Pharma Jan 2012 by Paul Howells

w w w. p h a r m a - m a g . c o m January/February 2012 ISSN 1746-174X

Volume 8 Number 1

R&D

Leveraging Knowledge and Collaboration

Excipients

Third-Party GMP Certification

Biologics

Cellular Therapeutics The global magazine for the pharmaceutical and biopharmaceutical industry

Achieving Flexibility

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DEVELOPMENT

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DELIVERY

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January/February 2012

CONTENTS

JANUARY/FEBRUARY 2012

Contents FOCUS TOPIC

Supply Chain

Corrine Lawrence, Via Media UK Ltd

A review of the Via Connect roundtable on “Achieving Flexibility in the Pharmaceutical Supply Chain.”

Software/IT

InfinityQS International.

Industry experts highlight a range of topics in the sector, including mobile CRM, real‑time quality control solutions and the new Annex 11.

FEATURES

Nutraceuticals: Food For Thought … and Health

Leonard M. Fuld — Fuld & Company

How can pharma get a share of the market and avoid being blindsided by consumer packaged goods?

Dianne Richardson — ediTRACK

In today’s social media age, where word of mouth spreads rapidly, a supply chain disaster can be devastating.

Contributing Companies: Qlucore, Kereon AG,

Infosys Ltd, Cegedim Relationship Management and

Supply Chain: Using Technology to Avert Pharma Supply Chain Catastrophes

Excipients: The Road to Third-Party GMP Certification

Dennis Reiswig — The Dow Chemical Company

Pharmaceutical manufacturers are showing increasing interest in ensuring their product ingredients are meeting the highest standards for purity.

Biopharmaceuticals: The Importance of CO2 Control During the Manufacture of Biopharmaceuticals

Kurt Hiltbrunner — Mettler‑Toledo Process Analytics

The Market Segment Specialist at Mettler‑Toledo Process Analytics talks to Pharma about CO2 monitoring and control.

Biologics: Cellular Therapeutics: Preclinical Safety Programmes and Study Design Considerations

R&D: Leveraging Knowledge and Collaboration to Refill the R&D Pipeline

Kiran Meekings, Hans Poulsen and John Cole — Thomson Reuters

There is a significant trend for more strategic partnerships, but what is the degree to which companies are willing to collaborate precompetitively?

Freeze Drying: Development of an Enhanced Methodology and Technology for Safe, Rapid Freeze Drying of HPLC Fractions Rob Darrington — Genevac Ltd

How two companies worked together to enhance fast lyophilization technology to deliver lyophilization success rates of 95% with wide‑ranging chemical libraries.

REGULARS

A Prescription for Sense

Showcase

Dr Kevin Robinson — Via Media UK Ltd

Is common sense our most effective weapon in the war against antibiotic abuse?

A selection of new products now available to the pharma industry.

Shawna M. Jackman, Douglas B. Learn and

Lauren E. Black — Charles River Laboratories

Will human cells act in animals as we hope they do in humans?

Supply Chain: A Multilayered Approach to Supply Chain Management

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

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Paul Davies — Rockwell Automation

Progressive producers and distributors can better combat organized crime and drive down costs.

January/February 2012

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STAFF

Contributors Editor Corrine Lawrence +44 (0) 771 517 7767 corrine.lawrence@via-medialtd.com Editorial Director Kevin Robinson +44 (0) 1392 202 591 kevin.robinson@via-medialtd.com Art Director/Production Paul Andrews Tel. +44 (0) 1372 364 126 paul.andrews@via-medialtd.com Content/Marketing Manager Claire Day Tel. +44 (0) 1372 364 129 claire.day@via-medialtd.com Account Manager Michael Lund +44 (0) 1372 364 124 michael.lund@via-medialtd.com Financial Officer Cherelle Saunders +44 (0) 1372 364 123

cherelle.saunders@via-medialtd.com

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

Editorial Advisory Board

The Editorial Advisory Board of Pharma comprises a distinguished panel of experts from various parts of the pharmaceutical industry. They review technical manuscripts, suggest topics for inclusion, recommend subject matter and potential authors, and act as the quality control department for the magazine’s editorial content and direction. Rory Budihandojo Director, Quality Systems Audit Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd Patrick Crowley Vice President Product Line Extensions GSK (US) Enric Jo Plant Director Reig Jofre Group Maik W. Jornitz Senior Vice President Global Product Management, Bioprocess Sartorius North America Inc. Alan Lahaise Key Account Executive Patheon

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

To subscribe

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

Registered Office:

Via Media UK Ltd 145-157 St John Street, London, EC1V 4PW, UK. The publisher endeavours to collect and include complete, correct and current information in Pharma but does not warrant that any or all such information is complete, correct or current. The publisher does not assume, and hereby disclaims, any liability to any person or entity for any loss or damage caused by errors or omissions of any kind, whether resulting from negligence, accident or any other cause. Pharma does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take any responsibility for any losses or other damages incurred by readers in reliance on such content. Copyright © 2012, 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

Quality in your hands

GUEST EDITORIAL

A Prescription for Sense As the war on antibiotics abuse rages on, isn’t is about time we delpoyed our deadliest weapon ... common sense?

pretty much stopped subscribing to consumer magazines a few years ago because they seemed to keep recycling the same batch of themes, topics and stories. Feelings of déjà vu would wander into my mind as I flicked through the glossy pages and the ever‑increasing subscription fees started to lose their appeal. You wouldn’t necessarily expect to experience the same phenomenon in a daily newspaper, but a recent issue of the New York Times proved me wrong. Perhaps the subject matter, a personal crusade of mine, made the story more prominent, but there it was, yet another “exclusive” on antibiotic abuse. We may well be living in a world beset with “an unprecedented wave of new and old infections,” but how often do we need the tabloids to tell us that antibiotics are frequently misused, overprescribed or incorrectly taken by patients, and recklessly fed to farm animals? As a result, states the journalist: “Lifesaving drugs lose effectiveness faster than new ones are being developed to replace them.” Each year, 100,000 people in the US die from hospital‑acquired infections that are resistant to antibiotics. In Europe, 31,000 deaths per year are attributed to such infections, and they are thought to contribute to another 110,000 deaths globally, says the World Health Organization. And yet, there seems to be such a simple solution. Improving how antibiotics are prescribed can do more than just curb resistance; it can save both lives and money by reducing adverse reactions and eliminating or shortening hospital stays. But why, I ask, is this not being done? On a positive note, the article went on to describe a new series of reports from the Mayo Clinic, aimed at physicians and patients, which “will help doctors and practicing healthcare providers to know when and how antibiotics should be used and, equally importantly, when they should not.” So much for a quality medical education then! And, although I applaud any attempt to improve this ongoing situation of drug misuse, I can’t help but feel slightly miffed that the reports also plan to help patients to better understand how and when antibiotics work best, and arm them with the right questions to ask when an antibiotic prescription is being considered. So, if I understand my condition, what drug is required, how it works and for how long to take it, can’t I just pop into a chemist and miss out

January/February 2012

the “middle man”? Obviously, I’m being facetious, and I do agree with the report’s message that we must avoid a “one size fits all” approach to antibiotics. There are many factors that must be taken into account to ensure the right drug at the right dose is given to the right patient. And, according to the newspaper: “It is often up to the patient to make sure the physician is aware of these influential factors.” No pressure there, then. It concerns me that the emphasis of responsibility for a lot of these factors lies in the lap of the patient. Of course, things may be vastly different in the US, but I would expect my doctor to have some idea of my age … and be willing and able to exercise a certain level of clinical judgement. Yes, the majority of people who get past reception with an inflamed throat, deep cough, high fever or unrelenting sinus pain actually need and would benefit from a course of antibiotics; but, all too often the cause of patients’ symptoms is not bacterial and may not even be an infection. In these cases, as I have stated before, taking an antibiotic — especially a broad-spectrum one — will do no good and could even be harmful. Viruses and connective tissue disorders will simply not respond to penicillin! The take home message has got to be that doctors, qualified experts in their field, prescribe drugs. Patients, however well educated, don’t. Only doctors (and vets) can effectively halt the tide of overprescription and prevent the further development of resistant superbugs and ineffective medicines. Simple procedures such as taking a culture of the infective organism could lead to the more accurate prescription of efficacious drugs, a decrease in the administration of pointless medicines and the reduced use of broad-spectrum, fire and forget treatments that don’t necessarily target a specific micro-organism, which, in the long-term, may well mitigate the need for long-term antibiotic therapy. The upshot of improved prescription practices is not just the better health and well-being of the general public, it reduces the risk of yet more bacteria becoming resistant and obviates the need for pharmaceutical companies to invest their time and resources into developing replacement drugs. Considering that it takes about 10 years and more than a billion dollars to get a new API from discovery to market, it’s not such an inconsequential matter when drug A or treatment B are no longer effective.

For further information Kevin Robinson Editorial Director Via Media UK Ltd

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

www.pharma-mag.com

SUPPLY CHAIN

ACHIEVING FLEXIBILITY IN THE PHARMACEUTICAL SUPPLY CHAIN

The supply chain issues facing the pharmaceutical industry are getting increasing attention and coverage as both the upstream supply chain gets longer, and works its way into emerging market countries, and its downstream equivalent gets more complex, dealing with issues such as counterfeiting and finished product tracking. Via Connect invited a group of experienced executives from the pharmaceutical, contract manufacturing and development industries to discuss these issues.

Critical Issues

The roundtable opened with the panel identifying the critical supply chain issues — upstream and downstream — which currently face the pharmaceutical industry. Peter Strong, Senior Vice President and Head of the Pharmaceutical Business at Codexis, explained that there are many critical issues gaining prominence in the business models of pharmaceutical and generics companies; it’s not because the industry is dysfunctional, Big Pharma is in a state of evolution and companies need to keep pace. As such, despite the cost reduction environment shaping the industry, Codexis is focusing on trying to establish something more than cost as a value proposition for its customers. Another critical issue, according to Strong, and one that is also evolving, is how sponsors manage contract manufacturing organizations (CMOs) and the resources that are employed to govern the relationship between the two. There is room, he noted, for improvement on both sides. Jim Mullens, CEO, Patheon, said that they are seeing certain products at different times of their lifecycle that have a lot of demand volatility; yet, there’s been a lack of contingency planning regarding the supply chain — rarely has there been detailed discussions with different partners in the supply chain in a way that they can really participate and help in. He stated that Patheon is also seeing companies with cost pressures; they are trying to run with leaner inventories, which, coupled with demand volatility, leaves little room for error when something goes awry in the supply chain. Other major problems in the supply chain are linked to increasing globalization and higher and more complex supply chains:

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counterfeiting, the adulteration of products, theft and unknown impurities. Thomas Zimmer, Senior Vice President, Corporate Quality in Environmental Health and Safety, Boehringer Ingelheim, explained that every month a new case of an unknown impurity comes to light, which is not covered by our traditional testing concepts. The regulators, however, have already reacted to this with the introduction of new regulations including the following: • t he US Importer Guidance, which stresses the mantra of ‘Know Your Supplier,’ to encourage full transparency • t he European Commission’s revised draft of Chapter 5 of the EU GMP Guide • t he European Council’s draft on good distribution practices (GDP). The obligation for oversight lies clearly with the marketing authorization holder. In the European GDPs, for example, there is a new function — the socalled Responsible Person, which is the supply chain’s equivalent of the Qualified Person in production. The new regulations and guidance will increase pressure … and affect both costs and budgets.

Implementing Lean Supply Chains

One delegate, Dianne Sharp from SCM Pharma (a contract development and manufacturing organization), advised that the lead times from drug companies are being reduced. Previously, the natural impact was that stocks were increased. This is now not possible. She suggested that the industry should consider implementing lean supply chains, borrowing models from other industries — such as the automotive industry — to get lean, reactive supply chains all the way back to two or three

January/February 2012

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SUPPLY CHAIN suppliers and offer very short lead times. For this particular delegate, a lean supply chain is reactive, responsive, but not by holding lots of stocks at every level. It’s about being able to make to order, quickly and effectively at every level of the supply chain. Strong agreed that sponsor companies are demanding greater reactivity from the companies they buy materials from, and that it’s a natural response to try to accommodate that with a lean supply chain. But, he warned: “If you’re creating a lean supply chain in response to a lack of information, you might be solving the wrong problem. If the sponsor and the CMO had a more efficient and complete discussion about demand and the situations that will create forecast variability, then there’s room to make a more optimal system.” Sharp disagreed and said that that doesn’t work. Continuing with the example of the automotive industry, she explained: “The basis and the way in which their lean systems are able to work is because they work to forecasts. They look at demand fluctuation and the relationship between the supplier and sponsor at each level, and share information widely. It is interesting to see the reticence from some of our sponsors about sharing where they think the market’s heading and what their demand fluctuations are likely to be.” An iterative process wherein everybody in the supply chain understands all the nodes is required to lean out the supply chain and make it robust, noted Mullens. He added: “Rarely does the customer want to discuss any other part of the node of the supply chain. Our ability to help the contingency plan, therefore, is nil … until disaster happens, then everybody has a problem. At the other end of the spectrum, paradoxically, the many mature, stable tail products are poorly managed from an inventory perspective. We see as many panics with these products because they are not being properly managed internally.”

level, this leaves a lot to be done in the case of an event. Establishing a second manufacturer, a second supplier, will shorten this activation time, but has cost implications.

