World Pharma 2011 Vol. 2

£25.00 €47.50 $58.00 2011 Vol. 2

Pharmaceutical outsourcingSpecial supplement:

GlobalData

Best medicine Mixed messagesThe WHO’s campaign to improve the quality of APIs

How to communicate with CMOs in emerging markets

Mission insoluble

Andreas Ohm, Bayer Healthcare, on targeting instability in formulations

WPF020_Cover2.indd 1 07/10/2011 10:58

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Healthcare_World pharmaceutical.indd 1 31/08/2011 13:33:31WPF020_Panalpina2.indd 1 04/10/2011 14:25

Foreword

www.worldpharmaceuticals.net

AlsointhisissuePage 49: Bayer HealthCare’s Andreas Ohm reveals how his company is addressing the challenges of solubility.

Page 77: Dr Antony Fake and Jacqueline Sawyer discuss the WHO’s Prequalification of Medicines Programme.

Page 101: Novo Nordisk’s Kim Steffensen explains how to successfully work with CMOs in emerging markets.

Choosing an API supplier

SusanneKeitel,director,EuropeanDirectoratefortheQualityofMedicines&Healthcare

World Pharmaceutical Frontiers2011 Vol. 2

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E uropean legislation places the burden of ensuring that the manufacturing of active

pharmaceutical ingredients (API) is GMP-compliant on the finished manufactured product. So, what are the important criteria to consider when selecting an API supplier? The quality of the API’s access to information on the route of synthesis and the resulting impurities are crucial starting points, but they need to be supplemented by the assurance that the API and, where relevant, the intermediates are GMP-compliant.

How can this be best achieved? A proper on-site audit by a skilled auditor will provide the necessary information, and, in order to optimise resources, it’s worth considering a shared audit with other companies or using an accredited audit company or consortium.

Another important issue is the ability of the API manufacturer to understand and fulfil the regulatory needs of its customer, an issue that will play out throughout the lifecycle of the finished product. An appropriate contract, including a quality agreement that specifies the client’s requirements, is indispensable.

When selecting an API supplier, cost issues should be carefully balanced with quality requirements. Should financial aspects overrule the need for quality in the

first place, repercussions during the lifecycle of the product may tip the balance in the medium to long term.

Bear in mind that the considerations and audits performed in selecting an API supplier are not carried out only once: ensuring API quality is a dynamic process that should include the lifecycle of the API in conjunction with that of the finished product. This means maintaining a close connection with the supplier and providing technical and regulatory support, if needed. It also means that the evolution of costs on the side of the API supplier needs to be monitored: changes in environmental legislation, occupational health or work safety concerns may, over the lifecycle of an API, require adjustments that will affect the cost of goods. An API supplier that cuts corners may be capable of maintaining the price, but will not necessarily be able to maintain the quality.

Lastly, it is important for finished product manufacturers to be prepared for a potential interruption of the supply chain; for example, an unexpected negative audit or inspection, the suspension of a Certificate of Suitability or production of the API being discontinued due to environmental concerns in the country of production. Having a contingency of suppliers will help the finished product manufacturer survive any such situation without an interruption to stocks.

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WorldPharmaceuticalFrontiers | www.worldpharmaceuticals.net 5

Contents

Andreas Ohm of Bayer HealthCare explains how the company is overcoming one of the most common formulation challenges: solubility.How cloud computing could help to keep clinical trials on an even keel.

market intelligence

8 newsA round-up of all the latest business and healthcare news.

10 events Key events in the coming months.

11 Vital statisticsIndustry facts and figures.

12 top ten generic pharmaWe profile the top ten generic companies most likely to benefit as Big Pharma patents expire.

14 Pharma’s emerging focusAs countries begin to recover from the recession, ICD Research explores how opportunities and demand in the pharmaceutical industry will change in 2011-12.

16 Pharma deals on the riseThe quantity of mergers and acquisitions are falling in the pharmaceutical and healthcare industry, but companies are responding creatively to economic uncertainty, according to GlobalData.

19 healthcare opportunities abound

How consumers look after their health has many implications for the pharmaceutical industry. Deloitte’s latest Global Survey of Health Consumers reveals the behaviours, attitudes and unmet needs of consumers in 12 countries.

regulation

22 Publish and be damnedThe pharmaceutical industry faces growing public demand for greater transparency in the publication of drug trial results, but, says the EFPIA, the risk of misinterpretation also needs to be considered.

regional focus

24 the cost of a deep cutCost-containment is a major thrust area for policy reforms of pharmaceutical reimbursement and pricing in Europe, writes Ranjith Gopinathan of Frost & Sullivan.

manufacturing

26 Greening the industryPfizer discusses the importance of staff participation in sustainability programmes and the significant strides the company has made in green chemistry and green design.

31 Process safety management

ABB

32 a clean balanceBürkert

35 Proactive energy management

Usource

38 embracing pharma’s needsLinde

41 a vital cog in the machineGiven the complex manufacturing process of biopharmaceuticals, achieving operational excellence is an organisational challenge. Dr André Overmeyer of Merck Serono talks to Nic Paton about the benefits of reducing the cost of goods sold.

cover story

4993

2241

Biopharmaceutical manufacturers are striving for operational excellence.

WPF020_Contents.indd 5 07/10/2011 11:48

Contents

45 Automatedsample preparation

Mettler Toledo

47 Advantagesofadvanced continuous-flowreactors Corning

Drugdelivery&formulation

49 SuspendedsolutionsOvercoming solubility issues is one of the most common formulation challenges facing pharmaceutical businesses today. Bayer HealthCare’s Andreas Ohm explains how his company is addressing the problem.

54 DoublewhammyLaboratoria Smeets

56 ChewanddeliverCafosa Gum

58 AqualitycombinationRAUMEDIC

61 Readyfortake-offControlled-release drugs have been around for some time and have many benefits, particularly for patients with chronic or autoimmune diseases, but ongoing research has revealed that this market’s potential is only now about to take off..

Packaging

121 CaughtinthenetThe internet has opened up a massive new market to counterfeiters, one that can be accessed at the click of a button. Desmond Hunt of the US Pharmacopeia and Merck Serono’s Andreas Maack explain how a global legislation effort

combined with multilayered packaging protection can help catch the copies.

124 AtrackandtracesuccessAntares Vision

126 RotaryBraille: aqualitytouch

BOBST

129 QualitycontrolBraille forpharmapackaging

Global Vision

130 OntopofpackagingDividella

132 BoardissuesMM Karton

Clinicalsupplies&logistics

135 BestlaidplansFrom securing a robust supply chain to encountering different comparator drug formulations, there are a swathe of variables to consider when conducting pharmaceutical research. But what is the best way to overcome such obstacles? Nic Paton asks H Lundbeck’s Dorthe Lerche Berg what strategies are needed to ensure a successful comparator drugs trial.

141 ComparativestudiesMultipharma

142 Professionalclinicaltrials foremergingmarkets

SafeLab & Logistics

144 Fivekeystosuccessful cold-chainlogistics inRussia,Ukraine andBelarus

IMP Logistics Russia

147 Pharmaceuticallogistics dedicatedtotheCEE

Cemelog

Coldchain

149 PlayitcoolLogistics systems in the developed world continue to evolve at breakneck speed, but their counterparts in emerging nations are lagging behind, meaning drugs and vaccines are not being delivered in optimum condition or in the correct quantities. Elly Earls talks to John Lloyd of Project Optimize about the initiatives underway to change this.

156 Keepingthecoldchain onthelevel

TSS

159 LogicallogisticsBiocair

160 Takefullcontrolof cold-chainmanagement Panalpina

Directory

161 Productshowcase

170 Index

Patrick DeLuca and Heidi Mansour of the University of Kentucky College of Pharmacy reveal why the sky’s the limit for controlled-release drugs.

WORLDPhARmACEUTICALFROnTIERS | www.worldpharmaceuticals.net6

Turntopage65forourspecialPharmaceuticalOutsourcingsupplement.

61

The campaign to ensure the purity of active pharmaceutical ingredients.

77

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R&D

GM plants may help prevent HIV

Market intelligence > News

WoRlDPHaRMaceutIcalFRontIeRs | www.worldpharmaceuticals.net8

An antiviral drug synthesised by genetically modified (GM) plants, which could be used to help prevent HIV infection, is being tested on a small number of women in the UK to establish its safety.

The drug was developed by Julian Ma, joint head of the infection and immunity research centre at St George’s Hospital Medical School in London, via a process known as ‘pharming’ (genetically modifying plants to produce useful drugs). The method demonstrates that it is possible for similar molecules – known as monoclonal antibodies – to be produced relatively cheaply in plants to the high standards needed for their use in humans.

The Pharma-Planta project was launched seven years ago and aims to use GM plants to cut the costs of drugs that are hard to produce and to increase their availability to the developing world.

“The driver was to produce these medicines economically and at a level that would satisfy global demand,” said Ma. “MHRA approval to proceed with human trials is an acknowledgement that monoclonal antibodies can be made in plants to the same quality as those made using existing

conventional production systems. That is something many people did not believe could be achieved.”

The most useful monoclonal antibodies, such as anti-cancer drug Herceptin, are still covered by major pharma patents, but when these expire, the new technique could offer a way to make more low-cost versions of life-saving medicines available in resource-poor countries.

GM plants could pave the way for HIV prevention.

In briefA federal court has backed Pfizer’s claim that one of its Viagra patents does not expire until October 2019, a ruling that means Teva Pharmaceuticals cannot move forward with its generic copy of the blockbuster drug. “Teva has not shown by clear and convincing evidence that the patent is invalid,” said US District Judge Rebecca Beach Smith. Teva was to start selling a generic version of the drug next year. In June, a Leerink Swann analyst told the Wall Street Journal that extended exclusivity could raise Pfizer’s earnings by 3% annually between 2013 and 2018.

Johnson & Johnson (J&J) and Gilead have received FDA approval for a new combination treatment for HIV, which is expected to earn over $500 million per year. Complera combines J&J’s Edurant with Gilead’s Truvada into one pill, which can be taken once a day. This new approval marks a step forward for J&J and Gilead, which have joined forces on new programmes, such as combining Gilead’s experimental cobicistat with J&J’s Prezista.

Bayer HealthCare has agreed to support the WHO’s Stop TB Partnership in the fight against multidrug-resistant tuberculosis (MDR-TB) by making 620,000 tablets of the antibiotic moxifloxacin available to the WHO. The tablets will then be provided to China’s national TB programme. Moxifloxacin is a broad-spectrum antibiotic indicated for the treatment of acute bacterial infections, such as respiratory tract infections. It is not currently approved for the treatment of TB, but the WHO has included it in treatment group 3 of its guidelines as part of a second-line TB regiment in patients with confirmed MDR-TB on the grounds of its demonstrated activity against Mycobacterium tuberculosis.

Former Pfizer employees have established a research networking firm to be based at their previous workplace in Sandwich, Kent, UK, which was closed in early 2011. Seven ex-Pfizer staff members will be part of The Research Network, According to CEO Andrew McElroy, the company would help biotech and pharmaceutical firms with partners for outsourcing research productivity.

R&D

Ms genes identified in large-scale study

Scientists have discovered 20 new gene variants implicated in multiple sclerosis (MS), one of the most common diseases of the nervous system, following the largest-ever study of the genetics of the disease. These discoveries have more than doubled the list of parts of the human genome that researchers believe contribute to MS.

The study involved 250 researchers in the International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium. It was led by Professor Alastair Compston from the University of Cambridge, UK, and involved scientists examining 600,000 locations in the DNA from 9,772 people with MS and comparing them with those of 17,376 unrelated healthy

people. Many of the genes identified by Compston’s team are involved in the function of T-cells, a type of immune cell responsible for destroying foreign invaders.

Of the new gene variants found for MS, approximately one third has already been linked to a range of autoimmune conditions, where T-cells malfunction and attack the other cells in the body.

The findings also show that four of the gene variants for MS are directly associated with drugs either already licensed or in clinical trials.

New gene variants linked to MS could help identify the risk factors and treatment of the disease.

ReGulatIon

Big Pharma says no to further price cutsUS pharmaceutical companies have warned the Obama administration that they will not accept any new moves to cut the prices of prescription drugs supplied through Medicare, explaining that these would amount to government price controls. In August, the US President signed a debt-ceiling deal that calls for further cuts in government spending to reduce the federal deficit by $1.5 trillion over the next ten years.

Leading democrats said they are revisiting plans originally put forward in 2005 to give the federal government authority to negotiate prices with drug makers and introduce rebates on medicines supplied to ‘dual eligibles’ (those who qualify for both Medicare and Medicaid). However, Ian Read, Pfizer’s chief executive, said his company would oppose any further changes.

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MMI028_Global Vision (all products).indd 1 04/10/2011 14:27

Market intelligence > Events

WorldPharmaceuticalFrontiers | www.worldpharmaceuticals.net10

october 201119th Annual BioPartnering Europe9–11 OctoberLondon, UKwww.techvision.com/bpe

Clinical Trials Supply Asia10–11 OctoberSingapore www.clinicaltrialsupplyasia.com

DIA 5th Annual Clinical Forum 201110–12 OctoberBasel, Switzerland www.diahome.org

Regulatory Requirements for Clinical Trials13–14 October London, UKwww.management-forum.co.uk

PDA’s 6th Annual Global Conference on Pharmaceutical Microbiology17–21 October Bethesda, USwww.pda.org/2011microbiology

Clinical Trial Supply East Coast 2011 19–20 OctoberPhiladelphia, USwww.clinicaltrialsevents.com/eastcoast2011

Outsourcing in Clinical Trials Canada 201125–26 OctoberToronto, Canadawww.arena-international.com/poutcanada2011

CPhI Worldwide25–27 OctoberFrankfurt, Germanywww.cphi.com

ICSE25–27 OctoberFrankfurt, Germanywww.cphi.com/icse

november 2011Pharmaceutical Packaging and Labelling 2011 2–3 NovemberLondon, UKwww.management-forum.co.uk

Pharmaceutical Serialisation and Traceability Summit 20112–4 NovemberGeneva, Switzerland www.pharmaserialisation.com

BIT’s 1st Annual Symposium of Drug Delivery Systems 3–6 NovemberShenzhen, Chinawww.bitlifesciences.com

BIT’s 2nd Annual Congress of Biomarkers 7–9 NovemberBeijing, Chinawww.bitlifesciences.com

The Universe of Pre-filled Syringes & Injection Devices Pharma Manufacturing Summit7–11 NovemberBasel, Switzerlandwww.pda.org

Drug Delivery Systems Americas 201116–17 NovemberBoston, USwww.visiongain.com

Pharmacovigilance, Drug Safety and Risk Management22–23 NovemberBrussels, Belgiumwww.arena-international.com/pharmaco

10th Annual World Drug Manufacturing Summit 201129 November – 1 DecemberBerlin, Germanywww.wdmsummit.com

Bio World China29 November – 1 DecemberShanghai, Chinawww.imapac.com

december 201163rd Indian Pharmaceutical Congress16–18 DecemberBengaluru, Indiawww.ipc-2011.com

January 20123rd Annual World Drug Delivery & Formulation Summit 2012 16–18 JanuaryBerlin, Germanywww.ddfevent.com

march 2012Biologic Manufacturing World Asia 2012 20–21 MarchSingaporewww.terrapinn.com

events diary october 2011-march 2012

WPF020_005_Events.indd 10 06/10/2011 12:03

Market intelligence > Vital statistics


43

Vital statistics

talKinG Points

There are hundreds of medicines in the pipeline for non-communicable diseases. These include 887 medicines for cancer, 235 medicines for diabetes, 299 medicines for heart disease and stroke, and 313 medicines for mental illness.Source: www.phrma.org/research/new-medicines

In 2004, 17.1 million people died from cardiovascular disease. Oncologic diseases had a 13% share in total mortality in 2008, with 7.6 million deaths worldwide. Respiratory diseases led to 7% of all deaths globally in 2005, with over four million deaths, of which three million were from chronic obstructive pulmonary disease. Almost 2% of deaths are caused by diabetes.Source: www.ifpma.org/fileadmin/content/Publication/AIPM _ brochure_210411_ENG.pdf

In 2004, non-communicable diseases (NCDs) caused 35 million deaths across the world, of which nine million or 25% were people under 60 years old. As of 2010, the global share of those who died from NCDs under 60 years increased to 14 million.Source: www.ifpma.org/fileadmin/content/Publication/AIPM_brochure_ 210411_ENG.pdf

Only one of every 10,000 potential medicines investigated by the US’s research-based pharma makes it through the R&D pipeline to be approved for patient use by the US FDA. Winning approval takes, on average, 15 years of R&D and costs more than $1 billion. Potential new medicines pass through several crucial stages on their way from research laboratories to the pharmacy shelf. Source: www.phrma.org/research/drug-discovery-development

US biopharma research companies are in the process of developing 277 medicines to help the millions of Americans that suffer from at least one skin disease. A study by the Lewin Group estimated that the total annual cost of skin diseases was $39.3 billion in 2005.Source: www.phrma.org/research/new-medicines

There are a record 887 medicines for various types of cancer currently undergoing clinical trials or awaiting US FDA-approval. This figure is more than double the number of drugs that were in the pipeline just six years ago. Source: www.phrma.org

53the number of countries in 2010 co-financing new and underused vaccines supplied by the GaVi alliance, a public-private global health partnership committed to saving children’s lives and protecting people’s health by increasing access to immunisation in poor countries.Source: GAVI Alliance 2010

267mthe amount of children immunised with the hepatitis B vaccine since GaVi’s launch in 2000.Source: WHO Department of Immunisation, Vaccines and Biologicals’ estimates and projections, November 2010

19the number of seconds before the next child will die from a vaccine-preventable disease.Source: WHO

79

the percentage of dPt3 coverage – three doses of diphtheria, tetanus and pertussis – in low-income countries in 2010. this increased from 66% in 2000 and is now at the highest level ever.Source: WHO Department of Immunisation, Vaccines and Biologicals’ estimates and projections, November 2010

medicines and interventional treatments contributed to a 45% decline in heart attack deaths and heart failure between 1999 and 2005.

20

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In-hospital heart attack deaths

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the percentage of GaVi vaccines produced by pharmaceutical companies based in emerging markets.Source: GAVI Alliance 2008

WPF020_004_Vital stats.indd 11 07/10/2011 11:49

Topten

The impending patent cliff will mean losses for Big Pharma, but gains for their generic competition. GBI Research’s Jay Mehta profiles the top ten generic pharma companies by 2010 revenue.

Market intelligence > Top ten generic pharma


generic pharma

The leading generic company in the US recorded an operating profit of $3.88 billion during the fiscal year 2010, an increase of 61% over 2009. Its net profit was $3.33 billion, an increase of 66.5% over 2009. Based in Tikva, Israel, Teva operates in 60 countries in Europe, Asia, North America and Latin America. It has 40 finished dosage pharmaceutical manufacturing sites in 19 countries, pharmaceutical R&D centres in 18 countries and employs more than 35,000 people worldwide. The total number of prescriptions for Teva products in the US increased to approximately 611 million in 2010 from 599 million in 2009, representing 21.1% of the US’s total generic prescriptions.

1

Headquartered in Holzkirchen, Germany, Sandoz International is a subsidiary of Novartis. It has 23,000 employees in 130 countries, ten global development centres and more than 30 manufacturing sites worldwide. The company’s operating profit was $123 billion during fiscal year 2010, an increase of 18.8% over 2009. Sandoz’s major product offerings include biosimilars, injectables, inhalables, patches and complex oral solids. The firm offers over 1,000 molecules to patients across 130 countries. Its top ten revenue-generating products worldwide are enoxaparin, amoxicillin/clavulanic acid, omeprazole, tacrolimus, losartan, fentanyl, lansoprazole, simvastatin, acetylcystein and amlodipine/benazepril.

2

During the fiscal year 2010, the operating profit of Mylan was $721.6 million, an increase of 37.9% over 2009. Based in Pennsylvania, US, the company’s net profit for 2010 was $345.1 million, an increase of 48.4% over 2009. Mylan markets over 1,000 products to consumers in more than 150 countries and territories, and employs over 17,000 people. Currently operating in the generics and speciality business segments, the company’s subsidiary Matrix Laboratories has direct access to one of the largest active pharmaceutical ingredient manufacturers. In the US generics prescription market, Mylan ranks second in terms of revenue and prescriptions dispensed.

3

Actavis operates in over 40 countries in North America, Europe and Asia Pacific, and has a 10,000-strong workforce. Thanks to proactive R&D work and robust product registration, the company, which is based in Zug, Switzerland, has 350 products under development and pending registration, and 830 products available in 60 countries. Its products come in tablet, capsule, injectable, suppository, spray, sterile powder, oral liquid and semi-solid forms. Major therapeutic areas in Actavis’s product portfolio include the central nervous system, cardiovascular, oncology, respiratory and dermatologicals.

4

teva (israel)2010 revenue: $11.03 billion (+17.1% over 2009)

sandoz (Germany)2010 revenue: $8.52 billion (+13.7% over 2009)

mylan (us)2010 revenue: $4.99 billion (+7% over 2009)

actavis (switzerland)2010 revenue: $2.52 billion (estimated – Actavis was privatised in 2007 and has not published its latest annual reports)

toP ten Pharma comPanies1. Pfizer: $67.8 billion2. Johnson & Johnson: $61.6 billion3. Novartis: $51.6 billion4. Bayer: $46.8 billion5. Merck: $46 billion6. F. Hoffmann-La Roche: $45.6 billion7. GlaxoSmithKline: $43.7 billion8. Sanofi: $42.7 billion9. Abbott Laboratories: $35.2 billion10. AstraZeneca: $33.3 billionSource: Nithiya Dhevi, GBI Research

WPF020_006_Top ten.indd 12 06/10/2011 08:53

Market intelligence > Top ten generic pharma


Hospira’s operating profit for the fiscal year 2010 fell to $482.4 million, a 4.1% drop from 2009. Its net profit was $357.2 million for 2010, a decrease of 11.6% from 2009. Headquartered in Illinois, US, Hospira has operations across the US, Europe, Latin America and Asia Pacific. The company’s generic business is operated through its speciality injectable pharmaceuticals division, which includes approximately 200 generic injectable drugs. Some of Hospira’s major generic drug launches in 2010 included docetaxel in Europe, oxaliplatin, piperacillin/tazobactam, gemcitabine and biosimilar erythropoietin Nivestim in the US, and irinotecan and gemcitabine in Japan.

5

Based in California, US, Watson Pharmaceuticals operates in three businesses: global brands, global generics and distribution. Global generics forms the key business segment, contributing approximately 66% of the total revenue. The company saw a decrease of 20.2% in its operating profit from 2009-10, with a figure of $304.9 million during the fiscal year 2010. Watson’s net profit also fell by 16.9% to $184.4 million in 2010. The company markets over 170 generic products in the US and 350 in international markets through its global generics business. Some of the key products in its generic portfolio include Wellbutrin SR, DDAVP, Marinol, Duragesic, Nordette, Nicorette and Yasmin.

6

Although it is renowned as a branded pharmaceutical company, Sanofi also has a strong generics division. It operates its business in two broad categories: pharmaceuticals and vaccines, with generics forming part of the pharmaceuticals division. Sanofi has been aggressive in the generics business, with acquisitions in emerging markets such as Eastern Europe and Brazil. In Europe, Sanofi rebranded all its generics businesses under Zentiva, a Czech Republic-based generics company that was acquired in 2009. In May 2010, the pharma giant established a new joint venture with Nichi-Iko Pharmaceutical, a Japanese generics market leader, to develop its generics business in Japan.

7

Based in New Jersey, US, Greenstone is a wholly owned subsidiary of Pfizer. The company is involved in the marketing of a broad line of authorised generics in the US. Strong distribution channels and sales support from its parent company ranked Greenstone eighth on our list, despite its large operations being focused only in the US. Major drugs in the company’s portfolio include alprazolam, azithromycin, benazepril, donepezil hydrochloride (ODT and tablets), fluconazole, levofloxacin, nifedipine, ondansetron, topiramate and zidovudine, while its recent launches include donepezil HCL, latanoprost ophthalmic solution and exemestane tablets.

8

The operating profit of Hesse-based STADA Arzneimittel was $215.2 million during the fiscal year 2010, a drop of 14.5% from 2009, while its net profit was €68.4 million, a fall of 31.9%. STADA operates its business through two segments: generics and branded products, with the generics division accounting for 69.1% of its total revenue. The top five generic products for the company in terms of sales were omeprazole ($67 million), simvastatin ($35.2 million), enalapril ($30.8 million), diclofenac ($30.7 million) and phospholipide ($29.7 million). STADA is highly focused on the European market, which contributes 96.3% of the total revenue of the generics segment.

9

Based in Hyderabad, India, Dr Reddy’s Laboratories is one of the country’s leading pharmaceutical companies and has a strong presence in the global generics market. The firm has subsidiaries in the US, UK, Russia, Germany and Brazil. Dr Reddy’s operates through three business segments: pharmaceutical services and active ingredients, global generics and proprietary products. Global generics, which includes branded and unbranded generics, forms the key segment of the Indian manufacturer, contributing 71.4% of the total revenue. The branded generics division has 200 products on the market in areas such as oncology, cardiovascular and dermatology.

10

hospira (us)2010 revenue: $2.35 billion (+13.3% over 2009)

Watson (us)2010 revenue: $2.27 billion (+38.2% over 2009)

7 sanofi (France)2010 revenue: $2.04 billion (+41.5% over 2009 – Generics Division)

Greenstone (us)2010 revenue: $1.72 billion (2009 revenue unavailable)

stada (Germany)2010 revenue: $1.5 billion (0.7% over 2009)

dr reddy’s (india)2010 revenue: $1.16 billion (16.7% over 2009)

Jay mehtaJay Mehta is a senior analyst in healthcare practice at GBI Research. Prior to joining the company, he completed his MBA in international management from the Management Development Institute in Gurgaon, India.

WPF020_006_Top ten.indd 13 06/10/2011 08:54

T hroughout the pharmaceutical industry, 56% of respondents of ICD Research’s Global Pharmaceutical Industry Outlook Survey 2011-2012 are ‘more optimistic’ about revenue

growth for their company over the next 12 months compared with the previous 12 months. Low GDP growth rates, reduced consumer spending and decreased government expenditure slowed the growth of the pharmaceutical industry in 2009.

As national economies began to recover from the global economic crisis, revenue growth expectations increased during 2010 and rose further in 2011. As a result, multinational corporations are no longer viewing emerging economies as mere production locations, but more as significant customer bases.

Although the US market will have the largest share of consumer spending in the global market, emerging markets are likely to have the highest growth rates, with China expected to record double-digit growth due to increased government and consumer expenditure.

According to 46% of the survey’s pharmaceutical manufacturer respondents, China is considered the most important region for growth among emerging markets, along with Brazil and India, which accounted for 38% and 33% of respondent opinion, respectively (Table 1, above right).

ChinaIn 2011, China is expected to be the third-largest market for prescription drugs. An ageing population, a rising rate of chronic diseases, expanding healthcare insurance coverage, urbanisation and increasing investment in rural healthcare services are major drivers for the growth of the country’s pharmaceutical industry. The Chinese Government is expected to invest $125 billion over the next few years for the development of its health system, with the goal of providing basic healthcare facilities to its 1.3 billion citizens.

Domestic companies are competing with multinational companies in the Chinese market; for example, Zhuhai United Laboratories, a Hong Kong headquartered pharmaceutical manufacturing company, expects to invest $151.42 million in the development of the domestic insulin market, which is usually dominated by foreign players.

According to 42% of survey respondents from the CRO and CMO industry both China and India were identified as the most important emerging markets (Table 2,opposite). The growth of China’s pharmaceutical industry offers high potential for the growth of the contract manufacturing business. As a result, multinational companies deem it profitable to outsource manufacturing functions to China as they have an established market to cater for. Furthermore, in the last year, contract manufacturing companies registered double-digit growth in China; for example, Wuxi PharmaTech, a noted CRO and CMO, posted a 16% growth in revenues for the first quarter of 2011.

IndiaCompanies that expect to outsource research operations to low-cost countries prefer India to China, because of its proven capabilities in the pharmaceutical sector. The Indian pharmaceutical market comprises companies that market branded generics to multiple countries across the globe via the development of various drugs; this is a direct result of effective R&D capabilities. Improved production capability, easier access to destination countries and low costs supports the growth of Indian CMO industry.

The Indian pharmaceutical market has progressed from being an industry that reverse engineered key products due to lenient patent laws, to that of a significant location for R&D and contract manufacturing. A competent workforce, strong patent laws, strong

Pharma’semerging focusAs countries begin to recover from the effects of the recession, ICD Research’s latest report on the global pharmaceutical industry explores how opportunities and demand are set to change in 2011-12, with emerging countries the main areas for growth.

Market intelligence > Industry in fi gures

WORLDPHARMACEUTICALFRONTIERS | www.worldpharmaceuticals.net14

The Chinese Government is expected to invest $125 billion over the next few years for the development of its health system.

Table 1. Demand in emerging markets by pharmaceutical manufacturer (%), 2011.

Country Market percentage

China 46

Brazil 38

India 33

Eastern Europe 33

Russia 31

Mexico 17

Turkey 15

Middle East 13

South Africa 9

Argentina 7

Vietnam 7

Indonesia 6

Source: ICD Research Industry Survey 2011Note: Responses are not mutually exclusive and therefore do not total 100%

WPF020_007_Industry review.indd 14 06/10/2011 14:24

Table 2. Demand in emerging markets by CROs and CMOs (%), 2011.

Country Market percentage

China 42

India 42

Eastern Europe 36

Brazil 21

Russia 18

Middle East 16

Argentina 12

Mexico 12

South Africa 9

Turkey 9

Indonesia 7

Saudi Arabia 6

Vietnam 5

Source: ICD Research Industry Survey 2011Note: Responses are not mutually exclusive and therefore do not total 100%

WORLDPHARMACEUTICALFRONTIERS | www.worldpharmaceuticals.net 15

manufacturing capabilities, double-digit growth of the industry and an increase in the population’s income are supporting the growth of the Indian pharmaceutical industry.

Leading pharmaceutical companies have entered India through acquisitions: the Indian Government allows 100% foreign direct investment in the pharmaceutical industry; for example, US-based Abbott Labs acquired the branded generics business of Piramal Healthcare for $3.72 billion in 2010, nine times higher than the value of the unit.

BrazilBrazil is the third-largest market in the American continent; the country’s pharmaceutical market is growing at a rate of 12% and is expected to be the world’s fifth-largest market by 2015. An expanding population, improved access to healthcare and an upwardly mobile generation that is increasingly opting for branded drugs are key factors supporting growth in the industry.

The Brazilian Government spent 10.8% of the country’s GDP on retail and hospital-prescribed pharmaceuticals in 2009. Interestingly, it is the government that purchases 90% of the total amount of vaccines and 20% of other drugs sold in the country.

Merging with or acquiring local companies is considered the best way to enter the market as these firms have knowledge of industry issues and strong relationships with distributors, pharmacy chains, hospitals and local authorities; for example, Amgen, a US-based pharmaceutical company, acquired Bergamo, a privately held pharmaceutical company for US$215 million.

Eastern Europe Respondents from the CRO and CMO industry identify Eastern Europe as the next important market for growth. Availability of low skilled labour, established infrastructure and government policies, superior intellectual property rights protection and an increasing uptake of biologics and generics are key factors for growth in Eastern Europe; however competition from low-cost Asian countries remain a significant challenge for companies in this region.

Supplier demand China and India were identified as the most important emerging markets by 22% and 21%, respectively, of respondents from the supplier segment of the drug manufacturing industry. As the outsourcing of manufacturing activities to India and China grows, multinational companies prefer to procure raw materials such as API and fine chemicals locally due to comparatively lower prices and reasonable lead times to reach manufacturing facilities; for example, AstraZeneca, a UK-based drug manufacturing company, decided to completely outsource its API needs over the next five to ten years; India and China were identified as its sourcing centres.

Merck, another major pharmaceutical company from the US, announced a shutdown of six manufacturing units in Italy, Portugal, Mexico, Brazil and Singapore. It expects to outsource the functions from these facilities to China and India.

The Indian Government allows 100% foreign direct investment in the pharmaceutical industry.

Market intelligence > Industry in fi gures

The information in this article was taken from the Global Pharmaceutical Industry Outlook Survey 2011-2012.

To purchase this report and for more information on sample provision, survey support or custom support solutions, contact [email protected].

Demand by region Respondents whose companies operate in North America and Asia Pacific consider China, India and Brazil to be the most important markets for growth, while respondents whose companies operate in Europe consider Eastern Europe to be more important than Brazil. The Middle East, Brazil and Mexico are identified as the most important markets by respondents whose companies operate in the Rest of the World. ■

WPF020_007_Industry review.indd 15 06/10/2011 14:26

W ith companies in the pharmaceutical and healthcare industry shifting their focus to the consolidation of their businesses through mergers and acquisitions

(M&As), deal values increased in the second quarter (Q2) of 2011, reaching $42.1 billion compared with $27.6 billion in Q1 2011, an increase of 52%. Conversely, the number of deals fell to 264 in Q2 2011 from 281 in Q1 2011. On a year-on-year basis, deal values were high and the number of deals was low in Q2 2011 compared with 313 deals worth $33.1 billion for the same period in 2010.

The highest number of M&As in Q2 2011 was reported in the central nervous system (CNS) and oncology therapeutics markets. The CNS sector recorded 28 deals worth $23.7 billion and oncology therapeutics had 27 deals worth $21.8 billion.

Major deals during Q2 2011 included Takeda Pharmaceutical’s agreement to acquire Nycomed International for $13.7 billion in a

bid to enhance its development expertise and commercialisation capability in Europe and

emerging markets. Teva Pharmaceutical agreed to acquire Cephalon for $6.8 billion

to expand and diversify its marketed products in CNS and mark its

commercial presence in the oncology and pain-management fields.

“The pharmaceutical industry is responding creatively to the growing forces of uncertainty [financial and regulatory environmental conditions] that are present in the pharmaceutical therapeutics market,” says GlobalData analyst Ravi Kishor Agrawal.

“To overcome this uncertainty, companies are coming up with innovative M&As, using expertise in one business segment and leveraging other companies’ business segments, to expand access to several emerging markets. The increase in M&As in the CNS and oncology therapeutics markets shows these segments will continue to grow in the near future.”

Decline in partnerships Partnerships in the pharmaceutical and healthcare industry fell during Q2 2011, with 231 deals worth $1.7 billion compared with 255 deals worth $5.7 billion in the first quarter of the year. Out of the 231 deals reported in Q2, 139 were co-development deals, 43 were co-marketing deals, 31 were joint ventures and 18 were related to other categories.

