the link between regulatory intelligence and operational strategy to ensure timely alignment with evolving regulatory interpretation.”

November/December 2011

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