Crisis Management

inventory with one of their biggest partners. This enables them to assess their stock levels, their partner’s stock levels and when material needs to be moved. This arrangement satisfies both parties. The question then posed was: Have pharma companies considered a similar approach with their partners? In answer to this question, Mullens said that they (Patheon) have no downstream visibility of what’s going on. For the largest and most sensitive products, they are forced to do their own research into understanding end-market demand. This, he described as “silly,” because the company’s not set up to do that kind of work. Because they lack this type of information, it is impossible for them, in isolation, do a lot of the risk analysis and contingency analysis. By contrast, when he was running a global

Crisis management and contingency plans were further expanded upon by the panel. Thomas Zimmer, Senior Vice President, Corporate Quality in Environmental Health and Safety, Boehringer Ingelheim, stressed the importance of activation time. “The volcanic ash cloud, for example, impacted air traffic for one week, but it had no impact on our supply chain. The nuclear disaster in Fukushima Daiichi (Japan) came closer to affecting our supply chain. A pandemic event, however, might be more serious because the normal duration of such an event is 3–4 months.” Zimmer advised that when setting up a risk management concept, it is essential to determine the right activation time for each type of event. If a contingency plan exists only at a paper

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Information Sharing

When asked about the extent to which Eli Lilly is effectively sharing information regarding forecasting and supply requirements with its third-party manufacturers, Sherman Whitfield, the company’s Director of Alliance Management, said that they have come to realize that they need their CMOs. Because it’s imperative that the CMOs understand Lilly’s process and supply chain, the company is working with strategic partners to ensure a win–win. “We’re not looking for the cheapest manufacturers,” he explained, “because somewhere they will have to cut costs and then we will suffer. We believe that one plus one equals three; that is, when Lilly and a partner join together, we emerge with a thorough process — a third benefit that neither of us saw in the beginning. This, in turn, is good news for our patients.” Sharing his perspective as an API manufacturer, one delegate said that they have been sharing SIP systems across

Natural Products

Are there special issues in the supply chain relating to botanicals and nutritional supplements that are similar to or different from what is seen in pharmaceutical products? Mullens answered: When you’re dealing with natural products, you have inherently less control of the manufacturing process for their extraction and more variability in the products themselves. Characterizing those and knowing what the most important impurities are becomes critical. They are more difficult substances to deal with and handle and so you need to reflect that understanding in your supply chain strategy.” According to Zimmer, it’s simply a question of risk management — there’s no difference between pharmaceuticals, food and dietary products and natural health products; the risk to health and safety if the same.

January/February 2012

SUPPLY CHAIN biopharmaceutical company, which was developing major products and going to launches, they did a lot of contingency, risk and failure analysis. He found that when the failure analysis highlights a problem, a lot of inventory is normally lost. Mullens explained: “It’s easy when you only have the one batch that clearly failed for a specific reason. But the reality is that if you run into a quality problem that affects 10, 20 or 30 lots because you can’t pinpoint the issue, you don’t know how far it went back in the supply chain.” He then stressed the importance of doing highly detailed failure analysis into what and how it can go wrong, from the API to all along the supply chain. Only by doing so can companies build in some contingency and work out where they’ll need to build in some buffer. With regard to sharing information, it was noted that collaborations are particularly successful when both parties don’t regard themselves as two separate entities. The relationship really works when it evolves to the point where the sponsor regards the CMO as an extension of their capabilities. CMOs benefit by getting a lot more information from the sponsor. Sponsors benefit by receiving the advantage of a self‑developing relationship with that CMO, who’ll feel more inclined to do favours and respond to the sponsor’s emergency.

Mutual Trust

Several CMOs, including Catalent and Patheon, have adopted Trace Link technology, which is meant to integrate the CMO and the customer; but have they witnessed much uptake or interest from their clients? Will Downy of Catalent said that there has been interest, but so far, uptake has been relatively low. “We would like to see much more of it, but I don’t think it’s the technology that gets in the way of information sharing, it’s mutual trust between organizations. When the industry is going through such a challenging time, this should be the moment when collaboration improves. So why is there so much reluctance to make that happen? Why do we have so few examples of inventory systems being shared when it’s where we all want to be?” The panel proposed that what appears to be reluctance is really a conceptual deficit concerning how to manage complexity. Complexity in the pharma industry starts with the portfolio. Boehringer Ingelheim, for example, has several thousand stock-keeping units (SKUs); behind these, the same complexity is found in formulation; and an even higher complexity in API and packaging materials. “This presents you with the question: What should I focus on?” said Zimmer. In response to his own question, Zimmer answered: “First, these complexities should be considered — there should be a process of pooling/

January/February 2012

consolidating and focusing the business model. This complexity is also found in the supply chain — upstream, the number of suppliers, downstream, the number of CMOs. We currently use 170 CMOs and, in the next few years, we plan to reduce that figure to 10.” Zimmer’s final statement was met with a significant silence as the enormity of that task registered. One delegate said that a fundamental cultural change and a shift in the way business is done are required … otherwise getting down to 10 CMOs is a “distant dream.”

Quality and Audits

With regard to quality, it was noted that a company who supplies materials, particularly raw materials from China or India, is not necessarily the party that manufactured the product. The product may, in fact, have gone through several hands before it gets to the

I don’t think it’s the technology that gets in the way of information sharing, it’s mutual trust between organizations. buyer. The inherent quality issues of this scenario are a growing problem and, for many companies, have meant an increase in auditing. The complexity of increased auditing is daunting and many companies have enlisted with the Rx‑360 Consortium and other initiatives to join the audit sharing programme. Mullens concurred with the view regarding the size and relevance of this issue. Companies simply don’t have the resources to go back further and further into the supply chain and audit these programmes. A consortium such as Rx‑360 that promotes quality is perhaps an industry solution to this problem. Strong endorsed ensuring that the more implicit incentives are aligned. “If I ask a supplier to do something for me that they don’t currently do, I establish a relationship with the senior management of the company. These

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SUPPLY CHAIN

issues can be looked at from the global relationship standpoint. If the partner doesn’t have a lot at stake and they make a mistake, you are inviting quality problems,” he explained.

Reducing the Number of CMOs

One challenge facing SAFC is making its customers’ drugs available and affordable, not only to western consumers in the years to come but also to a few more billion consumers, particularly in the emerging markets. Gilles Cottier, the company’s President said that this will be achieved by reducing costs and increasing volume. The quality of products is not something that is going to change; it may even improve. Consumers, wherever they are, will not tolerate any failure concerning the quality of a drug. To reduce the tremendous complexity issue, companies will have to reduce their number of suppliers, which will take time given the regulatory nature of the industry. Picking up on Zimmer’s point about reducing the number of CMOs to 10, Mullens explained: “The reality is that CMOs aren’t big enough for that to happen. So, it’s going to be incumbent upon big pharma and the large generic players to have more strategic relationships.” For the last 30 years, pharma has been treating about one billion people; yet, there’s an additional six billion people looking for low cost, high quality medicines. Finally, Mullens added: “Look at the capital structure, the access to the capital of the CMO business verses Big Pharma. The weighted average cost of Big Pharma capital is probably about 5% right now. I would say their access to capital in the CMO business is probably more like 10–12%. If we’re going to fund all that, the customers will end up paying the spread, unless there is a different strategic relationship and a different way to capitalize these things. If the intent of getting larger more reliable and strategic partners is real, it can’t possibly happen the way we’re going about it.”

SOPs

Adding to the complexity of contract manufacturing is the fact that every client seems to insist on having its own quality standard operating procedures (SOPs). There are, therefore, as many quality protocols as there are customers. It’s somewhat surprising then that there aren’t more quality problems coming out of

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CMOs. Whitfield explained that when, as an auditor. He visited a site that had more than one system in place, he would write five pages of violations, simply because operators cannot be asked to bear in mind whose product they are working on at any given time. Do they have to ask themselves ‘am I supposed to do it really good today; is this a good customer’? Whitfield urged the necessity of having just one system. By getting to know the people in the company, business takes on a more personal hue and ‘preferential’ treatment is given to those that have taken the time to build up a strong relationship. Having more than one quality system on a site is begging for trouble.

Downstream Supply Chain Challenges

In an attempt to tackle the real and serious problems of theft and counterfeiting in the industry, the Falsified Medicines Directive from the European Commission, which was published in June 2011, is now being transposed into national law by each Member State of the EU. Mass serialization is due to start in 2015. The European Federation of Pharmaceutical Industries and Association (EFPIA) piloted a system in Sweden to prove the concept of end‑to‑end verification on a 2D barcode, which is

January/February 2012

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January/February 2012

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Roundtable Panellists

•D r Thomas Zimmer, Senior Vice President, Corporate Quality in Environmental Health and Safety, Boehringer Ingelheim. • Jim Mullens, CEO, Patheon. • Peter Strong, Senior Vice President and Head of Pharmaceutical Business, Codexis.

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January/February 2012

SUPPLY CHAIN

Other major problems in the supply chain are linked to increasing globalization and complexity: counterfeiting, the adulteration of products, theft and unknown impurities. the preferred model of the member companies of EFPIA. The 2D barcode is considered to be the most affordable and effective model. There are, however, three ‘buts’ as Zimmer pointed out. “First, it is intended to be rolled out for prescription medicines only because of the issue of complexity. Second, the European Community consists of 27 Member States, and the uncertainty concerning grace periods may make for ‘unharmonized’ implementation. My final ‘but’ concerns the Internet because it’s not covered by definition, which is worrying given the number of counterfeit drugs that go directly to the customer.” In the US, federal legislation is lagging behind California, which is on the way to making a pedigree system. “In addition,” said Zimmer “are the individual company legislations. Worldwide, people are doing things differently, which, again, increases complexity.” Providing a perspective from the contract packaging segment was Steve Kemp of Brecon Pharmaceuticals: “We have certainly seen a lot more demand for and dealt with queries concerning serialization, and track and trace. We are now equipping ourselves to cope with this.” Kemp highlighted the trend in seeing more low cost countries being involved in manufacture and

January/February 2012

raised the question: “if these low cost countries were not involved in manufacturing, would we see such a demand for counterfeit products?” He continued to explain that fitting anticounterfeiting technologies is expensive, requires more audits and compliance requirements to ensure they are all working. Kemp asked pharma companies whether they have seen an increase in counterfeit products coming through since using low cost countries. Zimmer said that EFPIA and WHO statistics prove that the problem is rising. Data cannot, however, bring into existence statistical truth. He added that those statistics are only the tip of the iceberg and it can be assumed that there is much more going on than is known.

Summary

To conclude the roundtable discussions, the panel was invited to provide individual summary remarks regarding the direction they see the industry heading in terms of achieving greater flexibility in the supply chain. Strong said he was encouraged by the confirmation that the outsourcing industry is here to stay. “We are no longer just an occasional supply chain process for large or small sponsor organizations,” he said. “We are becoming a more significant part of normal operations. Looking ahead, I think the outsourcing industry is becoming the primary manufacturing place and as such we are still trying to figure out how best to interact with each other. Many of the problems we discussed today are things that we can control, particularly in how we interact.” Zimmer stressed the important of more talking between industry players so that they can understand problems and find common solutions. He identified a widespread lack of intellectual engagement to mechanistically understand what is going on. Using the Internet as an example, he asked delegates whether they knew how an Internet chain really works. “It took me months to understand it,” he said. “It’s clear, strategically, that most people in the industry are trying to move in the same direction,” concluded Mullens. The contract manufacturers are becoming the strategic suppliers and the information exchanged has got to step up to a corresponding magnitude. This, says Mullens, will require “a cultural shift and it has to start with the presumption that the people entering this have got to build relationships and trust, because with all the complexities, there will inevitably be issues and problems that require solutions.” Perhaps the leadership is not actually coming from Big Pharma, but rather from the specialty pharma companies and those that don’t have a significant internal manufacturing network.

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S Carl-Johan Ivarsson

For more information Carl-Johan Ivarsson President Qlucore Tel. +46 46 286 3110 www.qlucore.com

ome of the world’s most respected researchers are currently examining the role of biomarkers in cancer research. A biomarker is any characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers could play a major role in medicinal biology, as they can help with early diagnosis, disease prevention, drug target identification, patient stratification, drug response and more. As such, gene‑based biomarkers are an effective way of studying human disease. Researchers, however, face the challenge of trying to extract recognizable patterns from huge arrays of genes, proteins and/or RNA molecules when studying these type of genetic data. The extraordinary amount of data produced by gene expression experiments such as these makes it increasingly difficult to identify which genes are relevant and to what degree, particularly when working with tens of thousands of data points being generated by hundreds of different patients. Despite these challenges, scientists working in this area must still capture, explore and analyse this vast amount of data effectively, as this information is vital if they are to apply their findings to real‑world conditions. Fortunately, the latest software in this area is now helping to accelerate and facilitate the understanding of both the context and relationships of the information contained within large data sets by displaying them graphically, in real time. The simplicity of this interaction now makes it possible for researchers to work with powerful statistical analysis in entirely new ways. Furthermore, faster analysis frees up more time for scientists to test more creative theories, which in turn leads to better research results. When analysing this research data, scientists often rely on principal component analysis (PCA): a method that can be used to project high dimensional data down to lower dimensions. By using PCA, specialist software can then be used to plot the

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lower dimension data produced via PCA onto a two‑dimensional (2D) computer screen, so that full‑colour 3D images can be rotated and examined with the naked eye more easily. Software can then be used to manipulate the different PCA plots — interactively and in real time — complete with all annotations and other integrated links, as well as several powerful statistical functions, such as false discovery rates (FDR) and p‑values. By receiving all of this data in a highly comprehensible graphical format (3D), scientists can make decisions based on information that they can understand more easily. As a result, this level of data visualization can produce results in seconds, even if the researcher isn’t a trained statistician. Similarly, if the data has batch effects — or is paired with unwanted dependencies — these variables can be removed with just a few mouse clicks, so that the results can be delivered and analysed in real time. It’s therefore now possible to investigate the output of large clinical trials quickly, and test different hypotheses and explore alternative scenarios within seconds. As a result, scientists looking for new biomarkers can drastically shorten their analysis time when identifying relevant structures in their data. During the last 3 years, a major effort has been made to develop sophisticated data analysis software that is both extremely powerful and can help scientists to explore and analyse the high‑dimensional data sets interactively and in real time. With this approach, researchers are already able to analyse and explore extremely large data sets — even those with more than 100 million data samples — on a regular computer. More important, the latest, most intuitive software in this field will allow the researchers involved — the people with the most biological insight — to study the data and to look for patterns and structures, without having to be a statistics or computer expert. As a result, this kind of software will help to provide unprecedented insight for a wide variety of cancer research programmes, and will, therefore, play an invaluable role in the ongoing study of biomarkers.

January/February 2012

STRAP

January/February 2012

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SOFTWARE/IT

NEW ANNEX 11 EVOLUTION AND CONSEQUENCES On 12 January 2011, after a 3‑year long wait, the revised Annex 11 — Computerized Systems — to the European GMP Guide was released. This document, which is based on ICH Q9 principles and covers, more exhaustively than the first version, the life cycle of computerized systems, takes into account and focuses on a risk‑based approach.

he genesis of the revised Annex 11 is likely to be found in the written work for the PIC/S Guide PI 011. 1 Indeed, the purpose of this Guide, released in 2003 (that is, around 10 years after the first version of Annex 11), is to provide recommendations to the inspectors — and consequently to the regulated user and its suppliers — for reviewing the implementation of Annex 11. 2 During 1992–2003, the use of computerized systems dramatically increased and the industry developed various approaches for fulfilling possible regulatory expectations.