The oncology therapeutics market was ahead of all other therapeutics markets in Q2 2011, with 42 partnerships worth $289.1 million. The infectious disease therapeutics market followed, with 27 deals worth $47.5 million during the same period.

Pharma deals on the riseThe quantity of mergers and acquisitions is falling in the pharmaceutical and healthcare industry, but companies are responding creatively to economic uncertainty and seeing an increase in deal values of 52%, according to GlobalData’s latest report.

Market intelligence > M&As

The central nervous system and oncology therapeutics markets reported the highest number of M&As in Q2 2011. CNS had 28 deals worth $23.7 billion and oncology therapeutics had 27 deals worth $21.8 billion.

16

WPF020_008_M&As.indd 16 06/10/2011 08:56

drugs, ALS-2200 and ALS-2158. Hanwha Chemical entered a worldwide licensing agreement with Merck Sharp & Dohme Research, a subsidiary of Merck, to develop and commercialise HD203, a biosimilar form of Enbrel (etanercept), in a transaction worth $720 million.

Venture capital investments up 12% Venture capitalists continue to invest in the pharmaceutical and healthcare industry, because it is one of the most lucrative markets bringing a high return on investment. In Q2 2011, there were 140 deals worth $1.6 billion compared with 138 deals worth $1.4 billion in Q1 2011.

Deals in the growth/expansion stage made up 48% of the total deals in Q2 2011 and dominated the venture capital segment, followed by start-up stage financing with 60 deals, accounting for 43% of total deals. In deal values, start-up stage financing recorded $611.6 million in Q2 2011, followed by growth/expansion-stage deals worth $610.9 million.

The oncology therapeutics market remained one of the key therapeutics markets in terms of securing financing from venture capitalists in Q2 2011, recording 38 venture capital deals worth $507.3 million.

Surge in North American deal valuesWith the increase in deals in the growth/expansion stage and high unmet needs, coupled with the strong potential of targeted therapy, the oncology and immunology therapeutics markets remain an area of interest for venture capitalists, as these areas possess the highest return on investments, according to Agrawal.

“To avoid late-stage development failure in this segment, companies are also focusing on strengthening their R&D activities and, in doing so, are attracting venture capitalists,” he says.

In Q2 2011, North America recorded 38 deals worth $455.8 million in oncology, followed by 29 deals worth $378.9 million in immunology; however, with 28 deals worth $203.8 million reported in Q2 2011 in the CNS therapeutics market, this market is also an attractive investment opportunity for venture capitalists. ■

Market intelligence > M&As

WorldPhArmAceuticAlFroNtierS | www.worldpharmaceuticals.net 17

The oncology therapeutics market dominated the licensing agreements segment with 35 deals worth $2.1 billion in Q2 2011.

licensing agreements on the riseLicensing agreements registered an increase of 24% in deal value in Q2 2011 at $6.8 billion compared with $5.5 billion in the previous three months. The number of deals fell to 122 in Q2 2011 from 148 in Q1 2011.

The segment recorded a decrease in the receipt of upfront payments and a rise in milestone payments, with $458.3 million and $4.9 billion in Q2 2011 compared with $632.3 million and $4.7 billion, respectively, in Q1 2011.

Market-wise, oncology therapeutics dominated the licensing agreements segment with 35 deals worth $2.1 billion in Q2 2011, followed by the infectious disease therapeutics market with 18 licensing deals worth $1.2 billion.

In licensing by phase, products in the marketed stage recorded 112 deals, accounting for 28% of the total deals from Q2 2010 to Q2 2011. In second place, products in phase III represented 26% of deals during the same period. Phase III products accounted for 29% of total deal value, whereas phase II products constituted 27%.

Key licensing deals for Q2 2011 included Vertex Pharmaceuticals’ $810 million worldwide licensing agreement with Alios BioPharma to in-license two potential hepatitis C

Figure 1. Number of deals Q4 2010–Q4 2011.

1,800

1,200

600

0Q2 2010 Q1 2011Q3 2010 Q4 2010 Q2 2011

$1,342

$1,049 $1,151

$1,067

Source: GlobalData – Pharma eTrack Deals Database.

No

of d

eals

Ap

r 10

May

10

Ju

n 1

0

July

10

A

ug

10

S

ep 1

0

Oct

10

N

ov 1

0

D

ec 1

0

Ap

r 11

M

ay 1

1 J

un

11

Jan

11

Feb

11

Mar

11

Deal volume – last five quarters

$969

379

328

360

333

324

312

480

419

443

342

315

392

370

354

427

Figure 2. Q2 2011 Number of deals by region.

900

600

300

0North

AmericaRest of

the worldEurope Asia Pacific

Source: GlobalData – Pharma eTrack Deals Database.

No

of d

eals

722 663 310 266 208 206 149 160

■ Q1 2011 ■ Q2 2011

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WPF020_008_M&As.indd 17 06/10/2011 16:28

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Market intelligence > Business overview


i nterested in exploring how consumers actively manage their health, Deloitte surveyed more than 15,000 adults in 12 countries (Belgium, Brazil, Canada, China, France, Germany,

Luxembourg, Mexico, Portugal, Switzerland, the UK and the US) in early 2011. Among the findings was the fact that prescription medication use varies across these countries due to differences in disease prevalence, practice variations, insurance coverage and cultural norms when it comes to taking medication.

In addition, consumers vary in the extent to which they are actively involved in seeking a better understanding of treatment options, engaging in dialogue with medical professionals to make treatment choices, basing purchasing decisions on cost considerations, integrating alternative therapies and adhering

How consumers look after their health has many implications for the pharmaceutical industry. Sheryl Coughlin reveals Deloitte’s latest Global Survey of Healthcare Consumers, which examines the behaviours, attitudes and unmet needs of consumers in 12 countries.

0% 20% 40% 60% 80% 100%

US

UK

Canada

Brazil

Luxembourg

Mexico

Switzerland

France

Belgium

Portugal

Germany

China

■ Excellent/very good (ratings of 1 or 2)

■ Fair/poor(ratings of 4 or 5)

61%10%

56%14%

55%11%

53%12%

53%15%

48%10%

48%18%

39%25%

39%22%

38%21%

34%25%

26%29%

Source: Deloitte 2011 Survey of Healthcare Consumers

Figure 1. self-reported health status.

In general, how would you rate your overall health?

healthcare opportunities abound

sheryl coughlinSheryl Coughlin’s expertise covers healthcare research, organisational strategy and performance management in private and public sector healthcare organisations. She has worked in Hong Kong, Singapore, Australia and the US.

WPF020_009_Deloitte.indd 19 06/10/2011 12:05



to prescribed regimens. Anticipating that greater consumer engagement may lead to improved health and cost outcomes, the results of this survey point to opportunities for pharmaceutical manufacturers, healthcare providers and policy makers to meet consumers’ unmet healthcare needs.

health statusWhile consumers believe themselves to be in good health, over half have a chronic health condition. Having ‘excellent’ or ‘very good’ health is self-rated by over half of US consumers (61%), the UK (56%), Canada (55%), Luxembourg (53%) and Brazil (53%) (Figure 1, page 17); however, around half of consumers say they have been diagnosed with one or more chronic conditions, ranging from 40% in Mexico to 55% in Germany and in the US.

Prescription medication useConsumers use prescription medications and a mix of other products when managing a health problem or improving their health. Regular use of prescription medications ranges from around three in ten in China to almost six in ten in the US. Nearly half of prescription medication users in the US (48%) and in France (46%) take three or more medications on a daily basis (Figure 2).

Approximately four in ten Chinese respondents (42%) use over-the-counter medications, considerably more than in other countries, with 11% in the UK and 36% in the US. On average,

Figure 2. Prescription medication use.

all respondents among prescription medication users

country

% taking prescription

medications on a regular basis

one prescription medication on a

daily basis

two prescription

medications on a daily basis

three or more precription

medications on a daily basis

one prescription medication on a regular but not

daily basis

US 57 28 22 48 2

France 56 29 22 46 3

Belgium 54 36 21 39 4

Canada 50 34 23 41 2

Germany 49 37 25 36 1

Luxembourg 45 38 32 30 -

UK 43 35 23 40 2

Portugal 42 40 23 34 3

Brazil 40 51 27 20 3

Switzerland 39 40 23 34 3

Mexico 36 38 28 24 10

China 33 45 24 13 18

Figures are rounded and arranged in descending order of percentage of respondents taking a prescription medication on a regular basis.


three in ten consumers in European countries regularly use vitamins and supplements to treat a health problem or improve their health, whereas more than six in ten consumers in the US and Canada do so.

Consumption of functional foods (such as cholesterol-lowering and probiotic products) to treat a health problem or improve health is lower, ranging from just under half of respondents in China (49%) to 19% of French respondents (Figure 3).

alternative therapies and conventional careConsistently across all countries, around one in five consumers integrates alternative therapies with conventional care. In China, 42% say they consulted an alternative-care practitioner or advisor in the previous year.

Between 9% and 25% of prescription medication users practise alternative and/or natural therapies in addition to prescription medication, except in Mexico (33%) and China (44%). Between 3% (France) and 15% (Brazil) report substituting an alternative treatment approach or therapy for prescription medication in the last 12 months. In China, over one in three report substituting an alternative approach.

information resources Online resources play an important role in providing information to consumers, with 25-50% of all consumers looking online for treatment information. This ranges from 26% in Belgium to 54% in Canada among all consumers and from 30% in Belgium to 58% in Canada among current prescription medication users.

Consumers in all countries consider academic medical centres and medical associations/societies as their most trusted sources of information about the effectiveness and safety of treatment options. Consumers have less trust in such information from pharmaceutical, biotech or medical device/

Nearly half of prescription users in the US (48%) and in France (46%) take three or more medications on a daily basis.




product manufacturers, employers, insurers and government agencies. Internet search engines are not well-regarded as trusted sources of treatment information by most consumers in most countries.

Purchasing decisionsBetween 6% and 25% of all respondents report asking their doctor to prescribe a particular drug by name or brand or to ask whether it would be a better choice than the one prescribed. Between 13% and 27% of all respondents say they asked a pharmacist for his/her opinion about a medication that was prescribed by a doctor.

Depending on the healthcare system, cost is increasingly a motivating factor for some in their prescription medication purchases. In some countries, cost concerns prompt some prescription medication users to ask their doctors for generic drugs rather than brand-name drugs, as well as influence purchase decisions at the pharmacy counter.

Prescription medication users purchasing from a mail order or online pharmacy range between 1% and 4% (Luxembourg, Portugal, UK, Belgium, and Canada) to 26% (Germany) and 27% (US). Less than one in ten prescription medication users in all countries say they bought prescription medications from a source outside their country, with the exception of China (28%).

effectiveness, adherence and switchingPrescription medication users’ confidence in drug efficacy and effectiveness is high, ranging from 56% (China) to 85% (Mexico). Complete confidence (a rating of ten on a ten-point scale) ranged from 6% (China) to 42% (Mexico), with most falling around the three in ten mark.

Adherence by prescription medication users is generally high, with those saying they stopped taking a medication sooner than was prescribed ranging from 5% (Germany) to 23%

(China). Between 3% (Luxembourg) and 15% (US) admit changing the dosage or frequency of their medication without asking or telling their doctor.

A small number of prescription medication users report switching medications in the past 12 months. While this was mostly around one in ten, the range was from 4% in Portugal to 28% in China. Consistent across all countries, cost, side effects and a lack of effectiveness were key reasons for switching.

Consumers are clearly engaging in managing their healthcare: they look for information, adhere to instructions, consider alternatives, and seek value and effectiveness.

Given the extent of prescription medication use, it is clear that opportunities exist for pharmaceutical manufacturers, providers and policy makers to plot a course to better reach consumers, develop personalised and targeted products, position themselves as a trusted source of information, provide comparative information on treatment options, and develop strategies to more effectively engage with an active and involved consumer. ■

Figure 3. use of over-the-counter medications, vitamins/supplements and functional foods on a regular basis to treat a health problem or to improve health.

country% using

over-the-countermedications

% using vitaminsor supplements*

% using functional foods**

Belguim 27 33 24

Brazil 15 29 31

Canada 27 64 43

China 42 51 49

France 18 22 19

Germany 27 42 22

Luxembourg 19 23 22

Mexico 27 55 43

Portugal 16 22 20

Switzerland 18 39 21

UK 11 43 32

US 36 68 34

* Percentage of respondents who indicated they use vitamins/supplements on a regular basis to treat a health condition or to improve health.

** Percentage of respondents who indicated they use functional foods such as probiotic yoghurts and cholesterol-reducing spreads on a regular basis to treat a health condition or to improve health.


Prescription medication users’ confidence in drug efficacy and effectiveness is high, ranging from 56% (China) to 85% (Mexico).


As the pharmaceutical industry faces growing public demand for greater transparency in the publication of drug trial results, Nic Paton asks Christine-Lise Julou of the EFPIA about the risks of misinterpretation and the need to respect commercial confidentiality.

T he headline in the British Medical Journal in October 2010 could barely have been starker: “Patients and doctors are being misled by published data on

medicines”. The study it referred to, by a group of researchers at the German Institute for Quality and Efficiency in Health Care, argued that the drug reboxetine was, overall, an ineffective and potentially harmful antidepressant.

Even more worrying for the pharmaceutical industry, it concluded that nearly three-quarters of the data on patients who took part in trials of reboxetine had not been published until then, and that published data on the drug had overestimated the benefits and underestimated the harms of treatment, “all underlining the urgent need for mandatory publication of all clinical trial results”.

So, was this a clear-cut case of ‘nasty Big Pharma’ trying to pull the wool over the eyes of an unwitting public and, in the process, making a fast buck?

Absolutely not, says Christine-Lise Julou, director, scientific and regulatory affairs at the European Federation of Pharmaceutical Industries and Associations (EFPIA): “It’s not so much about people withholding information, it’s about an increased appetite for information. This has to be recognised and acknowledged.”

Publish and be damned

Christine-Lise Julou Christine-Lise Julou is director of the scientific technical and regulatory affairs department at the EFPIA. Prior to this she was senior director regulatory affairs at Rhône-Poulenc Rorer (then Aventis) and Gencell.

Insight > Regulation

WorLdPharmaCeuTiCaLFronTiers | www.worldpharmaceuticals.net22

WPF020_010_Trials and tribulations.indd 22 06/10/2011 12:33

“The regulations are already very broad and do not need to be tougher,” she says. “It is important to respect commercial confidentiality and to not have a negative impact on the pharmaceutical R&D that delivers new medicines for patients. We would have some concerns if there was a proposal to make all information on trials available before a product has been authorised for public use – there is no reason for that.

“While we support enhanced transparency within clinical trials information, it is important to maintain privacy for personal data and protection of commercial and contractual interests so as not to undermine the incentive for research,” she adds.

Support and accuracyThere are important clinical benefits associated with making clinical trial information more widely available, says Julou, but information shouldn’t just be available on public websites; it also needs to appear in peer-reviewed journals in order to facilitate proper scientific discussion. The information that the public can access needs to provide an accurate report of the trial findings, including adverse events. However, there are concerns that if this information isn’t put into context, or is viewed by individuals without the appropriate knowledge and experience to understand it, it could be misinterpreted. ■

Insight > Regulation

WorldPharmaceuticalFrontierS | www.worldpharmaceuticals.net 23

Nevertheless, for the EFPIA and other organisations, such as the International Federation of Pharmaceutical Manufacturers & Associations, the Japan Pharmaceutical Manufacturers Association and the Pharmaceutical Research and Manufacturers of America, this creates a potential headache.

Clearly, although pharmaceutical companies want and need to respond to this new climate of transparency as best they can, an information free-for-all would have serious ramifications, not only for issues around commercial confidentiality, but also in terms of ensuring the public get accurate and robust information about trial results and the efficacy of the drugs coming through R&D pipelines. Between them, the four organisations have published a number of joint position papers, and continue to monitor how the landscape is evolving in regards to this area.

Great expectationsLegislation in Europe and the US has been in place for some time, but the environment has evolved in the past 20 years or so, as have the expectations of patients and consumers, according to Julou.

“People used to be quite happy for the benefit and risk assessment of drugs to be left to the regulators,” she says. “The industry and regulators were, as a result, not very transparent

and did not particularly need to be. They were not required to give a huge amount of detail on everything. But expectations have changed, and people want to be better informed.”

Another issue for industry sponsors is the complexity of seeking to publish results of clinical trials in peer-reviewed scientific literature, while needing to place information on multiple databases worldwide. Finding the appropriate information on these multiple databases and literature sources can be complex. Yet Julou feels that the regulations already in place are both robust and adequate; for example, in Europe there are already public databases and procedures in place to populate them.

People used to be quite happy for the benefit and risk assessment of drugs to be left to the regulators... but expectations have changed, and people want to be better informed.

latest regulationsIn Europe, the requirements concerning the submission of clinical results to regulatory authorities are outlined in Directive 2001/83/EC and Regulation (EC) No 726/2004.

It is already a requirement that all data, positive and negative, is submitted to regulatory authorities. The requirements relate to the submission of the protocols and results to regulatory authorities, the assessment of these by regulatory authorities and the posting of study results on publicly accessible websites, says the EFPIA.

There are specific provisions that apply to medicinal products for paediatric use outlined in Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006, in particular in Article 41.

The German Medical Products Act also contains a number of national provisions, while in the US, the regulatory framework is outlined in the Food and Drug Administration Amendments Act of 2007.

Overall, there is no legal obligation in relation to publication in peer-reviewed journals. However, where study results are published in a peer-reviewed journal, they must not be deemed to be promotional or to suggest that a product may be used for an indication or a population in which the regulatory authorities have not (or not yet) approved its use.

the eFPia’s involvementThe EFPIA has published two position papers in conjunction with the International Federation of Pharmaceutical Manufacturers & Associations, the Japan Pharmaceutical Manufacturers Association and the Pharmaceutical Research and Manufacturers of America.

Both documents, Joint Position on the Publication of Clinical Trial Results in the Scientific Literature (June 2010) and Updated Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases (November 2009), outline a series of principles regarding the disclosure of information relating to clinical trials that the organisation has pledged to commit to, and which they have urged all sponsors of clinical trials to commit to as well.

In addition to this, the EFPIA has stressed that it and the rest of pharmaceutical industry will “continue to work to meet the public demand to have access to enhanced, reliable and informative results on clinical trials concerning medicinal products”.

WPF020_010_Trials and tribulations.indd 23 06/10/2011 12:34

I n 2010, a substantial drug price cut was made across Europe, a significant concern considering that Europe is the world’s second-largest pharma market, only

slightly smaller than the US. In Germany, the rebate that drug firms must pay insurers for drugs outside the country’s reference-price system was hiked by 10%.

Governments of various European countries have implemented several supply-side and demand-side measures to control rising healthcare costs. A range of policies exists, including generic substitution, patient co-payments, physician drug budgets and price controls. Such mechanisms influence the price setting of manufacturers indirectly.

There are multiple frameworks for the regulation of prices and distribution margins in Europe. Most European countries have price regulations for reimbursable medicines and pharmacy margins. Cost effectiveness, relative effectiveness and unmet medical needs are some of the key criteria for drug reimbursement decisions. Moreover, health technology assessment (HTA) is increasingly important as a criterion for decision-making.

Ensuring sustainable financing of health systems is critical for governments, because healthcare expenditure as a share of GDP is projected to rise further due to expensive new medical technologies and the growth in ageing populations. European governments are under immense pressure to cut pharmaceutical expenditure. As a result, they have even resorted to adopting various direct and indirect price control mechanisms.

Generics’ critical role Generics are widely regarded as the best route to allow access to safe, effective and high-quality drugs at affordable prices for the majority of patients. In addition, generics play a vital role in the development of sustainable healthcare models in European countries as they have a direct influence on pharmaceutical spending.

The generics industry throughout most of Europe is highly competitive and this works as an indirect factor by adding to the pressure on the pharmaceutical industry to develop newer, more innovative drugs. With factors such as ageing populations and

expensive drugs driving healthcare costs upwards, generic medicines have a critical role to play in the European pharmaceuticals market.

Individual countries in Europe have separate national legislation to govern the use of generic drugs. This reflects the underlying attitude towards the provision and financing of healthcare. In addition, government regulations determine the environment in which generic manufacturers need to operate and compete with others. Consequently, the cost savings obtained due to use of generics enable governments to reimburse these innovative drugs.

Reference pricing Reference pricing is a price control mechanism commonly used across Europe. It can be defined broadly as the maximum reimbursement price arrived at by national health authorities based on comparing drugs from a chemical, pharmacological or therapeutic equivalence perspective.

The main advantage of reference pricing is that it is relatively easy to implement and covers all new and existing drugs. The reference price may aid the generic markets if branded drugs are priced above this level; however, if branded companies reduce their prices below that of the reference price, then the generic manufacturers will suffer due to low profit margins.

Patient co-payment One of the key aspects of healthcare systems in Europe is patient co-payment. Most European governments reimburse a fixed amount based on either a per prescription model or, depending on the nature of drugs, the economic status of patients; however, there

The cost of a

European countries have been struggling with increasing pharmaceutical expenditure. Cost-containment is a major thrust area for policy reforms of pharmaceutical pricing and reimbursement in Europe, writes Ranjith Gopinathan of Frost & Sullivan.

Regional focus > Europe

WoRldPhaRmaceutIcalFRontIeRs | www.worldpharmaceuticals.net24

deep cut

Ranjith Gopinathan Ranjith Gopinathan is programme manager, life sciences and healthcare practice at Frost & Sullivan. He has over seven years’ experience in international marketing, consulting and business research.

WPF020_012_Frost Sullivan.indd 24 06/10/2011 12:37


is a significant variation in the way reimbursement is carried out in different countries. This factor is largely influential in helping the patient decide which drug to choose.

Although patient contribution to overall medicine costs is limited in most markets, the respective governments are aiming to involve patients further in terms of their contribution. Patient co-payments in Europe are dependent on the reimbursement structure of individual countries and their payment is usually based on the following mechanisms:

■■ a fixed amount per prescription■■ a percentage cost of the drug prescribed wherein the

government reimburses the rest■■ the difference in cost of the drug of their choice, in case of

expensive innovator medicines for certain diseases■■ a mix of all the factors above.

Patient co-payment is commonly practiced in most European countries and it strongly influences the patient’s choice of drug. Moreover, cost-containment is also an issue for high-income countries such as Germany and the UK.

Pricing and reimbursementReference price systems (for limiting the reimbursement amount) and external price referencing (international price comparisons) are being used more and more in several European countries; however, each country has its own pharmaceutical pricing and reimbursement system. For example, Denmark and Germany have a considerable free-pricing system, but this scenario could change with the implementation of healthcare reforms in 2011. In most European countries there is price control for generic drugs and free pricing for innovator drugs for reimbursement.

A statutory pricing is arrived at between the public payer and the pharmaceutical company for the reimbursement of drugs. In addition, in EU countries such as Cyprus and Ireland, the

Regional focus > Europe


reimbursement eligibility depends on the disease indication or the patient population. Denmark and Sweden have a consumption-based reimbursement eligibility, wherein the reimbursement coverage is proportional to the use of the drug.

In most EU countries, the reimbursement lists include drugs that are prescribed at the expense of a third-party payer; however, countries such as Germany, Hungary, Spain and the UK have negative lists that exclude certain drugs from reimbursement. Nonetheless, being included in the reimbursement list does not guarantee 100% reimbursement. In most EU countries, the essential and life-saving drugs receive 100% reimbursement.

health economicsHealth-economic criteria play a significant role in determining the reimbursement policy. Most European countries provide lower reimbursement rates or exemptions from co-payments for low income groups or people with chronic diseases; for example, France and the Netherlands have specific hospital budgets for orphan drugs and high-cost drugs.

Reference pricing alone is not a viable policy for lowering drug cost. Health technology assessment should also be incorporated to assess the value for money of new drugs in various indications and patient subgroups. For example, in the Netherlands, innovative drugs are subjected to health technology assessment in order to assess whether they should be placed in a new cluster and to establish the reference price for that cluster. Some countries like Germany have also introduced maximum reimbursement prices for drugs that are not subject to reference pricing based on HTA.

To successfully contain public pharmaceutical expenditure in the long run, countries should adapt their reimbursement and pricing policies continuously. ■

table 1. demand in emerging markets by cros and cmos (%), 2011.

european country

external price

reference

all drugs

reimbursabledrugs only

Prescription-only drugs

statutorypricing

Pricenegotiations

other/mix of

policies

Austria X X X

Denmark X X

Finland X X X

France X X X

Germany X X

Greece X X X

Hungary X X X

Ireland X X X

Italy X X X

Netherlands X X X

Poland X X X

Portugal X X X

Spain X X X

Sweden X X

UK X X

WPF020_012_Frost Sullivan.indd 25 07/10/2011 11:55

I n 2010, US-based magazine Newsweek ranked the largest publicly traded companies across the world in terms of how green they were, and no less than a fifth of the top 20

ranked organisations were global pharmaceutical firms. Johnson & Johnson, GlaxoSmithKline, Novartis and Pfizer all

made the top 20 in the publication’s ‘Green Rankings’. The results were compiled in association with MSCI ESG Research, a leading source of environmental, social and governance ratings; Trucost, which specialises in quantitative measurements of environmental performance; and CorporateRegister.com, the world’s largest online directory of social responsibility, sustainability and environmental reports.

While sustainability is still a relatively new concept regardless of industry, Big Pharma is clearly keeping up with its technology, banking and retail counterparts.

Pfizer is the perfect example. With environmental credentials stretching far beyond a few token sustainability initiatives, its programmes range from lighting upgrades to chemical waste reduction, from building design to manufacturing techniques.

Integrated approachIn 2009, the launch of Pfizer’s Environmental Sustainability Programme marked a new step in the pharmaceutical giant’s sustainability efforts. The initiative, according to Marty Brown, director of Pfizer Global Engineering, was created “to build on [the company’s] already established and recognised green

While some industries talk about going green, the pharmaceutical sector is already there. Elly Earls catches up with the team at Pfizer to learn about the importance of employee participation in sustainability programmes and the significant strides the company has made in both green chemistry and green design.

the industry

We have recently conducted a full ‘cradle-to-gate’ lifecycle assessment… and have found that, between 2007 and 2020, the new biocatalytic process will

eliminate approximately three million tonnes of CO2 emissions.

chemistry programme and carbon emissions reductions, and to fully integrate environmental sustainability into the company’s business operations”. The programme is governed by Pfizer’s Environmental Sustainability Council, which is made up of senior leaders from across the company.

Employees in Pfizer’s research and development (R&D) and manufacturing operations are continuously reviewing processes to identify opportunities to improve efficiencies and reduce material usage. Utilities, including heating, cooling, electricity, purified water and compressed air and nitrogen, are a key part of this.

“Systems producing and distributing each of those utilities need to be monitored for leaks, conversion losses and drifting set points,” says Brown. “In addition, employees are searching for ways to incorporate improved technologies into operations.”

Insight > Manufacturing

WorldPharmaceutIcalFrontIers | www.worldpharmaceuticals.net26

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improvement targets were set for individual operating sites,” explains Brown. “A web-based project tracking database is used to collect, report and share across the network of energy, water, greenhouse gases and cost-savings projects. We are pleased to confirm that we are on track to meet our goal.”

Without support and participation from employees across all departments, this goal would certainly not be met, which is why the company’s goals are shared with all members of staff. “From effectively managing the operation of energy-intensive manufacturing equipment to producing double-sided paper copies and recycling cafeteria waste, employee behaviour has a significant impact on conservation efforts across all areas of the business,” Brown notes.

“So to raise awareness of the impact employees can have, a number of communication channels are used. Newsletters, plasma screen messages, recognition programmes and dedicated awareness campaigns (such as Earth Day) are regularly used to inform and educate employees on how they can contribute to reducing the environmental impact of business operations.”

Pfizer’s Green Chemistry programme is one of the organisation’s most established contributions to sustainability. “It’s been running for more than a decade, and focuses on providing educational materials to scientists and engineers to facilitate the routine use of Green Chemistry principles in the way work is done,” explains Dr Peter Dunn, senior research fellow, Pfizer.

The company has also implemented a recognition programme to reward scientists for Green Chemistry achievements. “In the medicinal chemistry environment, we encourage greener solvent and reagent selection. This has resulted in a 99% reduction in our chloroform usage since 2007, and several other equally important reductions,” Dunn continues. “In the process chemistry area, solvent reduction goals for all new compounds are set in conjunction with process chemistry leadership and we were delighted to achieve our 2012 reduction goals two years ahead of schedule.”

An ongoing processWhen it comes to manufacturing, Pfizer’s second-generation process chemistry teams are dedicated to delivering new and greener processes, often taking advantage of improvements in biocatalysis. “A striking example of this is the enzymatic process to manufacture pregabalin,” Dunn remarks. “We have recently conducted a full ‘cradle-to-gate’ lifecycle assessment of this process, and have found that, between 2007 and 2020, the new biocatalytic process will eliminate approximately three million tonnes of CO2 emissions.”

A Quality by Design (QbD) approach to drug development and manufacturing is another method for achieving sustainability goals.


WorldPhArmAceuticAlFrontiers | www.worldpharmaceuticals.net28

From managing the operation of energy-intensive manufacturing equipment to producing double-sided paper copies and recycling waste, employee behaviour has a significant impact on conservation efforts.

Over the past seven years, Pfizer’s worldwide network of energy teams has implemented more than 2,400 energy-saving projects across the globe, reducing the firm’s annual greenhouse gas emissions by the CO2 equivalent of more than 600,000t.

Some of the more common energy- and cost-savings projects include:

■■ lighting upgrades■■ boiler combustion control improvements■■ waste heat recovery■■ shut down during non-production hours■■ chilled water control optimisation■■ retro commissioning■■ reduction of air exchange rates.

With HVAC (heating, ventilation and air conditioning) potentially accounting for 60-70% of a facility’s energy costs, this is something Pfizer has really been concentrating on.

“For the past several years, a number of on-site energy teams have been focused on optimising the operation of their HVAC systems using a risk-management methodology,” Brown elaborates.

Following this approach, changes to hours of operation, temperature set points, humidity control and air exchange rates have yielded significant reductions in energy usage and greenhouse gas emissions. “Management of HVAC operations has been the single biggest contributor to the efficiency improvements and operating cost reductions we have realised,” Brown emphasises.

Waste reduction and recycling are also important elements of Pfizer’s ESP, and the company currently has waste minimisation efforts for most of its hazardous waste streams at its larger sites. “We also have an internal goal to reduce our non-special waste (normal trash and other non-hazardous waste),” says Scott Smith, manager, environmental, health and safety audit, Pfizer. “A key

element of Pfizer’s waste minimisation plans includes the application of a waste management hierarchy

focused on avoidance, reduction, reuse and recycling.”

Ambitious goalsStill not satisfied with its achievements, Pfizer, which follows the World

Resources Institute Greenhouse Gas accounting protocols for reporting carbon emissions, set itself an ambitious goal to reduce greenhouse gases from internal operations by 20% between 2007 and 2012. “To help achieve this goal, energy efficiency




case study: Project sPrinGOne particular initiative Pfizer implemented, Project SPRING, involved improving the operation cost, performance and sustainability of a 50-year-old building housing offices and laboratories at the company’s site in Freiburg, Germany.

Using innovative, cost-effective ‘green’ building technologies and techniques such as a ventilation process that reduces air flow rates and a geothermal system that uses the natural heat storage capacity of the earth’s thermal mass to provide energy-efficient heating and cooling, the building was transformed into a modern, eco-friendly site.

The initiative saved $440,000 in annual energy costs, reducing gas and fuel by 3,325MW/h and reducing CO2 emissions by 1,200 metric tons.

Some of the green innovations included: nn Geothermal energy for cooling and heating — a first for Pfizer Europe. The temperature of the soil 130m below the surface is 12°C year round. This geothermic reservoir is used to store heat in summer and to supply heat in winter; pipes filled with a brine solution bring the energy into the building. Using low-temperature ceiling panels, offices can be heated in winter and cooled in summer.

nn Adiabatic cooling — incoming air is sprayed with water vapour. Evaporation of the droplets cools the air, allowing lower temperatures even without air conditioning.

nn New windows and innovative open office space — natural illumination is supplied by a two-zone window shade system, optimising daylight to supply light to all areas of the building. Additionally, energy from the sun is minimised by external ‘sun protection’ on the windows.

nn Heating energy minimised — heating produced from business equipment was significantly reduced by combining printers, copiers and scanners, using only one refrigerator per floor and minimising the use of individual printers.

nn Green technologies in labs — a reduced air flow rate in fume hoods was achieved by installing sensors that automated window shield closure. Closed systems for solvent refilling and waste handling operations were implemented, minimising solvent emissions. The ventilation of laboratories was reduced overnight, so the air exchanged decreased by half.

“QbD builds quality into manufacturing through process understanding and quality risk management,” explains Carla Wright, director of Pfizer Global Engineering. “Processes developed under the QbD approach can operate across an approved design space, giving manufacturers the flexibility to make the necessary changes to optimise performance and quality. Applying green-focused principles to a QbD approach can drive the minimisation of an environmental footprint.”

Another buzzword in the pharmaceutical industry is PAT, or Process Analytical Technology, which provides in-process measurement of critical attributes, enabling process understanding, process monitoring, real-time release testing and advanced process control (APC) strategies. According to Wright, environmental monitoring, solvent recovery optimisation and (indirect) energy reduction are three examples of PAT’s use in the pharmaceutical industry.

“Detailed process understanding gained though PAT helps identify sources of variability and ways to mitigate them, reducing process deviations, preventing re-processing, rejects and scrap, and improving energy and material use to increase capacity,” she explains. “The combination of PAT and APC provides robustness by automatically controlling process variability settings to achieve target product quality in the most efficient way.”

the way forwardLooking to the future, Pfizer’s Green Buildings Programme will contribute significantly to the company’s continuing commitment to sustainability. “The Green Design element of Pfizer’s Energy & Climate Change Programme has been developed to ensure that new facilities added to Pfizer’s real-estate portfolio are designed and built as ‘high performance’ facilities,” Brown confirms. “This minimises the resources needed to both build and operate the facility over its lifecycle.”

Key principles include careful site selection, capacity planning, incorporating newer and more efficient technologies, selecting materials that can be sustainably sourced, practising sustainable construction processes, and ensuring that building systems are

fully commissioned. “Collectively adopting these principles will contribute toward creating a facility that has minimal

impact on the environment and provides operational cost benefits over the life of the asset,” says Brown.