Main Evolutions

The draft of Annex 11 released in 2008 specified too many details and needed some improvements regarding consistency. It received numerous comments (more than 1200 within 6 months) from the pharmaceutical industry and its suppliers. The revised 2011 version, although very similar to the initial version, is smaller than the draft and develops consistently, where necessary, the topics covered in the initial version: • T he necessity of mastering the life cycle — from requirement to retirement — is now an explicit requirement. This principle has been extended to the control of processes. • I T infrastructures supporting regulated systems have to be “qualified” — they have to be kept under control throughout the life cycle of the supported systems. This requirement is not really new because it was widely implicit in the previous version of Annex 11, but explicit in PIC/S Guide PI 011, §17.3. It is also stipulated that internal IT departments, as well as external service providers, must be considered in the same way, particularly the need for formal service and operation level agreements (SLA, OLA) defining the operational conditions of supported applications and systems. • T he key principles of a science‑based risk management derive directly from ICH Q9

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focused on patient safety, product quality and data integrity. 3 Supplier management and service provider management rely on such consistent risk management as well. Although such requirements were not mentioned in the previous version of Annex 11, they were already part of PI 011. • D ifferent roles, such as system owner and process owner, are now clearly identified as major compliance players. Even though the definition of these roles is less detailed than described in GAMP 5, the stipulated responsibilities are essential. 4 • Within the framework of risk‑based compliance, supplier effort can be significantly leveraged provided they have been consistently assessed. It is expected, therefore, that “Quality system and audit information relating to suppliers or developers of software and implemented systems should be made available to inspectors on request.”5 • T he section concerning validation has been significantly improved and suggests the following: • T he need to maintain an up‑to‑date system inventory — already mentioned in Annex 15

Industry Responses to the Revised Annex 11

Generally companies to which the revised Annex 11 applies fall into one of three categories: • Mature companies that have to monitor computer system validation (CSV) activities and their results only a little more closely. • Young companies that have experienced considerable trouble with the initial version of Annex 11 and continue to struggle with the new version. At the same time, FDA suggests that those companies that have noticeable CSV deficiencies also experience significant GMP deficiencies • Companies that are unaware of the revised Annex 11, respectively ignoring European regulatory requirements and believing that only 21 CFR Part 11 is governing CSV. Surprisingly, such companies, including those in Europe, are common. Specific areas of concern: • applying a consistent risk-based approach • improving supplier auditing practice • managing suppliers efficiently • performing efficiently periodic evaluation.

January/February 2012

SOFTWARE/IT Figure 1: The revision of Annex 11 is the result of two decades’ worth of iterative process.

and promoted in PI 011 — is now emphasized in Annex 11. 6 • T he necessity to ensure a systematic traceability throughout the life cycle of the computerized system is now required. Furthermore, it is expected that this traceability is based on a documented risk assessment and GxP impact. • F or critical systems, it is expected that a system description showing the system configuration, data flows and security measures is available. • T he regulated user can provide evidence of the pertinence of test methods and that test scenarios could be demonstrated. In addition, automated testing is acceptable so long as the adequacy of testing tools and test environments is documented. As automated testing tools can ‘fit’ into the GAMP Software Category 1, applying the recommendations and approaches promoted by the GAMP Good Practice Guide: IT Infrastructure Control and Compliance is one way for keeping such tools under control. • F or data that need to be converted to another format or transferred between two systems, it is necessary to validate such conversion or transfer and to include data verification in terms of value and meaning. • T he electronic signature is now officially recognized without becoming mandatory. • T he requirements regarding the operational phase are primarily based on good business and operation practices. Such requirements were widely mentioned in the previous version of Annex 11; some, however, have been developed in the new version. • The operational requirements cover • data and accuracy checks • data storage • printouts • audit trails • change and configuration management • security

January/February 2012

• incident management • business continuity • archiving. • I n addition to Annex 15 clauses 23 and 45 (establishing since 2001 the need for a formal periodic evaluation), the new Annex 11 repeats explicitly this requirement for computerized systems.

Consequences

Although the new version of Annex 11 doesn’t represent a revolution, it does have some implications, including • Compliance decisions based on the results of risk management activities have to be justified. This expectation — already mentioned in PI 011 — is now mandatory, which implies that risk management activities must be conducted consistently and rigorously. • T he condition for leveraging supplier involvement is to put in place rigorous processes regarding supplier evaluation and selection, as well as supplier management. At the same time, the industry must make available audit information to inspectors, upon request (see clause 3.4). • F or critical systems, the need for a standalone, detailed description — in addition to the one embedded in the Validation Plan or in the User Requirements Specifications (URS) — as provided in the previous version of Annex 11 is reinforced. Such a document can be easily prepared based on the recommendations provided in GAMP 5, Appendix D6 “System Descriptions.” • T he yearly revision of Validation Master Plans (VMP) offers an excellent opportunity for reviewing and maintaining an up‑to‑date system inventory. • T he supporting processes to the operational phase — already mentioned in the previous version of Annex 11 — are clearly stated. In addition, the requirement to evaluate periodically the systems’ compliance enforces the importance of the operational supporting processes.

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SOFTWARE/IT

Yves Samson

Notes

1. PIC/S, Good Practices for Computerized Systems in Regulated GxP Environments (September 2007). 2. PIC/S PI 011, footnote 1: “Throughout this document the ‘users’ (owners of the good practice computerized systems being inspected) are collectively referred to as ‘regulated users’ for clarity.” 3. Within the European GMP, ICH Q9 has been initially established as Annex 20. Since February 2011, this document — as well as ICH Q10 — has been released as part of European GMP Part III. 4. ISPE, GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems (February 2008). 5. Annex 11:3.4. 6. Annex 15 to EU Guide to Good Manufacturing Practice (Volume 4) “Qualification and Validation” (2001). 7. The wording of this requirement is particularly important as it gives a more limited and pragmatic definition of the electronic signature than provided in the European Directives 1999/93/EC and 2000/31/EC. GAMP is a registered trademark.

For more information

Yves Samson Director Kereon AG Tel. +41 79 403 73 01 yves.samson@kereon.ch www.kereon.ch

the revised Annex 11 represents both a return to the roots and a significant evolution in compliance maturity. Annex 11 Versus 21 CFR Part 11

Annex 11 and 21 CFR Part 11 take different positions within their respective regulatory contexts. Whereas 21 CFR Part 11 discusses only the implementation of electronic records and electronic signatures within the GxP scope as defined in the predicate rules, Annex 11 focuses on the use of computerized systems in GMP environments. As such, the main requirements relating to system life cycle (until system retirement), supplier management, and qualification and validation activities as defined in Annex 11 can be summarized in 21 CFR Part 11 by paragraph 11.10(a), which stipulates that the validation of computerized systems is necessary and unavoidable for establishing electronic compliance. Furthermore, the revised Chapter 4 (concerning documentation) is much more detailed and prescriptive than 21 CFR Part 11. The electronic signature manifestation is not explicitly identical in the both texts. 21 CFR Part 11 requires the signature meaning as part of the signature. Annex 11 does require it implicitly as signature meaning is in all cases a requirement for GxP documentation as stated in Chapters 1 and 4. Yet, except for batch release, which is specifically discussed in Annex 11, the impact of electronic signatures as equivalent handwritten signatures is limited to the boundary of the company. 7 Within a different legal context than in the EU (see

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1999/93/EC and 2000/31/EC), 21 CFR Part 11 establishes electronic signatures as the “legally binding equivalent” to handwritten signatures. Nevertheless, both texts lay down the principle of an immutable link between the signature and the signed record as an essential compliance requirement. Annex 11 does not stipulate that organizations must submit a declaration regarding the use of electronic signature for GxP activities to the EMA or other national Agencies. Similarly, those using an electronic signature do not have to provide a specific certification regarding its use.

Revised Chapter 4

Together with the revision of Annex 11, Chapter 4 of the European GMP Guide has been revised. This revision is limited as the enhancements concern mainly the use of electronic documents within the GMP context. Chapter 4, however, is an important document; yet regulated users are insufficiently familiar with it and fail to consistently apply it. Chapter 4 summarizes the requirements of GMP‑related documentation activities, listing the various types of expected records and the corresponding retention periods, defining the processes for generating and controlling GMP documents, and reminding of the basic principles of Good Documentation Practices.

Convergence and Future Developments

The revision of Annex 11 — including Chapter 4 of the European GMP Guide — is the result of two decades’worth of iterative process (Figure 1). This process — based on a continuous sharing of experience between regulators and industry — has facilitated a demanding, but consistent, approach to electronic compliance commensurate to the criticality of the concerned processes to be defined. The convergence between regulatory requirements and industry recommendations, such as provided by GAMP, establishes a stable regulatory framework that enables the pharmaceutical industry and its suppliers to define a cost‑effective and efficient approach to compliance. The next version of the PIC/S Guide PI 011 should give regulators the opportunity to clarify the impact and the extent of some requirements, as well as details concernning the expected level of implementation. With regard to the draft for comment published in 2008, the revised Annex 11 represents both a return to the roots and a significant evolution in compliance maturity.

January/February 2012

SOFTWARE/IT

SHARING PRIVATE CLOUDS

Can cloud computing save the pharmaceutical industry from the rising tide of data? rug companies are struggling to cope with the mountains of complex data produced by modern pharmaceutical research methods. Cloud computing promises to be a panacea for many of the industry’s ailments, but there is still concern as to whether the technology can accommodate the stringent confidentiality and data security requirements that are holding back widespread adoption. For many pharmaceutical brands, hosting intellectual property and confidential customer information on a shared infrastructure is a risk they’re reluctant to take. Yet, this seems to be more an issue of perception than an actual technological challenge. Despite its general hesitancy, some within the pharmaceutical industry have already taken their first steps into the cloud. In April last year, the Pistoia Alliance (an industry body formed by informatics experts from leading pharmaceutical companies including AstraZeneca, GSK, Novartis and Pfizer) successfully completed a pilot scheme running clinical trials using cloud services. The Alliance works on overcoming difficulties in aggregating, accessing and sharing data that are essential to innovation. Its remit includes technology projects that support precompetitive collaboration among pharmaceutical companies worldwide. To that end, the Alliance has built a cloud‑based electronic laboratory notebook, which members can access and contribute their latest findings to a shared database using a secure private network connection. Cloud is also the enabler behind the growing interest in how pharmaceutical companies can use social networking services to garner customer opinions that can help them to develop more successful sales and marketing campaigns. Last year, Pfizer trialed cloud computing to conduct online clinical research with customers and is now using it to deliver real‑time information to its global sales team.1 Activities such as this are relatively low risk, and are fertile ground for testing the capability and reliability of cloud technology. Subhro Mallik

Reference

1. www.calliduscloud.com/ templates/newspress. aspx?id=4920

For more information

Subhro Mallik Associate Vice President Life Sciences Infosys Ltd subhromallik@infosys.com www.infosys.com

Overcoming Barriers to Adoption

So with these initial forays into cloud computing providing good proof of concept, what is holding companies back from embracing a technology that could bring innovation back to the industry? Apart from data confidentiality concerns, there’s the question of cost. Building a private cloud environment is expensive, particularly for global organizations employing many thousands of staff across multiple locations. The initial investment in hardware and software licences may be too high to justify the efficiency and collaboration benefits that cloud brings. One way round this is for multiple pharmaceutical companies to build a shared private cloud that meets the

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industry’s regulatory requirements and that can be securely partitioned. This method lets companies collaborate on public projects, to the overall benefit of the industry, without the burden of carrying the whole cost of the implementation. As long as data security and access management policies are fully transparent, this type of shared public cloud is a safe way to store and access valuable information. Once the cloud network has been set up, the pay‑per‑use model makes it a very cost‑effective network. Software, business processes and infrastructure can all be delivered through the cloud and consumed ‘as‑a‑service,’ allowing businesses to scale consumption up and down. In addition, by moving technology to an operational cost base would also help to keep maintenance and upgrade expenses under control. This shift from capital expenditure to operational expenditure is a benefit less recognized by the pharmaceutical industry, but one that could be a lifesaver in tough economic times.

The ‘Next Generation’ of Opportunities

Once pharmaceutical companies begin to engage with the cloud en masse, there are opportunities waiting that could breath new life in the industry. Among these is next‑generation sequencing (NGS). This development in DNA research promises to lower the cost of sequencing below what is possible with standard dye‑terminator methods. This has the potential to redefine the market landscape for pharmaceutical R&D. Yet, high‑throughput technologies such as NGS produce millions of sequences and a single research experiment can generate hundreds of petabytes or even zettabytes of data. Its success relies on a technology infrastructure that can store and quickly process vast quantities of data. Cloud computing can provide a virtually unlimited processing environment as and when required. Removing the capital expense and paying per use for technology will ultimately cut the cost of developing new pharmaceutical products and potentially open up new markets. The pharmaceutical industry is facing the harsh commercial realities of shrinking demand for new products, as well as attrition of its customer base as those customers begin to research products for themselves online. Brands need to cut through the uncertainty surrounding cloud technology and see that its reservations are grounded in their own misconceptions and not in the actual capabilities of cloud computing. This is the time for pharmaceutical brands to make the most of the opportunities cloud has to offer. Cloud is here to stay, whether the pharmaceutical industry chooses to adopt it or not … but if it does, the industry will have an unprecedented opportunity to reinvent itself.

January/February 2012

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January/February 2012

SOFTWARE/IT

MOBILE CRM COMES OF AGE

David Round, General Manager, Cegedim Relationship Management, explains why the arrival of technologies such as customer relationship management (CRM) on the iPad has combined with a technically savvy user base to finally enable the vision of a highly productive, informed and informative mobile sales force.

or nearly 20 years, the pharmaceutical industry has been talking about mobile working for its representatives. But despite making significant, sustained investment the field force, mobile technology is yet to be embraced to the extent it could be — primarily because of the shortcomings in hardware rather than a resistance to change.

Mobile Vision

The caricature of the ostentatious city professional with red braces, flash sports car and mobile phone complete with a separate battery pack may prompt laughter now, but for the pharmaceutical field force of the early 1990s, the adoption of new technology was far from amusing. It was around 20 years ago that the first pharmaceutical companies unveiled the laptop; their new secret weapon for the next generation of sales force. With the vision of transforming productivity by providing representatives with the ability to exploit downtime between visits to doctors, mobile access to Electronic Territory Management Systems (ETMS) was meant to herald a brave new world. The reality, however, was somewhat different. Likened to a small suitcase, and with a battery life measured in minutes rather than hours, few representatives embraced their new machines. Whether too embarrassed to be seen carrying one of these monstrosities around with them, permanently battered from lugging them around, or simply in fear of being mugged for a machine that cost in excess of £4000, the vast majority of representatives refused to use the laptop in front of the doctor. Furthermore, there was huge reluctance across the field force to adapt to this new way of working, particularly in the far less technologically aware age that it was. Yes, individuals could access corporate information from the laptop but, in a world with no wi‑fi or broadband, the laptop still had to go into the docking station at home to upload. Even then, waiting for the modem to tunefully — and often unsuccessfully — dial up was time‑consuming;

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data transfer rates were painfully slow and, given the general lack of commitment amongst some representatives to update information within the ETMS, data value was somewhat limited.

Customer Barrier

And so it has continued. Even when the first, somewhat shaky and unconvincing, talking head videos appeared on laptops a couple of years later, with a Key Opinion Leader (KOL) waxing lyrical about the value of a new therapy, pointing the way towards an e‑Detailing future, many remained unconvinced. The ETMS has been replaced by fully featured CRM software, enabling pharmaceutical companies to have far better information about customers and stakeholders, to track interactions and map performance. But even when laptops finally became lighter, smaller and more reliable, and the stigma associated with using them in public disappeared, the concept of mobile CRM has struggled to gain favour with representatives, certainly within the sales visit. Representatives are undoubtedly gaining value from a wi‑fi world where excellent mobile communications enable real‑time access to corporate information anytime, anywhere. But some are still struggling to introduce multimedia e‑Details, PowerPoint presentations or Excel‑based health economic models during the detail: the process of opening and booting up the laptop and searching for the presentation before passing it over to the healthcare professional completely breaks the interaction and makes for uncomfortable pauses in the sales flow. The detailing process has to be a seamless experience; any messaging or presentation must be delivered without interrupting the flow or creating a barrier between rep and customer. It is OK to plug the laptop into a projector to inform those at a meeting, but within a personal interaction, having to first find the material and then hand over the laptop to look through a presentation can create more problems than it solves.

January/February 2012

SOFTWARE/IT

New Tools

So what must change to enable the vision of mobile CRM to be realized? During the past 12–18 months a number of factors have come together that will, finally, enable effective representative mobility. Heard it all before? Well consider: today’s field force is highly technically savvy, representatives are using their Smartphone devices to send emails and update their Facebook pages. There is simply no technology resistance any more … and this applies to the healthcare professionals as well. With the arrival of devices such as the iPad, e‑Detailing suddenly becomes viable. There is no need to boot up or undertake time‑consuming searches for the right presentation: a tablet can be handed over to an individual who instinctively knows how to use and interact with it. This allows the representative to concentrate on the interaction and the reactions of the customer, rather than pressing buttons to find the next slide in the presentation. The inherently flexible technology allows the representative to choose from a raft of e‑Detailing material, from fully interactive multimedia presentations to PowerPoint or simple PDF data sheets, to meet the needs of diverse opinion leaders based on both role and drivers. The availability of CRM applications on the tablet has fundamentally changed the dynamic of customer interaction. When you add this detailing support to the benefits that are already being attained from real‑time access to CRM information on the move, suddenly the pharmaceutical companies can finally see the chance to realize a 20‑year old vision. The timing for mobile CRM could not be better. There is a rapidly changing customer base, with another new set of customer types. Yet opportunities to interact with new stakeholders are as rare as hens’ teeth right now — individuals need to be as well prepared as possible through excellent background research and understanding. Representatives have evolved into key account managers (KAMs) who need to be incredibly well informed about local influencers, strategy and KOLs. And they need to be flexible: even when a KAM gets an appointment there is no guarantee in this constantly evolving and ever changing NHS that the meeting will go ahead with the contact with whom it was booked. Never before has a representative needed more access to information or to feel confident that information is up to date. Across Europe too, the landscape in mobile CRM and rep interaction is changing with the approach to accessing key decision‑makers equally as important as the mobile technology used to plan and execute the meeting. Take for example, Spain — policies to mitigate healthcare costs by enforcing generic prescriptions dominate the country’s highly fragmented market. Thus, it is essential for pharma and biotech companies to gain a more valuable understanding of the new matrix of decision makers that operate at both national and regional levels. Competitive

January/February 2012

companies are leveraging the advantage of flexible CRM solutions to quickly enhance market access strategies and streamline commercial team operations in a globally cost‑controlled industry. Similarly in Portugal, breakthrough CRM solutions are the defining force in the country’s two‑tier healthcare structure in which a limited number of physicians must prescribe medications from cost containing formularies. As a result, companies continue to seek revolutionary solutions that drive sales force innovation and maximize efficiency by quickly adapting to an evolving healthcare structure and providing real‑time analysis of a commercial team’s performance. A complete view of customer interactions through instantly accessible, real‑time data enables companies to better leverage key relationships and more effectively manage commercial teams. Furthermore, governance over commercial teams and enhanced stakeholder targeting makes for sustained and long‑term growth. Inherently, life sciences commercial teams across the globe are now a mobile force interacting with their stakeholders on a daily basis. Consequently, the need for proven mobility tools that are intuitive, fast and that enhance interactions with healthcare professionals is considered a necessity rather than a luxury in today’s environment.

Perfect Storm

With the raft of mobile devices now available with their instantaneous access to almost anything, individuals can always track down the latest research on an organization or individual; they can use the CRM system to track interactions across KOL networks; and they can use tools such as Near Me, which provides a graphical view of individuals locally who could fit in with the call plan to maximize productivity. They can also collaborate effectively across the team — sending requests for additional information, such as research studies, direct to the relevant team member whilst in a meeting with the customer. This dovetailing of demand with technology is driving significant adoption rates for mobile CRM, with pharmaceutical companies developing ever more innovative solutions that include e‑Detailing and multimedia interaction with healthcare professionals. Critically, there is real commitment from the field force to use these CRM systems because they are gaining quantifiable value from the information. No longer do pharmaceutical companies have to bend activity to fit the technology: the mobile technology is available, the CRM solutions are in place and, critically, the field force is skilled and comfortable. The market has finally reached this perfect storm — all the components of mobile CRM are now in place to realize the pharmaceutical company vision of a highly productive, totally mobile field force.

David Round

For more information David Round General Manager Cegedim Relationship Management +44 1509 224 700 www.cegedim.com/rm

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SOFTWARE/IT

ONE VISION, ONE GOAL

Connecting the supply chain with real‑time quality control solutions.

Michael Lyle

For more information Michael Lyle President and CEO InfinityQS International www.InfinityQS.com

he motivations for maintaining an effective quality control (QC) platform in the pharmaceutical industry are clear: it hasn’t even been 2 years since Johnson & Johnson suffered losses of $665 million as a result of QC lapses across product lines, sites and business units. Products affected included children’s Tylenol liquid and adult Tylenol, Mylanta, Motrin, Pepcid AC and Rolaids. Manufacturers, particularly those within the pharmaceutical industry, have always watched their processes and production flows within their four walls very closely. Today, that is not enough. With increased competition, and stricter standards, regulations and initiatives, such as the US Pharmacopeial (USP) Convention’s proposed Good Distribution Practices set to be published in May 2012, it is more important than ever for pharmaceutical manufacturers worldwide to look beyond their own operations and implement real‑time QC solutions throughout their entire supply chain. This ensures the quality and safety of not only the final products, but also the raw materials and components produced along the way. Detailed reporting and analysis enable both forward and backward traceability to ensure compliance, determine origination or identify specific use within the manufacturing process. To do this, it is imperative for manufacturers to monitor their own processes, inspect incoming products, and have a true understanding of their entire supply chain and the quality of the products and raw materials they receive from their suppliers, as they are being produced. Manufacturers, therefore, need to find a way to monitor processes throughout the supply chain, in real time, to ensure products are cost effectively meeting quality expectations, whilst complying with the ever‑increasing federal and local regulations, and traceability requirements. The first step is to develop strategic supplier partnerships based on a shared approach to real‑time process data. The fastest way to mitigate adverse events is to monitor data and send real‑time alerts when process abnormalities occur. Doing so also provides a stronger understanding of supplier performance and generally results in a more efficient, streamlined supply chain. Through these partnerships, manufacturers can establish global quality initiatives based on the quality elements that are most relevant to their own processes, and know for certain that all products they receive meet inspection requirements. This high level of monitoring and analysis is achieved using real‑time statistical process control (SPC) and creates end‑to‑end visibility into manufacturing processes.

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The challenge of implementing a real-time QC or SPC system throughout the supply chain is how to best assimilate data from various supplier systems that previously had existed in individual, unique environments. By taking advantage of advancements in mobile technologies and hardware, there are a wide variety of flexible deployment options that accommodate nearly any established — or nonexistent — quality system. From full-scale, on‑premise implementations, to on‑demand Software as a Service (SaaS) deployments, or even a hybrid model that uses both, real‑time data can be easily collected and analysed in a central quality hub. By using this centralized quality hub, manufacturers and suppliers can monitor and analyse processes at all levels of the supply chain in real time, which offers the ability to identify, acknowledge and eliminate out‑of‑specification product before an entire lot or batch is affected. By ensuring such a high level of quality throughout the entire supply chain, pharmaceutical manufacturers can avoid the costly ramifications of a public recall of a defective product — from APIs to excipients — reaching the consumer. Such recalls can not only affect immediate sales as product is pulled from customer inventories, but also future sales based on the damage to the company’s reputation because a consumer was hurt, became ill, or worse, died. Selecting a real‑time QC solution that is flexible enough to adapt to and enhance a pharmaceutical manufacturer’s operational environment whilst integrating suppliers’ disparate systems, will ensure a smooth, successful transition to 100% supply chain visibility. Investing in the appropriate system and training employees to take ownership of quality objectives will quickly yield an exponential return on investment (ROI) through increased process performance and decreased waste. The ROI will only continue as users enjoy the benefits of automation, detailed SPC analysis and reporting, and real‑time data monitoring. The right quality system facilitates a smoother auditing process and maintains full compliance with regulations such as 21 CFR Part 11. In the pharmaceutical industry, the public safety risks are too high to cut corners in QC. Current technology allows for a more collaborative supply chain that drives efficiency using real‑time process data. A more streamlined supply chain is a competitive edge that increases speed-to-market and, most importantly, guarantees the safety of the pharmaceutical manufacturer’s loyal customers.

January/February 2012

NUTRACEUTICALS

FOOD FOR THOUGHT … AND HEALTH

How can pharma get a share of the market … and avoid being blindsided by consumer packaged goods (CPG)?

he pharmaceutical industry is in danger of ceding the large and growing nutraceutical market to the CPG companies. Thus predicts The Battle for Designer Foods, a public war game in which four teams from top business schools were tasked with stress‑testing the nutraceutical strategies of Abbott Labs, Danone, GlaxoSmithKline (GSK) and Nestlé. The global market for nutraceuticals — foods that, owing to addition or enhancement, provide health benefits beyond nutrition — is projected to be close to $250 billion by 2015, according to a report from Global Industry Analysts.1 The change in landscape that appears to signal the end of the era of the blockbuster drug and bring pharmaceutical companies face to face with expiring patents and slim pipelines means that the nutraceutical market could provide an alternative revenue stream — and a welcome one at that. Rather than posing the question of “can pharma compete here?” companies should instead ask what changes should be implemented by pharma to compete, and refuse to allow the obvious advantages of CPGs — such as strong track records in marketing foods directly to consumers — and the inherent obstacles of pharma companies — particularly a risk‑averse culture borne of strict FDA regulations — to prevent them from carving out a piece of this market. This is not to overlook the challenge that pharmaceutical companies must overcome to succeed; strict FDA regulations prevent them from simply putting their drugs into consumer products (although nutraceuticals are regulated by FDA, they are subject to different restrictions). Their traditional route to success, which encompasses a high reliance on science, clinical trials, the protection of intellectual property (IP) and reaping the benefits of years of patent protection, may have to be upended if pharma is to succeed in the adjacent nutraceutical market. This hesitancy could well be a classic case of what Clay Christensen describes as The Innovator’s Dilemma, in which the high revenue‑and‑returns bar set by large companies, and their reluctance to accept anything less, hinders innovation — pharma companies are accustomed to much higher product margins than packaged food companies. Having invested billions in researching drugs that treat or prevent diseases, will pharma companies be satisfied with something as apparently simple and relatively low‑margin as probiotic yoghurts, scientifically engineered nutritional drinks or even heart‑healthy breakfast spreads?

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Such solutions, promising profits that exceed typical packaged food products, are part of what makes the opportunity so appealing for the CPGs, who boast great expertise in creating and marketing mainstream products in addition to some experience in doing the same with less sophisticated enhanced food products, such as vitamin water. Food giants are beginning to make significant investment in this space; October 2010 saw Nestlé announce its planned investment of more than half a billion dollars in creating a standalone health science business to “pioneer a new industry between food and pharma.”2 Similarly, Danone has refocused its portfolio on nutrition during the last decade, a key example of which is its $17 billion purchase of Royal Numico, a leader in infant and clinical nutrition products. This deal, along with its blockbuster Activia probiotic yoghurt, provides Danone with a stronghold in the area of health and nutrition. The bottom line is that to compete successfully, it will be necessary for pharmaceutical companies to start thinking and acting as CPGs do. The recent war game exercise gave rise to some specific strategies that the pharmas can usefully employ.

Lose the Blockbuster Mentality

The extensive — and expensive — research, clinical trials and formulation required to obtain FDA approval for drugs have paid off for the pharmaceutical companies in the form of patent protection, IP and a ready made distribution network of hospitals, doctors, formularies and insurance systems. This has contributed greatly to the mentality of relying on blockbuster drugs. Instead of looking for blockbuster‑equivalent nutraceutical products, the pharmaceutical companies should consider taking smaller, measured steps and building a portfolio of products that incorporate ingredients already approved by FDA for use in foods such as fish oils, sterols and stanols.

Make the Public Health Case

High cholesterol, diabetes, obesity and heart disease are among the most serious and prevalent health risks in the developed world — and are all conditions that can be affected by nutraceuticals. Making the public health case is about solving a problem that already exists with already proven ingredients that don’t need drug‑level approval.