It seems that not a stone has been left unturned across Pfizer’s sustainability programme. Indeed, Brown aptly concludes: “As a science-based healthcare company, we recognise the of importance environmental stewardship.” ■

Management of HVAC operations has been the single biggest contributor to the efficiency improvements and operating cost reductions we have realised.


ABB Consulting provides technical and engineering services to improve performance in the areas of compliance, operations and engineering to customers in the pharmaceutical industries worldwide. Improving operational performance in the pharmaceutical sector through world class expertise in: asset closure; asset integrity & life extension; environmental services; industrial energy efficiency; inspection & risk based inspection; operations improvement; process safety & risk management; reliability; spreadsheet & database validation; technical training. www.abb.com/consulting

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World Pharmacuetical Frontiers (210x286) Aug 2011.indd 1 18/08/2011 14:43:26WPF020_ABB.indd 1 04/10/2011 14:28

Company insight > Manufacturing


rhian owen: ABB helps companies in an array of sectors to improve their management of process safety, but what are the challenges the pharmaceutical industry faces?

Phil eames: Manufacturing active pharmaceutical intermediates generally involves a large number of chemical components, including very toxic chemicals. Manufacturing processes usually require the extensive use of large quantities of flammable solvents and manufacturing sites employ a diverse portfolio of processes and chemistry types. Many of these processes involve complex reactions and flammable dusts that require extensive experimental work to define their hazardous properties, while some processes employ glass components and are therefore inherently less robust than typical process plants.

The ‘campaign’ nature of production presents a barrier to the building up of extensive process knowledge over long periods of time and also presents the additional hazards involved in breaking containment to reconfigure the process plant. The high value of pharmaceutical intermediates and products can draw attention away from the process hazards associated with site utilities such as steam generation and incineration.

does the pharmaceutical sector still need to improve process safety management (Psm)? Serious incidents continue to occur across the sector, including fires, explosions and toxic releases. The pharmaceutical industry acknowledges the need to improve PSM and, in common with the rest of the process industries, understands that process safety has received less attention since the advent of the personal safety revolution in the mid-1990s.

describe aBB’s approach to process safety. ABB has extensive experience in process safety, both in PSM systems (such as development, auditing and providing independent assurance) and in the technical aspects of process safety (for example, hazard identification, risk assessment and the design and management of protective systems). The firm believes that the understanding of process risk lies at the heart of process safety management and this is very much a core competence of ABB Consulting, which evolved from the organisation that invented the hazards and operability study technique.

ABB’s capabilities in terms of process safety, integrity management and functional engineering mean that it can offer a wide range of solutions; for example, not only process hazard identification and risk assessment, but also the implementation and ongoing maintenance of risk reduction measures.

explain why a process safety system is an essential part of Psm and what elements it needs to include.Effective control of process risk requires systematic and disciplined management, and that is why a PSM system tailored to the organisation’s hazards is essential. The critical elements of the system are process hazards analysis and risk assessment, management of safety-critical equipment and procedures, management of change, emergency preparation, performance measurement and ongoing assurance.

What’s the balance between effective leadership and a Psm system.Leadership in terms of process safety demands the development of a disciplined organisation and this can only be done through the effective deployment of the process safety management system. Leadership’s prime task is to promote the system and seek continual assurance that it is being applied effectively. Leadership cannot achieve success by simply demanding high performance, and just expecting the system to work and the people to get on with it; leaders need to take an active interest on a daily basis.

What are the benefits of attending an aBB Psm best practice course? The benefits are gaining an understanding of the elements of a PSM system and receiving practical advice on implementation based on ABB’s extensive operational experience and its knowledge of best practice, which comes from consulting some of the most respected organisations within the process industries.

What are the benefits of deploying aBB’s approach? The benefits are exploiting the knowledge and experience of ABB consultants involved in applying industry best practice for a wide variety of organisations. ABB’s competitive edge derives from the experience of its consultants and their ability to apply practical, tailored (not prescriptive) solutions, and from its diverse capabilities. This enables ABB to provide holistic solutions, helping to identify improvement opportunities and to identify and implement the answers; for example, ABB can provide expertise to conduct process hazards analysis such as hazard and operability studies, and to provide the multifunctional engineering and project management resources to implement the resulting recommended actions in a timely way. ■

Process safety management Traditionally, process safety management received less attention than personal or occupational safety. Phil Eames, principal consultant for ABB, explains to Rhian Owen the benefits for operations managers, senior process engineers and safety specialists of deploying an effective safety system within an organisation.

Further informationABBwww.abb.com

WPF020_ABB.indd 31 06/10/2011 07:55



e xcellent hygiene is paramount in pharmaceutical and biotech production, particularly in the process and plant area. This is enforced all over the world by stringent

HACCP and GMP regulations aimed at protecting consumers. Compounding this issue, companies operating in the competitive global market are forced to make their production processes as economical as possible, resulting in increased demand for automation solutions at the process level.

In the field of process valves, conventional automation solutions including control cabinets with valve terminals, I/O systems and field bus interfaces normally require costly hose connections and wiring. With this technology, the valves at field level are connected to the central control unit through a large number of long control air lines and discrete feedback connections.

As well as the high costs for the time-consuming planning and installation of such solutions, they are issues when it comes to hygiene. One alternative is the use of intelligent process valves from fluid technology specialist Bürkert. In contrast to control cabinet-based automation concepts, the only tasks left to the central process control system in Bürkert’s decentralised solutions are control and status monitoring. At the field level, pneumatically operated process valves are used. These can be equipped with all the required automation components such as pilot valves with manual actuation, electrical feedback units and optical status indicators, field bus interfaces and even positioners and process controllers.

one line for up to 62 valvesBy integrating an actuator sensor interface as a field bus interface, processors can take full advantage of the features decentralised automation has to offer. All that is required for power supply, feedback and communication is a two-wire line connecting the power line carrier (CLIENT query) with up to 62 valves. Each process valve is individually connected to the main compressed air supply line installed in the field, so these connections are kept as short as possible, which reduces the number and length of hose and wire connections and control cabinets to a minimum.

The valve systems are designed according to European Hygienic Engineering and Design Group guidelines for hygienic design and easy cleaning. They feature high IP protection as required for application and are made exclusively of detergent-proof materials, which means that the IP protection is not affected by long-term use in atmospheres with high air humidity or by frequent cleaning with aggressive chemicals. Compared with conventional automation solutions, these characteristics mark real progress in improved hygiene.

modular valve programme for customised solutionsAt entry level, decentralised automation based on intelligent valve systems starts with a process valve featuring integrated electrical feedback, simple optical feedback and an integrated pilot valve.

“The process valves require minimal space and can therefore be easily installed in the pipeline system of the plant,” explains Sebastian Kundel, product manager process valves at Bürkert. “Because they are made in extremely resistant materials, they are easy to clean and provide maximum availability, thanks to their excellent functional safety.”

Excellent availability is achieved mainly through the integration of the control air supply to the actuator chambers, which ensures that the spring chamber of the pneumatic actuator is supplied only with pure and clean control air. Moisture, dust and contaminants in the ambient air cannot enter the actuator units and there is no risk of the fungal spores produced in the spring chamber being ejected into the ambient air at each switching process, which is a common problem with conventional actuator design.

Through a combination of control air inlet and release, a constant overpressure is maintained inside the housing, while a certain volume of air is regularly replaced. This ensures that no condensate can build up inside the housing. The modular structure of systems based on intelligent process valves ensures that they can be adapted according to the actual situation and application, whereby such optimised solutions are always based on high-quality tried and tested components with a long service life. ■

a clean balanceProduction processes within the pharmaceutical industry must be of the highest level when it comes to cleanliness; however, ensuring such high standards can take a large chunk out of the production budget. Bürkert’s optimised automation of hygienic processes with integrated valve systems provides a hygienic process with low production costs.

Further informationBürkert Fluid Control Systemswww.burkert.com

Decentralised automation with integrated valve systems.

WPF020_Burkert.indd 32 06/10/2011 07:59

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With proprietary technology and deep market expertise, we help clients manage, control, and reduce electricity and natural gas costs. Collaborating with Usource gives customers unlimited access to the most timely market intelligence – gathered and interpreted by a dedicated team of experts. We provide constant contact, real-time information, and clear guidance in navigating the complexities of the energy commodity market. The sooner you work with us, the sooner you’ll start saving.

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World Pharmaceutical Frontiers: What is the role of an energy services broker?Thomas Withka: Usource represents industrial, commercial, institutional, and government customers – all consumers of natural gas or electricity (or both) – and brings them together with potential energy suppliers. We continually assess the marketplace, strategically time offers to buy and then present the best proposals from qualified energy suppliers at one time. We partner with our customers in securing the best price, terms and length of contract for their operations.

Elite brokers such as Usource dedicate sophisticated training and state-of-the-art tools to monitor commodity markets on an hourly basis. This provides customers with the most current market information for purchasing decisions. Through a diligent, continuous review of the supplier community in the market areas we serve, we ensure that customers receive reliable and competitive energy.

With an intimate knowledge of supplier operations and business practices, the right broker is an invaluable partner in continually evaluating complex contract provisions in supplier offers. In essence, Usource professionals serve as a specialised energy management employee on the client’s staff.

What makes deregulated energy markets particularly difficult to negotiate?Natural gas and electricity markets have similar characteristics to most commodity markets with volatile pricing changes, often moving several percentage points on a daily basis; for example, most energy price offers are valid at the time of the offer, but are rarely held overnight. This creates a complicated process of internal review and approval for most companies.

At Usource, we use a multi-step process to help customers manage this challenge. Our proprietary model tracks energy markets on a real-time basis, searching to match customer objectives. We help customers review supplier contracts before the bidding process, strengthening their position and avoiding the inequities often written into these contracts.

Our models generate pricing forecasts that help anticipate economic and business provisions prior to the bid date. As a result, our customers can take full advantage of energy markets and extract the optimal pricing and terms available.

This process forces suppliers to offer their best price first. On bid day, with standardised contracts, market objectives and aggressive pricing predictions in hand from Usource, the client can execute a contract with confidence.

What impact can the wrong energy management solution have on a facility’s ability to function properly?Unnecessarily high energy costs and poor contract business terms can dramatically affect facility financial performance, competitiveness and viability. If a company fails to renew or secure a new energy contract before an old one expires, it usually has to revert to utility supply or another market-based price – one that in most cases is higher than a competitively bid contract.

Proactive energy managementEnergy services company Usource has major clients engaged in global pharmaceutical production and research across multiple facilities. World Pharmaceutical Frontiers talks to managing director Thomas Withka about how the company provides cost and process efficiencies by strategically managing its clients’ energy supply in an integrated manner.

Usource customers can take advantage of energy markets and extract the optimal pricing and terms available.

Energy costs comprise a large portion of a facility’s annual budget. Usource’s first-and-best offers bring winning results to every customer.

WPF020_Usource.indd 35 06/10/2011 08:14



Further, the wrong company strategy in the hands of an inexperienced energy broker will result in missed opportunities and long-term cost increases; for example, firms that historically purchase energy on a fixed calendar may be unaware of certain risks. The fourth quarter of the year has extraordinary volatility, with pricing dependent on factors such as demand, economic activity, storage balances and weather. Often, prices are higher and customers lack the ability to wait for lower rates.

Firms that don’t manage energy on a strategic basis are unable to judge these market opportunities and consequently default to higher prices; even fewer firms employ people dedicated to continually evaluating the energy marketplace. Usource manages this review as an in-house resource, actively advising the customer about market direction and recommending precise energy procurement strategies.

are there any issues worth considering that are particular to the pharmaceutical industry?Since this industry has a relatively small number of large energy consumers, various energy supply aggregation programmes can be of significant financial benefit. These programmes group the energy requirements of multiple facilities in a manner that gives each location lower prices and better contract terms. Usource has successfully developed such aggregation programmes with many companies, including pharmaceutical companies such as Lonza (see Case study, p37).

On the natural gas side, multiple facility requirements can be effectively aggregated to reduce costs and employ the supplier in pooling operations to manage natural gas delivery risk. Commodity price risks can be managed from either a corporate or individual facility perspective. Usource often establishes risk targets with customers and then monitors the movement toward price objectives on a daily basis.

On the electricity side, multiple facility requirements should be aggregated to reduce cost through enhanced supply dynamics. Procurement programmes may include supply purchases that reflect fixed, variable and block pricing consistent with risk and pricing objectives. The level of corporate vs facility control in these risk management matters will vary by firm.

how can usource help a customer in the pharmaceuticals industry achieve a better deal? Usource helps all of its customers achieve exceptional energy deals through:

■ dedicated, informed market monitoring ■ broad solicitation of credible, qualified energy suppliers

■ a bidding process that yields the best supplier prices the first time

■ a collaborative evaluation of all the terms and conditions ■ assistance in aligning the best energy deal with our

customers’ business needs and energy requirements.

Most important, customer needs inevitably vary, especially in a highly competitive industry such as pharmaceuticals. Usource listens carefully to understand those needs; for example, one facility may have a very stable load profile and may be best served by a fixed price contract. Another company may have a more flexible usage profile and can secure lower prices by buying electricity on an on-peak, off-peak basis. Usource works hard to understand customer and industry needs and collaborates to establish a viable, profitable procurement strategy.

how can companies with multiple facilities across different markets benefit from usource’s offering?Usource has researched and developed procurement strategies for a number of customers with facilities that involve many combinations of utilities, states and power pools. As one of the largest energy advisors in the US, Usource is able to design and leverage the best possible strategy for a multiple-location company. We routinely secure customer pricing that incorporates large volume discounts. These, in turn, mean lower prices for each customer facility than if bid and priced on a stand-alone basis.

What is usource’s involvement in the pharmaceuticals industry? how do you see this evolving?Usource has provided services to the pharmaceutical industry since electricity markets opened in New England ten years ago. Today, Usource offers energy management and consulting services to a number of international firms. We typically begin service for a single pharmaceutical facility, demonstrate the benefits of our partnership, then add sister companies to the programme.

The best approach for a pharmaceutical client is to aggregate all of its business and energy requirements under an energy broker who can deliver the long-term strategy and the results that answer company objectives. This facility aggregation best ensures large volume discounts with maximum operational and risk management options.

Earlier this year, Usource entered a corporate agreement with Lonza, a large multinational pharmaceutical client. We agreed to provide energy management, consulting and brokerage services for the parent corporation in addition to each of Lonza’s US operating facilities. Usource has expanded its services to include a recent Lonza acquisition. As a result, Usource and Lonza are addressing a much larger energy supply programme that will benefit each company facility with enhanced production offerings and lower pricing.

Contracting for energy is not for the faint of heart. Energy costs comprise a significant portion of any facility’s

Usource offers energy-management and consultancy services to a number of international firms.

WPF020_Usource.indd 36 06/10/2011 08:14



annual budget. Usource’s unique process for securing first-and-best offers from a broad range of suppliers, along with continual monitoring of marketing pricing and conditions, and favourable contract terms bring a full time professional team and winning results to every energy customer.

case study: lonza usaA 2011 agreement forged between Usource and Lonza highlights the benefits of proactive energy management in the global pharmaceutical industry. Lonza is one of the leading suppliers to the pharmaceutical, healthcare and life science industries, with thousands of employees and dozens of facilities worldwide. The company also operates a major biologics production facility in Portsmouth, New Hampshire, US, near Usource headquarters.

Discussions between companies quickly targeted potential cost savings and energy efficiencies for the Portsmouth site. More importantly, they led to a strategically (and geographically) integrated plan to manage Lonza USA’s national energy demand.

As a global leader in the production and support of active pharmaceutical ingredients, chemically and biotechnologically, Lonza requires reliable, predictable and cost-effective power for its production and research facilities. To achieve this, it needed a unified and strategic energy plan for its sites. Collaborating with Usource allowed Lonza’s managers to closely align energy demands, business and financial criteria, and strategic operating goals for its US operations.

Usource and Lonza crafted a sustainable strategy for energy management, supported by state-of-the-art information tools, highly informed consultation and expert 24/7 market analysis. Usource provided the following basic tools and services:

■ a proprietary market tracking system with the latest energy market pricing

■ monthly indicative electricity and natural gas basis prices

■ a monthly natural gas commodity position report ■ quarterly meetings with Lonza managers to review the

market and purchasing strategy ■ round-the-clock communications to assess favourable

market opportunities and challenges ■ a monthly market analysis and regulatory

update newsletter ■ regular review of the invoices from energy suppliers

and/or utilities.

According to Bill Woodward, lead buyer technical equipment & services for Global Strategic Sourcing at the Lonza USA’s Walkersville, Maryland headquarters, the benefits of the Usource relationship have been measurable. Now just one energy broker manages all the energy needs for Lonza USA sites, leveraging the volume of this demand to ensure financial benefits for the company, he says.

Bundling these power requirements and securing transparent, competitive bids from multiple energy suppliers help Lonza to control infrastructure costs and sustain competitive advantages. The unified energy procurement process, procedures and guidelines that Usource brings to Lonza, further optimises already high levels of synergy among Lonza USA’s sites, according to Woodward.

“Usource is a very professional, competent, and capable energy broker organisation,” he says. “It has demonstrated the expertise and knowledge that provide Lonza with visibility of the energy marketplace and provide professional guidance and direction accordingly to the Lonza USA sites.”

In a volatile energy market, surrounded by a turbulent economy and increasingly competitive business environment, the Usource-Lonza partnership allows each company to do what it does best. ■

Collaborating with Usource allowed Lonza’s managers to closely align energy demands, business and financial criteria, and strategic operating goals.

As a global leader in the production and support of APIs, Lonza requires reliable, predictable and cost-effective power for its production and research facilities.

Further informationUsourcewww.usourceonline.com

WPF020_Usource.indd 37 06/10/2011 08:14



c ommercialising product development in the pharmaceutical industry is a complex task. After years of research, companies need to make sure that their

products are effective, cause minimal side effects and are environmentally friendly in order to be commercially viable. The drive to reduce risks associated with pharmaceutical treatments, coupled with minimising its carbon footprint are huge challenges.

A silent partner, The Linde Group is a leading supplier of gases and applications to the pharmaceutical industry. It has succeeded in developing solutions that meet the evolving needs of the pharmaceutical industry in a variety of applications across the production chain – from R&D to quality control.

Linde’s suite of applications targets the manufacturer’s needs, from gas solutions for several applications to improving the controllability of the lyophilisation process to yield enhancement through cold processing knowledge and to state-of-the-art technology that meets strict environmental regulations.

A key challenge in scaling up pilot processes is minimising the side reactions that generate unwanted compounds that can form in a commercial operation, but are not seen in the lab-scale process. In these cases, product yield can be significantly improved by cooling the reaction to a very low temperature..

uniform ice nucleation during lyophilisationLyophilisation is an important example of a downstream process and is critical for stabilising valuable compounds. The high value of lyophilised drugs, as well as FDA initiatives such as Quality by Design and PAT, demand improved process control to achieve good product quality.

Control of the product nucleation temperature is a critical issue in lyophilisation and can adversely affect the product’s uniformity because it can lead to less-than-optimal freeze-drying cycles. Linde has developed a novel technology through a collaboration with a leading freeze-drying OEM to address this ice nucleation step during the lyophilisation process and it is applicable to laboratory, pilot and production-scale freeze dryers.

Yield growth through cold temperature processingA key challenge in scaling up pilot processes is minimising sidereactions that generate unwanted compounds, which can formin a commercial operation, but are not seen in the lab-scaleprocess. In these cases, product yield can be significantlyimproved by cooling the reaction to a very low temperature.

As drugs become increasingly complex, the demand for synthesis and crystallisation at very low temperatures also grows. Low temperature cooling of process fluids is both necessary and beneficial to achieve a high degree of process control and stability

that will increase product quality, yield and selectivity. Linde’s CUMULUS® Fluid Temperature Control system is the optimal solution for rapidly bringing the process down to very low temperatures. It uses liquid nitrogen as a cooling medium to automatically cool process fluids in a highly controlled manner.

reduce volatile organic compound emissionsConcerns about greenhouse gases also place pressure on pharmaceutical manufacturers to minimise volatile organic compounds (VOCs) as these can create health and environmental hazards. Linde’s CIRRUS® vapour emission control systems are a comprehensive approach to minimising the release of VOC.

The nitrogen-based cryogenic process is chlorofluorocarbonfree that does not generate wastewater. Furthermore, there is no secondary pollution in the form of nitrogen oxides, acids, gases and dioxins. The inert nitrogen does not come into direct contact with the VOC, which means that the condensed VOC and evaporated nitrogen can be recycled and reused for other purposes in a customer’s process, thus significantly reducing operating costs and increasing sustainability.

cost-effective and adaptable solutionsCustomer needs and environmental regulations are constantly changing, which means that pharmaceutical companies require partners that are swift and can adapt to the industry’s evolving needs. Linde’s solutions are a proven portfolio of cost-effective solutions, targeted to meet these demands. ■

embracing pharma’s needsGetting medicinal products to market presents significant challenges for the pharmaceutical industry. The Linde Group works as a silent partner to provide solutions that meet the requirements of a constantly changing environment.

Further informationLindewww.linde.com

The high value of lyophilised drugs demands improved process control to achieve good product quality.

WPF020_Linde.indd 38 06/10/2011 08:07

Evolving with the needs ofthe pharmaceutical industryImproving the sustainability of manufacturing processes and minimizing their environmental impact place significant commercialchallenges on pharmaceutical companies. Our solutions can help you meet evolving challenges across all stages of the productionchain from research and development to quality control and production.

Linde North America Inc575 Mountain Ave, Murray Hill NJ 07974, USA, Phone +1.908.464-8100, www.lindeus.com

Linde LLC is a member of The Linde Group. Linde is a trading name used by companies within The Linde Group. The Linde logo is a trademark of The Linde Group. © The Linde Group 2011.

WPF020_Linde.indd 1 04/10/2011 14:31

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m anufacturing pharmaceuticals has never been a game for the faint hearted. From research and development right through the production cycle, distribution and marketing,

it is an expensive business, with heavy and lengthy start-up and development costs and, even then, no guarantee of a lucrative revenue stream at the end of it.

Against that backdrop, doing anything to drive efficiency or curb costs is going to give a pharmaceutical company an element of competitive advantage, which is why what Merck Serono has achieved over the past five years is so compelling and, feasibly, an object lesson for other pharma firms.

The company has, since 2006, put in place a series of efficiency pilots, programmes and models that are now reducing costs which, according to the BMI’s Pharmaceutical Manufacturing Efficiency Index (PMEI), has led to the company spending a smaller proportion of total sales on manufacturing than any other pharmaceutical player. And this is despite the company’s drug portfolio being weighted towards traditionally more expensive biologics products.

This emphasis on reining in the ‘cost of goods sold’ (COGS), encompasses an array of different programmes, modelling software and, crucially, cultural and mindset shifts, all under the common goal of providing the highest quality products to Merck Serono’s customers and patients, argues Dr André Overmeyer, the company’s head of strategy and operational excellence.

“Bio-pharmaceuticals have more complicated manufacturing processes,” he explains. “The raw materials tend to be more expensive, so process modelling and a generic production platform strategy based on standardised cell lines and chemically defined

media becomes very important. There is a clear need to have programmes in place to facilitate operational excellence and direct learning from each other.”

cost savingsThe company runs intensive programmes focusing on these areas, and continual improvement means that, since 2006, it has cut costs by approximately 5% a year. For Merck Serono, COGS encompasses everything that relates to production processes and costs.

“We were at a point where we could see our costs were rising year by year, so it was about focusing on best practice, sharing good practice and expertise, and harmonising our learning so we were better able to embed global business practices,” says Overmeyer.

Given the complex manufacturing process of biopharmaceuticals, achieving operational excellence is an organisational challenge. To do this and drive efficiency at the same time is a benchmark worth emulating. Dr André Overmeyer of Merck Serono talks to Nic Paton about the benefits of reducing the cost of goods sold.

efficient manufacturingFor every $1 Merck Serono spent on COGS in the first quarter of 2010, it generated $6.39 in revenue, giving it a score of 6.39 on the BMI index.

This was despite the fact that some of the Geneva-based firm’s leading products, such as Rebif (interferon beta-1a), are biologics, which because they are typically produced within specially engineered cells, can be expensive to culture.

An expansion project is currently being developed to increase the manufacturing capacity of the plant to allow for production of additional medicines, including the targeted cancer therapy Erbitux (cetuximab).

Of the ten firms in the BMI’s PMEI for the first quarter of 2010, seven saw their score decrease, indicating other drug makers were becoming less efficient in manufacturing.

WPF020_021_COGS.indd 41 07/10/2011 13:18



coGs: a definitive viewDifferent companies use different definitions of ‘cost of goods sold’ (COGS). Some firms will include expenditure, such as ‘cost of sales’, while others simply limit it to ‘materials and production costs’.

Generally, however, COGS is defined as the direct costs attributable to the production of goods sold by a company.

To this end, it will include the cost of materials used in creating the goods, along with the direct labour costs, but exclude indirect expenses such as distribution costs and salesforce costs.

COGS appears on income statements and, according to the BMI, is divided by total sales to give its PMEI score.

andré overmeyerAndré Overmeyer is head of the strategy and operational excellence group within Merck Serono technical operations. Previously, he led the expansion of the Merck Serono Biotech Center in Corsier-sur-Vevey, Switzerland.

When a new product comes on to the pipeline we have a number of tools to simulate the cost of manufacture. This allows us to test and better direct our processes as they develop.

The company’s global programme, ‘House of Operations’, fosters cooperation in different areas with the aim of raising the standards according to predetermined measures. The global roll-out of its Six Sigma and Overall Equipment Effectiveness programmes were a priority for the company, and successful examples of elements within the House of Operations.

“With biopharmaceuticals, one of your priorities has to be increasing and improving yield, gaining more products while reducing unit cost for the drug,” says Overmeyer. “In 2010, we put in place Six Sigma, which has led to yield improvements in a number of process steps and some substantial cost savings.

“It is about focusing on process improvement; just doing things in a better way. The trigger has been to look at things in a much broader perspective, to look at our processes and see how we can move people away from a silo mentality to one where there is more co-operation across departments, businesses and across our site network, where there are more holistic solutions.”

a coordinated approachMerck Serono focused on a greater exchange of knowledge and information, and more contact between people. It also encouraged looking at the global perspective. Global projects within the Six Sigma programme concentrated on production and manufacturing processes from A-Z, covering end-to-end lead-time processes, and cross-departmental and organisational procedures.

“It was also about coordinating the exchange of information and knowledge between different sites and facilities,’ says Overmeyer. “For example, people from Italy working within our packaging businesses might be encouraged to speak to staff within API or people from the selling end in a bid to improve best practice.”

One of the key tasks was bringing people together to share their problems and solutions, with the aim being to foster cultural change and to facilitate a rethink of methodologies.

“There was an emphasis on encouraging cooperation and an exchange of information that was not happening before,”Overmeyer adds. “This could have been down to human nature, and the result of having global sites where there may be distance, time-zone or language barriers, as well as different ways of working. One practical change in this context was to introduce a common organisational language and terminology to express facts, results and achievements; for example, the cost structure or the measurement of cost benefits, so that staff could understand each other clearly and easily. It helps give the business much more of a global framework.”

The company also implemented a programme that streamlines its packaging lines in different locations and connects them more to its distribution and sales teams. This provides better forecasts, which allow it to produce economically optimised batch quantities. Merck has also made a considerable investment in IT tools and in processes to align and harmonise orders, products and production.

“We have 50-60 selling subsidiaries, so it’s important to be able to adapt to local needs and regulations,” says Overmeyer. “You need to be flexible within your supply chain. We’ve also invested in tools for process simulation at different stages of production. When a new product enters the pipeline we have tools to simulate the cost of manufacture. This allows us to test and better direct our processes as they develop.”

design qualityAnother significant issue has been instilling the concept of Quality by Design (QbD) throughout the business.

“We have been using QbD since 2006, which has been invaluable in developing cost-effective manufacturing processes. It is also an important way to understand the manufacturing processes, especially in bio-pharmaceuticals. It helps to reduce variation within processes, and introduces a much greater stability,” says Overmeyer.

Ultimately, while cost savings have been a clear, tangible benefit of COGS, there are equally intangible benefits: a changed mindset, attitude, global outlook and harmonised culture. They have all proved important as well, emphasises Overmeyer.

“There are also advantages that come from creating a culture of and emphasis on operational excellence. It is about wanting to do things right, and to do them better all the time,” he says. “The improvements we have been able to deliver in the manufacturing chain; for example, have saved costs but also made our supply more flexible and responsive, which is very important. Before, as a company with different sites, each with a different history, we used to be more fragmented; there were a lot of island to island solutions. So it has been important to foster and facilitate a mentality that does not involve working in silos, but rather one where people are collaborating instead of competing with one another. It is vital people learn from each other, and share and exchange information to improve processes.” ■

WPF020_021_COGS.indd 42 06/10/2011 12:14

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Automation Eliminates Variability50% of Out-of-Specification results in QA/QC are caused by manual sample processing steps or human error. Automated sample preparation addresses this laborious part of the analytical workflow. Register for this webinar to find out more: www.pharmtech.com/preventing

The revolutionary Quantos weighing technology accurately and efficientlyprepares specific concentrations of sample and standards by accurately weighing substance and solvents.

More than 50% of the world’s leading pharmaceutical companies have already chosen Quantos. When will you?

www.mt.com/quantos

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o ut-of-specification (OOS) investigations in analytical R&D and QA/QC laboratories are

costly and time-consuming. Although analytical instrumentation has seen impressive innovations in speed and efficiency over the last ten years, sample preparation techniques have remained virtually unchanged for 75 years.

Sample preparation is now reported to be the most time-consuming, labour-intensive and error-prone element of the workflow, with approximately 50% of OOS errors attributed to either sample processing steps or human error. These errors could be prevented by automation.

consequences of oos resultsBased on OOS results, many groups find themselves consuming valuable testing and material resources by conducting or supporting an analytical lab investigation. This frequently leads to an uncomfortable deviation report and an even more expensive corrective and preventive action (CAPA).

CAPAs can mount over time and a full-blown root cause analysis along with follow-up quality/compliance audits quickly exponentiate costs. Seasoned managers are valued for efficiently pulling together the right resources and groups including QA/QC, method development, R&D and validation to determine the root cause and laboratory-related errors.

Substantial literature addresses the handling of these investigations; however, there remains a need for more theoretical and practical information related to the prevention of such occurrences.

accuracy of solutionsMettler Toledo is changing the way that samples and standards are prepared in modern analytical laboratories. It is universally accepted that a gravimetric measurement is intrinsically more accurate that a volumetric measurement. Pipettes and volumetric measuring equipment are even calibrated using gravimetric methods. Why then do we still weigh our solids and powders on a weighing paper, transfer them into a volumetric flask, and subjectively read the meniscus to prepare an accurate concentration?

Surely it makes more sense to also add the solvent gravimetrically to achieve pinpoint accuracy. In this way, the

exact amount of substance dispensed by spatula or automated dosing head is recorded and used to precisely adjust the amount of liquid added.

Any under or overshoot in powder weighing doesn’t require you to waste time adding a tiny amount more or scooping material off the weighing paper with your spatula. The automated liquid dispensing compensates for this and calculates the exact amount of solvent that needs to be added. This allows you to achieve the perfect concentration every time.

save substance and solventAutomated solution preparation also allows

you to significantly downscale your consumption of substance and solvent. You profit from two effects: firstly, you are able to weigh out a smaller amount while adhering to USP regulations due to the lower minimum weight achievable with automated dispensing, which saves material.

Secondly, you can prepare the exact amount of solution that you need for further use, rather than being constrained by the volumetric glassware available. There is no need to round up the volume prepared to the nearest flask size; for example, preparing a 1mg/ml concentration to within ±10% requires dosing of 90-110mg into a 100ml volumetric flask. With Quantos you can weigh in only 10mg and still comply with USP. There is ample solution for a typical HPLC injection (10-20µl); you simply have 90% less to dispose of.

Gravimetric dispensing Gravimetric solution preparation has several clear advantages. Automated dispensing of the solvent reduces the variability in the concentrations, which will give you increased confidence in your analytical results. Using automation removes the contribution of human error to the overall process.

In addition, data transcription or labelling errors are eliminated as data is recorded and printed automatically. The amount of substance and solvent used can be reduced by up to 90%, with the added benefit is that analyst exposure to potent substances is greatly reduced. ■

automated sample preparationReducing variability in samples and standards preparation is essential for tackling 50% of out-of-specification results in QA/QC. Mettler Toledo shows how precise concentrations make it easier to identify trends in analytical results before they cause OOS issues.

Further informationMettler Toledowww.mt.com/quantos

Figure 1. Quantos automated powder and liquid dispensing system.

WPF020_Mettler Toledo.indd 57 06/10/2011 08:09

WPF020_Corning.indd 1 04/10/2011 14:33



c orning’s Advanced-Flow™ reactors are made of either glass or ceramics and provide easy scalability, adaptability to market demand,

short transitions between R&D and production, and a substantial economic advantage.

The Advanced-Flow glass reactors are constructed from sets of interconnected standard glass fluidic modules. Each module has a reaction layer containing millimetre-scale channels, which are integrated with heat transfer, allowing a precise temperature control along the entire reactor path. Fluidic modules can manage several unit operations such as feeding, premixing, preheating and reagent mixing, and provide different residence times depending on their relative position in the reactor, the number of inlets and their internal design.

Corning’s Advanced-Flow glass reactors are well known by researchers and application and process engineers working in the areas of process improvement and intensification in pharmaceuticals, crop protection and other speciality and fine segments of the chemicals industry. Combining excellent mass transfer with heat transfer characteristics, Corning’s Advanced-Flow glass reactors can successfully increase production yields, improve process selectivity and shorten production cycles, while improving the safety and economics of chemical production.

ceramic modelThe latest member of the Corning family of Advanced-Flow reactors is the ceramic Advanced-Flow G4 reactor, which enables very high flow throughput, outstanding thermal heat transfer performance and great corrosion resistance. The reactor’s abilities are made possible by integrating the superior thermal conductivity of the ceramic with the unique design qualities

of the Advanced-Flow reactor. From the combined expertise of Corning and Mersen/Boostec, this reactor makes simple, high-quality and cost-effective continuous-flow chemical processing possible. It conducts under the same operating and constructive principles of the Advanced-Flow reactor family and has a mixing chamber design and a fully metal-free reaction path. The G4 reactor is comprised of sintered ceramic fluidic modules, Perlast® gaskets and

a stainless steel frame, all fully compatible with the chemical production environment.