Experiment Outside the Lab

Pharmaceutical companies are accustomed to basing their experimentation in the lab; indeed, it is at the very

January/February 2012

NUTRACEUTICALS heart of what they do. There is, however, an overarching need for this zeal to be redirected toward the marketplace; companies must be willing to trial different enhanced‑food products and establish what customers will buy and

Five Predictions from ‘The Battle for Designer Foods’

On 8 April 2011 in Cambridge (Massachusetts, USA), four leading business schools (MIT, Kellogg, Tuck and Yale) represented four companies with a stake in the growing nutraceuticals market: Abbott, GSK, Danone and Nestlé. As the teams attempted to present and defend their strategies, whilst addressing opposing teams’ questions and a barrage of issues by the judges, a series of predictions surfaced. Consumers will steal the march on pharma • Food companies, represented by Nestlé and Danone, are more likely to see mainstream success than the pharma-oriented companies in the short‑term. • The food/CPG companies appear to have much more expertise in making mainstream functional foods, rather than just products for infants, geriatric patients and exercise enthusiasts. • Consumer companies are willing to cut more deals and experiment with joint ventures or small acquisitions than pharmaceutical companies. • Although clinical trials and the science that is intrinsic to pharma are important in designer foods, these are only two of many elements needed for market success. Measured steps, not high science will win in the short-term • Food companies could begin to incorporate a variety of specialized ingredients that are already available, including fish oils, plant sterols and stanols, herbal extracts, vegetable and dairy proteins, probiotics and other beneficial bacteria. • CPG companies, particularly the major ones, have been notably adept at microsegmentation — producing niche products that are accompanied by effective branding — whereas pharma companies have relied heavily on blockbuster products. • Food/CPG companies are likely to experiment slightly more than pharmaceutical firms until something big catches on. Consumer education is critical in building a consumer market • Companies will have to reach out directly to consumers rather than employ the traditional doctor‑referral approach. • CPG companies seem to have more experience at direct consumer education. Simple products that can build a ‘public health case’ will forestall regulatory interference and win in the market • ‘Simple’ functional foods, such as dairy products, have long established their case with regulators by selling a food (dairy) that has already gained wide acceptance — despite Danone’s Activia misstep. • Products that solve a public health problem will win in the long‑term. • Embedding a drug into a food to create a functional food will trip regulatory alarm bells. • Overextending health claims will damage brands; this may hamper the selling proposition for more complex functional food products. Mergers will become more common, but collaboration is the hidden trump card • Competitors will be forced to collaborate to succeed — in certain cases by building on each other’s brands rather than acquiring brands (Unilever and Starbucks, for instance). • Companies must tap into ‘adjacencies.’ The days of only‑invented‑here are over. Breakthroughs will come through university and government laboratory collaboration (for example, National Institutes of Health). • CPG companies will realize that they must acquire their way to growth — and proceed to do so at a rapid pace. • Pharmaceutical companies are averse to the risk of merging with a consumer brand, concerned that CPG corporations might damage their science‑based brands. On 30 April 2012, this war game will be acted out in the UK between top business students from Oxford and Cambridge. It will take place at Said Business School, University of Oxford, where students from Cambridge Judge Business School, University of Cambridge, will compete for the prize. It will be interesting to compare the predictions made in the US in April 2011 with those resulting from this game.

January/February 2012

realize that testing a food that may bomb with consumers in one version and moderately succeed in another is not the same as putting out a drug that is found to have severe side‑effects. The consumer marketplace for nutraceuticals may offer a different risk–reward equation when testing for a winning product. Food companies recognize this distinction and are constantly tinkering with packaging, ingredients and brand extensions — although this is not always successful (new Coke, anyone?). It is this flexibility and willingness to fail occasionally that constitutes a part of their success.

Educate Consumers

Despite marketing directly to consumers, pharmaceutical companies lack expertise in creating and exploiting a broad, populist market need. The key will be in raising consumer awareness about the efficacy of nonmedicinal products to manage certain health conditions, conditions for which they are already deeply involved in treating or preventing in many cases. The nutraceutical product simply provides another approach to addressing the same problem.

Be Willing to Collaborate

Although mergers will increase (Pfizer has recently announced its willingness to sell a portion of its nutrition business), collaborations with CPGs will likely be a key basis for success. This is also an area in which pharmaceutical companies tend to be wary, afraid that the marketing, packaging expertise and distribution channels of CPGs will put them at a disadvantage in any deal. In the short‑term, however, collaboration may be the easiest and quickest route to enter the market. All this should not suggest that the barriers to entry and potential success are too high for pharmaceutical companies — they may be better equipped than CPGs to endure the costly and time consuming R&D required for more sophisticated products that the market may eventually call for. There have been some limited Big Pharma success stories; Abbott Labs is a leader in both child and adult nutraceuticals with its high science Pedialyte and Ensure products. GSK Consumer Healthcare has successfully launched several of its nutritional beverage products in China and India, the revenue growth from which could motivate the company to take a more aggressive approach with these products in other markets, such as the US. The size of the opportunity presented by this sector and their need for fresh revenue streams are pressing reasons for pharmaceutical companies to assert themselves in the market. It is in collaboration that their best hope for success lies — borrowing strategy, and perhaps even talent, from the CPGs. A shift in attitude will also be needed; the risks may be greater, but so may be the rewards. To ignore the potential of this market would be a mistake for an industry that can no longer rely on its former business model as its only means of success.

Leonard M. Fuld

References

1. P . Malik, “Value-added Nutrition,” Can. J. Cardio. 23(12), 956 (2007). 2. I ndustryweek.com (27 September 2010).

For more information Leonard M. Fuld CEO Fuld & Company www.fuld.com

To see excerpts of the Fuld & Company The Battle for Designer Foods war game, please visit www.fuld.com/Services/ WarGames.html.

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EXCIPIENTS

THE ROAD TO THIRD-PARTY GMP CERTIFICATION The road to third‑party Good Manufacturing Practices (GMP) certification for excipients has become quite busy in North America. In fact, that road may soon need to be expanded for similar efforts in Europe.

A Brief History

The move toward third-party certification in North America has always been at the forefront of efforts by the International Pharmaceutical Excipients Council (IPEC). IPEC, formed in 1991, quickly understood there was a need for an independent third‑party auditing programme for excipients. Thus, in 2000, International Pharmaceutical Excipients Auditing (IPEA) was formed as a wholly owned subsidiary of IPEC. With encouragement from FDA, IPEA received accreditation of its excipient certification programme from the American National Standards Institute (ANSI) in 2010. IPEA continues to work with FDA and ANSI to further develop the programme with a proposed ANSI Standard for GMP Compliance Certification. Current certifications are a measurement of substantial conformance to the “IPEC‑PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients 2006.”

omentum on the road to third-party GMP certification has recently increased dramatically. The Senate Health Education Labor and Pensions (HELP) Committee recently held a hearing on “Securing the Pharmaceutical Supply Chain.” During the hearing, IPEC‑Americas was invited to submit a written testimony for the record. A statement was prepared and submitted by Dale Carter, chair of IPEC‑Americas.1 In his statement, Carter notes: “IPEC’S proposal would mandate that individuals or companies not be allowed to import into the US a drug or excipient used in the manufacture of a drug if the product or ingredient was manufactured or produced outside the US by an entity which has not been certified by FDA or an FDA‑recognized third‑party auditor.” The drafted legislation to this effect is designed to help eliminate a current and serious FDA shortfall — only 1.3% of drug imports are sampled by FDA and only 0.3% are tested. These industry conditions motivated and lead DOW PuraGuard Propylene Glycol USP/EP (The Dow Chemical Company) to earn the first and only third‑party quality certification from IPEA for this product.2

Dow’s Journey

Early in 2010, the proposal was made to Dow’s Propylene Glycol USP/EP (PG USP/EP) business team to obtain third‑party certification for the Freeport, Texas and Plaquemine, Louisiana, propylene glycol manufacturing plants in North America. As with any business decision of this nature, solid justifications and the support and commitment of all functions within the business were required. Both the Freeport and Plaquemine propylene glycol manufacturing plants have been in successful operation for more than 50 years. Preparation efforts at both Dow plants began with in‑depth gap analysis obtained from internal audits conducted by ISO Lead Auditors that were also experts in excipient GMP compliance requirements as defined in the current “Joint IPEC-PQG Good Manufacturing

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Practices Guide for Pharmaceutical Excipients.” Both plants have been ISO Certified since the mid‑1990s so documentation was strong, but areas for improvement were still identified. Teams were formed to address the gaps and work proceeded for more than 3 months to the dates chosen for the IPEA certification audits. The in-depth audit and validation process proved to be an invaluable learning experience by all functions involved in the Dow PG USP/EP business. This experience, however, became an added bonus when the team’s efforts were rewarded by separate certifications being awarded to Dow’s Plaquemine, Louisiana facility in February 2011 and Dow’s Freeport, Texas facility in March 2011.

The Journey Continues

The acceptance of third-party GMP certification currently appears to be under pressure. Although FDA has shown support of IPEC’s legislative work in this area, it has yet to formally endorse the use of third‑party certifications for excipients. This lack of

Third‑party GMP audits and certifications are an efficient way for excipient manufactures to reduce their people resource demands. January/February 2012

EXCIPIENTS formal endorsement and the lack of communications from FDA addressing this issue leave pharmaceutical companies in a quandary. Work toward third‑party auditing and certification is also in the forefront of efforts by European organizations such as CEFIC European Chemical Industry Council. CEFIC, similar to IPEC, is not a governmental agency, but works closely with legal entities within their perspective global areas. If IPEC’s legislative efforts come to fruition, it can be expected that third‑party certification will not only be accepted by pharmaceutical companies, but will most likely become a global standard for doing business. The motivations and justifications for an excipient company currently seeking third‑party certifications are numerous and substantive. As a result of FDA’s recent emphasis on the entire supply chain process, customer on‑site audits of excipient manufacturers have increased notably. On‑site audits are a significant drain on the excipient manufacturer’s people resources, which may already be stressed because of the current economic situation. Third‑party GMP audits and certifications are an efficient way for excipient manufacturers to reduce their people resource demands. Pharmaceutical companies should see similar benefits with reductions in people

resource demands and significant reductions in associated travel costs. With the anticipation of new legislation concerning GMP certifications by third‑party auditing groups, it can only be expected that the interpretation and expectation of compliance requirements for excipients will tighten significantly on a global basis. Consequently, it is in the best interest of all global excipient manufacturers to evaluate their current GMP compliance programmes and identify any gaps that may need to be addressed well before this anticipated new legislation becomes law. Those involved in the pharmaceutical and excipient manufacturing industries must also consider the global efforts toward product safety. Excipient contaminations have caused 570 deaths in the last 20 years. As recently as 2009, more than 80 infants died from adulterated teething syrups contaminated by diethylene glycol in Nigeria. Global acceptance and support of third‑party auditing may have helped to prevent those deaths. Although third-party certification hasn’t yet received FDA’s formal endorsement, pharmaceutical manufacturers are showing increasing interest in ensuring their product ingredients are meeting the highest standards for purity.

Notes

1. T his statement is available at www.ipecamericas.org 2. Dow’s Propylene Glycol USP/EP is sold under the brand name DOW PuraGuard PG USP/EP in North America. In all other regions, it is currently sold under the generic name.

For more information

Dennis Reiswig Senior Quality Specialist Propylene Glycol The Dow Chemical Company DRReiswig@dow.com www.dowpg.com DOW PuraGuard is a Trademark of The Dow Chemical Company (Dow) or an affiliated company of Dow.

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BIOPHARMACEUTICALS

The Importance of CO2 Control During the Manufacture of Biopharmaceuticals

Kurt Hiltbrunner, Market Segment Specialist at Mettler‑Toledo Process Analytics, talks to Pharma about CO2 monitoring and control. pH and dissolved oxygen control are important during fermentation and cell culturing. Why has in situ CO 2 control not reached the same level of importance? To maintain optimal growth conditions to maximize yield, a constant pH, appropriate oxygen supply and sufficient nutrient levels are key. In many processes CO2 can act as a stressor or even a toxin to the culture and has to be controlled. CO2 is a critical control parameter, mainly in mammalian cell cultures, but the lack of a reliable in situ CO2 measuring system had impeded implementation until the first Ingold solution. Off‑line sampling and measurement with a blood gas analyser is quite common, but real‑time control is not possible with this procedure. Accurate in‑line measurement is a must for real‑time process control. What can you tell us about the history of CO 2 measurement solutions from Mettler Toledo Ingold? The first generation of Ingold’s CO2 sensor, released in 1980, was the only sterilizable CO 2 sensor on the market. Although it accurately measured CO2, it required a calibration procedure, which was not straightforward. So, for the second generation of the sensor, released in 2002, calibration and maintenance were greatly simplified. This sensor shows an excellent correlation if compared to blood gas measurement. The sensitivity in the critical range of 80–200 mbar CO2 partial pressure allows accurate measurement and efficient control. The durability of the CO 2 sensor is highly affected by conditions during sterilization such as temperature and duration. To increase sensor lifetime, the new third generation of sensors feature a redesigned measurement system that includes a microprocessor in the sensor head that digitizes the

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analog measurement signal. With this technology, which we call Intelligent Sensor Management (ISM), the new sensors are highly tolerable of sterilization procedures. Also, the digital signal is almost immune to electrical interference from other equipment and loss of signal over long cable lengths. What are the other benefits of ISM? ISM features advanced predictive diagnostics that mean any maintenance required can be conducted before sensor performance is affected. ISM dramatically increases sensor lifetime and, therefore, the number of batches a sensor’s good for.

the slope of the internal pH electrode in the new CO2 sensor is very stable, even after sterilization. January/February 2012

BIOPHARMACEUTICALS

Furthermore, the slope of the internal pH electrode in the new CO 2 sensor is very stable, even after sterilization. Calibration of the pH electrode prior to sterilization is, therefore, unnecessary. The only calibration step needed is a process calibration after cooling down. If a blood gas analyser is available, just measure a sample of the medium and adjust the transmitter accordingly. This is the easiest way to make a process calibration. Alternatively, sparging and saturation of the medium with a CO 2 containing gas can be used. How important is the CO2 level during fermentation? The measurement of CO 2 produced in mammalian cell fermentations can provide an overall measure of changes in central carbon metabolism and mitochondrial function. High CO2 can inhibit cell growth, nutrient utilization, and product formation and in some cases alters protein utilization. Many companies continue to focus on the use of nutrient feeding to increase volumetric productivity, either by increasing cell density or by increasing specific productivity. Basic batch suspension in stirred tank

January/February 2012

bioreactors has become increasingly less common because nutrient‑feeding schemes can reduce waste accumulation and nutrient fluctuations, which allows higher cell densities and productivities to be reached. Recently designed suspension processes are of fed‑batch and perfusion types. How can CO 2 levels be controlled and what effect on yield can be expected? In real batch processes, nitrogen or air sparging can be used, together with in‑line measurement of CO 2, to control the level of accumulated dissolved CO 2 to acceptable levels. In fed‑batch processes the CO2 level is controlled simply by changing the feeding of the nutrient media. If the CO2 level is excessive, just lower the addition of glucose. Our customers have reported an up to 40% increase in yield after implementing such CO2 monitoring and control. In addition, control of glucose dosing avoids the inhibition effect that occurs when glucose levels are too high. Conversely, if the CO 2 level is too low growth rate is not optimal, but this is easily corrected by increasing the glucose feeding rate.

Kurt Hiltbrunner

For more information

Kurt Hiltbrunner Market Segment Specialist Mettler‑Toledo Process Analytics process.affiliate@mt.com www.mt.com/pro_pharma

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BIOLOGICS

CELLULAR THER APEUTICS

PRECLINICAL SAFETY PROGR AMMES AND STUDY DESIGN CONSIDER ATIONS

A successful preclinical programme for a cell therapy product requires a well‑characterized cell product, clinically relevant and robust animal models, and robust methods for cell detection. These tools are used in translational studies to show proof of concept, cell fate (in the animal model), local and systemic toxicity, and frequently, tumorigenicity risk. Animal studies of human cell products are always complicated by considerations of cross‑species reactivity — will the human cells act in the animals as we hope they do in humans? As written regulatory guidance is sparse, sponsors can borrow from traditional toxicology objectives to craft a custom programme of studies. They benefit from an interdisciplinary approach, varied expertise, and partnerships with regulatory and CRO professionals to achieve a programme that can be relied upon to predict risks to patients.

ell-base therapeutics for various diseases and injuries are now in clinical use following marketing approvals in the US. As cell‑based therapies are usually human in origin, they present unique study design challenges to toxicologists involved in human safety prediction assessment. Unlike bone marrow transplantation therapy, the preclinical research for “manipulated cell products” must be submitted in an Investigational New Drug (IND) filing for FDA review before initiation of clinical trials, and the product’s attributes should be mirrored in the preclinical programme to predict human safety. This can seem impossible, but the preclinical toxicology programme can be successful if it follows classical drug toxicology objectives and takes all steps necessary to ensure that the cells endure/act in the animal as they would in humans. How do cell therapy developers (sponsors) make the human cells reveal the same benefit and risks that they will in humans, but in animals, and ensure safety and efficacy?

Toxicology Programme Aims

Drug safety programmes characterize human effects and risks before human exposure, and cellular therapies are no different. The studies characterize effects of the drug in an animal model that responds to the test article and if desired, permits engraftment of the cell product. This model is further utilized to characterize local and systemic pathologic reactions, fate in the body (cell survival, local tissue migration, differentiation, systemic distribution, proliferation)

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and tumorigenic potential of engrafted cells. Care must be taken in selecting relevant animal models, mimicking human dosing methods, selecting control groups, handling the cells, including adequate group size, gauging appropriate study duration, and selecting sensitive cell detection technologies. Cell safety studies differ in design from traditional drug safety studies by specific variables such as animal model compatibility with the (foreign) cell test article; for instance, traditional drug programmes usually employ healthy animals. A cell product, however, may require a particular disease/injury micro‑environment to differentiate or endure as intended in humans. This specialized animal model serves as one part of the multistudy, preclinical programme especially because few human diseases are well‑emulated in rodents. Reviewers at the Center for Biologics Evaluation and Research (CBER) within FDA highly encourage sponsors to request a pre‑pre‑IND meeting from the Office of Cell, Gene, and Tissue Therapy at the start of product development process to familiarize both the review staff and the sponsor with current standards of practice and the specific cell therapy. Discovery and development for advanced medicines such as cells is blurred and lessons learned from basic research often find new application in toxicology programmes; for example, proof‑of‑concept studies that reveal the activity and benefits of the cell product may also reveal an animal model useful in toxicology characterization. Likewise, well‑characterized cell product manufacturing practices and controls that

January/February 2012

BIOLOGICS assure product quality and consistency are essential to the safety programme. This research will establish biomarkers and assays that reveal pharmacologic actions that are then used for lot release and serve as tools for evaluating in vivo safety. Classic toxicology International Conference on Harmonisation (ICH) safety guidelines, particularly ICH S6 and ICH M3, listed on the FDA CDER website guide the regulatory approach, help to clarify programme objectives and spell out some standard timelines for preclinical development. These guidelines can be easily ‘translated’ and applied to cell therapies by reframing their suggested approaches into a series of questions, as outlined below.

What are they?

Cell Source and Product Characterization Impact on Toxicology Assessment The cell source and immunologic nature pose different levels of safety concern. The product’s character will be immunologically ‘self” or ‘foreign,’ and the degree of departure from ‘self’ reflects a potential increase in risk, and is influenced by the effects of tissue and cell product manipulation (for example, by growth factors, gene transfection, in vitro expansion). Minimally manipulated cells for homologous use require the least amount of testing. More‑than‑minimally manipulated cells and nonhomologous cells require more extensive preclinical testing. These cells require IND approval, clinical trials and marketing approval similar to small molecules and biologic drugs. Identity and potency attributes are linked to toxicology because they describe the cells in both morphologic and functional ways that (optimally) are connected with their clinically beneficial action, but are rarely established at the beginning of a programme. As such, the assessment of influence of production processes on cell product character and its toxicology must, therefore, be strictly controlled to help eliminate as many variables in production as possible so that toxicology studies conducted on one lot describe the toxicity of all lots. Establishing the process, biomarkers, test methods and cell product specification before initiating preclinical studies must, therefore, precede toxicology testing.

What Do they Do?

Product Activity and Animal Model Selection The function of the cell product is demonstrated often in one or more animal models of disease. Reversing or slowing progression of disease, and and/or demonstrating translational biomarkers (for example, insulin release in vivo from pancreatic

January/February 2012

cells in an animal model of diabetes) are key points in establishing an effective administration route, dose range and dose regimen, along with any other key factors such as cell engraftment, local migration, acute versus chronic effects and re‑dosing as necessary to justify the clinical regimen. Any animal species that permits the cell to engraft and/or reacts to the cells in the manner intended for humans should be considered as a candidate toxicology model — this may be a rodent model of a human disease state. The model should be robust and the disease state should be understood as well as possible. In addition, the disease should be expressed to a relatively uniform degree of severity. Finally, the model should also be predictable in terms of its natural history such that effects of the cells can be discriminated from the usual disease course. Immunocompromised rodent models or alternatively the use of immunosuppressive drugs, can influence the host animal’s reaction to the cells, and thus interpretation of safety and the choice of animal models is a key point of discussion with FDA reviewers and other animal model experts.

Where Do they Go and How Long Do they Stay?

Preclinical Biodistribution Understanding of the biodistribution of the cells including survival, proliferation, distribution,

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BIOLOGICS

differentiation and integration into the host physiology, is critical. Survival, implantation, host tissue integration and local migration from a site of implant can be evaluated with cells altered with marker genes, dyes or particles, but in good laboratory practice (GLP) studies, the actual clinical product must be studied using other technologies, most commonly Polymerase Chain Reaction techniques or immunohistochemical labeling for cell‑product specific antibodies. Early biodistribution assessments can help in the choice of animal model and the duration of toxicology studies; using a small number of animals at continuous study intervals will develop a basic understanding of these endpoints. Later, biodistribution studies can be built into ongoing toxicology work to conserve animals and contain programme costs.

Are They Safe?

Lauren E. Black

For further information

Shawna M. Jackman PhD* Senior Research Scientist Charles River Laboratories *to whom enquiries may be directed shawna.jackman@crl.com www.criver.com Douglas B. Learn PhD Director, Photobiology and Cellular Therapeutic Safety Charles River Laboratories Lauren E. Black PhD Senior Scientific Advisor, Navigator Services Charles River Laboratories

Toxicity The toxicology/safety concerns for a cell‑based product are the same as for small molecule and biologic drugs. Studies demonstrate dose‑response correlations and toxic effects on critical organs using classic endpoints such as behavioral observations, body weights, feed consumption, ophthalmology, clinical pathology and histopathology. Similar to biologic drugs, adverse effects of species‑specific effects (for example, cross‑species loss of potency at receptor) and immunogenicity can be offset by emphasizing pharmacology and cell product biology, and evaluating measures of cell activity along with immunogenicity and toxicology. Cell therapies typically do not follow classic chemical drug programme frameworks — for example, routine testing in two species, genotoxicity batteries, safety pharmacology batteries and carcinogenicity assessments — but focus most on issues specific to the therapy’s properties and potential risks. For instance, a testicular cell implant might well be evaluated for impact on male reproductive tissues, sperm and male fertility; it might also include assessment of indirect effects on the female reproductive tract and offspring.

What can they Turn into?

Tumorigenicity The phenotypic stability (for example, tumorigenic potential or ectopic tissue formation) of a cellular product is a serious concern for most cell therapies and must be addressed. Tumorigenicity studies include a positive control cell line and the cell‑based product is injected by the subcutaneous route or by the clinical

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The phenotypic stability of a cellular product is a serious concern for most cell therapies and must be addressed. route of administration, and the animal — typically a single species of immunocompromised rodent — is observed for specific endpoints including clinical observations and body weights, palpation for mass formation, complete necropsy and histopathology and/or PCR evaluation of selected tissues. Any masses or ectoptic tissues identified are assessed to identify the source of the mass, be it host (mouse) or graft (cell product).

Conclusion

A successful preclinical programme for a cell therapy product requires a well‑characterized product, clinically relevant and robust animal models that allow for characterization of exposure and effects expected in humans and robust, reliable and sensitive methods of cell detection. These tools are used in characterization, proof of concept, pilot and definitive biodistribution studies, as well as the toxicity studies. As well as using available guidance and objectives from traditional toxicology programmes, sponsors are advised to take a multidisciplinary approach, and build a team of toxicology experts, immunologists, discovery scientists and regulatory advisors, and work closely with regulatory reviewers at CBER and other regulatory authorities to ensure their success.

January/February 2012

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SUPPLY CHAIN

A MULTILAYERED APPROACH TO SUPPLY CHAIN MANAGEMENT Global supply-chain, industrial and retail requirements bring the pharmaceutical industry to the leading edge of serialization, and track and trace technology. Progressive producers and distributors can better combat organized crime and drive down costs.

he global marketplace that efficient, automated high‑speed mass production has helped develop has brought new challenges to the pharmaceutical industry in recent years and will continue to do so. Harmonizing global standards is a lengthy process and is still far from being as simple as producing a single product that is saleable under identical conditions around the world. Accountability, however, is one area where there are similar approaches throughout the supply chain, which suggest a positive trend for manufacturing compliance. The flexibility required by modern pharmaceutical manufacturers to sell products into different markets and comply with differing regulations can be bewildering, but it is also an opportunity to develop processes and solutions that will keep the management of their supply chain, assets and overall equipment effectiveness (OEE) sustainable, agile and compliant … now and for years to come. The huge increase in counterfeit drugs sales during the past decade has sparked a rapid upturn in compliance requirements and legislation around the world. Counterfeit drugs are not simply illicit versions of the real thing; they can kill. It has been estimated by the Centre for Medicine in the Public Interest that 200,000–300,000 people in China die from taking bogus prescription medicines each year.1 This is just one of a number of astonishing statistics. INTERPOL has reported finding rat poison in some fake medicines, which are part of a multibillion dollar worldwide illicit trade. And worldwide it truly is — US Customs intercepted 50 shipments of fake Tamiflu that was being stockpiled in anticipation of the 2009 bird‑flu epidemic, and Europe saw a five‑fold increase in fake medicines during 2005–2006. According to The World Health Organisation, the increase in the counterfeit drug trade reached $70 billion in 2010: an increase of more than 90% since 2005. Ensuring people are getting the real ‘prescribed’ medicine has become an issue of supply integrity for regulators, who, through various national and international guidelines, have

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January/February 2012

SUPPLY CHAIN required more responsibility from manufacturers to make their goods track‑and‑traceable. In Turkey since the start of 2010, all pharmaceutical products distributed must have the ECC200 data matrix barcode made up of a global trade item number, serial number, expiration date, batch number and human‑readable text. In Europe, legislation came from the European Parliament in 2011 that required member countries to take action during the next 2 years to guarantee the authenticity of prescribed medications, based on mass serialization using 2D barcodes on individual packages or bottles. FDA published recommendations in March of 2010 with “Guidance for Industry Standards for Securing the Drug Supply Chain — Standardised Numerical Identification for Prescription Drug Packages.” Although non-binding, these are an “initial step in FDA’s development and implementation of additional measures to secure the drug supply chain.”2 To a degree it could be said that this is exactly the kind of vague regulation/ guideline approach that is making companies hesitant to fully invest in a solution, many preferring to take a ‘wait and see’ approach. But some companies are seizing the opportunity to get ahead of the curve. The necessary processes for supply traceability can be mapped out, starting with the shop floor where the initial serialization data is made; any further layers of information, including carton packaging, bundles, pallets or containers must be recorded. As production in a single plant often involves several process lines or stages, serialization data from each need to be collected and handled on a plant‑wide layer. Then, at the internal supply chain layer, information has to be added regarding product shipments between plants for further distribution. Finally the delivery of the drugs to distributors, pharmacists, wholesalers and hospitals must be recorded at the external supply chain layer. Technology to effectively meet such guidance and regulation exists. Indeed, technology that is adaptable and scalable enough to help cope with the demands of the regulators when the guidance becomes legislation and more is required to show a deeper understanding and tracking of the supply line to customer from manufacturer, is also available. In fact, much of it has been around for several years, and is designed and sold on the basis of having a provable ROI regardless of helping to meet any specific compliance issues in the pharmaceutical industry. At Rockwell Automation, for example, we have worked with manufacturers worldwide to implement manufacturing execution systems (MES) that turn data into meaningful business information from every part of the manufacturing process, from raw materials to units, to packaging and further down the supply chain to warehousing, delivery and so on. This information is available in real time and can be overlaid with OEE, key performance indicators (KPIs), energy consumption, supply issues, resource management and more at the enterprise management level to improve the

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bottom line through a variety of means, be it reduced energy consumption, lower stockpiling, “just in time” production methods, more efficient line changing, decreased unplanned downtime or improved machine life‑span. With specific reference to the supply chain management requirements of the pharmaceutical industry, consider a modular, scalable serialization solution founded on a multilayered model, such as the FactoryTalk PharmaSuite (Rockwell Automation). Such a system has the flexibility to meet developing regulations in different countries and helps address the challenges on the shop floor and the plant layer whilst also connecting, in real time, with the enterprise layer and further down the supply chain. Such a solution also benefits from retrofit capabilities with old packaging lines, as well as integrating with new ones. The basis is a central server, on‑site database and client application with human–machine interface (HMI), as well as the ability of the software and hardware to operate with other manufacturing and business systems. It supports the delivery of serialization information to other management systems such as SAP or IBM‑supported platforms, as well as to international data vaults, databases from governments or other recognized authorities. The line controller connects to a PAC controller with a dedicated wireless communication control network. From a single add‑on cabinet the system integrates the control of all of the serialization components such as vision‑inspection cameras, RFID equipment and data‑matrix barcode printers, as well as offering support to modular serialization libraries for packaging lines. The fact that this level of control can be integrated via an add‑on solution, which reduces interruption to production, is also particularly important to the pharmaceutical manufacturer whose packaging lines may produce anything up to 400 boxes/min and for whom downtime means a big drop in potential revenue. It is abundantly clear that the industry and regulatory bodies are taking action to combat the global counterfeiting issues of the 21st century, and manufacturers and other companies in the supply chain must be able to quickly adapt their systems to flexibly comply with the various local and international requirements. Staying competitive and sustainable in such a competitive market though, brings restrictions of its own. Forward looking companies are building the integrated architecture and MES systems that will allow them to adapt to changing regulations whilst still achieving a competitive advantage. Improvements to supply chain management may be necessary, but if approached logically using the latest automation solutions and manufacturing techniques it can be made to help achieve more accurate order fulfilment and shipping, make it much easier to recall products, and collect and manage valuable KPI and OEE data along the way while demonstrating a ROI for all stakeholders.