The consistent design of the reactor modules allows easy and fast scale-up from a small glass reactor to a large ceramic reactor.

ideal uses for the ceramic reactor Taking into account the superior heat transfer characteristics of the ceramic material and its strong resistance to corrosion by chemical media, the Advanced-Flow G4 reactor is ideal for use in highly exothermic reactions and reactions using highly corrosive components. In cases where glass reactors are not able to handle

specific chemical media, such as strong bases at high temperatures or HF acid, the ceramic reactor provides a superb alternative.

Corning’s new Advanced-Flow G4 ceramic reactor is ideal for production at industrial-level capacity (see Table 1). With an internal volume of up to six litres, it is able to deliver up to 300kg of product per hour. ■

advantages of advanced continuous-flow reactorsPharmaceutical manufacturers are always looking to increase production yields, reduce time-to-market and increase the quality of their products while lowering energy use and their environmental impact. Corning’s continuous-flow reactors offer a robust and efficient solution.

Further informationCorning Incorporatedwww.corning.com/reactors

Corning Advanced-Flow reactors; G2 (left) and G3 (right).

table 1. operating parameters of corning’s advanced-Flow G4 ceramic reactor.

operating conditions Process passHeat exchange pass

temperature (°c) -25 up to 200 -25 up to 200

Pressure (barg) up to 18 Up to 6

The ceramic G4 reactor makes high-quality and cost-effective continuous-flow chemical processing possible.

WPF020_Corning.indd 47 06/10/2011 08:02

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solutionsWith medicinal drugs becoming ever more complex, overcoming solubility issues is one of the most common formulation challenges facing pharmaceutical companies today. Bayer HealthCare’s Andreas Ohm tells Nic Paton about some of the ways his company is addressing the problem.

Insight > Drug delivery & formulation


Suspended

i t is estimated that some 50% of new chemical entities entering drug development pipelines suffer from low aqueous solubility. For Dr Andreas Ohm, head of early development in

global pharmaceutical development at Bayer HealthCare, the fact that drugs must be in a solution in order to reach their site of action in the patient makes solubility an absolutely essential element of the formulation development process.

“When you consider infusion formulations it becomes crystal clear that the drug must be dissolved in a restricted volume of vehicle that is suitable for parenteral administration [via a route

that involves piercing the skin or mucous membrane] – and this is water-based,” says Ohm.

“In the case of orally administered drugs, solubility and dissolution kinetics are important because drug particles have to

dr andreas ohmDr Andreas Ohm is head of early development at Bayer HealthCare. Previously, following the merger of Bayer Pharma with Schering in 2008, he was appointed head of pharmaceutical technology of Bayer Schering Pharma.

Cover story

WPF020_015_Top form.indd 49 06/10/2011 16:15



solubility: facts and figuresA drug is defined as very slightly soluble if its aqueous solubility ranges from 0.1mg/ml to 1mg/ml, and insoluble or practically insoluble if its solubility is less than 0.1mg/ml.

A drug is called soluble when the intended oral dose dissolves in 250ml of aqueous buffer in the physiological pH range of one to eight. Here, the dose is a key parameter for the definition of solubility. The higher the dose, the more critical the solubility of a drug compound.

The dose/solubility ratio describes the amount of water necessary to dissolve the dose intended for oral administration. A drug with a solubility of 1µg/ml and an intended oral dose of 100mg will require 1,000l of water to dissolve – too much for anyone to drink.

It is estimated that two out of three compounds in the drug discovery pipeline have aqueous solubilities of less than 0.1mg/ml, which means they are defined as insoluble or practically insoluble. Therefore, there is a need for different drug delivery systems to help overcome the effects of low solubility. The most important technologies applied in formulation development to enhance solubility and dissolution include particle size reduction, salt formation and amorphous systems, as well as co-solvents, complexants, surfactants and lipid formulations.

One key parameter in formulation development is the so-called relative bioavailability (Frel). It describes the bioavailability of a drug candidate when administered as an oral tablet or suspension in relation to its bioavailability from an oral solution. Hence, the Frel gives a first assessment of the in vivo situation: in the case of low relative bioavailability, drug dissolution and solubility are critical parameters in the overall absorption of the drug.

Sources: US Pharmacopoeia and National Formulary, Biopharmaceutical Classification System.

be dissolved before the drug molecules can be absorbed by the patient. That is why it is so important to have tools and tricks in place to overcome poor aqueous solubility and dissolution speed.”

advanced techniquesAdvances in chemistry such as high throughput screening – where researchers use a combination of robotics with complex liquid handling devices, fast analysis and data processing software to run chemical, genetic and pharmacological tests with multiple thousands of compounds – are now allowing scientists to increase the potency and selectivity of many drugs. As a result of these advanced screening tools, however, more and more water-insoluble and lipophilic drug candidates are detected that would probably not have been found previously.

“In research, a lot of effort is made to identify potent new drug compounds that would be highly effective in the respective disease models,” says Ohm. “When later selecting a drug candidate for clinical development, one must not only look at the pharmacological efficacy of the drug, but also at its efficacy in combination with its aqueous solubility. There are drugs in pipelines and in the market place that won’t be orally bioavailable when administered in conventional oral dosage forms – for example, tablets containing the drug in finely dispersed crystalline form.”

Alongside this, multiple and complex technologies are becoming available to scientists to improve active pharmaceutical ingredient solubility and dissolution kinetics for oral dosage forms.

“There are various measures to enhance the apparent aqueous solubility and the dissolution speed of poorly soluble drugs,” Ohm explains. “All of these technologies are derived from the basic understanding of the respective laws of nature. Well-known and established techniques include increasing the drug’s surface by milling, helping the drug particles to be moistened by water through hydrophilisation of their surface – for example, by polymer coating or surfactants – complexation to ’pre-dissolve’ the drug in

a more water-soluble form, or just selecting the right polymorphic form or salt of the chemical entity. But formulators are in greater need of even more complex and sophisticated technologies to dissolve the drug, as, in many cases, these established technologies are no longer sufficient.”

amorphous non-crystallised drug forms One way of enhancing gastrointestinal solubilisation is through the use of amorphous non-crystalline drug forms.

“The key advantage of the amorphous state is not only the fact that the drug dissolves faster in water, but that it produces a super-saturated solution, which means it can achieve a solubility much higher than its thermodynamic solubility,” says Ohm. “With a super-saturated solution, you can dissolve more of the drug within

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the gastrointestinal tract for a certain period of time, sufficiently long for absorption of the dissolved drug by the patient. What we are doing is dissolving the crystal lattice of the drug particles and dispersing single drug molecules in a solid water-soluble polymer matrix – you could say we ‘pre-dissolve’ it.”

One of the key issues pharmaceutical companies need to be aware of when using such complex technology is the shelf life of amorphous drug formulations. Amorphous forms of pure drugs are often unstable and can recrystallised easily.

“An amorphous state may have the greatest advantage when it comes to solubility, but its propensity to revert back to other, less soluble crystalline solid-state forms on storage can provide a headache for pharmaceutical companies,” he says.

“One major challenge in the development of amorphous drug formulations is how to stabilise the amorphous state. It may be a case of finding the right amount of polymer in relation to the drug, or choosing the right type of polymer. It may be a question of looking at residual water and uptake of moisture during storage, the use of aluminium foil and so on.”

Future applicationAlthough the science behind drug solubility is complex, scientists have made incremental advances and introduced further innovative approaches to overcome poor solubility. As well as amorphous systems, lipidic self-emulsifying systems and nanosized particle-based formulations are two further options for improving active pharmaceutical ingredient solubility and dissolution speed for oral dosage forms.

“These three technologies are highly sophisticated techniques,” says Ohm. “They will be applied more and more in the future to meet the increasingly poor solubility of new chemical entities.”

Despite the continuing need for new solubility-enhancement techniques, Ohm does not expect to see any further major technological innovation in the immediate future.

“The probable trend is likely to be more of the same, or just small steps leading to bigger advances,” he explains. Researchers are identifying wonderful new drugs, but most of them will only work when applying these kinds of solubility enhancing techniques.” ■

One major challenge in the development of amorphous drug formulations is how to stabilise the amorphous state.

400 Pleasant Street, Watertown MA 02472, USA Tel: +1 (617) 926-5000 Fax: +1 (617) 926-5050 www.psivida.com

Focused Therapeutics / Visionary Science

pSivida develops miniature drug delivery systems for controlled release of drug for months up to years. Two platform technologies, Durasert™ and Biosilicon™, have primarily focused on ophthalmic indications, yet technologies are applicable to any number of applications.

Products/programsinclude: Tethadur™ Injectable Protein Delivery System - Designed to provide sustained release for days/months of peptides, proteins (even antibodies) & Biosimilars Vitrasert® CMV FDA approved 1995, licensed to Bausch & Lomb Retisert ® Uveitis - FDA approved 2005, licensed to Bausch & Lomb ILUVIEN® DME - currently awaiting FDA decision, licensed to Alimera Sciences Durasert (Posterior uveitis) - open IND- investigator sponsored, supported by pSivida Durasert/Latanoprost (glaucoma) - Phase I/II, pSivida with Pfizer Durasert technology under evaluation for Osteoarthritis at Hospital for Special Surgery

pSivida:DrivingtheEvolutionofMiniaturizedDrugDeliveryProducts

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DRUG DELIVERY SERVICES

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Our product portfolio includes single dose & multi dose reusable & disposable auto injectors & pen systems, which are suitable for a wide range of primary containers, including plastic syringes and pre-filled glass syringes and cartridges.

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OEMservice_A4ad.indd 1 14/3/11 18:43:50WPF019_Owen Mumford.indd 1 04/10/2011 14:35

Company insight > Drug delivery & formulation


P oorly soluble drugs present a challenge: no matter how potent the active ingredient, there are problems of incomplete absorption and low

bioavailability. The recipients are thus unlikely to benefit from the full clinical effect. This is particularly the case for medicines belonging to class II (poorly soluble, highly permeable) and class IV (poorly soluble, poorly permeable) of the biological classification system. Where such drugs are administered via drinking water, only a small proportion of the active ingredient is released: tests have shown figures as low as 15%.

In response to this situation, Labo Smeets has pioneered its latest technology. In collaboration with Ghent University, the Belgian pharmaceutical powders company has developed a granulation technique for converting poorly soluble drugs into highly soluble granules.

“If a drug is to be administered via drinking water, dissolving it is key,” says managing director Jef Verplaetse. “Our granules guarantee dissolution of 100%.”

The benefits are obvious: high solubility leads to a swift release of the active pharmaceutical ingredient (API), which in turn increases bioavailability. This minimises wastage, because less API is needed to produce the same effect.

twin-screw technologyAlthough the Twin Screw Granulator used for this purpose did not become operational until January 2011, the technology was first envisioned decades ago.

“The concept of using twin screw extruders for the granulation of drug preparations started in the mid-1980s,” says Verplaetse. “However, granules were not homogeneous and required a great deal of optimisation.”

A drug load of up to 60% can be achieved for drugs of class II and class IV of the BCS system.

The technology now ensures a very intense and effective blending under strictly controllable conditions, which helps ensure the stability of APIs. Moreover, the continuous granulation process, as distinct from batch production, is speedy and straightforward.

“The main problem of batch production is the scale-up from laboratory to industrial production capacity,” explains Verplaetse. “Such problems can be avoided with a

double whammyIn collaboration with Ghent University, Labo Smeets has developed a new technology that enables the continuous production of water-soluble granules. Managing director Jef Verplaetse explains how twin screw extruders can improve the bioavailability of medicines that are not easily soluble in water.

The technology ensures a very intense and effective blending under strictly controllable conditions, which helps ensure the stability of APIs.

Why use a twin screw extruder?The pharmaceutical industry is becoming ever more interested in continuous process technologies. Such technologies present many benefits, not least the fact they enable a larger production capacity, reduce time and costs, and avoid scale-up problems.

Twin screw extruders have been used for continuous production processes for many years. Particularly prominent in the plastics industry, in which polymers are mixed with additives to give plastic compounds, they facilitate a very intense and effective blending under strictly controllable temperature conditions

Generally, twin screw extruders are preferred to single screw extruders because they give better mixing at lower melt temperatures, and benefit from greater flexibility in terms of their design.

Despite the long pedigree of this technology, only now is the pharmaceutical industry starting to reap its benefits. With recent developments focusing on the optimisation of the screw profiles and the choice of materials used, twin screw extruders may now be used for producing homogeneous granules for drug preparations.

The Twin Screw Granulator (Pharma TSG 24) used by Labo Smeets is supplied by Thermo Scientific, an important player in the production of twin screw granulators and extruders. It has been operational since January 2011 and, in its production of water soluble granules, has been put to the most pioneering of purposes.

The advantages of the Twin Screw Granulator are a continuous process, limited upscaling problems and the absence of solvents.

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Further informationLaboratoria Smeetswww.labosmeets.be

continuous granulation technology, in which the only parameter that needs to be changed is production time.”

Finally, the low temperatures at which the blending process occurs offers interesting perspectives for temperature-sensitive APIs.

solubility needsAt present, Labo Smeets’ focus is the veterinary market. While mixing drugs with animal feed is arguably simpler than dissolving them in water, it is difficult to control the concentration level in feed granules or to estimate batch sizes with any accuracy. Highly soluble drugs are therefore a pressing need. Applications in the human drugs market may also be on their way. Labo Smeets has, for example, successfully developed a paracetamol suitable both for animals and people.

“Bioavailability is going to become ever more important for human medicines,” says Verplaetse. “APIs that are taken orally should be available for the body and not simply wasted. Improved bioavailability also means that the effect of the drug as a function of the given doses can be better understood.”

new horizonsTwin screw granulation has many possible applications, which are yet to be explored. While Labo Smeets has concentrated mainly on melt granulation with a

hydrophilic matrix, the same technology can be used with a lipophilic matrix. This should bode especially well for the manufacture of tablets.

“Another field we are looking into is wet granulation,” says Verplaetse. “The excellent blending properties of the twin screw extruders can make a high-quality granulate. Finally, we are considering polymer granulation applications for controlled release, using ethyl cellulose or polyethylene oxides as carriers.”

The new patented technology offers new opportunities for the lifecycle management of drugs. The major advantage of the technology is that, as well as improving solubility and bioavailability, it enables the creation of new lifecycle opportunities for old molecules. In a time when patents are expiring, new creative ideas are needed to ensure the continued value of those products: Labo Smeets’ twin screw granulation process is one such innovation. ■

The new patented technology offers new opportunities for the lifecycle management of drugs.

New: Twin Screw extrusion for improvingthe water solubility of APIs.

[email protected]

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F aced with soaring R&D costs, an impending onslaught of patent expirations, mega-merger mania and increasing consumer demands for improved

medications, pharmaceutical companies are relying heavily on advanced drug delivery technologies to help sustain the high growth and profit margins they have enjoyed since the 1990s. Against this background, pharma companies are recognising that drug delivery technologies are a powerful strategic marketing tool to differentiate products and extend product lifecycles, thereby overcoming marketplace challenges.

The application of drug delivery is a valuable, cost-effective lifecycle management resource. By infusing drugs with new and innovative therapeutic benefits, drug delivery systems extend products’ profitable lifecycle, giving pharmaceutical companies competitive and financial advantages, and providing patients with improved medications. Formulation development is being used in the creation of new dosage forms for existing products, which not only reduces the cost and time of new drug development, but also helps with patent protection and bypassing existing patents.

drug delivery gumMedicated chewing gum (MCG) is a drug delivery system that consists of an active ingredient incorporated into a chewing gum and released by the mechanical action of chewing. The first MCG product, ‘Aspergum’, which contained acetylsalicylic acid for headaches, was launched in 1928. The success story of nicotine chewing gum in the 1980s led to a more general acceptance of chewing gum as a drug delivery system.

MCG is a good vehicle for administering active ingredients in pharmaceuticals and nutraceuticals. It offers a highly convenient, patient-compliant way of dosing medications, particularly for people with swallowing difficulties such as children and the elderly. It is also an ideal dosage form for drugs that help cure or relieve oral diseases, including toothache, periodontal disease, bacterial and fungal infections, and aphthous and dental stomatitis. MCG containing chlorhexidine is used to treat inflammatory conditions such as gingivitis.

medicated challengesThe potential of medicated chewing gums has not yet been fully exploited because the manufacturing process requires different technology from that used in pharmaceutical production. This consists of equipment and facilities involving hot-melt processes, which are rare in the pharmaceutical industry.

The recent availability of directly compressible chewing gum excipients enables rapid, safe and low-cost development of MCG as a drug delivery option. The launch of the Health in Gum® (directly compressible powder gum) range of products in 2009 by

leading gum base supplier CAFOSA initiated growing interest from the pharmaceutical world. Health in Gum is a coprocessed chewing gum powder excipient containing a mixture of gum base, polyols, plasticisers and anticaking agents. It complies with food chemical specifications and is ‘generally regarded as safe’, as regulated by FDA title 21 C.F.R. Section 172.615. Chewing gum made by this material can be directly compressed on a pharmaceutical in-house tablet compression machine, which enables rapid and low-cost development of MCG. As it does not require a high temperature, thermosensitive APIs can also be processed. This method is also ideal for water-sensitive drugs. Formulations made with Health in Gum are similar to a tablet in appearance, but incorporate chewability as in a standard gum.

mcG potentialMCG is gaining new support; in 2012 the European Pharmacopoeia will include the only commercially available device for in vitro release testing of medicated gums: a mechanical masticator that is being used by medicated gum manufacturers. Further in the future, the concept of chewing gum as a drug delivery system may be used in preference to other oral mucosal drug delivery systems for the local and systemic delivery of most prescribed drugs as a result of higher patient acceptance and compliance. Using the MCG formulation, the revitalisation of old products and the reformulation of new patented products will differentiate them from upcoming generics competition. Thus, the potential of MCG for direct systemic delivery with higher patient compliance, its fast onset of action and the opportunity for product-line extension make it a likely drug delivery system. ■

chew and deliverMedicated chewing gum, launched in 1928, is becoming increasingly popular as a method for drug delivery. Aliasgar Shahiwala of the Dubai Pharmacy College explains the benefits for the pharmaceutical industry.

Further informationCafosa Gumwww.cafosa.com

Medicated chewing gum contains an active ingredient that is released by the mechanical action of chewing.

WPF020_Cafosa.indd 56 06/10/2011 08:00

Innovating in oral drug delivery systems is easier than ever

Health in Gum is an oper door to innovation. It is a step further in medicated chewing gum. Health in Gum is an excipient, a directly compressible powder gum with excellent flow and compactibility properties. You only have to select the Health in Gum powder that meets your requirements, add your API and mix it in a powder blender. Then it is ready to be compressed with standard tabletting equipment.Health in Gum allows the use of thermo/water sensitive APIs. With Health in Gum you can explore new bioavailability profiles for your APIs.

Innovating in oral drug delivery systems is that easy.

A POWDERFULWAVE OF INNOVATION www.healthingum.com

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i njection moulding, extrusion, polymer compounding and product assembly; each of these technologies is offered by RAUMEDIC, a leading manufacturer of systems and

components for the medical and pharmaceutical industries. From polymer-based drug administration systems to catheter couplings for anaesthesia, the company is fully equipped to meet each customer’s pharmaceutical needs.

“Our customers have the initial idea, and then we develop this into a product concept,” says Dr Thomas Jakob, RAUMEDIC’s director of business unit moulding and pharma solutions. “We already support our customers when choosing the right material, and then we build all the necessary equipment – we’re talking about millions of products per year.”

RAUMEDIC has a long industry pedigree, having been in operation for over 60 years. Originally part of REHAU AG + Co, which employs around 15,000 people worldwide, it split off from REHAU in 2004. The company thus combines the benefits of experience with the dynamism of a new and rapidly expanding team. The company has approximately 450 staff, with headquarters in Münchberg, Germany, and two further production facilities in Germany. All its capabilities and technologies are based in house.

“We are very fast-growing,” says Jakob. “We took on 86 new employees last year alone.”

Fluid-handling and pharma packaging programmesChief among its pharmaceutical solutions is the fluid-handling programme, which reflects RAUMEDIC’s considerable expertise in the interactions of polymer with flow media. Consisting of FluiSil (a silicon tubing range) and FluiSet (complete assembled sets), the programme is optimally designed for biopharmaceutical manufacturing and filling processes. RAUMEDIC also offers individually tailored sets and customised parts.

“The possible applications of our products are very broad,” says Jakob. “For example, we develop and produce secondary and primary packaging, innovative drug delivery systems and injection systems.”

Such applications fall under the remit of the company’s Pharma Solutions programme, which creates high-quality polymer-based products according to customer specifications. A team of engineers, chemists and managers completes each project, processing a wide range of tailor-made plastics.

user-friendly focusWhen it comes to drug delivery systems, RAUMEDIC is faced with the dual challenge of ensuring exact dosage while being user-friendly. Its solutions include dose-sipping devices and injection systems.

Perhaps most ingenious is the company’s dose-sipping syringe, which has a double function: it can be used like a syringe or a straw. This method is particularly suited to children whose reluctance to take medicine is counterbalanced by their enjoyment of sucking straws. Here, as with all RAUMEDIC products, patient safety and comfort are paramount.

Quality standardsRAUMEDIC adheres to the highest standards of quality control: its quality management systems are in line with ISO 13485 and ISO 9001; its quality assurance systems conform to appendix II of the EC directives 93/24/EEC and 90/385/EEC; and its clean room manufacturing meets ISO 14644, class 7. In addition, the company excels in R&D.

“We have a very big R&D department with all kinds of capabilities,” says Jakob. “There are engineers from a wide range of backgrounds, including biologists and chemists. We also have a medical advisory board, bringing us into contact with doctors and specialists in certain application fields. This gives us very detailed information about all kinds of different applications from our customers.”

RAUMEDIC does not wish to supply one solution to all, but rather to find the correct solution in each individual case. The imperative, however, is always the same: to improve patients’ quality of life.

“We are aiding people’s recovery through the development of innovative application and acute therapy systems,” says Jakob.

As such, the company will settle for nothing less than the provision of the highest quality services and products. ■

a quality combinationCombining 60 years’ experience with the dynamism of a young and flexible company, RAUMEDIC provides the highest quality systems, components and services. Dr Thomas Jakob explains to Abi Millar how RAUMEDIC tailors its products to meet its clients’ needs.

Further informationRAUMEDICwww.raumedic.com

RAUMEDIC’s fluid-handling programme reflects its expertise in the interactions of polymers with flow media.

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ExtrusionMouldingAssembly

RAUMEDIC AG – Hermann-Staudinger-Str. 2 – 95233 Helmbrechts – GermanyTel: +49 9252 359-0 – Fax: +49 9252 359 1000 – [email protected] – www.RAUMEDIC.com

PharmaSolutions High qualitypolymer productscustomised developedand produced.

Polymer-based primary and secondary packaging

Innovative drug delivery systems

Intelligent injection systems

Complex modules and devices

5,500 m² clean room production ISO 14644 (class 7)

Quality management system according to ISO 13485

GMP orientated production

WPF020_Raumedic.indd 1 04/10/2011 14:38

Innovative Device Solutions for Drug Delivery

Introducing a diversified portfolio of innovative, differentiated systems to helpenable, enhance and extend the lifecycles of liquid stable and lyophilized drugs

Proprietary technology platforms include primary drug containers with integrated

safety features, patient-self-injection systems such as auto-injectors and large-volume subcutaneous infusion systems, and novel devices for organ delivery

See us at CPHI, Frankfurt (Oct 25-27 Booth 41G32), AAPS, Washington D.C (Oct 24-26 Booth 908) and PDA, Basel (Nov 7-11 Booth 25)

www.unilife.com [email protected]

WPF020_Unilife.indd 1 04/10/2011 14:39

I t’s not hard to see the benefits that can come from the controlled-release (or sustained-release) injectable delivery of drugs. Unlike the single hit that a patient

might get from simply taking a drug orally or through a conventional injection, controlled-release delivery offers reduced dosing frequency, better therapeutic control, fewer side effects and, consequently, a better acceptance of the dosage form by the patient.

Although advances in polymer material science, particle engineering design, manufacturing and nanotechnology have all contributed to the introduction of more sustained-release products on the market, with a large amount of cutting-edge

Controlled-release drugs have been around for some time and have many benefi ts, particularly for patients with chronic or autoimmune diseases, but ongoing research has revealed that this market’s potential is only now about to take off, as Patrick P DeLuca and Heidi M Mansour of the University of Kentucky College of Pharmacy explain to Nic Paton.

WORLDPHARMACEUTICALFRONTIERS | www.worldpharmaceuticals.net 61


Ready fortake-off

Dr Patrick P DeLucaDr Patrick P DeLuca is emeritus professor and Sullivan Medallist at the University of Kentucky College of Pharmacy and former president of the American Association of Pharmaceutical Scientists.

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R&D work ongoing, the concept of controlled-release has been around for years, says Patrick P DeLuca, emeritus professor at the University of Kentucky College of Pharmacy, Kentucky, US.

“Sustained-release has been around for a long time so it is not new,” he says. “It developed first within the oral form with the aim of prolonging the levels of certain drugs that were rapidly absorbed into the blood and therefore got eliminated quickly; for example, prolonging the residency or transit within the gastro-intestinal tract.”

Drugs cannot be prolonged in the gastro-intestinal tract for long periods, which means that by using oral forms of sustained-release, the patient may need to take the drug once or twice a day. This depends on the clearance of the drug from the bloodstream, which can take from 30 minutes to three to four hours; however, with controlled-release injectables, it is much easier to target the delivery of the drug within the body and, crucially, how long it stays in the patient’s system.

“You can actually have a depot site where you can localise the drug in the tissue, either intramuscular or subcutaneous,” explains DeLuca. “But the main advantage is that it can then be prolonged for a much longer time, perhaps three or four months.”

Chronic situationSuch novel methods of delivery can be particularly helpful when it comes to treating a range of chronic or autoimmune diseases such as multiple sclerosis or arthritis, according to Dr Heidi M Mansour, assistant professor of pharmaceutics and pharmaceutical technology at the University of the Kentucky College of Pharmacy.

“There are products for osteoporosis and prostate cancer that are hormone-based and ideally need to be sustained-release, but for which you do not want people having to inject themselves every day, week or month,” she says.

“Similarly, with mental disease such as schizophrenia there are issues with the patient remembering when they need to take their medication, so this sort of advance can really help with compliance and disease management, as well as help with maintaining costs.”

Long-acting polymersThe development of advanced drugs using long-acting biodegradable polymers, especially peptide and protein-based drugs, has contributed immensely to this trend, points out Mansour. The past few years have seen a number of controlled-release products containing polypeptide drugs and protein drugs, or ones that retain their therapeutic activity over


WorLdPharmaCeutiCaLFrontiers | www.worldpharmaceuticals.net62

Respiratory and pulmonary conditions such as asthma or COPD could benefit significantly from sustained-release inhalation aerosols directly to the lung.

pharmaceutical timescales following encapsulation in biodegradable materials, enter the market.

“Sustained-release is often used with polymer-based drugs, with a lot of polypeptide biological drugs starting to come through, although it very much depends on the polymer and the chemical structure,” she explains. “In the initial design development stage, which polymer to use can be an issue. The encapsulation of the drug can be another challenge, as can scaling up to manufacture.

“Most of the time the process will be tweaked so that the drug inside the polymer stays that way throughout the development process, or it is a question of trying another polymer or increasing the amount of the drug.”

DeLuca expects to see new polymeric systems enter the market, ones that can help achieve a steady state of blood levels over an extended period of time. Other types include pen-based polymer devices for administering insulin and other biological drugs.

“It is about making the treatment more advantageous by having it in controlled-release form,” says DeLuca. “There are some conditions that are difficult to treat unless they are in controlled-release form, so that is where a lot of the research is currently focused. What is certain is that we will in time come up with a lot of systems that can be applied to a wide range of drug classes.”

Potential advancesMansour predicts that there will be an increase in the number of sustained-release injectable products being approved for human use, particularly in the sphere of protein and peptide-based drugs, and especially those used by the elderly population where there tends to be more frequency of chronic disease, as well as in areas such as cancer, autoimmune diseases and schizophrenia.

dr heidi m mansourDr Heidi M Mansour is assistant professor of pharmaceutics and pharmaceutical technology at the University of Kentucky College of Pharmacy. She also holds an appointment at the UK Center of Membrane Sciences.


www.gerresheimer.com

Gerresheimer innovation: New multilayer parenteral vials | High performance plastic design

| High barrier properties

| Superior resistance

WPF020_Geresheimer.indd 1 04/10/2011 14:39



table 1: examples of us Fda-approved long-acting formulations on the market.*

drug Brand name

dosage(mg/ml) Form administration dosing

frequencytheraputic

area company

Fluoxetine hydrochloride

Prozac 90 Capsule Oral Once a weekMajor depressive

disorderEli Lilly

Alendronate sodium

Fosamax 70Tablet/solution

Oral Once a week Osteoporosis Merck & Co

Risedronate sodium

Actonel 150 Tablet Oral Once a month Osteoporosis P&G

Ibandronate sodium

Boniva 150 Tablet Oral Once a month Osteoporosis Roche

Ibandronate sodium

Boniva 3/3 Injection IV bolus Every 3 months Osteoporosis Roche

Zoledronic acid Reclast 5/100 Injection IV infusion Once a year Osteoporosis Novartis

Goserelin acetate Zoladex 3.6, 10.8 Implant SCEvery 1–3 months

Advanced prostate cancer

AstraZeneca

Buserelin acetateSuprefact

depot9.9 Implant SC Every 3 months

Advanced prostate cancer

sanofi-aventis

Leuprolide acetate Viadur 72 Implant SC Once a year Advanced prostate

cancerALZA

Etonogestrel Implanon 68 Implant Subdermal Every 3 years Hormone therapy Merck & Co

Dexamethasone Ozurdex 0.7 Implant IntravitrealEvery 2–3 months

Macular edema Allergan

Ganciclovir VIitrasert 4.5 Implant IntravitrealEvery 5–8 months

Cytomegalovirus retinitis

Bausch & Lomb

Fluocinolone acetonide

Retisert 0.59 Implant IntravitrealEvery 30 months

UveitisBausch &

Lomb

* Does not include injectable sustained-release drug-delivery systems. IV: intravenous SC: subcutaneousCredit: Rhee YS, Park CW, DeLuca PP and Mansour HM. ‘Sustained-Release Injectable Drug Delivery Systems. An Invited Paper’. Pharmaceutical Technology: Special Issue Supplement-Drug Delivery. (2010) November: 6-13.

“These advances are coinciding with advances in other areas, such as particle engineering, which is pretty exciting in terms of their potential,” she says.

With insulin, this means that instead of injecting once or twice a day, there will be the potential to make it once a week or even longer, according to DeLuca.

“It could potentially be for any condition where the patient is going to be on medication and it is not something where they have to be monitored in terms of blood levels,” he says.

As well as many chronic diseases that require patients to accept a lifestyle of ongoing medication, respiratory and pulmonary conditions such as asthma or chronic obstructive pulmonary disease could also benefit significantly from sustained-release inhalation aerosols directly to the lung. One of the important advantages is reducing the frequency of inhaled dose administration for these chronic pulmonary diseases.

“It can be helpful for patients needing to take a drug for a chronic condition and for which they will need to take it for their lifetime,” explains DeLuca. “If you inhale a solution into the lungs, inevitably it is going to clear quite quickly. But if you can incorporate the drug in a nanoparticle and localise it in the lung, it can remain there for a lot longer and will be released slowly. So it may just be, say, one puff a day, which would be a big advantage.”

Mansour and DeLuca predict that there will be more research carried out, particularly in the pulmonary area.

“It is easier for the FDA to approve a tablet or a liquid in injectable form,” says DeLuca. “But they need to look at the controlled-release form as well. It may be that you must have another clinical trial and that you need to extend the patent base.”

From DeLuca and Mansour’s predictions, it appears that controlled-release drugs have an exciting future, particularly for the patient, who will be the main beneficiary, with potential for areas such as vaccines or developments that can be used in developing nations. ■


Pharmaceutical outsourcing

CONTENTS

66 Open sesame AstraZenecaoutlinesitslatest strategicalliancesindiscovery researchandinnovation.

70 In the pipeline AccordingtoGlobalData,2011 willbeanothersuccessfulyear forbiologicalapprovals.

77 Best medicine DrAntonyFakeandJacqueline Sawyerdiscussthebenefits oftheWHO’sPrequalification ofMedicinesProgramme.

86 On the right track Howpharmamanufacturers canselecttherightexcipient fortheirformulation.

93 Clouds of change MollieShields-Uehling,SAFE- BioPharmaAssociation,onusing acloudcomputingmethodto conductaclinicaltrial.

101 Mixed messages NovoNordisk’sKimSteffensen onhowtosuccessfullywork withCMOsinemergingmarkets.

113 Perfect fit AbiMillartalkstoFrancesGrote, MillenniumPharmaceuticals, abouthowtoachieveexcellence withinoutsourcedrelationships.

TECHNICAL PAPERS

75 Stemming the MS tide MPIResearch

81 Simple formulations that fulfil healthcare needs RoquettePharma

85 A quality approach SasolWax

90 A counter ion that fulfils all needs MerckMillipore

92 Your business is our business TAPI

97 Get the right staff KellyScientificResources

98 Quality medicines, from molecule to market SGSLifeScienceServices

108 Keys to commercial success Patheon

111 Sustainable solutions DSMPharmaceuticals

112 Healthy manufacturing AlkaloidADSkopje

117 Laboratory automation SOTAX

119 Poland’s preclinical paragon IPOBranchPszczyna

WPF020_Supplement Cover.indd 91 06/10/2011 08:49

Insight > Drug discovery & development

With the developing trend towards externalisation across the biopharmaceutical industry, strategic research alliances and outsourcing of core capabilities are increasingly important in early drug discovery. Jin Li and Alan Lamont of AstraZeneca outline the company’s latest strategic alliances in discovery research, and explain how they will aid the search for innovative medicines to treat serious diseases.

Open sesame

I n recent years, there has been a noticeable increase in the number and variety of collaborations and alliances in the biopharmaceutical industry. These partnerships can vary in

size, scope and objectives, from the more traditional product or technology-based collaborations and licensing with biotech and academia, through to the more innovative, multi-party models; for example, using consortia comprising private and public entities.