Paul Davies

References

1. w ww.cmpi.org/in-the-news/ testimony/counterfeit-drugsand-china-new 2. w ww.fda.gov/downloads/ RegulatoryInformation/ Guidances/UCM206075.pdf

For further information Paul Davies Business Leader Safety, Sensing and Connectivity Rockwell Automation Tel: +44 207 043 8847 www.rockwellautomation.co.uk FactoryTalk is a registered trademark

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SUPPLY CHAIN

USING TECHNOLOGY TO AVERT PHARMA SUPPLY CHAIN CATASTROPHES

In today’s social media age, where word of mouth spreads rapidly, a supply chain disaster in any industry can have a huge and harmful impact on an organization — never more so than in the pharmaceutical industry, where mistakes can be life‑threatening.

reater levels of public scrutiny mean it has never been more important to manage product availability, risk and compliance. Pharmaceutical companies should respond by taking greater control of their supply chains. Those who adopt new web‑based technologies — which enable companies to track and measure their critical paths to make informed decisions, and cut lead times and costs in producing and distributing drugs worldwide — are gaining unprecedented visibility of their supply chains.

Supply Chain Catastrophes

Mistakes made in managing pharmaceutical supply chains can have devastating consequences. Without adequate control of the supply chain, how can a pharmaceutical company be certain there won’t be any mix‑ups between source and destination? Such mistakes can mean the difference between life and death … and destroy brands in the process. In a world where more than 800 million people use the same social network, negative word of mouth spreads far and fast.

Visibility and Control

The key to avoiding catastrophes is to improve processes, and the key to that is having visibility and control of the supply chain. Technology plays an ever‑growing and critical role in how organizations achieve this tight control. The aim is to pull together data from all the systems that suppliers, manufacturers, partners and customers use, so everyone can see what’s happening at every stage from source to destination. Then, using web‑based portals, these parties can communicate to make the right decisions, at the right time, when producing and shipping pharmaceutical goods. Let’s look at the impact of having visibility and control — specifically, how it helps pharmaceutical organizations to minimize delays, get stock levels right, ensure product quality, maximize profits and comply with regulations.

Minimizing Delays

A fashion retailer who experiences delays in sourcing product might miss out on selling a few thousand dresses in the short-term, but can take comfort in knowing that they will probably sell eventually. Life is more complicated for

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pharmaceutical companies looking to bring new, patented drugs to market. Sourcing delays are far more damaging because they have a finite period in which to take advantage of their patents before competitors can start selling the same drugs. Every day of their market window they miss can equate to millions of unrecoverable dollars in lost sales. Supply chain and sourcing systems play a big role in avoiding these delays and reducing time‑to‑market. When an organization has visibility of its supply chain, it can proactively identify and anticipate problems before they occur; its systems alert it to problems early enough for it to act and avoid costly delays. Other delays to avoid occur during manufacture through to supply — during production, through quality assurance, dispatch and at each intermediate stage. At every point, supply chain tracking and monitoring systems help the different parties in the supply chain to manage their activities, so reducing the time wasted. Their purpose is to make the processes as efficient as possible, tracking all of the steps on the critical path, and alerting supply chain managers and their partners whenever a step isn’t being performed on time. The use of dashboard traffic lighting indicates where idle time is happening, or better still forecasts where it will happen, in time to avoid the delays.

Getting Stock Levels Right

A huge challenge for pharmaceutical companies is getting stock levels right. Get it wrong and they either hold too much stock and risk it exceeding its expiry date, or not enough and risk not satisfying their customers. Many have poor visibility of stock levels in transit and inaccurate forecasts, so by default they order more than they need. There is a clear opportunity for these companies to reduce stock holdings, using IT to more accurately manage forecast demand, and track and order stock. Those that can see exactly what stocks they are holding in each location and how many orders they have in progress, can be confident about making the right decisions about order quantities. Stock levels can present complex problems on a global scale. Consider that pharmaceutical companies now sell to — as well as source from — multiple countries worldwide, and, therefore, must ensure that the packaging they use for their drugs is appropriate for each local market. The difficulty of

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custom packaging for each specific market is that it restricts the flexibility on stock movements: companies have to hold stock in different countries, but if they are overstocked in, for example, the Chinese market, and under-stocked in the UK, they can’t just move Chinese‑language packaged product to Europe and sell it there. One solution is to use the same generic packaging for all countries, and simply add local language labels when needed. This reduces the amount of stock held globally and reduces the quantity at risk of expiry. This seems such an obvious solution … but not a simple one. Why? The logistics of having generic stock and local country labelling is difficult to perform efficiently without timely and visible information. To achieve this, a company must have • Accurate and detailed visibility of their country demand forecasts. • Generic stock holding in strategic geographical locations across the world. • Central visibility of stock — holdings, in‑transit and on order across the sales base. • Rapid and efficient methods of selecting and applying labels for stock moves. • Speed of stock to the country market. In short, a key factor in the speed and efficiency of this process is visibility and proactive control of the critical path, which is not simple.

clarity and accuracy in meetings and calls with partners: the fact that everyone will be looking at the same information in their portal, helps ensure that suppliers, manufacturers and all other parties have been doing what was agreed or contracted. Everyone can see the facts — what has and hasn’t happened — and valuable time is not wasted disputing individually compiled disparate information.

Ensuring Product Quality

Complying with Regulations

It may sound dramatic, but if the quality of a pharmaceutical product is less than 100%, there’s a risk that someone, somewhere will become ill or worse. Supply chain management technology ensures people are accountable for executing quality checks, and record when they have performed the task and its result. It’s imperative for pharmaceutical companies to be able to hold their suppliers to account in this way and have management information to analyse and support their decisions. Pharmaceutical companies also want to avoid finding themselves at the mercy of their manufacturers. The nature of global sourcing can sometimes lead to a dependency on the use of spreadsheets, which brings inherent issues, such as information telling them one thing, whereas their manufacturers’ spreadsheets tell another. The problem with suppliers using spreadsheets is that it creates multiple versions of the ‘truth,’ so the suppliers and manufacturers are, in effect, accountable to nobody. Only when a supply chain manager has a method of ensuring all parties access common information — a shared, single version of the truth — is it possible to make them accountable for their actions. Then, he or she can have

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Maximizing Profits

With this type of system in place, it is possible to monitor, for example, that all of the stock comes from manufacturers with contracted pricing, and to check whether suppliers consistently meet quality, delivery and price requirements. The manufacturers themselves are required to add all of the relevant data at source into portals so that the system tracks their performance histories. This level of control helps pharmaceutical companies to maximize their profits. They can collate key performance indication data, analyse league tables of manufacturers, identify who offers the best contracts and prices, and then ensure they do actually use those manufacturers. The technology puts them in a position to ask for discounts or to penalize suppliers if they fail to deliver on time and in full. Suppliers are more likely to offer better prices knowing that their customers, who have other options for sourcing generic drugs, are monitoring and benchmarking their performance.

Supply chain management IT also helps pharmaceutical companies to prove to regulatory authorities, such as MHRA and FDA, that they have control of the product they manufacture, buy and distribute. They must also be able to prove where the money goes following each transaction. Tough regulations are in place to control bribery and corruption, and pharmaceutical companies must ensure they have total visibility of all their product and financial transactions. Unlike standard financial systems, supply chain management systems provide visibility of individual products at every level from order- down to lot- and batch‑level. These systems keep track of purchase orders, deliveries, invoices and payments. An organization can use these data to prove it is taking steps to control corruption, by having that control and proof at the lowest level of detail. To take charge of every aspect of a supply chain and minimize the risk of catastrophes, it is crucial to have visibility of what’s happening when, where, how and why. A company that tracks and measures its supply chain activities is in a stronger position to improve product availability, cut costs, and increase sales and profits.

Dianne Richardson

For more information Dianne Richardson Consultant and Project Manager ediTRACK www.editrack.com

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R&D

LEVERAGING KNOWLEDGE AND COLLABORATION TO REfILL THE R&D PIPELINE There is a significant trend across biopharma and academia for more precompetitive collaborations or strategic partnerships pooling the knowledge and resources to accelerate the discovery of novel drugs. Less clear, is the degree to which companies are willing to collaborate precompetitively and how far they are prepared to go.

n October 2011, approximately 80 representatives from the pharmaceutical industry, government and academic institutions met for 3 days at the World Pharma Innovation Congress 2011 to discuss methods of overcoming the innovation deficit through collaboration and open innovation.1 In a roundtable discussion hosted by Thomson Reuters Life Sciences Consulting, R&D executives and government strategists met to discuss opportunities for greater collaboration and the likely issues companies will face in pursuing open innovation operating models. The delegates attending the roundtable discussion unanimously expressed their opinions that pharma must be seen to be more open to sharing information. To date, the industry’s track record has been patchy. The public perception is that companies only provide information when they are forced to. Equally, smaller companies remain concerned that Big Pharma’s involvement in collaborative initiatives poses a threat to the smaller players in any collaboration. Nevertheless, the delegates all expressed the opinion that collaborations can benefit all stakeholders in the pharmaceutical industry. This is an opinion shared by Thomson Reuters Life Sciences Consulting, who are increasingly encountering clients looking to work on shared topics through industry consortia. Although precompetitive sharing is a relatively new concept for the pharmaceutical industry, lessons can be learned from other industries. The pharma industry should not be afraid of working with its competitors. The focus for the discussion centered on three key questions.

What Should the Industry Collaborate on?

The group first discussed the areas that industry should collaborate on to derive maximum benefit for stakeholders. Suggested areas of collaboration included clinical trial data, postcompetitive data and clinical trial databases. As Hans Poulsen, Head of Thomson Reuters Life Sciences Consulting, summarized: “It was clear from the congress that there is an increased desire for the pharmaceutical industry and its partners to collaborate in new ways and there is a growing

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list of supportive examples. It was also clear that the boundaries for collaboration, and the consideration of what is precompetitive versus competitive information, are being moved. As such, information that the industry would not have considered sharing just a few years ago are now being discussed openly in a sharing context.” Clinical Trial Data • The sharing of precompetitive data, in particular biomarkers, would allow the construction of drug/ disease models of use to the whole industry. • Sharing of negative trial results would allow the rapid dissemination of the reasons behind the failure of a compound. In particular, whether failure was down to the drug or the target. It was suggested that such information could be shared via a rapid editorial peer‑reviewed format. The delegates reinforced the moral imperative to share this information to prevent patients from being exposed to compounds that others in the industry know to be failures. It was also noted, however, that such an initiative would require a critical mass of companies to sign up. A note of caution was sounded for smaller biotech companies where announcement of failure could threaten the future of the entire company. The group agreed that it should be possible to share information about failures whilst providing suitable incentives/safeguards for smaller players; for example, an information ‘bourse’ that could provide payouts to smaller biotechs if the information they shared on failures was to have a value for participating companies. Such an initiative would advance the interests of the group as a whole whilst mitigating the risk to biotechs. • Postcompetitive data: The group discussed the need to share data from historical new drug applications (NDAs) and data on older drugs to increase knowledge and provide repurposing opportunities. To an extent, this is already being done by NCAT (National Cancer Action Team) translational services, which is looking at abandoned products. • Clinical trial databases should be opened up so that industry can learn from the patient data contained therein.

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R&D Inter-Company Standards The group noted the need for more standards regarding the differing technologies used and clinical trial methods and processes. Compliance There was a round‑table discussion on the disconnect between industry and the patient and the need to share patient‑level data to increase compliance. Participants described the need for a 360° view of innovation by building innovative tools for patients — at the moment there is a disconnect between pharma and patient, in particular patient compliance. John Cole, Director of Thomson Reuters Life Sciences Consulting summarized the patient‑centric focus: “There is a strong desire around this table to ensure that industry collaborations are focused on addressing patient needs and delivering the best outcomes for this crucial stakeholder group. In this respect, the industry has much to learn from the type of innovative, customer centric collaborations fostered by fast moving consumer goods (FMCG) companies.” Predictive Safety Testing The group described the possible benefits of predictive safety testing and the sharing of toxicology data to expedite the drug discovery process and improve the probability of pipeline success. There was a unanimous opinion that the sharing of toxicology data would be immensely valuable, but it requires a critical mass of companies to sign up. As more and more companies start view toxicology data as being ‘less competitive’ it will become more likely that this data will be successfully shared.

How can we Encourage Collaboration?