Pharmaceutical companies have a long history of externalisation activities to access innovation, to license products or to acquire small and medium-sized enterprises (SMEs) to enhance their product portfolios or R&D capabilities. Recently, these activities have received heightened attention internally within pharma companies, and externally as major pharmaceutical companies push hard to bridge the R&D productivity gap. It is also the case that, overall, the industry is undergoing a fundamental restructuring, such that externalisation is no longer considered a largely opportunity-driven activity, but rather a fundamental and integral part of business and R&D strategy.

This point is more clearly illustrated by an analysis of the company origins of FDA-approved drugs during 1950 and 20082. The study by Bernard Munos in Nature Review Drug Discovery showed that in the 1950s, 80% of FDA-approved drugs came from major pharmaceutical companies and 20% from SMEs. Since then, the numerical contribution of the major pharmaceutical companies has been steadily decreasing, while that of SMEs has been increasing. By the late 1990s, the two groups’ contributions had reached a crossover point, and major pharmaceutical companies and SMEs were broadly accountable each for 50% of all FDA-approved drugs.

Since the authors have only considered data based on companies that submitted new drug applications (NDAs), the contributions of SMEs (and by extension, the academic units with which they have been working) will likely account for a greater percentage of the actual origins of inventions for the NDAs, attributable to the ongoing early-stage licensing activities of major pharmaceutical companies with the SME sector. This is a significant finding and its

WorldPharmaceutIcalFrontIers | www.worldpharmaceuticals.net66

dr Jin liDr Jin Li is director of computational sciences in the Discovery Enabling Capabilities and Sciences organisation of AstraZeneca R&D, responsible for hit finding and improving predictive capabilities in chemistry and biology.

dr alan lamontDr Alan Lamont is business development director in the Strategic Planning and Business Development Science and Technology Licensing group at AstraZeneca, responsible for identifying new enabling technologies and platforms.

WPF020_013_Joint enterprise.indd 66 06/10/2011 08:26



To succeed in the challenging environment within which the biopharmaceutical industry operates, collaboration is increasingly seen not as an optional activity, but as an obligatory one.

Source: Bernard Munos, ‘Lessons from 60 years of pharmaceutical innovation’, Nature Review Drug Discovery

the percentage of Fda-approved drugs originating from large pharma companies and smes.

1950s

Late 1990s

Large pharma companies 80%

SMEs 20%

Large pharma companies 50%

SMEs 50%

key message is worth highlighting: it provides a strong and clear rationale to view external partnerships and alliances as an integral and fundamental process of pharmaceutical R&D, rather than something to do every now and then. Thus, to succeed in the challenging environment within which the biopharmaceutical industry operates, collaboration is increasingly seen not as an optional activity, but as an obligatory one.

transparent collaborationCollaborations between large pharma and SMEs/academia are not new – they have been occurring almost as long as the drug industry has been active. These are often stimulated by the flow and transfer of scientific personnel from academia to industry, and the continuing links between industrial scientists and academic mentors. What has changed, however, is the nature and scope of these collaborative interactions.

Historically, pharma often viewed the external environment as an opportunity to gain additional confirmatory data to support their internally generated molecules and hypotheses. Thus, a ‘typical’ collaboration might involve the provision of exploratory compounds to test in new biological disease models run in academic labs. In the case of biotech companies, a straightforward collaboration would involve licensing new molecules to bring in-house within the pharma to complement their established discovery and development portfolios in key disease areas of unmet need.

While these types of typical collaborations still exist, these are

increasingly being replaced by partnerships which are characterised by a more open and collaborative mindset from the pharma side, leading to more transparent interactions between the parties – in effect, replacing the normal practice of working with the external environment to identify specific solutions, with a strategy of collaborating to provide greater clarity for the underlying problem first, before attempting to address the solution. Logically, this makes great sense.

The majority of scientific innovation happens outside the relatively narrow confines of the industry’s laboratories. By adopting a more open approach to sourcing, identifying and partnering with this external innovation, pharma stands to benefit to a much greater extent than it has previously.

Within AstraZeneca, this change can be seen in the novel types of collaborations that have been established in recent years, in particular with academic centres of disease excellence. Understanding the increasing complexity of biological effect mechanisms underlying chronic diseases is clearly the preserve of these centres of excellence and we have sought to develop relationships with leading centres to access this innovative science; for example, the recent strategic collaborations with the University of Pennsylvania in Alzheimer’s Disease and with the University of Manchester Collaborative Centre for Inflammation Research represent two such disease biology-focused collaborations. This latter case also represents an interesting example of an open collaboration between academia and groups of





pharma companies (in this case AstraZeneca and GlaxoSmithKline), with the intention of leveraging resources from multiple partners in pursuit of the same objectives.

Innovative partnering structures have also been used to support improvements in R&D productivity at other parts of the value chain; for example, in the case of the recent collaboration between AstraZeneca, Cancer Research UK and its commercialisation arm Cancer Research Technology (CRT), the academic partner will take one of AstraZeneca’s experimental compounds into a clinical study using the charity’s extensive clinical network. CRT will manage the initial phase I/IIa trial for the compound and, if successful, AstraZeneca can elect to take it further into development. If AstraZeneca chooses not to, the rights will be given to CRT to secure an alternative partner and ensure the drug has every possible chance of reaching patients. In either case, the charity will

receive a share of any future revenues generated by the drug. Finally, a further principle that is generating new models of

collaboration is one of leveraging pharmaceutical assets to access innovation in target biology, a concept that underlies the recent partnership between AstraZeneca and the UK’s Medical Research Council Technology (MRCT) organisation. In this example, up to 100,000 compounds from AstraZeneca’s corporate screening compound collection are being combined with the MRCT compound library of 50,000 compounds, and these will be screened for activity against novel biological targets arising from research groups supported by MRC’s academic research funding. A joint steering committee will review these hits and decide how to advance promising compounds. Individual projects chosen to go forward will trigger option fees, and the parties will negotiate further research and licence agreements to progress compounds

that have the potential to become innovative medicines.

These novel collaborative structures are characterised by more openness and transparency between pharma and its prospective partners, and are being used to bring more innovation into the challenge of improving R&D productivity. The use of new collaborative models will increase in prominence to the point where, perhaps, the ‘typical’ is no longer the norm, when pharma contemplates how best to work with external parties.

Pre-competitive consortia – more for less?As the principle of open collaboration between different parties increases, so there has been a growing realisation that, in several areas, there is an opportunity to leverage assets and resources between a number of partners to address common challenges and share solutions of common interest. These are often termed ‘pre-competitive’ areas of drug discovery research and are typically characterised not just by the significant size and scope of the challenge that is presented, but also by the acceptance that even if one party working independently were to achieve a particular solution, this would not per se result in a significant competitive advantage for that party.

The most prominent example of this type of collaborative structure in recent years has been the Innovative Medicines Initiative, a joint undertaking between the EU and the pharmaceutical industry association European Federation of Pharmaceutical Industries and Associations, which

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seeks to identify and support innovative collaborative research projects in pre-competitive areas of research.

To date, the research themes have broadly focused on areas such as improving the understanding of fundamental mechanisms of disease biology, addressing mechanisms of drug toxicity, and developing common standards and language for data manipulation and knowledge engineering. In the future, boundaries between pre-competitive and competitive areas of drug research will continue to evolve, potentially opening up further new models of collaboration in the pharmaceutical industry.

Future explorationIt’s clear that major pharmaceutical companies need to fundamentally change their R&D strategy and operating model in order to respond effectively to the severe productivity challenges facing the industry. Externalisation in the form of collaborations, licensing and strategic acquisitions are increasingly becoming a

systematic and integral part of R&D processes, and it is hoped that this will underlie the much anticipated improvement in productivity that is needed to address the increasing demands for better healthcare in both the developed and developing worlds.

Looking forward, how will this outlook change in the forthcoming years? Financial and cost containment pressures exist in the pharmaceutical industry, as they do in all other segments of commerce. With the anticipated best-case scenario of a constant level of R&D spend in the coming years, it will be necessary to continue to evolve the model and explore more innovative ways of externalisation.

Major pharmaceutical companies have a considerable range of highly valuable assets and capabilities; for example, high-quality compound libraries, advanced high-throughput screening facilities, extensive bioreagents expertise, informatics sources and expertise in drug hunting. These assets can have value outside the pharma environment, for example, within academia and biotech companies, and could form the bases for robust collaborations, particularly at the early phases of research where project attrition is at its highest.

Collaborations and alliances based on more innovative contributions of assets, expertise and skills from the partners will not only be relevant between major pharmaceutical companies, SMEs and academic institutions, but also between major pharmaceutical companies. More open and cross-industry collaborative ways of working such as these will contribute to enhancing innovation, as well as reducing the overall cost of R&D in bringing new medicines to the market. ■

By adopting a more open approach to sourcing, identifying and partnering with external innovation, pharma stands to benefit to a much greater extent than it has previously.


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Pharma companies are engaged in pipeline portfolio diversification, with a focus on speciality products for diseases with high unmet needs, including cancers, infectious diseases and immunological disorders. According to GlobalData’s analysts,2011 will be another successful year for biological approvals.

T he pharmaceuticals pipeline is burgeoning with oncology projects, followed by those in neuroscience, cardio-metabolic and infectious disease sectors. Immunology,

inflammatory and respiratory projects are also notable in the pipelines of the top pharmaceutical companies, according to GlobalData’s ‘2011 Pharmaceutical R&D Landscape’ report.

Oncology The oncology pipeline is populated with oral multi-kinase and vascular endothelial growth factor (VEGF) inhibitors and monoclonal antibodies. New oral and injectable products will be of prime importance in the coming years. Multi-kinase and VEGF inhibitors in clinical development include GlaxoSmithKline (GSK)’s Tyverb (Tykerb) and Pfizer’s Axitinib, Neratinib and Bosutinib.

Cancer monoclonal antibodies comprise Pfizer’s Inotuzumab ozogamicin and Lilly’s Ramucirumab. An emerging field in cancer therapy is cancer vaccine development. Cancer vaccines to look out for include Merck’s cervical cancer vaccine, BioVex’s OncoVEX and Oncothyreon’s Stimuvax.

Central nervous system Alzheimer’s disease drugs in the pipeline include Janssen’s Bapineuzumab, Pfizer’s Dimebon and Eli Lilly’s LY2062430 (solanezumab). Anti-psychotics for bipolar mania and schizophrenia include Forest’s and Gedeon Richter’s Cariprazine and GSK’s Histamine H3 antagonist.

The anti-depressive pipeline candidates include AstraZeneca’s and Targacept’s TC-5214, and GSK’s Orvepitant. The highlights in the multiple sclerosis pipeline this year include Biogen’s BG-12 and sanofi-aventis’s Teriflunomide. Analgesics in development include J&J’s Nucynta (extended-release formulation), Cerimon’s Diclofenac patch, Elite Pharmaceuticals’ ELI-154, Transdel Pharmaceuticals’ Ketotransdel, Omeros Corp’s OMS103HP, Durect’s Posidur, Zogenix’s ZX002, Pfizer’s Lyrica and GlaxoSmithKline’s Losmapimod.

Infectious diseases Vaccine development continues to boom in the infectious disease segment. Hepatitis C drugs in the pipeline include protease inhibitors such as Merck’s Boceprevir, and interferons such as

WOrldPharmaCeuTICalFrOnTIers | www.worldpharmaceuticals.net70

Bristol-Myers Squibb’s polyethylene glycol-interferon lambda and Biolex’s Locteron. Anti-HIV medications include HIV integrase inhibitors, chemokine receptor antagonists and non-nucleotide reverse transcriptase inhibitors.

Cardiovascular and metabolic Major cardiovascular therapeutics such as cholesterol-lowering agents and anti-hypertensives face stiff generic competition and will lose considerable market share. The cardiovascular market for 2011 is dominated by anti-thrombotic and anti-platelet products, including Pfizer’s Apixaban, Novartis’s Elinogrel, Daiichi’s Edoxaban and Merck’s Vorapaxar and Betrixaban.

The diabetes market is predicted to feature glucagon-like peptide-1 compounds and sodium glucose co-transporter-2 inhibitors. Novel candidates with unique modes of action also feature in the current pipelines.

Eli Lilly’s Empagliflozin, sanofi-aventis’s Lixisenatide, GSK’s Albiglutide and Bristol-Myers Squibb and AstraZeneca’s Dapagliflozin are at the forefront of anti-diabetic therapy this year. GSK’s Otelixizumab is a type 1 diabetes monoclonal antibody in development. Regulatory guidelines requiring higher patient enrolment in diabetes trials could cause delays in the approval of diabetic drugs already in the pipeline.

respiratory The respiratory drug pipeline is dominated by anti-asthmatics and treatments for COPD. Forest Labs’ Aclidinium, GSK’s Relovair and Novartis’s Indacaterol, as well as cystic fibrosis candidates Pharmaxis’ Bronchitol and Vertex’s VX-770, are some of the drugs for which activity can be expected.

Big Pharma pipelinesGSK has a dense pipeline, with drugs catering to a wide number of diseases. It has many late-stage drugs with several in phases I and II. Infectious diseases, oncology and neurology are the main areas of focus, followed by respiratory and metabolic disorders. The GSK pipeline features many speciality drugs, the majority of


In the pipeline

WPF020_016_In the pipleline.indd 70 06/10/2011 12:07


which are monoclonal antibodies and vaccines for cancers and infectious diseases. Vaccine development for infectious diseases also features. GSK’s anti-malarial, tafenoquine and influenza candidate Relenza is in the company’s extensive anti-infective pipeline, along with many infectious disease vaccines. The anti-inflammatory/respiratory pipeline covers COPD, asthma and Crohn’s disease. Type 2 diabetes and age-related macular degeneration (AMD) appear to be the focus in the metabolic and ophthalmology segments, respectively.

One of the vast drug pipelines is that of Pfizer, which features over 100 candidates with more than 20 in phase III and a significant number in registration. Pfizer’s acquisition of Wyeth has broadened the former’s portfolio, with oncology, neurosciences and cardiovascular drugs populating the pipeline, and significant numbers of candidates under development for respiratory/allergy and inflammatory disorders. Pfizer’s speciality drug focus covers many biologics, including vaccines catering for areas such as cancer, Alzheimer’s disease, ophthalmology,

inflammation and infectious diseases. Ophthalmology drugs are targeted at AMD, diabetic macular degeneration and edema. Pfizer’s allergy and respiratory pipeline features drugs for asthma and COPD, with type 2 diabetes reigning in the metabolic sector. Anti-inflammatories are centred on rheumatoid arthritis, psoriasis and inflammatory bowel disease, while anti-infectives include antibacterials for Staphylococcus aureus infections, pneumococcal disease and tuberculosis, antivirals for hepatitis C virus infections, and antiparasitics for malaria and onchocerciasis.

Sanofi-aventis’s pipeline contains more than 50 projects in clinical development. Phase I and II candidates constitute the majority of the company’s pipeline projects, with over 15 in phase III and beyond. The salient feature of the sanofi-aventis pipeline is the focus on infectious diseases, oncology and neurological domains. Biologics are prominent, with anti-cancer monoclonal antibodies and infectious disease vaccines under development. Drugs are being developed for neurological disorders such as multiple sclerosis, depression, Alzheimer’s disease and pain. Diphtheria, tetanus, pertussis, dengue, meningococcal and influenza vaccines, anti-diabetics, antineoplastic agents and antithrombotics are some of the advanced therapeutics under development.

With its acquisition of MedImmune and Novexel, AstraZeneca has a robust pipeline focused on producing small molecules, vaccines and biologics to address unmet medical needs in oncology, neuroscience, respiratory and inflammation, infection, cardiovascular and gastrointestinal areas. Asthma, COPD and rheumatoid arthritis are some areas of interest in the respiratory and inflammation sector. Anti-infectives include vaccines and

With looming patent expiries and huge impending financial losses, companies are faced with the daunting task of creating billion-dollar value blockbusters to compensate.

antibodies for viral and bacterial diseases. The oncology pipeline features kinase inhibitors and antibodies. Pain, depressive disorders, Alzheimer’s disease and attention-deficit disorder are prominent in neuroscience drug development.

Merck’s pipeline showcases more than 30 drugs from phase II to registration stages. The key therapeutic areas of focus are oncology, neurosciences and ophthalmology, infectious diseases, cardiovascular, diabetes and obesity, respiratory, immunology, dermatology, women’s health and endocrinology. Merck is developing biological molecules in the areas of cancer, infectious diseases and women’s health.

With a pipeline featuring 140 projects and with 16 important filings last year, Novartis is actively involved in biologics research, with a significant portion present in exploratory development. Advanced stage candidates include drugs for

table 1. Biologics that cleared Fda approval this year.

Biologic company condition

BenlystaHuman Genome Sciences and GlaxoSmithKline

Systemic lupus erythematosus

Yervoy Bristol-Myers SquibbMetastatic melanoma

Corifact CSL BehringCongenital factor XIII deficiency

AnascorpRare Diseases Therapeutics

Treatment of scorpion envenomation

Viibryd Merck and ForestMajor depressive disorder in adults

Edarbi TakedaHypertension in adults

Daliresp Forest and Nycomed COPD exacerbations

Horizant GSK and XenoPortRestless leg syndrome

Zytiga J&JLate-stage prostate cancer

Promacta (full approval)

GSK

Chronic immune (idiopathic) thrombocytopenic purpura

TradjentaBoehringer Ingelheim and Lilly

Type 2 diabetes

Victrelis Merck Hepatitis C infection

Edurant J&J HIV-1 infection

Incivek Vertex Hepatitis C infection

Dificid OptimerClostridium difficile-associated diarrhoea

Potiga GSK and Valeant Epilepsy

Nulojix BMS Kidney transplant

Arcapta Neohaler

Novartis COPD

Xarelto Bayer and J&J

Reduction of risk of blood clots after hip and knee replacements

Brilinta AstraZeneca

Reduction of cardiovascular death and heart attack in acute coronary syndrome patients





depression, myelofibrosis, heart failure, pathologic myopia, infectious diseases and pulmonary arterial hypertension.

Bristol-Myers Squibb (BMS) has a pronounced oncology pipeline, with the majority of cancer drugs present through all the stages. The takeover of Medarex and Kosan Biosciences strengthened BMS’s cancer and immunology portfolio. Other major areas of focus are cardiovascular, metabolic disorders, immunology, neurology and infectious diseases, with specific focus on indications including atherosclerosis/thrombosis, Alzheimer’s disease, diabetes, obesity, HIV/AIDS and rheumatoid arthritis. The pipeline has become more voluminous since 2009, with around one-third of the compounds in development being biologics. BMS actively seeks to engage in partnerships to mitigate risks and focus on bigger development programmes across various therapeutic areas.

Eli Lilly is engaged in generating treatments for diseases such as cancer, diabetes, osteoporosis, arthritis and Alzheimer’s. Oncology tops the company’s clinical pipeline, followed by CNS for depression, Alzheimer’s disease, schizophrenia and alcohol dependence. Anti-diabetic and rheumatoid arthritis drugs also feature in Lilly’s clinical programmes. Biological drugs occupy a considerable share of the clinical pipeline and dominate the cancer therapeutic segment.

J&J’s pharmaceutical segment is focused on drugs for cancer and neurology, including pain management and anti-psychotics, infections, cardiovascular, contraception, dermatology, hematology, gastrointestinal, urology and immunology. Oncology, cardiovascular and CNS therapies are at the forefront of J&J’s clinical R&D focus.

Pharma r&d strategiesThe pharmaceutical and biotechnology pipelines for 2011 are brimming with projects that strongly feature oncology, neurology and anti-infective products. Complexities in the clinical study design for these drugs, including larger patient enrolment, patient sustenance and protocol complications, result in trial initiation delays and high costs.

Biologics are becoming more prominent across the pipelines of many companies especially in oncology, immunology and infectious diseases. The number of biological approvals is also on the rise, with 2011 bearing bright prospects for biological approvals. Companies are interested in investing in biologics, despite the associated high costs, development times and stringent regulatory measures.

There is tightened control over pharmaceutical R&D spend as drug development costs are spiralling, with related expenses translating into billions of dollars. Growth in R&D investments

has slowed. With the average time to deliver a drug to market being 13 years, the time taken for neurology or oncology drugs, which have high market demands, is around ten years. Antineoplastic agents usually consume the most development time, followed by neurological and anti-infective drugs. CNS drugs are estimated to be the most expensive class of drugs in terms of development. Rapid escalations in time and cost can be expected in therapeutic development for particular sectors, thereby causing setbacks in patient drug reach and patient care.

With looming patent expiries and huge impending financial losses, however, companies are faced with the daunting task of creating billion-dollar value blockbusters to compensate for the ones expiring this year onwards. Companies will face huge losses, with approximately $100 billion in sales predicted to be lost in patent expiries in the next few years.

The number of pipeline entries is also dwindling and the quantity of new drug applications has decreased over the past two years due to drug failures and subsequent pipeline attritions. Pharmaceutical companies are aggressively devising counter R&D strategies to cope with abundant pressures to eliminate unsuccessful candidates, enhance the speed of drug development and reduce R&D expenditure.

Strategies to recompense the financial setbacks include mergers and acquisitions, in-licensing and collaborations, increased focus on specialty medicines and emerging markets, cost-cutting initiatives across the production chain and the adoption of new drug discovery technologies. Nevertheless, given the stringent regulatory measures, dipping new drug approval rates and incessant surges in drug development time and cost, pharmaceutical companies will have a long way to go to overcome development and regulatory obstacles in order to generate successful returns on investment. ■

Biologics are becoming more prominent across the pipelines of many companies, especially in oncology, immunology and anti-infective products.

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Company insight > Drug discovery & development


s tem cells are critical during the development of regenerative cell therapy and migrate to different locations in the organism, such as bone marrow.

Embryonic stem cells are pluripotent and are found during very early development, while adult stem cells function to maintain and repair their tissues of origin. Adult bone marrow contains at least three cell types:

■ haematopoietic stem cells ■ non-haematopoietic stem cells such as very small

embryonic-like stem cells ■ mesenchymal stromal cells (also known as mesenchymal

stem cells (MSCs).

MSCs were originally described as a non-haematopoietic bone marrow component but were isolated from other tissues, such as adipose, synovial fluid, placenta, muscle and articular cartilage, as well as organs such as the lung, liver and spleen. These cells exhibit a number of surface antigens but lack haematopoietic markers such as CD34, CD45 and CD11b.

MSCs influence a broad range of immune cell types and migrate to sites of tissue damage or inflammation. Interestingly, the improvement levels observed in different animal disease models treated with MSCs do not correlate with the levels of cell engraftment and differentiation, which suggests MSC regenerative properties are due to paracrine influences on resident cellular repair processes, including activation of endogenous tissue progenitor cells.

inflammatory disease treatmentThe immunomodulating properties of MSCs indicate this cellular therapeutic class has application in inflammatory disease treatment. MSCs inhibit T and B cell proliferation and differentiation, attenuate natural killer cell activity, and support T regulatory cell production. These activities depend on soluble factors released by the MSCs and direct interactions of the MSCs with inflammatory cells present at tissue injury sites. Indoleamine 2,3-dioxygenase, iNO synthase, PGE2, TGF-1 and other regulatory proteins mediate MSC anti-inflammatory properties.

Recently, pro-inflammatory activities mediated by toll-like receptors were also identified for MSCs. A recent hypothesis suggests pro-inflammatory or immunosuppressive phenotypes of the MSC may result from different temporal stimulation related to either early tissue injury or the later tissue resolution responses. Regardless, the majority of current findings support the use of MSCs for treating inflammatory components of various diseases and autoimmune dysfunction.

animal disease modelThe use of animal disease models identified and characterised potential therapeutic applications for MSCs. Experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis (MS), is induced by immunisation with peptides found within proteins of the axon myelin sheath, such as proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG). These models exhibit ascending tail and limb paralysis, which becomes evident approximately ten days after immunisation.

Intravenous administration of mouse MSCs to C57BL/6J mice with MOG35-55-induced EAE before disease onset significantly reduced disease severity, based on clinical sign scoring. Reduced CNS demyelination and decreased T cell and macrophage infiltration of the CNS parenchyma were also observed in the diseased animals compared with controls based on histopathology. Similarly, allogeneic transfer of MSCs isolated from C57BL/6J mice into PLP139-151-immunised SJL recipients at 12 days post-immunisation resulted in significantly reduced clinical and pathological scores, compared with non-treated EAE controls. Ex vivo analysis demonstrated decreased T cell proliferation, lower TNF and IFN production and less PLP-specific antibodies. Furthermore, eGFP-labelled MSC colonised the lymphoid organs and infiltrated the CNS, although transdifferentiation of the MSCs into neural cells was not detected.

The use of mouse EAE models sheds light on the cellular and molecular mechanisms responsible for MSC therapeutic effects. Studies in these models also validated the rationale for exploring the use of MSCs as a treatment option for MS. Thus, autologous or allogeneic MSCs were well tolerated by human patients, and new multicentre clinical trials are being launched to further characterise the safety and efficacy of MSCs for the treatment of some forms of MS. ■

stemming the ms tide Research is ongoing, particularly in regenerative cell therapy, for the effective treatment of immune diseases. Thomas Vihtelic, director of experimental therapeutics at MPI Research, explains why mesenchymal stem cells might have a role to play in treating multiple sclerosis.

The majority of current findings support the use of MSCs for treating inflammatory components of various diseases and sutoimmune dysfunction.

Further informationMPI Researchwww.mpiresearch.com

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Insight > Chemicals & raw materials


Good-quality active pharmaceutical ingredients are vital to the production of good quality medicines. Dr Antony Fake and Jacqueline Sawyer explain how the World Health Organization’s Prequalification of Medicines Programme facilitates access to quality medicines through assessment of products and inspection of manufacturing sites.

Best medicine

Good-quality active pharmaceutical ingredients (API) are the building blocks of good-quality medicines. In their absence, commercialisation

of good quality medicines is slowed and patient access to safe and efficient treatment is impeded.

The globalisation of markets compounds quality-of-medicines issues; for example, API manufacturers are increasingly based in China, whereas most manufacturers that have had finished pharmaceutical products (FPP) prequalified by the World Health Organization (WHO) are based and manufacture their products in India.

Information asymmetry, communication problems due to lack of a common language, and trade across different jurisdictions exacerbate difficulties in sourcing APIs of a high standard. These problems are acute for therapeutic areas such as tuberculosis (TB); manufacturers of anti-TB medicines complain increasingly that they cannot obtain good-quality APIs.

Yet FPP manufacturers are responsible for ensuring the quality of their products, including that of the constituent APIs. Thus, having located an API source, an FPP manufacturer must also verify its quality, which includes verifying that the API is manufactured in compliance with good manufacturing practice (GMP).

This necessitates obtaining certificates of on-site inspections and conducting paper-based audits of technical documents. For manufacturers in developing countries, this task can be burdensome, if not impossible, particularly if an API has been purchased through a broker.

eliminating poor-quality aPisExperience has repeatedly shown that manufactured APIs may fail to comply with internationally accepted GMP. This is not surprising given that adoption of ICH GMP standards among API manufacturers is not yet equally widespread across all geographic regions.

In 2006, the International Conference of Drug Regulatory Authorities highlighted the need for high-level action aimed at improving API quality. The WHO responded by developing and

API manufacturers who have not undergone SRA assessment can apply for API prequalification without having to submit an associated application for FPP evaluation.

dr antony FakeDr Antony Fake has worked with the WHO Prequalification of Medicines Programme for the past 18 months. He coordinates the assessment of API information and, since October 2010, WHO prequalification of APIs.



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publishing a procedure for WHO prequalification of APIs. As the procedure notes: “A proper system of qualification of suppliers can promote the constant sourcing of active ingredients of appropriate quality and thereby safeguard public health interests.”

Taking this procedure as its starting point, the WHO Prequalification of Medicines Programme (see ‘The WHO/PQP celebrates a decade’, right) launched a project in 2010 to prequalify APIs by issuing its first invitation to API manufacturers to submit an expression of interest for evaluation. A second, more-extended expression of interest was issued by the WHO/PQP in March 2011. The WHO’s evaluation procedure is open to a variety of APIs used in medicines for treating HIV, TB and malaria, and for reproductive health (see Figure 1, opposite). APIs that are evaluated and found to be manufactured in compliance with WHO GMP are publicly listed.

Who prequalification of aPis: a unique serviceThe WHO/PQP is not replicating efforts made by national medicines regulatory authorities (NMRAs). Other regulatory schemes for API assessment exist, but these do not necessarily include those APIs that are urgently needed for the manufacture of FPPs in the aforementioned therapeutic categories. Moreover, many regulatory schemes assess an API only if it is submitted in relation to an application for medicine registration. Even if an NMRA does assess an API with respect to such an application, this does not necessarily include verification of compliance with GMP, or making public the details of the API if it receives approval. By assessing the quality of APIs, verifying the GMP standard of their manufacturers and publishing details of successful applications, the WHO/PQP is providing a unique service.

This does not mean that national regulators and the WHO/PQP are never called on to evaluate the same API. But this is not a common occurrence and the scope of the assessment is often different.

In any event, the WHO procedure takes this possibility into account by allowing for the findings of the assessment and inspection reports from stringent regulatory authorities (SRAs) to be incorporated into the WHO/PQP’s decision-making process.

how does the process work?The principal components of the API prequalification evaluation process are assessment of the quality components of the application, and evaluation of the GMP standards under which the API is manufactured. Full details can be found on the WHO/PQP website at www.who.int/prequal.

The quality assessment is based on an evaluation of the manufacturer’s Drug Master File, which covers the API information found in the ICH Module 3.2.S. (The Drug Master File is referred to

as an APIMF within WHO/PQP.) The recently published Guideline on Submission of Documentation for a Multisource (Generic) Finished Pharmaceutical Product (FPP): Quality Part describes the information that the WHO/PQP requires regarding APIs. If an API manufacturer has already submitted an APIMF in connection with evaluation of an FPP and the APIMF was found to be satisfactory, an abridged APIMF assessment is undertaken.

Who procedure for prequalifying aPisWith respect to the evaluation of GMP, applicants can choose between submitting evidence of the GMP status of their manufacture of the API undergoing assessment or undergoing a WHO inspection. The evidence submitted must include:

■■ GMP certificates ■■ inspection reports■■ corrective and preventive action reports■■ site master files■■ annual product review reports.

the Who/PQP celebrates a decadeThe WHO/PQP celebrated its tenth year in 2011. Located at the WHO headquarters in Geneva, Switzerland, the programme was launched in 2001 in response to uncertainty expressed by UN agencies and other organisations regarding the quality of medicines for treating HIV/AIDS, which were being procured in increasing numbers. Since then its scope has expanded to cover not only priority medicines for treating HIV/AIDS, but also those for malaria and tuberculosis, as well as influenza-specific antiviral medicines, zinc for managing acute diarrhoea and products for reproductive health.

The WHO/PQP’s guiding principle is ‘Good quality medicines for everyone’. It works towards attainment of this global public health goal by evaluating finished pharmaceutical products (FPPs) and quality control laboratories (QCLs), inspecting pharmaceutical manufacturing sites and QCLs, and building national capacity for the manufacturing, regulation and quality control of medicines.

FPPs and QCLs that meet the WHO requirements in terms of assessment of the submitted dossier and inspection of the sites involved are listed on the WHO List of Prequalified Medicinal Products and the WHO List of Prequalified Quality Control Laboratories, respectively. UN agencies and other organisations involved in the bulk purchasing of medicines use the list of prequalified medicines to guide procurement decisions.

The list of prequalified QCLs is of value to any organisation or treatment programme that wishes to test medicine quality using standards and expertise that are known to meet international criteria. In late 2010, the programme initiated the prequalification of active pharmaceutical ingredients to support manufacturers in manufacturing good-quality FPPs.

Jacqueline sawyerJacqueline Sawyer is liaison officer for the WHO’s Prequalification of Medicines Programme, with responsibility for communications and programme management. For more information about WHO/PQP, visit: www.who.int/prequal.


The WHO’s evaluation procedure is open to a variety of APIs used in medicines for treating HIV, TB and malaria, and for reproductive health.


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Any evidence provided regarding GMP status must meet several important criteria with respect to the issuing authority, and the specificity and date of the inspection. If the evidence provided is considered to be insufficient in terms of establishing that GMP at the manufacturing site is acceptable, a WHO-led GMP inspection will be required, which will also be necessary if evidence of GMP is unavailable. In addition, an API manufacturer can request a WHO inspection of its manufacturing site.

Subject to acceptance of the APIMF, and verification that the API is manufactured in compliance with WHO GMP requirements, the API will be prequalified by the WHO. Information about the prequalified API will be added to the WHO List of Prequalified APIs, including:

■■ WHO application number■■ international nonproprietary name■■ name of applicant■■ site(s) of API manufacture■■ APIMF version number■■ API specification version number■■ primary and secondary packaging components■■ assigned re-test period■■ recommended storage conditions.

Further useful information will be obtainable from the WHO Public Inspection Report (WHOPIR). This will have been posted on the WHO/PQP website when the API manufacturing site(s) passed WHO inspection. WHOPIRs summarise inspection findings and are frequently consulted by procurement agencies that seek information about the operations of a manufacturer in general, as well as on a particular API.

The API manufacturer will be issued with a Confirmation of API-PQ document. This will specify the re-test period, storage conditions, API specifications, assay test methodology and related substance test methodology that were accepted as part of prequalification.

The API manufacturer may distribute this document to third parties and it can be submitted by FPP manufacturers

to NMRAs as supporting evidence of the quality of their API source.

Taken together, the information made publicly available and the information provided in the Confirmation of API-PQ document, provide recipients with the most important details of the API and the dossier on which the decision to prequalify was made.

Who benefits from Who prequalification of aPis?WHO prequalification of APIs benefits API manufacturers, FPP manufacturers, the United Nations and other international procurers, and NMRAs. For FPP manufacturers, clear identification of APIs that have been evaluated and confirmed as being manufactured in compliance with WHO GMP standards – and for which quality regulatory documentation is maintained – is invaluable because it saves them time and money in locating and registering sources of API.

For API manufacturers, WHO prequalification will confirm that they are API manufacturers that prepare quality APIs, manufacture in compliance with GMP and maintain excellent regulatory documentation. Prequalification of APIs is of particular relevance to those API manufacturers that are currently supplying only their domestic markets, and who have limited or no experience of registering their products with SRAs.

For these manufacturers, working with the WHO/PQP is an opportunity to enhance their quality systems and regulatory documentation, and to assess their level of compliance with GMP. Evidently, a company must generally assume costs when improving its manufacturing standards. But the WHO/PQP does not levy either application or inspection fees. Moreover, for manufacturers producing APIs that are urgently needed, the WHO/PQP can organise assistance to resolve specific technical problems.

API manufacturers who have not previously undergone SRA assessment will be interested to know that they can apply for API prequalification without having to submit an associated application for FPP evaluation. This is generally not the case

the first Who-prequalified aPisWHO/PQP has received a steady number of applications for API assessment since October 2010. Three APIs for antimalarial medicines — one lumefantrine API and two artemether APIs — have already been prequalified. Details can be found at on the WHO/PQP web site. Prequalification of further APIs is anticipated in the very near future.

Figure 1. aPis included in the second invitation to submit an expression of interest for aPi evaluation to the Who/PQP programme – march 2011.

therapeutic category invited aPi

HIVAbacavir, atazanavir, darunavir, didanosine, efavirenz, emtricitabine, etravirine, lamivudine, lopinavir, nevirapine, raltegravir, ritonavir, stavudine, tenofovir, zidovudine

Anti-malarial Amodiaquine, artemether, artesunate, dihydroartemisinin, lumefantrine, mefloquine, piperaquine, pyrimethamine, sulfadoxine

Anti-tuberculosisAmikacin, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, levofloxacin, moxifloxacin, ofloxacin, para-aminosalicylic acid, prothionamide, pyrazinamide, rifampicin, streptomycin, terizidone

Reproductive healthDesogestrel, estradiol, ethinylestradiol, etonogestrel, levonorgestrel, medroxyprogesterone, mifepristone, misoprostol, norethisterone, norgestrel, oxytocin



In some cases, the API manufacturer could make changes to the manufacturing process or sites without notifying the NMRA or without drawing the attention of the NMRA.

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with NMRAs. This could be an important point for API manufacturers that have not yet attracted an FPP manufacturer partner. Such manufacturers will not have been able to obtain approval of their API from an NMRA. Nevertheless, they will be keen for FPP manufacturers to be aware that their APIs meets SRA requirements. The WHO/PQP offers them a means of raising this awareness.

For manufacturers that are already manufacturing to international standards, WHO prequalification will serve as further confirmation of quality assurance. For medicines procurers, use of a prequalified API is a strong indicator that the overall quality of an FPP is acceptable, even if the FPP in question has not been prequalified by the WHO.

For NMRAs within developing countries, the benefits of WHO prequalification of APIs will be quickly apparent when they review an application for marketing authorisation for an FPP that uses a WHO-prequalified API. Full evaluation of an API

supplier is a cost-intensive and resource-demanding activity, which only a few NMRAs can afford to undertake. As a result, in-depth API assessment rarely forms part of the process of granting marketing authorisations to FPPs. This means that the quality and safety of marketed pharmaceutical products can be undermined: if an API is not assessed in depth, it will be registered with fewer details, meaning that control over the quality of the manufacture of that API will be less.

In some cases, the API manufacturer could make changes to the manufacturing process or sites without notifying the NMRA or without drawing the attention of the NMRA. This lack of information about an API makes it difficult for other NMRAs to verify whether an API supplier is legitimate.

The published details of WHO-prequalified APIs, together with the Confirmation of API-PQ document, will enable NMRAs to quickly identify whether the API details presented to them when an FPP is submitted to them for registration are identical to those relating to a WHO-prequalified API.

The WHO’s API prequalification procedure also allows for sharing of assessment reports with NMRAs, subject to the protection of any commercially sensitive, confidential or proprietary information.

The primary and most important beneficiaries of the WHO-prequalification of APIs will be patients. Easier identification of sources of good-quality APIs by FPP manufacturers should facilitate enterprise between API and FPP manufacturers, and lead to increased volume and choice of medicinal products. ■

For manufacturers that are already manufacturing to international standards, WHO prequalifications will serve as further confirmation of quality assurance.

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WPF020_017 WHO APIs.indd 80 07/10/2011 09:15

Company insight > Chemicals & raw materials


r oquette Pharma is a global manufacturer of pharmaceutical excipients and actives. For over 30

years, the firm has focused on customer satisfaction through developing products that meet the most stringent quality standards for the healthcare industries.

Roquette Pharma continues to dedicate a large part of its resources to innovation, with the development of new excipients for unmet needs, along with associated services and innovative solutions. Throughout 2011, the company launched new ways of helping its clients create more valuable and successful products.

taste-masking technology The bitter taste of medicines has always been an issue. Roquette Pharma’s new taste-masking technology is applicable for a wide range of dosage forms including liquids, chewable tablets, orally disintegrating tablets and suspensions. This technology is a cost-effective solution for over-the-counter and nutraceutical/herbal products.

The technology also offers new perspectives in developing new dosage forms for the paediatric market. KLEPTOSE® Linecaps is a pea maltodextrin, which forms a flexible adaptable amylose helix that is freely soluble in water, while Amylose is capable of masking the bitter taste of drugs by decreasing the overall amount of drug particles exposed to the taste buds.

scaling-up simulation technologyFrom design to manufacturing, Roquette Pharma is committed to its clients’ success. Its team of development scientists and pharmacists enable an effective technical interface between the pharmaceutical industry and the company.

There is an increasing need for expertise sharing in the tablet field to guarantee seamless manufacturing development. Roquette Pharma can offer customised solutions for formulation development, including the prediction of manufacturing settings on industrial equipment to address compression simulation issues.

Roquette Pharma and the Institut de la Garonne have pooled their expertise to provide a new high-predictive

compression simulation service. This enables the optimisation of the client’s choice of excipients (such as diluents, binders and lubricants), and the selection of the best tablet press. The customer will be able to:

■ determine the critical tableting parameters for a given formula by simulating different tablet presses (for example, the influence of main compression force, precompression ratio and tableting speed)

■ maximise their choice of the best tablet press for a given formula

■ analyse and troubleshoot (such as capping and sticking).

This service will be disclosed at CPhI 2011 in Frankfurt on 25-27 October 2011 at stand 42G24, Hall 4.2).

on-site assistance for film coatingRoquette Pharma’s new film coating technologies LYCOAT® and ReadiLYCOAT® offer great potential. Using the natural inert polymer and the ready-to-use system for fast aqueous film coating will save clients up to 50% in costs and will reduce production time. On-site assistance, colour matching and training are available online at www.readilycoat.com.

continuous industrial investmentTo be closer to the source of demand, Roquette Pharma is constantly strengthening its worldwide presence and continuously developing its capabilities in Europe, the Americas and Asia.

The firm has recently completed an investment in an injectable grade carbohydrate facility in France to support the increasingly sophisticated demands of the injectable industry in terms of quality and regulatory constraints. It has also strengthened the supply chain through its US back-up carbohydrates production facility. ■

simple formulations that fulfil healthcare needs Global manufacturer of pharmaceutical excipients and actives Roquette Pharma has pursued a commitment to customer satisfaction through the development of products that meet the highest quality standards for healthcare.

Further informationRoquette Pharmawww.roquettepharma.com

KLEPTOSE® Linecaps forms a flexible adaptable amylose helix that is freely soluble in water.

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Whateveryour requirement, you can relyon ROQUETTE. We deliver !

Film forming and coating polymers

Fast dissolve and chewable tablets

Diluents and fillersfor tablets/capsules

Direct compression

Binders for wet granulation

Molecular encapsulation,taste-masking and dissolution enhancer

Syrups, semi-solids and softgels

Disintegrants and superdisintegrants

Dietary fiber,protein and mineral supplements

Pyrogen-free carbohydratesfor injectable and dialysis solutions

www.roquettepharma.com

11297_AP_Corporate_GB_REVUE: WORLD PHARMACEUTICAL FRONTIERS_FRT: 210x286mm x2

VISIT US AT CPHI

Oct. 25 – 27, 2011 FRANKFURT

Hall 4.2Stand 42G 24

WPD020_Roquette Freres.indd 2 04/10/2011 14:43

Whateveryour requirement, you can relyon ROQUETTE. We deliver !

Film forming and coating polymers

Fast dissolve and chewable tablets

Diluents and fillersfor tablets/capsules

Direct compression

Binders for wet granulation

Molecular encapsulation,taste-masking and dissolution enhancer

Syrups, semi-solids and softgels

Disintegrants and superdisintegrants

Dietary fiber,protein and mineral supplements

Pyrogen-free carbohydratesfor injectable and dialysis solutions

www.roquettepharma.com

11297_AP_Corporate_GB_REVUE: WORLD PHARMACEUTICAL FRONTIERS_FRT: 210x286mm x2

VISIT US AT CPHI

Oct. 25 – 27, 2011 FRANKFURT

Hall 4.2Stand 42G 24

WPD020_Roquette Freres.indd 3 04/10/2011 14:43

Sasol Wax Personal Care – We invest in your future!

Sasol Wax is the leading specialist in innovativewax technology. Our high quality excipient are paraffin waxes, microcrystalline waxes, Fischer-Tropsch hard waxes, paraffin oils and petrolatums.

Sasol Wax products are supplied worldwide into many different markets and are used in a diversity of applications.

www.sasolwax.com

Sasol Wax GmbH

Worthdamm 13-2720457 HamburgGermany

Phone: +49 40 78 115-481Fax: +49 40 78 [email protected]

Stand 31H53

WPF020_Sasol.indd 1 04/10/2011 14:44



t he Sasol Wax Group is a leading specialist for natural and synthetic paraffin waxes, petroleum jellies and pharmaceutical paraffin oil. Available worldwide,

Sasol Wax products are used in a variety of markets and end products and are produced around the world at its specialist facilities in Germany, South Africa, Egypt and the US. The company’s headquarters in Hamburg, Germany, specialises in products made from mineral oil hydrocarbons. In Sasolburg, South Africa, Fischer-Tropsch waxes are produced by synthetic means.

The Sasol Wax sales teams are part of a global network that can advise and supply clients in any location. Alternatively, the company base in Hamburg covers the whole world and will provide advice on applications technology. Sasol Wax is committed to working with the client to seek new opportunities for its products.

Quality characteristicsSasol Wax’s range includes hard paraffin wax (Ph.Eur/USP-NF/FDA), microcrystalline wax (DAC/USP-NF/FDA), petroleum jelly (petrolatum) white and yellow (Ph.Eur/USP/FDA), synthetic paraffin wax (USP/FDA) and pharmaceutical white oil/liquid paraffin (Ph.Eur/USP-NF/FDA). The firm’s solid, semi-solid and liquid paraffin products of pharmacopoeia quality are produced by high-pressure hydrogenation at high-quality standards in an environmentally friendly and safe way. Sasol Wax products are largely free of all impurities. Constant product properties guarantee safe use.

The quality characteristics of the company’s products are tested and recorded for each batch by an extensively equipped quality control laboratory. In collaboration with customers, Sasol Wax develops tailor-made products using quality control methods, which have made it possible to implement unique tests for many products, the results of which have been used successfully in applications.

In addition to customer-specific requirements, Sasol Wax defines its own standard specifications in such a way as to make them considerably more stringent than the broadly

formulated pharmacopoeia limits, thus guaranteeing a higher level of safety in each application.

Sasol Wax is committed to production in accordance with the basic GMP regulations and works to the Joint IPEC/PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients. It has achieved a standard that has received unconditional approval from the VFA, the German Association of Research-based Pharmaceutical Companies.

Future investmentQuality and security of supply is the main focus of Sasol Wax. As one of the largest producers worldwide, it operates a comprehensive management system for securing resources and sources of supply. Constant adaptations to technical progress also guarantees quality and supply capacity in the future.

Expansion of its capacities for Fischer-Tropsch waxes, which is already underway, is helping the company to increase its independence against a backdrop of diminishing crude oil reserves and will enable the continued use of paraffin waxes and petroleum jellies as indispensable inactive substances in the production of pharmaceuticals in the years to come.

To confirm its presence on the global stage, the company will present its pharmaceutical product portfolio at this year’s CPhI in Frankfurt, Germany, from 25 to 27 October. ■

a quality approach Dedicated to producing the highest quality of products and specialist facilities throughout the world, Sasol Wax’s extremely pure waxes, petroleum jellies and white mineral oils are available to the pharmaceutical industry any time, anywhere.

The quality control characteristics of Sasol Wax’s products are tested and recorded for each batch by an extensively equipped quality control laboratory.

Further informationSasol Waxwww.sasolwax.de

Sasol Wax produces paraffin and speciality waxes for a wide range of industries and production processes.

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Excipients can enhance product performance, patient acceptability and compliance. But some also interact with the active ingredient, thereby compromising performance. We talk to Professor Luigi G Martini, of King’s College London, and Patrick Crowley, of Callum Consultancy, about how pharma manufacturers can select the right excipient for their formulation.

V irtually all medications contain excipients. They may be included for reasons linked to manufacturing, quality or patient acceptability. They can also modify a drug’s action, rendering it

more effective or safer. Therefore, it is important during product and process development, manufacturing, testing, troubleshooting or process enhancement that their behaviour is taken into account.

multifunctional aspects of excipients Excipients may have more than one function (Table 1, right). Multi-functionality can be exploited to reduce the overall excipient load; for example, microcrystalline cellulose can aid flow, compression and disintegration of tablets. An unwanted effect might concern over-mixing magnesium stearate, compromising wettability and dissolution rate. Secondary attributes may not always be important. It depends on the drug, or drug-excipient environment; however, when considering using a material with a desirable functionality it is wise to be aware of other characteristics that make it unsuitable for the drug or dosage form.

excipient sourcesExcipients can be synthetic, mineral or biological in origin. They may be natural products, semi-synthetics, relatively pure or a complex mixture of materials. They can usually be multisourced and their use is not confined to medications. Far greater amounts may be used in foodstuffs, beverages and other products. The pharmaceutical manufacturer’s offtake is relatively tiny, making it difficult to obtain bespoke materials; however, were pharmaceutical manufacturers to present a united front requiring excipients of appropriate quality for their use (most dosage forms of a particular kind contain essentially the same excipients), a vendor might be willing to provide ‘specials’ at a suitable price.

excipient impurities Impurities in excipients may comprise residues from starting materials, processing or isolation. They may be acquired during storage or transport. Levels may be extremely low but, if drug content in a dosage

Onthe

form is low, the excipient-drug ratio is high. If the nature of the dosage form is such that interaction between impurity and drug is feasible, then drug-related impurities may be formed.

The most common residue in excipients is water, being present at the outset or adsorbed from the environment during handling and storage. In some cases it can accentuate excipient functionality. Dried microcrystalline cellulose has poorer compressibility than when hydrated; however, moisture can cause hydrolysis in susceptible drugs in the solid state because of its following properties:

■■ high vapour pressure – facilitates penetration through solids■■ low molecular mass – a little can go a long way in reactivity.

Some excipients may contain additives, residues or impurities. These can interact with some drugs under appropriate conditions. Historically, pharmacopoeial monographs did not usually contain such information; thankfully this is changing. Monographs on vegetable oils and lipids now invariably require that the nature and level of added antioxidant be

track

luigi G martiniLuigi G Martini is Professor of Pharmaceutical Innovation at the Institute of Pharmaceutical Sciences, King’s College London, UK. His research interests are in emerging markets, personalised medicine and drug delivery. Martini has extensive experience of developing differentiated generic drug products (supergenerics).rightPatrick crowleyPatrick Crowley is founder of Callum Consultancy and former VP in Pharmaceutical Development at GSK Callum Consultancy, Philadelphia, US. He has spent 42 years in dosage form development in the UK and US. Crowley has played significant roles in commercialising 16 pharmaceutical products.

table 1. Functionalities and other attributes of tableting excipients.

material Functionality other attributes

Magnesium stearate

Lubricates punch/die interface

Hydrophobisity (inhibits dissolution/release)

Microcrystalline cellulose

Compression and flow aid

Can adsorb agents, hygroscopic

Polymeric materials (eg, cellulose-based)

Granulation aids, release modifiers, viscosity enhancers etc

Low molecular mass residues

Colloidal silicon dioxide

Compression aid (solids)Adsorbent, can catalyse degradation

Polyvinyl pyrollidone

Binder, release modifierCan contain peroxides

GelatinCapsule component, release modifier

Can pass moisture to contents

WPF020_018_Excipients.indd 86 06/10/2011 08:43

listed. Residues in polymeric excipients, mostly monomers or structural deviants, are being increasingly named in monographs. This makes it easier to consider the potential for and risks of interaction.

The presence of residues does not necessarily lead to interactions. Conditions and environment must be favourable. Even drugs susceptible to hydrolysis can tolerate some moisture. Factors such as diffusion rate (water vapour) or relative hygroscopicities of excipient and active can determine sensitivity. Impurities may be so strongly associated with the excipient that they are non-reactive. Heat of friction during operations such as size reduction or compaction may drive off volatiles, but could also free those that are tightly bound. It is important accordingly to use drug-excipient compatibility studies that reflect the process and proximity in the dosage form (for example, test compacts of drug and excipient).

Impurities in excipients may change during storage or handling. Ethoxylated surfactants such as the Tweens and polysorbates are oxidised by atmospheric oxygen to hyper peroxides, peroxides and carbonyl compounds such as formaldehyde. Peroxide levels in Tween 20 increase following opening and storage in fluorescent light at ambient conditions. Air oxidation of polyethylene glycol (PEG) can also generate peroxides, aldehydes and carboxylic acids. Low aldehyde liquid PEGs and polysorbates are now available commercially, but the effects of storage conditions and use on product quality should be evaluated so that storage and usage conditions are defined.

Biopharmaceutical agents can be particularly susceptible to excipient-related effects. Their multiple modes of degradation present many possibilities for interaction, with potentially severe consequences if reaction products are immunogenic. Such degradation may be process or formulation-induced. Succinate buffer was shown to crystallise during freezing in a lyophilisation cycle, generating lower pH and unfolding of the gamma interferon active. When the human growth hormone was lyophilised in the presence of sodium chloride, aggregation, precipitation, oxidation and deamidation followed.

Safety of excipientsMany products have been reformulated to remove undesirable components such as alcohol in child medication. Some preservatives have also been removed, particularly in parenterals. Controversy still surrounds many in use. Table 2, overleaf, summarises some reported side effects with preservatives.

There have been calls for the removal of preservatives from injectables and making

products in preservative-free single dose units; however, increased use of auto injectors and patient-friendly devices that facilitate parenteral administration to treat chronic conditions (those not requiring frequent injection) need to be considered in such discussions. The potential for undesirable reactions needs to be balanced against the benefits of better modes of dosage, enhanced compliance and better therapy with such devices, and a consequent need for multidose presentations.

Many drug candidates are poorly soluble, stimulating interest in their solubilisation to enhance delivery and absorption. Notable advances have been made, but there have been reports of adverse events with some solubilisers in parenteral products. Cremophor EL is a polyethoxylated castor oil, used as a solubiliser in parenteral formulations of the anti cancer agents, paclitaxel, docetaxel and ixapebilone, the immunosuppressant cyclosporin and the antifungal miconazole. It is possible that, without this material, these valuable

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therapeutic agents could not have been developed as practical medications; however, there have been reports of anaphylactoid hypersensitivity, erythrocyte aggregation and peripheral neuropathy ascribable to its presence. These products treat patients with severe clinical conditions. Use of such excipients should be considered in a risk-benefit context. Cremophor EL does not seem to elicit the above-mentioned reactions when used in oral or topical products.

excipients as solubilisersDrugs with good specificity and potency can be poorly soluble. This can constrain absorption on oral dosage and prevent parenteral admin-istration. Strategies to solubilise include dissolution in cosolvent-water mixtures (for parenteral administration), use of surfactants or solubilising agents, or a combination of these. Organic solvents used in injectables include ethanol, propylene glycol, benzyl alcohol or PEG. Products containing them are invariably diluted with aqueous systems at administration, requiring adequate drug solubility in the diluted system. Use is frequently limited to medication for severe clinical conditions.

Surfactants usually comprise vegetable oils or fatty acids/esters that have been covalently linked with polyoxethylene or sorbitan structures to confer balanced hydrophobic and hydrophilic properties. They have limited utility as solubilisers, unless they comprise part of an emulsion for a liquid product. Levels need to be low if the product is for injection.

If a hydrophobic drug can interact with a complexing agent that is water soluble, such that the complex disguises the hydrophobic moiety while presenting hydrophilic groups to the aqueous environment, it may be possible to design a soluble drug product. Dissociation (release) can occur in the gastrointestinal tract, the drug being displaced from the cavity by materials such as cholesterol or bile salts. Release on parenteral administration is facilitated by the presence of similar endogenous materials in systemic circulation. The cholesterol metabolite, sodium cholesteryl sulphate has been used to solubilise the antifungal amphotericin B. Complexation also alters drug distribution, reducing systemic toxicity.

Cyclodextrins are cyclic glucose polymers with a hydrophobic inner core and hydrophilic external groups. The dimensions and nature of the internal environment facilitate complexation of aromatic structures of a molecular mass of about 500 – many drug substances. The external groups determine solubility. The original α, β and γ cyclodextrins have limited aqueous solubility. Modified β cyclodextrins in contrast have much better solubility, being one of the few novel solubilising excipients that have become available in recent times. They are safe, available in low-endotoxin form and are suitable for oral or parenteral use.

modifying drug release Excipients play key roles in controlling drug release from dosage forms to optimise absorption, onset or duration of drug action or align performance with clinical or patient requirements. They can be broadly categorised as::

■■ cellulose-based or similar polymers that constrain release by means of a coat or matrix, which must dissolve, or through which the drug must diffuse for release.; polymers can be water soluble or insoluble

■■ pH-sensitive (enteric) polymers applied as a coat or as a drug/polymer matrix to localise delivery in a specific region of the gastrointestinal tract; they can prevent release at low pH or deliver to the proximal or distal regions of the small intestine.

Such functionality may be provided by a single material or mixtures providing the requisite hydration, swelling or erosion properties. Agents such as ‘pore formers’ can be included to influence release rates; plasticisers are added to maintain coat flexibility.

The majority of controlled release medications concern oral dosage; however, the vagaries of the gastrointestinal tract in terms of transit and absorption and the advent of more user-friendly injection devices have increased interest in parenteral delivery. Concepts are similar to oral delivery but excipients may differ due to the need for systemic biodegradability, low endotoxin content and capability to be sterilised. Lipids and sterols are used, although they must be given by intramuscular injection unless formulated as oil in water emulsions or liposomes. They can be good vehicles for lipid-soluble drugs but drug solubility must be very high or drug dose low.

drug targetingTargeting drugs to cancerous organs or tissues may enhance efficacy and reduce toxicity. Lymphatic targeting illustrates the concept. Lymph is a primary pathway for tumour metastasis, with evidence that immunomodulators are more active in lymphatics than in blood. Lymph could be an important thoroughfare for delivery of oncology drugs. Oral delivery to lymph requires a drug to be highly lipophilic (Log P>5) and solubility in long chain triglycerides (>50mg/ml). Parenteral delivery does not require such properties. Intramuscular or intradermal dosage seems to be a better gateway for lymph targeting than intravenous administration. Materials such as dextrans, gelatin, polylactic acid and lactide-glycollide copolymers are being evaluated for lymphatic targeting in preclinical models. ■

table 2. common preservatives and reported side effects/cautions.

Preservative comment

Benzyl alcohol Not recommended for parenterals

2-Phenylethanol Can be a mild irritant to skin, eye and mucous membranes

Benzoic acid Gastro-irritant; mildly irritant to skin, eyes and mucous membranes

Sorbic acid Sensitisation reported but relatively uncommon

Parabens Unsuitable for parenteral or ophthalmic use due to irritancy

Chlorocresol Irritant to skin, eyes and mucous membranes. Cannot be used in intrathecal, intra-cisternal or peridural injections

Quaternary ammonium compounds (eg benzalkonium chloride)

Irritants; can exacerbate pre-existing dermatoses, particularly mucosal tissues. Should not be used in contact lens solutions as can bind to lenses and induce ocular irritation

Thimerosal Potent sensitiser, particularly in topical products

Phenylmercuric salts Skin irritants at concentrations exceeding 0.1%


The Powerhouse for API Solutions

F.I.S. – Fabbrica Italiana Sintetici S.p.A.Viale Milano, 26 - 36075 Montecchio Maggiore - (Vicenza) - Italy www.fisvi.com




d uring the formulation of pharmaceutical drugs, many properties must be optimised to create an active pharmaceutical ingredient

that will be delivered in the right amount, at the right time, at the right place in the body in order to achieve the desired effect. In addition to classical properties such as dissolution and disintegration for solid dosage forms, or stabilisation for liquid dosage forms that can be supported by excipients, the solubility of the active drug substance is critical to success.

For liquid dosage forms, aqueous solubility under the right buffer conditions plays an important role for the successful storage of a pharmaceutical drug. Even more important is solubility under physiological conditions within the body, a property that is independent from the chosen dosage forms.

enhancing solubility Interestingly, the solubility of new drug substances has been decreasing. Fortunately, additives can help change the solubility of active drug substances. One option for enhancing solubility is complexation of the drug substance. This can be achieved by, for example, cyclodextrines forming stable aggregates; however, kinetics of the release from these complexation agents has to be studied in order to ensure the pharmacokinetics of the active drug substance remain adequate.

Another option involves the chemical transformation of a drug molecule by changing the protein kinase A (pKa) of the drug through the formation of an applicable salt. In most instances, the salts resulting from the synthetic routes of chemical entities are the sodium, calcium or potassium salts in the case of anionic moieties, which are numerous among known drug substances. All the counter ions are derived from strong bases with pKa values above 12. Nevertheless, a large number of active ingredients are derived from rather weak acids. Therefore, the solubility of such actives can be enhanced significantly by exchanging these counter ions with weaker organic counter ions with pKa values of 8-9.

meglumine as a counter ionSelecting the right counter ion for a drug substance is an important factor for enhancing the solubility of a drug. A counter ion frequently used to enhance the solubility of active ingredients is N-Methyl-D-glucamin, known as meglumine, which is an amino sugar derived from sorbitol with a pKa of 8.03. Meglumine is used to replace sodium because it has a comparable osmotic activity and is

impermeable towards cell membranes. Examples of current products with meglumine as a counter ion are meglumine antimonate (for human use) and flunixin meglumine (for animal use). Meglumine is

also widely used in the manufacturing of contrast media in combination with iodine containing compounds.

As the counter ion closely interacts with the drug substance, the quality and supply chain security of the manufacturing process for these substances should be considered carefully. For human use, the quality standard both in purity and the manufacturing process should be equal to the standard of the API itself. As such, manufacturing with a tight quality control under an ICH Q7/A standard provides the most security and peace of mind.

Unfortunately, organic counter ions such as meglumine, tromethamine or piperazine are frequently derived from technical sources due in part to a lack of suppliers who can offer grades manufactured under cGMP.

improving bioavailabilityMerck Millipore provides meglumine that fulfils the stringent requirements of drug manufacturers. Its meglumine is an API grade that is accompanied by full documentation including DMF and CEP.

Counter ions of this quality open new possibilities for drug manufacturers. Therefore, Merck Millipore will dedicate itself to offer more such materials as it strives to help drug manufacturers to enhance the bioavailability of drugs. ■

Selecting the right counter ion for a drug substance is an important factor for enhancing the solubility of a drug.

a counter ion that fulfils all needs The solubility of an active drug substance is critical to a successful dosage delivery. Dr Steffen Denzinger, Merck Millipore’s head of technical marketing pharma raw materials, reveals how meglumine can improve the solubility of an anionic drug.

Further informationMerck Milliporewww.merckmillipore.com

CH3

NH

CH2

OH

OH

OH

H

H

H

HO H

OH

CH2

The structural formula of meglumine. Under physiological conditions, the amine is partly protonated, resulting in a weak cationic counter ion.

WPF020_Merck.indd 90 06/10/2011 07:46

Raw materials. Service. Expertise.The fine art of pharmaceutical composition.It takes outstanding raw materials and great skills to create something unique. Which is what Merck Millipore does for you: by striking the balance between innovation and supply chain security, with services like EMPROVE® and extensive regulatory support. It’s how we find solutions together with you that contribute to the big picture: your success.

www.merck4pharma.com

Merck Millipore is a division of

anzeige_parteck_210x286_4c.indd 1 29.09.11 10:03WPF020_Merck.indd 1 04/10/2011 14:44


O ver 70 years of excellence in the pharmaceuticals sector has taught us that customer service is paramount to achieving success. Helping to keep

you and your organisation efficient and competitive is an important part of our business. Accordingly, we are committed to meeting our customers’ needs and expectations at every level.

TrustworthinessTeva API (TAPI) is currently the world’s leading international supplier of active pharmaceutical ingredients (APIs). With €641 million in third party annual API sales and a workforce of almost 5,000 professionals worldwide, the organisation offers a rich portfolio of about 300 APIs.

TAPI’s financial strength, global production capacity and long-term commitment to the pharmaceuticals industry are key ingredients of its success.

Superior qualityAt TAPI, quality is the cornerstone on which the company builds its business. Our quality departments are evidence of the priority it places on ensuring compliance with your specifications, as well as all relevant regulatory requirements, including current GMP standards, USP and EP, among others.

All of our plants are regularly inspected by the FDA, by other authorities and by our customers. Additionally, TAPI equips its production facilities with cutting-edge technologies and state-of-the art computerised systems to maintain its consistently high product quality, while continuously improving productivity and reliability.

Specialised expertiseThe organisation’s customers benefit from the knowledge and abilities of a dedicated team of 760 top R&D scientists, specialising in the fields of:

■ chemical synthesis ■ fermentation ■ enzymatic process ■ high potency ■ plant extracts

■ synthetic peptides ■ vitamin D derivatives ■ analytical and solid-state R&D.

ValueTAPI competitively distributes its APIs to manufacturers worldwide. By looking for better raw material sources and eliminating non-value-added activities on an ongoing basis, it is able to provide you with reasonable pricing throughout the full life cycle of the product.

On-time deliveryFocused on its commitment to you, the company’s professional service agents proactively manage your shipments. Keeping on top of all parties involved, they orchestrate the logistics to achieve on-time deliveries, so you can focus on other priorities.

Here to serve youAs the leading generic API supplier, this organisation maintains its leadership by providing its customers with exceptional services. TAPI thinks of itself as a pioneer, paving the way to new service standards in the API industry, setting the bar higher than ever before.

Customer-centricTAPI recently revolutionised its business with the 24-hour customer support centre. Its main goal is to provide its customers with immediate access to TAPI’s customer services, at any time, from any location around the world, through a choice of communication channels (see our website, below, for details).

Our customer support centre provides customers with prompt replies to a variety of requests, ranging from compliance, through product information, up to safety and ecology.

You can rely on us to fulfil your requests for relevant regulatory documentation and quality methods and standards, as and when you need them.

Engaging the expertise of our scientists and technologists, we manage the process of defining your particle size distribution and other solid state specifications. Our customer-centric view means that we always focus on your needs. ■

Your business is our business As the leading international supplier of active pharmaceutical ingredients, TAPI is committed to quality, global production and, above all, customer care.

Further informationTAPIwww.tapi.comEmail: [email protected]

TAPI’s research scientists are specialised in areas such as plant extracts, chemical synthesis and synthetic peptides, among others.

WOrldPHarmaCeuTiCalFrOnTierS | www.worldpharmaceuticals.net92

WPF020_Teva.indd 36 06/10/2011 12:02

Mollie Shields-UehlingMollie Shields-Uehling directs the business and strategic activities of the SAFE-BioPharma Association and serves as the primary liaison with members of the growing SAFE-BioPharma community.

WorldPharMaceUticalFrontierS | www.worldpharmaceuticals.net 93

a new window has opened to the future state of clinical trial management. With it came an invigorating gust of fresh experiences that make it easier and

safer to collaborate online with partners, vendors, suppliers and regulatory agencies.

The world’s largest sponsor of cancer treatment clinical trials collaborated with two global biopharmaceutical companies to demonstrate how to get a clinical trial off the ground in record time and with less cost by eliminating reliance on paper forms. By using the cloud computing model, they placed the start-up letters, agreements, forms and other documents into the network and equipped researchers with interoperable digital identities so they could securely access, review, sign and exchange them using the internet.

The participants were scientists working for the National Cancer Institute in the US and their counterparts at Bristol-Myers Squibb and sanofi-aventis. They were able to show dramatic time savings for all document flows requiring multiple signatures, they got research underway more quickly and, depending on the specific documents involved, they eliminated hours, weeks and months in the document workflow process.

At the core of the study are interoperable digital identities. The ones used by the NCI researchers were issued by the US Government. Those used by the industry researchers are compliant with the SAFE-BioPharma digital identity and digital signature standard. Even though the researchers only knew each other via cyberspace, they were able to have full trust in their respective identities because SAFE-BioPharma and US Government identities are fully interoperable.

Digital identities are unique because they are closely linked to the holder’s actual vetted identity. Without getting into the behind-the-scenes cryptographic technology that creates the close link, it is real and it results in being able to trust another similarly equipped party anywhere in cyberspace.

The management of clinical trials is a time-consuming and costly process involving many bodies providing and requiring information at different times. Mollie Shields-Uehling, SAFE-BioPharma Association, explains how the cloud computing method employed by the National Cancer Institute can help keep clinical trials on an even keel, heralding the dawn of a new, secure digital future.

Insight > Clinical trials

cloudsof change

Even though the researchers only knew each other via cyberspace, they were able to have full trust in their respective identities because SAFE-BioPharma and US Government identities are fully interoperable.

WPF020_011_Safe Biopharma.indd 93 07/10/2011 12:01



The cloud computing model allowed SAFE-BioPharma to collaborate with two biopharma companies to conduct a clinical trial in record time.

developed the SAFE-BioPharma digital identity and signature standard. The result of their efforts is a standard that provides maximum data and identity security for the organisations that use it. They include Pfizer, Bristol-Myers Squibb, Merck, Lilly, GSK, sanofi-aventis, Roche, AstraZeneca and J&J, as well as other smaller companies that are integrating the SAFE-BioPharma standard into their daily business operations.

The standard mitigates the multiple risks inherent in electronic transactions within the biopharmaceutical and healthcare communities. Part of risk management is complying with government regulations: the SAFE-BioPharma digital standard is compliant with US and European regulations.