The second topic involved a discussion of how to put in place appropriate mechanisms to encourage an environment of increased precompetitive collaboration. The discussion centered on the governmental/industry climate and the required changes in senior and corporate leadership teams. Governmental/Industry Associations The mediators had asked whether government should be helping further to increase collaboration, but the group suggested that governments are already doing a lot to invest in R&D and innovation. It was noted, however, that infringement rules currently hamper collaboration and that a change in these regulations would prevent current problems of sharing candidate libraries. As one delegate, Ted Torphy, pointed out: “It would help if governments softened infringement rules as at the point of infringement, there is not yet any market value.” The group also suggested the need for a third party to manage the collaboration and handle sensitive information, thus

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Collaborative success stories put forward around the table

• ‘The Predictive Safety Testing Consortium:’ 15 companies worked around discovering five new renal biomarkers — one that has resulted in the simultaneous filing of a new drug. • Six companies have formed a consortium to sponsor an external company to review 60 different new technologies for them each quarter. All members of the consortium have access to the technology assessment, giving each company 240 new write‑ups per year (that is, more than what one company could hope to do alone). So far, four new ventures have been launched based on the write‑ups.

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R&D

Kiran Meekings

Hans Poulsen

John Cole

Reference

1. World Pharma Innovation Congress 2011 (Jumeirah Carlton Tower, London, UK, 18–20 October 2011).

For more information

Kiran Meekings Consultant Thomson Reuters Life Sciences Consulting Hans Poulsen Head of Consulting Thomson Reuters Life Sciences Consulting John Cole Director of Consulting Thomson Reuters Life Sciences Consulting Tel. +44 207 433 4313 john.cole@thomsonreuters.com http://lifesciencesconsulting. thomsonreuters.com

preserving companies’ assets and ensuring no single company takes all the risk. Required Corporate Changes The group discussed how large pharma’s organizational structures are not conducive to an entrepreneurial spirit. It was suggested that smaller units or adopting a new mindset might help to foster innovation. One delegate drew parallels to other industries and suggested corporations could leverage novel methods of entrepreneurism to increase innovation. He described how in Korea, every technology student sponsored by Samsung is encouraged to become a paid employee. Students are funded by cash or by cash plus a proportion of the proceeds from any invention they submit to Samsung. The group noted the need for integration through product development. The overwhelming opinion of the roundtable was that the inventor should take the idea the whole way through development, thus capturing the inventor’s passion and commitment. It was suggested that scientists should not be pulled away from the science; they should be encouraged to take ideas forward. The group noted the success of drug ‘champions’ or ‘intrapreneurs,’ which they described as innovators of drugs with the right passion and scientific leadership to take ideas forward. It was suggested that the lack of scientific leadership has resulted in shift from entrepreneurism to process‑driven leadership. The group debated whether the pendulum has swung too far in favour of processes and debated whether large pharma will ever be entrepreneurial at the discovery stage. As well as fostering open collaboration, some participants believe that many companies need to enhance methods of internal collaboration. It was suggested that there is currently too much red tape within organizations, too many processes: it simply takes too long to get things done. “We have a fear of failure internally, but also a fear of success by going externally. We need to take more risks on the outside, but also have internal support to be able to change the closed innovation mindset,” said Jackie Hunter, OI Pharma Partners. Another delegate suggested that executives’ compensation should be based on their value to the company, not on the size of the pyramid they support.

How can we Make Collaborations Work?

Finally, the delegates discussed how participating stakeholders should work to get the best out of precompetitive collaborations. They highlighted the need to be more opportunistic and nurture entrepreneurs, the need to collaborate internally and externally and the need to be culturally aware.

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the inventor should take the idea the whole way through development, thus capturing the inventor’s passion and commitment. There was much discussion about what currently works in forming a successful partnership or collaboration. The group summarized that successful collaborations resulted from having the correct level of engagement, with the right relationship between the parties, with the collaboration being held in appropriate geographies. It was suggested that collaborations should involve a process by which partnerships are fostered and success stories are shared within the companies. This will gradually result in a cultural shift that will encourage further collaborative sharing with external parties. It was suggested that organizations need to put in place the right processes and mechanisms/incentives to support collaboration and open innovation to facilitate this change in the corporate ‘DNA.’ Companies and their employees need to see collaboration working successfully. People need to see that open collaboration can work and that it is actively encouraged by an organization. Many staff are tentative about moving to more open and collaborative working models until they see the real, tangible benefits and the necessary management support. “Innovation is akin to electricity: it follows the pathway of least resistance and if there are blockages, the whole system can shut down,” said Jackie Hunter, OI Pharma Partners. Of course, the ongoing sticking point in the majority of collaborations is the issue of intellectual property (IP). Progress for collaboration within the industry is still being held back by the IP landscape; for example, RNAi silencing — the technology is effectively blocked by IP protection.

January/February 2012

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January/February 2012

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FREEZE DRYING

DEVELOPMENT OF AN ENHANCED METHODOLOGY AND TECHNOLOGY FOR SAFE, RAPID FREEZE DRYING OF HPLC FRACTIONS High performance liquid chromatography (HPLC) purification fractions of water and acetonitrile normally need to be dried before further downstream processing and/or sample storage. The most desired form for storage is a dr y powder. The typical methodology for producing powders from aqueous solution is lyophilization (or freeze dr ying), which cannot normally accept acetonitrile. To develop a solution, Acetelion Pharmaceuticals and Genevac worked together to enhance the Genevac fast lyophilization technology to deliver lyophilization success rates of 95% with wide‑ranging chemical libraries.

rying HPLC purification fractions, principally comprising water and acetonitrile, is a routine yet essential task in many laboratories. The requirement is to dry the samples to a powder form, such that samples can be accurately weighed, easily subsampled and redissolved. Freeze drying is, therefore, the preferred technology; large‑scale traditional freeze dryers, however, may have difficulty processing the organic solvents that can boil out of the samples and damage the vacuum pump. To overcome this issue, Actelion Pharmaceuticals adopted the fast

lyophilization (LyoSpeed) methodology developed by Genevac, and implemented this using the Genevac HT‑12 centrifugal evaporation systems.1 This method concentrates the organic solvent with the centrifuge controlling boiling preventing sample loss. The system then drains the organic solvent from the condenser and then lyophilizes the remaining water. This works well for hydrophilic samples, but problems may arise where the sample cannot dissolve in only water — when the organic solvent is removed — the sample then crashes out and/or forms an oil. Such samples require further processing to achieve the desired dry powder form.

Limiting Factors

Figure 1: Genevac HT-12 with VC6000 condenser.

Figure 1

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The success rate (fully lyophilized versus oily compounds) over a standard compound library was averaging approximately 50% with the extremes being as low as 30% or as high as 90%, depending on the compound properties. The simple route to achieving a higher success rate would be to lyophilize the samples with acetonitrile still present in the samples. Unfortunately, this was not possible with the existing equipment. The limiting factor lies within the hardware, in particular the temperature performance of the solvent condenser (VC3000) of the HT‑12 evaporator. The minimum temperature that the VC3000 can achieve is –50 °C. This in turn limits the vacuum level that can be achieved in the evaporation system. For

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FREEZE DRYING

good lyophilization, the vacuum should be as low as possible, and ideally below 0.1 mbar. For example, at 0.5 mbar pure water will boil at –32 °C; at this low vacuum, however, the boiling point of acetontrile falls to –61 °C so it will boil out of the cold trap and choke the vacuum pump, causing the pressure in the evaporation system to rise. As the pressure rises, so does the boiling point of the solvents, leading to poor lyophilization results, and possibly to complete lyophilization failure. The aim of the LyoSpeed methodology is not true lyophilization, such as may be achieved during production of vaccines, but production of a dry, amorphous powder, rather than an oil. As with true lyophilization, the better the vacuum, the better the result.

Developing an Superior Solvent Condenser

The solution to the problem seemed clear; a colder condenser was required — one that could condense and hold acetonitrile at a low vacuum. Working with the engineering team at Genevac, a series of trials was initiated to benchmark the VC3000 against a VirTis Benchtop K –85 °C freeze dryer (BTK), connected to the HT‑12 evaporator. The results from this lead to the development of a new condenser for the HT‑12, called the VC6000 (Figure 1). The design of the VC6000 evolved from the BTK and has been enhanced for higher condensing power, shorter defrosting times, along with the high levels of solvent resistance of a Genevac system.

Materials and Methods

The Genevac HT-12 evaporator was used connected to the VC3000, the BTK or the VC6000 condenser. Samples comprising 10 mL of a 50:50 mix of water and acetonitrile were prepared in 16‑mm diameter by 100‑mm tall glass vials, wall thickness 1.2 mm. Twenty‑four tubes were held in a solid PVDF plastic sample holder and placed in the swing of the HT‑12 evaporator. The solvent in each tube contained either: no chemical compound, 20 mg Diovan or 20 mg of a commercially available, rather lipophilic building block, phthaloyl‑beta‑alanine (AI028492). Diovan and AI028482 are both known to be difficult samples to lyophilize from HPLC fractions, and so constitute a “worst case” sample. Each condenser was tested under two load conditions, either with four racks of samples — 96 tubes or a full load of 12 racks — 288 samples. The method used for all samples and each condenser was the same: 1. Dri-Pure vacuum ramp for 1 h to control boiling/ bumping. 2. Full vacuum with no heat for 3 h.

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Table I: Lyophilization results for each test condition.

Table I

3. Full vacuum with heat to the sample holders at 40 °C for 4 h. 4. Full vacuum with no heat for 18 h. Stage 4 was excessively long and was used in this way for testing; the actual time to dry can be determined from the chart of logged data.

Results

Following lyophilization, the condition of the compound in each tube was evaluated as lyophilized successfully to a diffuse powder or had formed a light oily sample, or the residual volume of solvent in each tube was estimated (Table I). The drying time is taken as the time to temperature convergence of the sample holder and the sample.

Discussion

Where no sample was present a 100% success rate was expected; it was, therefore, surprising that two of the 96 samples in the BTK failed to dry. As this result was not replicated with the higher sample load it was not investigated further because it appears to be an aberrant result. The performance of the VC3000 when processing real samples was the least successful. The Benchtop K had a better performance, but had an inner volume too small for lyophilization of 288 vials, with the VC6000 performing most successfully, which was in line with expectations. There were two points of interest: 1. Why was the performance of the VC6000 with Diovan so different between the low load and the high sample load? The drying time for the lighter load is also much longer, which is counter intuitive. 2. Given that in each test, the sample in every position is exactly the same, having been drawn from the same stock solution, why is the drying performance so variable between tubes? The reason for the difference between two Diovan containing tests with the VC6000 is apparent when studying the data plots from the trials, shown in Figure 2a and 2b. In Figure 2a, showing the light sample load, the yellow line shows the sample temperature; this never converges with the pink line of the sample

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FREEZE DRYING

Figure 2a: Data plot from light sample load (96 samples) with Diovan on VC6000. Figure 2b: Data plot from high sample load (288 samples) with Diovan on VC6000.

Figure 2a

Figure 2b

holder temperature. This would indicate that samples were still wet, as is born out in the results. The reason for this was not immediately apparent and required further investigation. It was found to be inadequate vacuum, approximately 1.5 mbar, where samples are less likely to freeze and do not dry well. The ultimate cause of this problem was slight deterioration of vacuum performance of the Scroll vacuum pumps (Edwards Ltd, UK)”. The choice of Scroll pump is ideal for a system that processes organic solvent vapours, having no oil, which may suffer attack. As with any pump, regular service is required to ensure the optimum performance and to gain the best results. For the Scroll pump, routine attention to the tip seals

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every 3 months maintains performance, is easily done and creates little mess. If we study the pressure curves for the three different condensers on processing the same samples, in this case just pure solvent under heavy load, shown in Figure 3, the more powerful and colder condenser (VC6000) keeps the pressure low, indicating superior trapping of the solvent. There are two important elements to maintaining the low pressure required for successful freeze drying: good vacuum, and a sufficiently cold and powerful condenser. It is difficult to account for the variation in drying performance between tubes in each test. The results for the VC6000 were accurately mapped — one such

January/February 2012

FREEZE DRYING

Figure 3: Data plot of pressure performance of all 3 Cold traps under high load. Figure 4: Location of wet tubes following lyophilisation from high load test using AI02492 with VC6000. Key - Yellow = <0.5ml Red = <4.5ml White = dry powder

Figure 3

Contamination was ruled out as a cause because of scrupulous use of clean, new glassware, solvent and samples for every test. Alternatively, it could be explained by the film formation over the surface of the sample by the compound itself, which would present resistance to, or a total block to, evaporation. The concept of “cake resistance” is well described by users of true freeze‑drying systems and increases in probability as the depth of sample increases. Results from drying libraries of real research compounds has shown that samples where a film is formed presents a total block to drying, resulting in several millilitres of liquid remaining. Those working with samples report that some libraries with certain chemical properties are prone to form a film. In the case of the trials with AI02492 (Figure 4), it remains unclear as to why a few samples failed to dry. Although film formation is one possible cause, it cannot be explained why 14 samples failed to dry, whereas 274 dried fully. Figure 4

is shown in Figure 4. As is evident, the tubes that do not dry tend to be those on the edges of the sample holder; here are, however, some more centrally located tubes that also do not dry. Figure 4 is typical of all results. One theory that could account for this pattern is that the centrally located tubes benefit from the cooling effect of the neighbouring tubes, and so freeze and dry more effectively. Yet, were this the complete explanation, then one would expect to see every peripheral tube fail to dry. Close observation of the tubes that failed to dry shows no tide line, and suggests that the sample froze, lyophilized and thawed/collapsed — can we conclude that they only subcooled and evaporated? Although this may be true, it fails to provide a complete explanation.

January/February 2012

Summary

The tests have shown that the VC6000 delivers superior freeze‑drying performance, particularly under high load, to the other systems tested. Vacuum performance of the system is critical to achieving good results, which requires a vacuum tight system and a sufficiently cold, sufficiently powerful condenser. The VC6000 condenser has been implemented into the daily workflow and similar evaporation results for “real libraries” of samples containing a wide range of compounds with highly variable solubility patterns (some eluting in 90% organic and others eluting in 90% water) are routinely observed. Some samples are now processed in tubes held in aluminium sample holders, providing identical results.

Rob Darrington

Acknowledgements The author gratefully acknowledges Viktor Ribic, Senior Lab Technician in the Chemistry Department at Actelion Pharmaceuticals (Allschwil, Switzerland) for his many hours of experimental work and for providing the results data presented here.

Reference

1. I . Abeysena and R. Darrington, “Developments in Laboratory Scale Lyophilisation for Purification Laboratories,” Genevac (2006).

For more information Rob Darrington Genevac Ltd Tel. +44 1473 240 000 www.genevac.com

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January/February 2012