Interoperability is another important benefit of the SAFE-BioPharma digital identity standard. SAFE-BioPharma identity credentials are trusted by a growing community of pharmaceutical and healthcare organisations, government agencies (for example, the National Institutes of Health, the US FDA and the European Medicines Agency) and companies in other industries. It’s like being part of a club where one of the benefits is to be trusted wherever you go. You don’t need to wait by the red rope: you and your signature are accepted whenever they are presented to a participating group.

nci’s pilot studyThe needs of the National Cancer Institute, one of the US National Institutes of Health, set the stage for creating a pilot study that successfully demonstrated how interoperable digital identities are

Once that identity vetting process has occurred, the identity credential – a form of software placed in the cloud or installed on a computer, mobile phone, tablet, iPad or other device – can be used to access information and to apply legally binding digital signatures to electronic documents. Every time the credential is used, whether to gain access to a record or to apply a signature, the identity is authenticated. This assures a high level of identity trust – an essential element for the protection of intellectual property and for compliance with regulations across global jurisdictions

how does this study apply to the future?On the one hand, the clinical trial process is expanding geographically, increasingly including sites in China, India and other regions of the developing world. On the other hand, the entire industry has become highly collaborative, requiring a constant flow of confidential information involving` researchers, healthcare providers and regulators worldwide. Secure and trusted internet communication is the only practical way to manage these ever-expanding relationships, which is what the coalition of companies and regulatory bodies had in mind when they

Secure and trusted internet communication is the only practical way to manage these ever-expanding relationships.




key to accelerating the clinical trial start-up process. The mission of the NCI’s Cancer Therapy Evaluation Program (NCI/CTEP) is to improve the lives of cancer patients by finding better ways to treat, control and cure cancer. The programme has over 900 active clinical trials and activates approximately 130 new protocols a year.

During the protocol lifecycle – from concept to closure – each protocol produces signed and exchanged documents among multiple participants, including cooperative groups – of physicians and/or medical institutions, cancer centres and academic institutions. NCI/CTEP was mandated to more quickly initiate clinical trials to patient accrual, reduce costs, streamline document management while assuring greater document security, and to have environmentally sound procedures. The NCI and industry researchers were provisioned with interoperable digital identity credentials and the electronic documents were placed in the cloud.

Using their digital identity credentials and a SAFE-BioPharma-hosted digital signing service, the researchers were able to access the documents and digitally sign them immediately. Prior to the study, the signature process was delayed by using courier services, faxes and travel.

To pilot the digital signature process, NCI/CTEP selected its randomised phase II and phase III trials conducted through cooperative groups. The protocol process is as follows:

■■ A cooperative group submits a concept/letter of intent (LoI) for CTEP review and approval.

■■ After the CTEP review, a signed letter is sent to the cooperative group, along with a consensus review of suggested changes.

■■ The collaborating pharmaceutical company receives a copy of the LoI or concept and submits a signed drug approval letter. This allows the CTEP to approve the LoI/concept so the group can create and submit a protocol.

■■ Once the CTEP receives the protocol, a signed acknowledgement letter is sent to the cooperative group.

■■ Once the protocol is reviewed by CTEP, a signed comment letter is sent back to the cooperative group.

■■ A revised protocol is then resubmitted (there may be multiple revisions before final protocol approval is granted).

■■ CTEP approval or disapproval of the revised protocol is sent via a signed letter.

■■ Amendments to protocols follow the same last few steps for review, revision, and notification of approval or disapproval.

The pilot demonstrated dramatic time savings for all document flows that require multiple signatures from participants working on or off-site. Streamlining the signature workflow allowed research to get underway more quickly. Depending on the

specific documents involved, it eliminated hours in the document workflow process.

■■ Using paper forms, an average of 10% of the documents are shipped overnight and 10% are shipped by courier service; using digital signing, those costs are eliminated.

■■ Paper processes are time-consuming and often require physically shipping documents to signatories. Typically it takes 3-5 business days per signature. The pilot demonstrates that each signature can take minutes.

■■ Lost or misplaced documents were eliminated. Using digital signatures establishes an audit trail of when the email was sent to alert the signatory that the document is available for signature, and when the document was actually signed.

■■ As well as saving money, time and reducing document loss, the pilot lowers the carbon footprint. Moving to an electronic process eliminates the use of paper and ink and document shipment, and minimises storage and retrieval needs.

What does it mean for the future?In order for global collaboration – in general or for clinical trials specifically – to be secure, transactions with external parties need the combined strength of a digital identity and digital signature that is tightly bound to the identity of the signatory.

As the NCI pilot has clearly demonstrated, using interoperable digital identities reduces risk, cost and time, and given the industry’s current economic environment, those are welcome benefits. The tools for a secure digital future are available now. Welcome to the future. ■

A detailed explanation of the process and architecture is described in the

white paper ‘Research collaboration in the cloud: How NCI and Research

Partners are using Interoperable Digital Identities, Digital Signatures and

Cloud Computing to Accelerate Drug Development’. For more information,

visit: www.safe-biopharma.org/whitepaperform.htm.

The NCI pilot demonstrated that using interoperable digital identities reduces risk, cost and time – those are welcome benefits.


transform your clinical trial outsourcingOver the years, clinical trials have become increasingly costly,

more complex and difficult to coordinate. Additionally, the

global need for patient recruitment, combined with increasing

regulatory pressure, has stretched the capability of current

business practices.

This has resulted in high levels of dissatisfaction in the

process for the most relevant functional areas, including trial

coordination, patient recruitment, regulatory affairs, medical

affairs, and clinical data set management.

Kelly Services®, as a strategic alliance partner, has developed

an approach that mitigates the root causes of cost overlap,

increased delays, and regulatory non-compliance. Our

Synchronized Clinical Outsourcing (SCO) approach is unique in

how sponsors, vendors, and supporting workforce interact to

drive process improvements and optimize world class expertise,

while eliminating unnecessary inefficiencies and costs.

An Equal Opportunity Employer. © 2011 Kelly Services, Inc. W0072

Transform your clinical trial outsourcing. Today.

Contact [email protected] for more information regarding this

market-leading workforce solution.

Predictable outcomes: Clinical trial cost reduction

Increased speed to market

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WPF019_Kelly.indd 1 04/10/2011 14:45


Company insight > Clinical trials

i n line with increasing levels of drug development, the pharmaceutical industry is undergoing a period of transition. No longer monopolised by large

conglomerates, smaller entities are now seeing a considerable share of general revenue.

In recent years, the market has also become more flexible, with employment positions being found on a temporary or contingent basis across the entire supply chain, from the preclinical and manufacturing, to sales and marketing. As a result, a seamless recruitment process has become paramount when it comes to filling positions efficiently and ensuring that the employee fits the ethos and image of the respective company.

Consequently, Kelly Scientific Resources has adapted its workforce solutions. While employing approximately 8,500 scientific professionals in a range of temporary, contract and permanent positions, predominantly in North America and Europe, it has also expanded into the more specialised fields of R&D, clinical, IT and engineering.

“We do a variety of things,” says Alan Edwards, vice-president and product leader of Kelly’s Americas Product Group, Science. “Looking at recent developments within the pharmaceutical environment, companies are looking to the likes of Kelly to provide talent in a staged deployment. This means that talent is used when and how they need it.”

a tailored approachGiven pharma’s recent period of robustness and dynamism, Kelly has honed an ear-to-the-ground approach in sizing up market trends so it can provide customised solutions.

“In the US, in particular, there are not enough scientists to fill the number of job openings out there,” says Edwards. “We have to make sure that we are well-integrated within the scientific communities on a local and global scale.”

Edwards also alludes to versatilability™, a criterion that underpins Kelly’s approach to the recruitment process. Using its team of consultants and managers, most of whom hail from scientific backgrounds, this refers to the need for candidates to have a mix of ability and readiness in

order to ensure productivity within the workplace from the outset.

“Today, companies are no longer willing to hire someone and then train them up for six months,” he says. “Over the last year, we have heard more and more clients talking about an ingrained understanding of the cultural fit as being essential to the recruitment process.

“We take the pulse of the company and assess its culture and what types of individuals would fit in; for example, a biotech environment can be very different compared with a classic pharmaceutical company as it has a very different mindset and resources to work with. It’s not just a case of someone walking through the door and saying, ‘Here I am’; employees need to have soft skills, too.”

These soft skills pertain to how candidates function as an individual as well as in a team; a great deal of emphasis is now placed on sourcing employees who hold the right balance of technological know-how and communicative attributes.

“This is the biggest issue for people coming out of academia and going into the workplace,” says Edwards. “Employees need to be able to understand how to mix their technical skills with soft attributes, which are necessary in the societal culture of companies today.”

competitive edgeLooking to the future, Edwards sees Kelly’s competitive edge continuing to lie in its ability to tailor its services to industry trends, while developing strong partnerships with clients.

“Currently, demand in the marketplace is greater than supply,” he says. “This is causing people to do things differently; for example, the 25-30 year career job doesn’t really exist in our society anymore.

“Most jobs are temporary, therefore we are starting to look more at strategic and transactional work across locations and companies, because this is the preference for a lot of employees these days. You also have to partner with companies in a way that you have never done before by becoming part of the network model and the supply chain.” ■

Get the right staff Operating under its parent company Kelly Services, Kelly Scientific Resources is the world’s largest scientific staffing agency. Alan Edwards, vice-president and product leader of its Americas Product Group, Science, explains how keeping abreast of changing trends within the pharmaceutical industry can facilitate a seamless recruitment process for clients and employees.

Kelly has honed an ear-to-the-ground approach in sizing up market trends so it can provide customised solutions.

Further informationKelly Scientific Resources www.kellyservices.com

WPF020_Kelly Services.indd 97 06/10/2011 07:45

Company insight > Clinical trials


s GS has 35 years’ experience as a global contract service organisation providing integrated solutions, from preclinical activities to phase I-IV trials,

bioanalysis, analytical development and quality control testing. With the recent acquisition of M-Scan in November 2010, SGS enhanced its service portfolio for the characterisation of biologics with GLP/GMP contract analytical services, consultancy and training based on high-end mass spectrometry and chromatography.

With 1,200 employees, state-of-the-art clinical pharmacology units and the world’s largest network of GMP-compliant laboratories, SGS serves the pharmaceutical, biotechnology and medical device industries across Europe, the Americas and Asia with 25 facilities in 14 countries. Thanks to its global presence and broad range of services, SGS is often a preferred partner of the top 20 pharmaceuticals and biotechnology companies.

Biologics and vaccinesSGS has R&D Centres of Excellence specialising in the analyses of biopharmaceuticals including peptides, proteins, vaccines and glycoproteins such as monoclonal antibodies at all stages of development. The analysis of biopharmaceuticals requires different skills from those of small chemical entities. Many analytical techniques, such as LC/MS/MS, and capillary electrophoresis or RT-PCR, have emerged from an R&D setting into routine operation. SGS’s fully integrated, specialised services from molecule to market have the following advantages:

■ lead qualification and optimisation ■ molecule characterisation to FDA/ICH guidelines ■ regulatory intelligence along the drug development process ■ a global view with customised local services delivered by

an extensive laboratory network ■ a harmonised lab network allowing for method transfer

across sites ■ best-in-class biologics characterisation.

laboratory servicesOperating a global network of 17 laboratories in 11 countries, SGS’s Lab Services team provides regulatory-compliant (cGMP/GLP and/or ISO) analytical services. All laboratories have been inspected by local regulatory authorities and, where applicable, the US FDA or EMA. SGS’s QC and bioanalysis services include:

■ a harmonised network of analytical labs and consultancy in major markets

■ quality-control testing as the company’s core competence

■ analyses that comply with cGMP, GLP, ISO 17025 and ISO 9001

■ comprehensive breadth and depth of tests performed in one source

■ leading European CRO in bioanalysis, featuring mass spectrometry and immunoassays

■ industry-leading turnaround times.

clinical research services SGS is one of Europe’s largest first-in-human pharmacology centres, including two phase I units (in Paris and Antwerp), with a combined total of 172 beds. With seven trial management offices covering Europe and the Americas, SGS has the expertise to develop and deliver complex trials supporting screening or large-scale trials and analysis, from phase I to IV. Benefits of SGS’s clinical development department include:

■ European leader in exploratory and pharmacology trials ■ global expert in clinical trial management, focusing

on infectious diseases, gastroesophageal disease, CNS and cardiology

■ strong biometrics team pioneering the use of EDC systems, which are CDISC-compliant

■ regulatory affairs and pharmacovigilance.

With innovative study designs, an R&D Centre of Excellence, optimal facilities and strong regulatory intelligence, SGS can significantly help its clients to ensure the quality, safety and effectiveness of drugs, make the right ‘go-no-go’ decisions and reduce a product’s time to market. ■

Quality medicines, from molecule to market The mission of SGS Life Science Services is to safeguard the quality of medicines by providing professional clinical research, analytical development and quality control testing of pharmaceuticals, biologics and medical devices. This creates value for its clients and provides benefits for patients.

Further informationSGS Life Science Serviceswww.sgs.com/lifescience

Laboratoryservices

Preclinical Exploratorydevelopment

Confirmatorydevelopment Post-approval Routine

productionTrade

distribution

BioanalyticalBiopharmaceutical

R&D/Quality control

Clinicalresearch

Phase I-IIa

Phase II-IV

SGS offers a comprehensive range of life science services.

WPF020_SGS.indd 98 06/10/2011 07:52

EuroMEEtingCo p E n h a g E n 2012

2 4 t h a n n u a l

26-28 March 2012 | Bella Center | Copenhagen, Denmark

Register by 27 January 2012 and save €150!

To download the preliminary programme and register online, visit www.diaeurope.org/EuroMeeting2012

For more information call the DIA in Europe at +41 61 225 51 51 or email: [email protected]

WPF020_DIA.indd 1 04/10/2011 14:46

Experiencefor the Future

Biopharmaceutical Developmentand Manufacturing• recombinant proteins• plasmid DNA• vaccines

Manufacturing Capabilities• from strain development to API production•

• full development up • global in- and out-licensing of

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Richter-Helm BioTec GmbH & Co. KGNordkanalstrasse 28D-20097 HamburgGermanyTel.: +49 40 23 75 0Fax: +49 40 23 75 18 45E-Mail: [email protected]

from lab scale to 1500 L large scale manufacturing

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WPF020_Richter Helm.indd 1 04/10/2011 14:47


Information often gets ‘lost in translation’ when outsourcing business to emerging markets. Nic Paton talks to Novo Nordisk’s

Kim Steffensen about how to successfully work with CMOs in emerging markets on the effective planning and management

of geo-separation issues and risk mitigation strategies.

Mixedmessages

Kim steffensenKim Steffensen is an expert on the CMO market and has been head of contract and licence manufacture at Novo Nordisk since 2004, responsible for evaluation, establishment and support to local manufacturing partners.

Insight > Contract manufacturing

F rom a business and communications perspective, the world may be shrinking, but for the global pharmaceutical firm wrestling with an intensely

competitive commercial environment and the potential of key emerging markets such as China and India, that doesn’t make managing a contract manufacturing organisation (CMO) located halfway around the globe any easier.

Equally, getting it right with CMOs is an issue that pharmaceutical companies cannot afford to ignore. In 2009, a report by market researcher Business Monitor International predicted that the pharma market for CMOs would be worth $33.7 billion by 2014, with the pipeline for biologics products one of the key factors driving this growth.

WPF020_019_Lost in translation.indd 101 06/10/2011 12:08

Key pharma CMO pressures and opportunitiesDownward pressure on drug prices and the emergence of new markets in Asia, Eastern Europe and Latin America are opening up market opportunities and creating new potential CMO/partner opportunities.

■■ Fewer new drug approvals mean that pharma companies are having to work harder to leverage costs and ensure their production and manufacturing processes are much leaner: working with CMOs is an obvious solution.

■■ The cost of maintaining and establishing expensive in-house manufacturing sites versus moving wholesale to a CMO model, or even simply acquiring a manufacturer in a local, emerging site, can make a CMO an attractive option.

■■ An imperative is to ensure the CMO is using all its facilities to the full, perhaps embracing just-in-time production methods and enterprise resource planning systems, as well as effectively managing its supply chain to create more value.

■■ A country-specific approach to compliance can smooth out many of the regulatory headaches that can arise from CMOs.

■■ Being keenly aware of cultural distinctions or differences in working methods and approach is a key element of successful CMO activity.


WOrldPharMaCeutiCalFrOntiers | www.worldpharmaceuticals.net102

Challenges of working with a CMOThe attractions of CMOs are not hard to fathom: the lure of being able to reduce your fixed costs by using someone else’s expensive manufacturing facilities, while driving down your own costs and (hopefully) tapping into the growing expertise of many CMO destinations. But, according to Kim Steffensen, head of contract and licence manufacture at Novo Nordisk, one of the key challenges that pharma firms face when dipping their toes into the CMO market is that of information getting ‘lost in translation’ when manufacturers over-confidently or complacently outsource, particularly within emerging markets.

“There can definitely be cultural differences and a lack of understanding sometimes,” says Steffensen. “It can go right back to the basic contract negotiations with both sides having different views on a lot of things.

“The key is, simply, to ensure the CMO and the company are aligned, and that is something that has to happen from the initial negotiations all the way through to when you come into more operational issues. Each side has to understand the plan that has been agreed; they have to know what the milestones are.”

Key areas of misunderstanding can include different requirements regarding the level of documentation and regulation required between one market and the next, and issues over validation or product sophistication.

“A lot of companies, especially in emerging markets, are trying to harvest the benefits of CMOs without the right guidance or rules,” explains Steffensen. “CMOs are now big business, but the whole market has become blurry, because there are so many different forms of outsourcing.

“It is also about purchasing and in-sourcing as well as conventional CMOs, with many big pharmaceutical companies now deciding that it can be more cost-efficient simply to buy up other companies rather than outsourcing or contracting to them. From a production point of view, this has the advantage that it mitigates their risk, with the buyer company remaining more in control.”

But, says Steffensen, whatever option you choose, what is important is to take a country-specific approach rather than assume you can work to a single, one-size-fits-all CMO template.

“For example, ten years ago we [Novo Nordisk] did not have a very strong presence in South America, so in order to develop a stronger footprint in an area where we saw considerable opportunities, we ended up buying one of the larger insulin manufacturers in Brazil,” he says. “It meant we were buying into something that already had its own footprint as well as an up-to-date product facility. So, while it was about going into somewhere new to gain a larger piece of a market, it was also about being aware of it being a local South American player.

“In comparison, in India we were content to go with a more conventional CMO and that has worked for many years. We can still import products from Denmark or Europe without compromising business there.”

Full engagement requiredThere are many new CMO markets emerging, primarily within the economic powerhouses of India and China, with huge potential for pharmaceutical companies. Moreover, the technical skills and knowledge being taught to the upcoming generations in these markets is giving them an increasingly competitive edge compared with traditional Western manufacturing sites. But issues such as geo-separation and supply chain and risk mitigation must be considered not only before taking the plunge, but also throughout the CMO relationship, advises Steffensen.

“It has to be more than just coming out from Europe or the US once in while,” he explains. “You need to be engaged and make a proper investment in terms of time and money, and give the CMO the knowledge and know-how in order to get there.”

Outsourcing within emerging markets is often at a distance, so it can be more difficult to control. Then there are the logistical issues, the different demands and restrictions of country authorities, as well as the need to be, in some way, local. It does not necessarily mean a company always has to be everywhere, but it can often be important to have a presence of some form on the ground.

“Novo Nordisk has worked in many emerging markets for a number of years,” says Steffensen. “At the beginning it may have been a small presence, but having that presence has meant we have been able to build better relationships and understanding. So we know each other better and why we do things and how to diminish risk. There is, simply, much less chance of things being lost in translation or lost between the two companies.”

When it comes to buying outright, there may be equally challenging complications, not least difficulties around process and people integration and, again, the need for cultural awareness and understanding. “There is the danger when you make a very large purchase you are imposing your own organisation on the CMO, that the way you work and operate may simply not be appropriate for the local conditions,” says Steffensen. “So there can be big contradictions. There needs to be attention paid to the requirements

Good CMO management is little different to good multinational or global office management.

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of the culture that you are going into and an understanding of that. There also needs to be a local presence and the establishment of someone from your organisation on the ground.

“If you go in force to take over, you need to be a little bit humble and try to understand how things work; for example, Novo Nordisk has very clear internal guidelines of how we need to behave and the steps we need to follow.”

living the value In many respects, good CMO management is the same as good multinational or global office management; for example, pharmaceutical firms have to learn how to demonstrate good cultural and process understanding, focusing on communication and recognising that the learning may not all be in one direction; however, the relationship is technically weighted, argues Steffensen.

“It’s all about demonstrating throughout your organisation that you are living your values in everything you do, not just talking about them,” he says. “The way we go out and approach CMOs and suppliers has to be with the strong set of values that we have grown into and lived with over a long period. If you really want to change perceptions on the ground, there has to be much more than just presentation. It is often less about new products and more about new markets.”

Steffensen stresses the importance of the global pharma firm assessing its pharmaceutical portfolio, its areas of operation, how it will be divided up in the countries in which it will operate, where

cmos: questions to ask to avoid cultural misunderstanding

■■ Is a CMO still a viable option that will show financial benefits, or might outright purchase be a more efficient use of resources?

■■ How can I effectively plan and manage geo-separation issues and cultural differences to ensure the CMO is established and maintained?

■■ What are the risk mitigation strategies I need to employ to provide a shield against failure?

current and future customers are likely to be located, how they will access the CMO footprint and what their demands and priorities will be in the future.

“The world is getting smaller, especially from the pharmaceutical perspective, so there are fewer barriers,” he explains. “There is much better and faster communications and IT systems, but, if anything, a globalised outlook that works with and reflects the local as well as the international market is something pharma has been a little late in adopting. There has been some regard of it, but there is still an element of having to catch up within many organisations.

“You need to decide whether you are going to go down the CMO route or simply take over a local company; what is the best and most efficient way to go into this country or market; and what are the barriers.” ■

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Company insight > Contract manufacturing


P atheon has spent 30 years providing contract dosage-form development and manufacturing services to the pharmaceutical industry. It follows four key

strategies that help build success into biopharmaceuticals.

Face today’s challenges without creating new onesAfter years developing a biologic, it is often jarring to shift gears into the development of the pharmaceutical product. New challenges your team will face include inherent instability, light and temperature sensitivity, and cold chain logistics. Meanwhile, business pressure to get the product through clinical trials and out to market is immense.

Pragmatic choices need to be made about highly complex science to obtain a suitable formulation quickly. These choices have the potential to take time and cost a lot of money. What you need is expert advice, so it is wise to engage your centralised data management office (CDMO) early. While you want to be efficient, you need to know that you can manufacture what you develop and safely administer it to patients in clinical trials.

Formulation technologiesThe goal is to find the best way to take what you have in the lab and deliver it intact to patients. To accomplish this you must explore as many suitable formulation options as time and budgets allow. No single analytical technique is capable of measuring all of the different types of degradation to which a biopharmaceutical is susceptible.

Find a CDMO that offers a broad range of options. Ideally they’ll have the capability to design an early formulation that can change between liquid or lyophilisation. They should also be able to manufacture at an appropriate scale to meet clinical test material requirements. And if they offer multiple fill/finish options, better still. Make sure you give your molecule the broadest range of options to enable it to become a viable product, and don’t be limited by a contractor with limited offerings.

never underestimate the value of consistencyFormulation, analytical development and process design are so interrelated that it makes sense to consolidate them under one roof as much as possible. Transferring methods and processes from one contractor to another often causes costly delays and redundant revalidations.

Potential pitfalls include additional steps (and missteps) in communication, untimely response from former vendors, and differences in equipment; for example, cell-based assays are notorious for behaving in unexpected ways in different laboratories. By adopting a consolidated approach with a single CDMO, you’ll be better able to optimise the timing, achieve

smooth transitions from one stage to the next, establish streamlined channels for providing feedback and addressing concerns before they become problems, and maximise limited quantities of highly expensive early-stage biologic material.

Team continuity is crucial. Having the same people working on various stages of your project will preserve knowledge and experience of complex methods. You also get to maintain momentum and build interpersonal relationships – the most difficult chemistry of all to master. The bottom line: when you minimise transfers, you minimise risk.

When choosing your cdmo choose experienceYou should partner with an experienced CDMO in order to benefit from their scientific expertise and for the depth of their existing organisational capabilities and resources. A contractor with auditing preparedness, systematic record-keeping, and a stellar regulatory track record can help you avoid unnecessary delays. A CDMO with a broad client base typically demonstrates a broad array of in-house capabilities to satisfy the needs of your product. It also indicates the organisation has the equipment to produce clinical test materials in appropriate quantities and to seamlessly scale up manufacturing.

A contractor that is financially stable will be around to complete the development cycle, and if your product is a commercial success, they will have the means to scale up to meet commercial demand and support you over the long haul.

Not only is an experienced CDMO best able to help you bridge the gap from early development to formulation, the chances are it already has that bridge built and waiting. ■

Keys to commercial success The commercial canyon in biopharmaceutical early development can be found between the laboratory bench and clinical trials; however, with a consolidated approach, firms both small and large can bridge the gap. Adopting Patheon’s four key strategies can make a difference.

Further informationPatheonwww.patheon.com

An experienced CDMO will help a pharmaceutical manufacturer take the product from the lab stage and deliver it in the best condition to patients.

WPF020_Patheon.indd 108 06/10/2011 07:49

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Visit us at CPhI booth #42G05

SustainabilityAt DSM, our purpose is to create brighter lives for people today and generations to come. This mission is supported by sustainability as a core value and one of four pillars in our Quality for Life™ commitment. Its philosophies and metrics are evident in everything we do, highlighted by a top ranking in the Dow Jones Sustainability Index in the global chemical industry for 10 consecutive years. Sustainabiity is also an increasingly valued criterion for vendor selection, so it’s not only a responsible approach, but a strategic business driver.

DSM Pharmaceutical Products45 Waterview Boulevard, Parsippany, NJ 07054-1298 USATel: +1 973 257 8011www.dsmpharmaceuticalproducts.comwww.dsm.com

QualityReliabilityTraceabilitySustainability

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t he theme of sustainability has shifted from that of good citizenship to a genuine business driver for companies. As a result, greener solutions now make up a

considerable part of the genetic make-up of leading manufacturers within the pharmaceutical industry.

As part of the Royal DSM NV group, which in September retained its position as the chemical industry’s premier company in the Dow Jones Sustainability World Index for the third year running, DSM Pharmaceutical Products is one company benefitting from an onus on sustainability.

“In terms of material and life sciences, lowering our footprint is now part of our business model,” says Alexander Wessels, group president and CEO. “DSM is on track with its 2011-2015 sustainability aspirations. In the first half of 2011, 87% of DSM’s innovation pipeline were ECO+ solutions (compared with an aspiration of over 80% for 2011-15). For DSM, ECO+ benefits can be created at any stage of the product lifecycle, from raw materials through manufacturing and use to potential re-use and end-of-life disposal. Lifecycle assessments are therefore an important way to validate the ECO+ scores of our products.

“In the past, there were companies who thought of it purely as a means of good advertising; however, the world is truly shifting towards developing sustainable solutions; it constitutes the corporate mission for companies within the pharma space.”

in-house capabilityDivided into five separate divisions: DSM Pharma Chemicals, DSM Exclusive Synthesis, DSM Biologics, DSM Pharmaceuticals and DSM BioSolutions, Wessels also attributes the group’s progress to its Quality For Life™ ethos, which aside from sustainability, also highlights quality, reliability and traceability of its products.

“When you look at DSM brand values across all our businesses, quality is the one thing that always stands out,” says Wessels. “These values especially apply to the pharmaceutical space. Recently, we have focussed on traceability and sustainability.”

In order to develop in-house technologies and supply and outsource them across the entire pharmaceutical value chain,

DSM makes use of its extensive in-house R&D capabilities, setting aside a percentage of its revenue each year for technological investments. According to Wessels, the group is in the process of analysing its sales over the last three years so it can see how products can be consolidated and further developed.

“The yardstick we are using is very strict,” he says. “We have some unique technologies in each of our designated fields that have really made a dent in the industry; for example, if you take our biologics division, our XD® technologies allow for a much smaller footprint while achieving the same output.

“With regards to green chemistry and micro reactors, we are developing more projects that are of interest to customers in need of proprietary technologies.”

In every technologically advanced company, success usually rides on how it manages to balance innovation with customer relations, and DSM is no exception. Wessels is adamant that the two are inextricably linked.

“I would say that technology and quality are the key factors for us in developing customer relations,” he says. “If you take the outsourcing part of our business, we can offer peace of mind to our customers as we have a proven regulatory track record, which is imperative in this industry.”

consolidated futureIn a stringently regulated industry, DSM finds itself in an enviable position; its facilities have been approved by the US Food and Drug Administration and similar agencies in Europe, the Middle East, Africa and Japan.

Bearing in mind these legal parameters, which are set to evolve further, in line with advancements in the pharmaceutical industry, how is DSM looking to expand in the future?

“In terms of organic growth in a regulated market, it will come from further supply chain integration,” says Wessels. “A lot of things that we have seen in other industries are now surfacing in the pharmaceutical sector, which I think we are well positioned to deal with.

“In fact, if you look at the entire commercial manufacturing space, it is inevitable that we will see further consolidation. We are prepared for this.” ■

sustainable solutions DSM Pharmaceutical Products is a leading provider of custom contract manufacturing and development services to the pharmaceutical, biopharmaceutical and agrochemical industries. According to president and CEO Alexander Wessels, its success derives from a mix of high customer service and sustainable state-of-the-art technology.

Further informationDSM Pharmaceuticalswww.dsm.com

In every technologically advanced company, success usually rides on how it manages to balance innovation with customer relations, and DSM is no exception.

WPF020_DSM.indd 111 06/10/2011 07:44



a lkaloid AD Skopje has 75 years’ experience manufacturing drugs, botanicals, cosmetics and chemical products. As a joint stock company

employing an international team of 1,300 people, the firm operates worldwide through its sister company Alkaloid KONS (responsible for distribution and marketing of other producers’ products) and its subsidiaries in Serbia, Montenegro, Kosovo, Albania, Bosnia and Herzegovina, Croatia, Slovenia, Switzerland, Bulgaria, Romania, Ukraine, the Russian Federation and the US.

In 2010, Alkaloid AD Skopje achieved total consolidated sales of €96.5 million. The firm offers a broad range of pharmaceutical products, from solid to liquid forms. In 2002, it finished building two new factories: one for solid dosage forms with an annual capacity of two billion dose units; and the other for semi-synthetic cephalosporins (200 million capsules and 3.5 million bottles of dry powder for oral suspension). Both facilities meet international quality standards ISO 9001 and CGMP. Being GMP-certified by the MHRA, Romania’s National Medicines Agency and Slovenia’s JAZMP allows Alkaloid to position its solid dosage forms, cephalosporins and non-sterile liquids throughout the EU. The CE Marking of Conformity issued by KEMA Quality also grants Alkaloid the right to place its haemodialysis solutions

and X-ray films in the EU. With more than 1,000 marketing authorisations worldwide, in 2010, PC Pharmaceuticals’ products were available on the markets of 21 countries. With profound regulatory, marketing and sales and expertise in south-east Europe, Alkaloid is open for all kinds of cooperation, including:

■ licensing of registration dossiers ■ co-development ■ contract manufacturing in solid dosage forms, cephalosporins,

non-sterile liquids and haemodialysis solutions ■ marketing or co-marketing ■ distribution activities ■ mutual launching of new products, gaining mutual

access to new markets.

Alkaloid also participates in the niche market of morphine-based products, performing its own API synthesis of semi-synthetic alkaloids and organic chemicals. ■

healthy manufacturing

Further informationAlkaloid AD Skopjewww.alkaloid.com.mk

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When business professor James Quinn dubbed outsourcing ‘one of the greatest organisational and industry structure shifts of the century’, his words

were more than mere hyperbole. Indeed, as the practice grows more widespread, it is becoming virtually indispensable. A high proportion of companies now outsource at least some of their operations, and the market for contract research organisations (CROs) is estimated to be worth $29 billion.

Nowhere is this more the case than in pharmaceuticals, in which outsourcing has changed from a niche pursuit to one of the bedrocks of the industry. With drug development beset by spiralling costs, and companies experiencing diminishing returns on their R&D investments, classic ways of doing business are starting to seem untenable.

“It now costs anywhere from $800 million to $1.1 billion to get a drug to market,” says Frances Grote, senior director of outsourcing at Millennium Pharmaceuticals.

“All companies are scrambling for ways to reduce that total. Part of that reduction would be lowering your fixed priced cost, which means that you outsource instead of having your own personnel.”

riding the outsourcing waveMillennium, a Massachusetts-based pharma and biotech company with a focus on oncology, is riding the crest of this outsourcing wave. Delegating not just some, but all of its operations to three different CROs, it is in many respects the prototype of a 21st-century pharma firm.

The company has long recognised the value of business partnerships; since its inception in 1993, its development has

been dominated by the instigation of new strategic alliances. It was a merger with Leukosite in 1999 that brought the company’s first drug, Campath, tantalisingly close to market. And when Velcade was granted approval several years later – the first treatment for multiple myeloma in more than a decade – this was on the basis of a low-priority project started by Leukosite and brought to the forefront by Millennium.

Not until 2008, however, did Millennium’s current business model fall into place. The company became a fully owned subsidiary of Japanese pharma giant Takeda, and along with the merger came a dramatic broadening in scope. With a level of growth impossible to accommodate in-house, Millennium began to outsource in earnest.

“We don’t have a global presence ourselves, but we want to file our drugs, hopefully simultaneously, in multiple global markets,” says Grote. “For us, the principal advantage of outsourcing is to get expertise, balance and resources in markets where we don’t have our own personnel.”

Even the largest pharmaceutical companies do not have sufficient in-house research capabilities to discover the next therapeutic breakthrough. Partnering with contract research organisations is essential, but managing these relationships has its pitfalls. Abi Millar talks to Frances Grote, Millennium Pharmaceuticals, about how to achieve excellence within outsourced relationships.

A high proportion of companies now outsource at least some of their operations, and the market for contract research organisations is estimated to be worth $29 billion.

Perfect fit

Insight > Contract services

WPF020_020_Safety Comes First.indd 113 06/10/2011 08:48



This shift has had major ramifications for Millennium’s in-house workforce. Rather than conducting processes themselves, their role is now one of leadership, with staff overseeing and managing established operations while themselves spearheading change.

“I don’t know if we are 100% successful in our vision as yet,” says Grote. “It’s easy enough to say to our employees they have to delegate authority to the CRO, but at the end of the day, people feel a personal responsibility for the quality of what’s being done. We’re still working on training our team about the best ways to delegate authority.”

Benefits and challengesThe impact on a company’s existing personnel is just one of the challenges posed by outsourcing. For all the probable benefits, outsourcing throws up a whole new dimension of potential

complication, and success or failure largely hinges on how well companies manage

relationships with their CROs. Should relations turn sour, they’re unlikely to effectively harness the new intellectual

capital at their disposal.It is the job of Frances Grote

and her team to ensure that Millennium works harmoniously

with its partners. This task is far more complex than

overseeing a single, vertically integrated organisation. Because CROs are

independently structured bodies

in their own right, the emphasis is on ensuring that nobody is working at cross purposes. Key to this mission is effective communication.

“The most basic and fundamental level of communication is project team to project team, following an integrated model,” says Grote.

“This means that we and the CROs have trained our teams to work together, as opposed to Millennium outsourcing and then using the outsourced resources.”

While a CRO should not be regarded as a replica of its sponsor, if the two teams work collaboratively then something of the company culture may be assumed to translate. This is

crucial; because the risks associated with outsourcing are often attributed to a sponsor’s loss of control over the process, it is vital that that sponsor remains integrally involved.

This involvement is by necessity bureaucracy-laden. A strong company culture depends on adhesion to shared values, and while such values are often unspoken, if a firm is outsourcing, it needs to make them overt. The first step, then, is to define goals and motivate the CROs to stay in line.

“We have multiple levels of goals here at Millennium,” says Grote. “We start out by sharing all of these with the partner CRO, and we make some of the payment milestones in their contract contingent upon achieving them, so they have a financial incentive to support our goals.”

Next, you need to implement strong systems of governance, making sure leaders communicate on a regular basis. Millennium holds quarterly meetings between governors from both sides of the divide, giving them a forum to air any operational and strategic issues that have arisen.

Finally, a formalised conflict resolution process should be put in place.

“We have a representative at Millennium, not concerned specifically with outsourcing, whose job it is to mediate if necessary,” explains Grote. “And if that’s not sufficient then we have an issue escalation pathway that allows project teams to rapidly get guidance from the most senior levels of both organisations.”

Working as oneWhile communication is essential if you’re looking to foster warm relations, the ultimate aim is loftier. In an ideal world, there would be full transparency between the parties, with discrete organisations working together as an integrated whole.

In Millennium’s case, all its CROs are conceptually committed to this cause. In fact, two are public companies, which means that Millennium can clearly see their business models and work out how its own numbers feed into theirs. Their third CRO, however, is private, and as such is not legally required to be so forthcoming.

“We have to ask them for financial information, which they’re not obligated to give,” says Grote. “Although we have a pretty good idea what their mark up is and how that translates into profit margins, we really don’t have full visibility on their cost structure.”

In such instances, a number of the particulars can only be taken on trust. Lack of transparency is a perturbing issue in the precarious world of drug development. With few guarantees that an investment will yield results, a sponsor organisation needs to find ways of ensuring it’s not being swindled.

As well as the risk of fraud, hazards include loss of data, delays in study completion and various types of regulatory infraction. In short, the consequences can be serious.

One way around this problem is to enter into a risk-sharing arrangement. The CRO takes on part of the financial burden of drug development, in return for ownership of the drug once it goes to market. Or, under an alternative model, the CRO is not paid upfront, but rather receives a royalty in return for the services it provides.

A strong company culture depends on adhesion to shared values, and while such values are often unspoken, if a firm is outsourcing, it needs to make them overt.



While such strategies are commonplace, Millennium is taking a slightly different tack.

“We have chosen instead to minimise our financial risk by controlling what we spend on our contract,” says Grote. “We’ve instituted a model where our own estimates are binding unless we ourselves have issued a change in scope.”

This is something of a novel approach in a marketplace in which, historically, CROs have had free reign to alter their terms of contract. For the most part, these companies have tended to issue a change in scope if their initial budget turned out not to cover all their profit margins. Millennium, however, retains its own best estimates based on a long process history of performing operations in-house.

From strength to strengthOutsourcing is in many ways still subject to experimentation. It is a relatively recent shift, propelled to a large degree by the

pace of technological change. As the scientific landscape becomes more specialised, it becomes increasingly harder to develop the necessary depth and breadth of scope in-house. And as investment cycles are compressed, there is greater pressure on pharma companies to develop drugs at speed.

This trend shows few signs of abating. Frances Grote for one envisages that the growth in outsourcing will continue. She is adamant, however, that the models in place at present will be subject to change.

“CROs developed in an environment where sponsor companies wanted CROs to function as mirror images of themselves,” she says. “So, if the sponsor had ‘x’ kind of personnel doing the job in a certain way, they would demand that their provider had the same kind of personnel before they handed it over.

“What I think the entire industry has discovered is that it’s not very efficient. We don’t have a real efficient model yet for how to develop drugs, but there are lot of people working on what that model might be. In the future, things will be far more consolidated, with multiple service offerings from one source. I’d say that once someone has figured it out, the outsourcing industry is going to be in a much stronger position.” ■

Outsourcing is in many ways still subject to experimentation. It is a relatively recent shift, propelled to a large degree by the pace of technological change.


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What SOTAX Automation customers are saying?

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Company insight > Contract services


l aboratory automation spans pharmaceutical and nutraceutical discovery, development, manufacturing and quality testing. To the uninitiated, a logical

starting point for understanding automation is to compare an automated process to an existing manual technique; however, before a comparison can begin, the scope that the automation encompasses must be defined.

semi and fully automated systemsThe definitions of the terms ‘semi’ and ‘fully automated’ are subjective and require knowledge of the unit of the work being automated. In drug dissolution testing, the unit of work was designed around a six-sample model and the type of apparatus used is well-defined and regulated. In this context, a semi-automated system offers complete walk-away from a single run of six samples; however, if more than a single set needs to be run, the user must intervene since typical semi-automated systems do not provide media preparation, nor do they automatically clean, prepare and initiate subsequent runs.

Fully automated dissolution systems extend the work envelope of what is automated to encompass the preparation and cleaning of the vessel, allowing the system to cycle through multiple individual runs without user intervention.

throughput Throughput is a well-accepted term, referring to the number of samples, runs or other units of work to be accomplished. A common misconception is that fully automated processes bring greater return on investment (ROI) to an organisation due to higher throughput. While this is sometimes true, if the unit of work to be accomplished contains a time-dependent step such as a long high-performance liquid chromatography (HPLC) run time or a dissolution time, then the bottleneck in the automation of the process may be the method itself rather than the instrument.

A good example of this is the automation of controlled release dosage form testing. These assays often cannot be accelerated beyond certain limits without compromising the assay quality. For the same capital investment, multiple semi-automated systems operating in parallel can achieve a higher throughput than a fully automated system that sequentially processes batches of six samples. There will be more user intervention required, so managers need to weigh throughput against walk-away time before deciding on the best ROI for their laboratories.

sequential, parallel and scheduled processingSequential processing refers to a system that handles one sample at a time through a multistep process to completion. Parallel processing is a ‘brute force’ automation approach

where copies of the same automated system are used to run multiple assays simultaneously. These systems may be linked to share information and sort data; for example, if the bottleneck in a process is the speed of the HPLC run, multiple LC systems would be connected to the same automated system in order to accomplish greater throughput, but this is not common due to the higher capital investment required.

Scheduled automation takes advantage of waiting times to complete other tasks; for example, in a fully automated dissolution system, media is prepared for a subsequent run while the current run is underway to reduce the cycle time between runs.

method development considerationsWhen validating or transferring existing methods into automated methods, remember that you are not confined to the same limits as a manual procedure; for example, in automating laboratory assays, you are no longer limited to the available volumetric glassware sizes and dilutions are not limited to typically available manual pipetting ranges.

Filtration, which may not have been possible due to the forces required or ergonomic health concerns, may take the place of centrifugation. Consider validation of the automated system holistically, taking into account the reaction space and the sampling system. Also consider the advantages of designing method parameters as variables, thereby opening up the assay design space to the application of design of experiments packages to achieve more robust assays. ■

laboratory automationAutomation within the pharmaceutical industry is a complex process, made even more challenging because the terminology used is inconsistent. Pharmaceutical testing services provider SOTAX explores examples of and considerations for automated method development.

Further informationSOTAX www.sotax.com

Scheduled automation takes advantage of waiting times to complete others tasks, such as preparing media for a subsequent run.

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WPF020_IPO.indd 1 07/10/2011 10:03

Company insight > Contract research


W ith the present worldwide economic crisis in mind, it is obvious that pharmaceutical companies are struggling, with many cutting

costs, particularly those concerning R&D. One solution to this problem may be using small contract research organisations (CROs) that offer competitive prices and are flexible in terms of substantive requirements. One such CRO is the Institute of Industrial Organic Chemistry, Branch Pszczyna (IPO Branch Pszczyna).

Preclinical testing is an important phase in drug development, with the main goal being to establish a product’s ultimate safety profile. Mistakes made in the determination of the toxicological profiles of candidate compounds can pay off badly in clinical trials, increasing the total cost of introducing new drugs to market. Therefore, spending fewer resources on preclinical safety testing does not seem to be a good strategy; however, in times of economic downturn and turbulence, companies tend to cut their R&D spending, especially costs that are connected directly to preclinical safety testing.

The other important issue (particularly in economic terms) is an ecological risk assessment of active pharmaceutical ingredients (APIs). It should be remembered that the presence of APIs in the environment is being reported worldwide in peer-reviewed scientific literature. Low levels of APIs are being found in drinking water, surface water (rivers and lakes), ground water and sediment. It is generally recognised that the toxicological safety of the candidate compound and its ecological risk assessment are taken into account during drug development. Ecological risk assessments are performed in compliance with the European Medicines Agency’s guideline on environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00).

A question emerges: how can a firm comply with all the legal and economic requirements of developing a new drug while keeping costs in the lower range? The answer may be to use a small CRO that offers expertise, competitive prices, flexibility and a high quality of work, which is often confirmed by compliance with good laboratory practice (GLP).

the pull of PolandIPO Branch Pszczyna is a Poland-based CRO that provides preclinical services in the fields of toxicology and ecotoxicology. Founded in 1947, it is a leading R&D centre that cooperates with domestic and foreign companies on toxicological and ecotoxicological studies.

During its 60-plus years of existence, IPO Branch Pszczyna has continuously changed and developed. Its assets are highly qualified scientific personnel and technicians, modern equipment and experience amassed through completed studies. The company holds GLP certificates that entitle it to perform complex toxicological and ecotoxicological studies of APIs, and is notified to the national registry of institutions entitled to perform experiments with animals. It offers the following toxicological services:

■ acute toxicity studies (rats) ■ acute eye or skin irritation studies (rabbits) ■ skin sensitisation tests (guinea pigs) ■ sub-chronic/chronic studies, repeated dose toxicity (rats, mice) ■ neurotoxicity studies (rats) ■ reproduction toxicity studies (rats, rabbits) ■ carcinogenicity studies (mice, rats) ■ toxicokinetics studies (rats) ■ local tolerance tests (rabbits).

Its ecotoxicological services include: ■ aquatic toxicology (fish; crustaceans; sediment-dwelling

dipterans; duckweed; algae) ■ soil toxicology (earthworms; springtails; soil

microorganisms) ■ Avian toxicology (Japanese quail) ■ fate and behaviour in the environment ■ analytical chemistry (analysis of determining the residues

of chemical substances in different matrices).

The scientific studies performed by IPO Branch Pszczyna’s specialised research teams are solely for domestic companies. Its research services are exported to firms in European nations, including Germany, Belgium, Holland, Denmark, UK, Ireland, France, Czech Republic, Slovakia, Switzerland, Italy and Austria. Increasingly, it is cooperating with businesses in Australia, Japan, US, South Africa and Israel. ■

Poland’s preclinical paragon Pharmaceutical companies may have to cut R&D expenditure as a result of the economic downturn, but they still can’t afford to let preclinical drug development standards slip if they want to survive. IPO Branch Pszczyna explains how its expertise as a contract research organisation could provide a much-needed shot in the arm.

Mistakes in the determination of the toxicological profiles of candidate compounds can pay off badly in clinical trials.

Further informationIPO Branch Pszczynawww.ipo-pszczyna.pl

WPF020_Inst Warsaw IPO.indd 119 06/10/2011 07:44

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A ccording to a report by internet security firm Commtouch Software, around 81% of spam sent during the first quarter of 2010 was pharmaceuticals-related. The

internet has blown down the door for counterfeiters, their ability to bring products to market no longer hindered by geography and the need for a bricks and mortar base. At the same time, as manufacturing operations move east, the supply distribution chain is becoming stretched and weakened.

“Globalisation is definitely one of the main issues we are dealing with,” explains Dr Desmond Hunt, of NGO US Pharmacopeia (USP), which sets standards governing the quality, purity, identity and strength of medicines. “A lot of products are going to multiple jurisdictions, each with their own regulations, frameworks and penalties. Counterfeiters, who aren’t by nature the most ethical people, will look for holes in the system and these are growing in number.”

Although counterfeit medicines make up less than 10% of pharmaceuticals for sale in the developed world, in some emerging markets they account for as much as 25% of the total, according to WHO figures. In the case of certain drugs, this figure is higher.

“When we talk about drugs that are popular among counterfeiters, it’s going to be high-price clear solutions, such as injectable products,” Hunt says. “You get a glass vial, a crimp – who can tell if something has been tampered with? Then there are the lifestyle drugs, the biggest of which is Viagra. Counterfeiters are very savvy and will often find a

way to include the active ingredient in their product. You’ll get an effect because, like a drug dealer, they want you to come back.”

Counterfeit measuresThe first line of defence is packaging. It is universally accepted that no single form of protection is effective enough and layered prevention methods must be used in combination to find the best solution. Many of the more advanced methods being developed by pharmaceuticals companies, particularly those that make use of forensic technology, are so confidential that even employees are unaware of how they work.

“When you start talking about forensics, that information is possibly more valuable and held more closely to the chest than even a company’s patent secrets,” Hunt says. “If something is suspected of being counterfeit it can be pulled right off the shelf, sent to the lab, and within a day or so they will have used forensic markers to decide on its authenticity.”

Track and trace methods are also beginning to gain traction. Swiss biopharmaceutical company Merck Serono has introduced electronic radio frequency identification (RFID) tracking technology on a number of its products in the US, allowing the company to monitor a package along the entire supply distribution chain.

“The gradual introduction of tamper-proof elements and the electronic pedigree of track and trace allow us to precisely track any drug package from production plant to pharmacy,” explains Andreas Maack, the company’s head of corporate security. “We are also developing a new type of tamper-evident seal. This will serve to protect against tampering and also help with product authentication.”

Great gains have been made in the analysis and identification of fake pharmaceuticals. Merck Serono has developed a product known as the GPHF-Minilab, a mobile laboratory that is currently operational in 70 countries worldwide.

The internet has opened up a massive new market to counterfeiters, one that can be accessed at the click of a button. Desmond Hunt of the US Pharmacopeia and Merck Serono’s Andreas Maack explain how a global legislation effort combined with multilayered packaging protection can help catch the copies.

Insight > Packaging

In some emerging markets counterfeit medicines account for as much as 25% of the total pharmaceuticals for sale.

WorldPhArmACeutiCAlFrontiers | www.worldpharmaceuticals.net 121

Caught in the net

Andreas maack Andreas Maack is head of corporate security for Merck. He joined Merck in 2010 and is responsible for governance issues and prevention measures in security, especially case and incident handling (counterfeiting and product-related crime).

WPF020_023_Phoney War.indd 121 07/10/2011 13:19

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“The mobile laboratory was developed to identify counterfeit drugs quickly and cheaply,” Maack says. “It provides drug quality verification and counterfeit medicines detection in a compact laboratory comprised of two suitcases filled with portable lab material. They are distributed through the Global Pharma Health Fund (GPHF), a charitable organisation initiated and funded exclusively by donations from Merck.”

Both Maack and Hunt agree that these technological advancements can only be fully effective in tandem with a global regulatory consensus. “An issue we are having in the industry at large is how you define counterfeit,” Hunt explains. “Just look at the discussions we’ve had around track and trace. Which technology do you use? How do you use it? If you opt for RFID, then at what frequency do you have it?

“With the European Medicrime Convention of December 2010, we have for the first time among the EU member states a valid legislative instrument for the phenomena of counterfeit drugs,” Maack says. “The Convention contains so-called ‘dedicated acts’, which call on industry to introduce anti-counterfeit measures on packaging as a way of increasing levels of security. A final decision on which technology is to be used for this legal requirement is still pending.”

Education vs regulationEven if a global regulatory solution emerged regarding packaging and distribution, trying to enforce restrictions on the internet trade is another thing entirely. Not only does the worldwide web provide counterfeiters with a massive potential market, but a website closed by authorities can be back online within hours, under a new name and at a new address; however, Hunt is hopeful that as new generations grow up with the internet, a broader awareness will develop.

“When I go home and talk to my grandparents’ friends, for them the internet is new,” he explains. “They have no idea that illegal practices could actually be occurring. The website looks good, they appear to be asking the right questions, so the user doesn’t think about the health consequences. When you say to consumers that they can buy their pills for 40% of the cost price, it is real.”

As for USP, its general chapter on seminal good storage and shipping practices, 1079, has recently been updated for publication in the early part of next year. With money tight in the industry, it can be difficult to introduce new regulations in a way that isn’t perceived as burdensome or a hindrance to profitability. Constant cooperation is necessary if mutually desirable outcomes are to be achieved.

“The real dialogue occurs when a standard is actually written and published in Pharmacopeia form and we ask for feedback,” Hunt says. “Sometimes companies have serious concerns about its impact on their product or operations, but our job is not to run people out of business. We try to make sure that quality drug products are being produced, but at no extra cost. These companies have done nothing wrong; they just suffer from having a good product.”

For all the progress made in the fight against counterfeit pharmaceuticals, it is a war that can’t be won. Anything that a manufacturer can do, a counterfeiter can learn to do as well; however, with well-enforced global regulations, continued advancement in packaging technology and improved education about the dangers of fake medications, the damage can be greatly reduced. ■

WPF020_023_Phoney War.indd 122 06/10/2011 12:16

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Company insight > Packaging


t he choice of a supplier for a large strategic project such as track and trace is not an easy task, particularly because it involves many key aspects

that need to be evaluated. To enable the selection of the right supplier, a major drug group set up a team that included experts in the fields of production, engineering and information and communication technology, and coordinated by a project manager with considerable experience.

All relevant aspects were assessed, including the overall software architecture, the ergonomics and functionality of machines, the capacity to provide all related services (such as installation, training and maintenance) for the long term and on a worldwide basis to the organisational and structural details of each company, while considering financial aspects.

The first screening involved major industry players and led to the final selection of two companies: Antares Vision was one of those candidates.

Antares Vision is an Italian-German company that provides inspection systems to the pharmaceutical sector. The firm is the technological partner of the IMA Group for all its artificial vision and inspection applications and has quickly become a force to be reckoned with within the track and trace sector, thanks to its pragmatic approach to the issues of packaging lines being integrated with a powerful software architecture.

Antares has enjoyed increasing success over the years and now has over 250 serialisation and aggregation lines installed across Europe and Turkey.

to the testIn selecting the best supplier, the pharmaceutical group compared the two technical solutions with a pilot project: the competitors were to implement a complete aggregation system on two separate lines with similar characteristics and demonstrate their capabilities in every critical aspect of the supply, covering performance, product ergonomics, lead times, installation times, reliability, adequacy of documentation and training.

The test took place in Turkey, where in just a few months the entire plant (one of the country’s largest) was to be adapted according to the second phase of the Turkish regulations.

comprehensive solutionsBecause the Turkish deadline for phase II (aggregation) was quickly approaching, the time schedule to set up the pilot line was very short. Despite the tight schedule, Antares implemented and demonstrated a global solution – one that not only met the specific requirements of the single line in question, but also set up a showcase of solutions that would become essential for other types of lines in other countries.

A complete range of solutions in aggregation provides the ability to construct the parent/child relation in any condition on the lines. Normally this relationship is best done by directly reading the serial codes during the aggregation phase (wrapping and/or case packing), but what happens if, due to machine and line configuration, this is not feasible? It raised the following questions:

■ How can such a relationship be constructed when multiple layers of products are stacked?

■ How can the problem be solved if the plastic wrapping is preventing a direct read from the cameras?

■ What should be done when old wrappers or case packers have no physical space to host the cameras inside?

Thanks to its long experience in this field, Antares Vision could demonstrate solutions of all these potential problems. Its strict respect of the tight time schedule was crucial in its selection, particularly with the Turkish deadline for aggregation quickly approaching. After the pilot, over 30 production and distribution lines with different layouts, machine manufacturers and operating procedures have to be implemented. This is one of Antares Vision’s strongest points: the ability to develop customisations in very short time frames to fulfil the client’s specific needs.

This capability is becoming more crucial as the time to meet standards set by the US, Brazil, Korea, India and European countries nears. In Antares, customers will have a reliable, attentive partner who is ready to keep up with technological advances, quickly develop the necessary software

a track and trace successThe introduction of anti-counterfeiting track and trace regulations by a growing number of countries is leading major drug multinationals to launch new pilot projects to select their own technological partners. Antares Vision reveals its involvement in one such project.

The Antares Tracking System is a complete track and trace solution designed specifically for the pharmaceutical sector.

The processed image inside a case packer.

WPF020_Antares.indd 124 06/10/2011 07:55

customisations, and construct new machines calibrated to the specific requirements of plants. Antares’ tracking taskforce includes the world’s best specialists who are always on hand to share their experience with line personnel in order to build the best solutions together.

“We listen to and understand the client’s needs,” explains Antares Vision’s technical director Massimo Bonardi. “We established a clear, constructive relationship with all members of the client’s team to create new developments in line with requirements and with very rapid implementation times.”

A flexible abilityOne of Antares Vision’s strongest points is its ability to create highly flexible products that meet the needs of production lines rather than imposing standardised products with little capacity for adaptability.

“We have demonstrated skill in subject areas such as IT, machine construction and integration into lines,” said Bonardi. “For us, every project is a challenge and that challenge lies in being able to quickly create the right response to the client’s needs.”

A widespread track and trace solutionThanks to this model of business, Antares Vision has quickly gained a share in the track and trace market, and this continues to expand as more customers turn to the firm to implement their aggregation phase so that they comply with Turkish regulations after having developed the serialisation phase with minor suppliers.

With over 250 lines – 40 with full aggregation – operational starting from 2008, and at least 120 lines that will be fully operational in aggregation by the end of 2011, Antares Vision demonstrates a very high commissioning capability.

The Antares Tracking System (ATS) is a complete track and trace solution designed specifically for the pharmaceutical sector. It includes a suite of software modules, printing and reading systems especially designed for drug tracking. The reasons for its success are simple:

■ It has eight different models for serialisation with printing, checking, labelling, and weighing options.

■ It has a high-performance inkjet print system for obtaining excellent print quality.

■ It offers a complete set of high-performance cameras for monitoring all aggregation phases, from cartoning to palletising.

■ Antares Vision’s powerful software architecture is capable of integrating all production and warehouse data with the enterprise resource planning (ERP) system.

■ Its flexible, user-friendly interface facilitates the operator’s daily tasks.

■ The ATS taskforce is a team of technicians and engineers with multidisciplinary skills ranging from ICT, production, warehouse to product inspection.

ATS has its own database that is updated in real time with information from all the packing cells in the line, including

which serial was produced, where and when, and which container it was placed in and where it was shipped. At a higher level, ATS modules interface with the company’s ERP systems to receive the univocal codes and transmit the parent/child relations for each package (wrap, box and pallet). At the end of each production batch, the system communicates the database data to the company’s ERP. It is this very integration between ATS and the ERPs that enables each product to be tracked after shipment, updating the product’s history until it has been used/destroyed.

The general philosophy is that in each packaging cell the control cycle is carried out by vision systems specially designed for the different levels of the production and packaging line, starting from the single package to the wrap, the box and finally the pallet. Each packaging cell checks the codes at the inlet and, once the container is complete, prints the relevant code, checks it is legible and that it contains all the content. Even partially filled containers can be dealt with. Each cell is independent of the others, thanks to the inlet and outlet controls: the ensuing redundancy allows for absolute reliability and maximum OEE, even if the packages are removed or damaged in the conveying zones between two stations.

Ready for morePharmaceutical packaging lines are under pressure by the implementation of serialisation and aggregation procedures: any unmanaged exception that may occur along the packaging line may potentially result in tracking errors, because it would break the chain of parent/child relationships. Typical production faults, such as conveyor belt jamming, pack damage, incorrect closure or bad application of labels on packs must be immediately detected and corrected.

The implementation of tracking systems, as well as a software solution at plant and line level, requires specific operations on lines, which may have to be designed on a case-by-case basis and have an effect on production organisation.

“For this impact to be kept to a minimum, systems need to be absolutely reliable and extremely simple to use for supervisors and line operators,” explains Antares Vision CEO Emidio Zorzella. “We have clearly demonstrated that we are capable of designing and commissioning such systems as projects of this type are exactly what our business model is all about.”

After its success in Turkey, Antares Vision is ready for the new challenges once the next countries start implementing track and trace. ■


WoRldPhARmAceuticAlFRontieRs | www.worldpharmaceuticals.net 125

Further informationAntares Visionwww.antaresvision.com

In Antares, customers will have a reliable, attentive partner who is ready to keep up with technological advances.

WPF020_Antares.indd 125 06/10/2011 07:56



t he BOBST ACCUBRAILLE system, now used by packaging manufacturers worldwide for applying Braille to pharmaceutical packaging, has become a

Best of Year award winner for innovative technology. The unit, which can be fitted on to a wide range of Bobst folder-gluer lines, resolves many difficulties associated with the traditional means of Braille embossing using a die-cutter.

Brazil’s Embanews Awards, now in its 20th year, recognises the best in packaging manufacturing and innovative packaging technologies. In 2011, it awarded first place to the ACCUBRAILLE system in the machinery, equipment and systems category. Dirceu Fumach, CEO of BOBST Group Latinoamerica do Sul, said that ACCUBRAILLE has revolutionised the process of applying Braille embossing to cartons.

“With ACCUBRAILLE on a packaging manufacture line, make-ready is very quick compared with die-cut and embossed make-ready, and much quicker than the two make-readies needed if you carry out embossing as a separate run,” he says. “The system can be set in less than five minutes, a massive improvement on the time needed for traditional methods.”

rotary’s upper handThe problems faced when embossing Braille using a die-cutting press include difficulty in setting and maintaining good Braille dot definition, the die-cutter’s restriction on embossing that must be no closer than 5mm to a cut or crease line and the feed issues created in the folder-gluer by blanks that have had Braille embossed on them by a die-cutter.

The ACCUBRAILLE module is a highly controlled rotary embossing unit placed between the blank aligner of the folder-gluer and its pre-breaker. The male die, which is made up of four lines of Marburg Medium Braille text and bespoke for each drug/dosage combination, rotates in perfect synchronisation with the arrival of the carton, while a universal female die provides the counter for the male.

Because the rotary process is low impact, tools last much longer than those used in die-cutter embossing and, because the lower ACCUBRAILLE tool is universal, only one male embossing tool is required per job instead of the one per station needed using a die-cutter. Together, these characteristics mean that tooling costs are significantly reduced by using an ACCUBRAILLE system and the quick and easy manufacturing of these tools means that packaging makers can reduce the lead time required to get a carton to market.

Maintaining Braille dot definition on a die-cutting press also requires careful setting and control of the machine pressure and the operator has to keep a continuous watch for wear of the embossing dies. The rotary system, once set, requires little or no

operator intervention and can process millions of blanks per tool before changing. Additionally, because it is applied after the sheet has been die-cut, the Braille can be applied to the edges of the carton, increasing designer options.

The ACCUBRAILLE system offers a further advantage over die-cutter embossed Braille: blanks embossed on a die-cutter often misfeed at the in-feed section of a folder-gluer because Braille dots interlock. Blanks for rotary embossing are perfectly smooth and so do not misfeed in this way, thus improving productivity. Additionally, the ACCUBRAILLE unit has been designed to keep pace with the folder-gluer, even at 100,000 cartons per hour.

spirit of excellenceWinning the Embanews award involved the ACCUBRAILLE system going through an in-depth examination and testing process by a committee of 70 representatives from professional organisations, with the objective of acknowledging companies that ‘excel in their activities’.

Continuing this spirit of excellence, BOBST will launch its in-line quality control device at the end of 2011. Called ACCUCHECK, the unit will turn the folder-gluer line into a high-speed packaging print checker and is the result of over 13,000 hours of R&D activity. These and other BOBST developments will help pharma packaging manufacturers meet the increasing pressure from brand owners to deliver zero-fault packaging. ■

rotary Braille: a quality touchApplying Braille to packaging can be a challenging process. Packaging specialist BOBST has developed an award-winning rotary embossing system that provides quicker make-ready times, lower tooling costs and wider design options.

Further informationBOBSTwww.bobstgroup.com

ACCUBRAILLE’s rotary system, once set, requires little or no operator intervention and can process millions of blanks per tool before changing.

WPF020_Bobst.indd 126 06/10/2011 07:59

ACCUCHECK

Actually, they are.

Because the human eye has its limits, trust the BOBST ACCUCHECK. This completely new device will turn your folder-gluer into an in-line high-speed carton print checker with a 100% quality guarantee.

Coming autumn 2011.

Are these lines parallel?

WPF020_Bobst.indd 1 04/10/2011 14:53

MMI028_Global Vision (Braille).indd 1 04/10/2011 14:54



a s of October 2010, legislation requires that the product name, strength and dosage appear in Braille on all pharmaceutical packaging. The EU has led the

way in this endeavour, but other countries are quickly following suit; Brazil has already implemented a national requirement for Braille labelling on all pharmaceutical packaging.

Braille is not a language: it is a tactile way of reading and writing text for blind and partially sighted people. The Braille cell consists of six dots, positioned like the figure ‘6’ on dice, in two parallel vertical lines of three dots each. All Braille characters are combinations of dots within this framework.

There are many specifications for setting Braille type; however, the Marburg Medium specification, as recommended by the EU, is the industry standard. Marburg Medium precisely dictates the distance and elevation between Braille dots to ensure readability (see Figure 1).

methods of applying BrailleThe variety of carton and packaging types plays a key role in how Braille is applied. The two most common methods for applying Braille to packaging are embossing and screen-printing. Embossing is mostly used on cartons while screen-printing is primarily used on labels. Both techniques pose their own QC issues.

The challenges for pharmaceutical packaging are numerous. Firstly, blind and partially sighted people need to be able to read the Braille text – the goal of Braille legislation is to assure that vital information is accessible to everyone. When embossing a carton, each Braille dot needs to be high enough to be easily read, but not too high that it perforates the packaging. In addition, whether embossing or screen-printing, the manufacturer must ensure that Braille dots are not malformed or missing. Spacing is also critical for accuracy. One misplaced or malformed dot in a standard six-dot Braille cell could turn a 40mg dose into a 50mg dose, leading to costly lawsuits and product recall expenses – and so the need for true Braille quality control becomes crucial.

Braille inspection technologiesThe two types of technologies for inspecting Braille are optical and physical measurement. Optical technologies check Braille quality by casting a light on the Braille dots and measuring the resultant shadow. The benefit of an optical system is speed. The drawback is that Braille dot shadows vary depending on the packaging’s background colour. Detecting and measuring shadows on a dark background

Quality control Braille for pharma packagingSetting Braille on pharmaceutical packaging poses specific quality control challenges. Global Vision’s software ensures the precision of Braille embossing on cartons and labels.

Further informationGlobal Visionwww.globalvisioninc.com

Figure 1. Marburg Medium specification.

makes validation difficult. In the case of screen-printing, clear glue dots may not cast enough of a shadow (or one at all) to enable accurate measurement.

The more reliable method for measuring Braille dot height is to use a handheld calliper, similar to those used by the aeronautical and automotive industries for measuring small parts. The advantage of callipers is that they are highly precise. The obvious disadvantage of manual calliper inspection is that it is time-consuming. To ensure validation, a true Braille QC system needs to be as quick as the optical method and as precise as the calliper measurement.

Global Vision’s Braille Qc solutionIn response to the drawbacks of optical and physical measurement, Global Vision developed BraillePoint™, an automated Braille inspection system that provides the speed of optical measurement and the precision of calliper measurement. Global Vision’s BraillePoint is the only system on the market that ensures the precision of all embossed and screen-printed Braille found on cartons and labels.

Global Vision’s software takes hundreds of thousands of readings per second and compiles them into complete dot specifications. Height, width, spacing and other critical information can then be easily verified by looking at the on-screen representation. Readings are independent of colour background and can be easily validated. ■

a – 2.5mmb – 2.5mmc – 6mm between two charactersd – 12mm hyphenatione – 10mm line spacing

ab

c d

e

WPF020_Global Vision.indd 129 06/10/2011 08:04



t he packaging of a parenteral, like any pharmaceutical product, is an important part of its commercial success. As well as being

durable and easy to store, package designs must be user-friendly if the product is to stand out in an increasingly competitive market. According to Dr Manfred Zurkirch, managing director of pharmaceutical packaging specialists Dividella, top-loading technology has the versatility to fulfil all of these needs. With 40 years’ experience in the pharmaceutical industry, Dividella is a leader in the secondary packaging of ampoules, vials, syringes and other difficult-to-stack medical devices. The company specialises in developing cardboard-only packaging solutions and the machines on which they are produced.

“Over the last 20 years we have been developing top-loading or cardboard-only packaging,” Zurkirch says. “The outside box is cardboard, but on the inside there are cardboard partitions instead of plastic trays.”

single-material benefitsThe benefits of this single-material method are numerous. The box and partition are formed on a single machine, which greatly reduces manufacturing costs. The packaging material is supplied in flat carton and partition blanks and therefore takes up minimal stacking space. Furthermore, the cardboard partition provides product protection benefits such as eliminating glass-to-glass contact and, with it, the cost accrued from damaged cargo.

“If you take the average ten-syringe pack, it isn’t untypical to save 50% of the volume using our solution,” Zurkirch explains. “For products such as oncology drugs, we design the boxes in conjunction with the customer. This process results in packaging that you can throw on the floor, with the product remaining intact.”

The company’s top-loading method has also proved popular with end users. With increasing numbers of products going over the counter, presentation and user-friendliness have become vital from a marketing perspective.

“With cardboard you can always print the inside of the box and once opened you have an easy overview in a nicely displayed fashion,” Zurkirch says. “It is important that the customer can see that everything is there, take something out, put something back in – this is much more difficult with a side-loader. Once you pull it out of the box, you can’t stuff it back in the same way.”

close relationship Dividella designs all of its machines and products in close collaboration with its customers throughout the package design, manufacturing and marketing process. This is particularly advantageous in an industry where many players have extensive

packaging portfolios and need boxes that fulfil the requirements of the product, yet are uniform in appearance. In addition, all of the company’s packaging is sustainable, environmentally friendly, and fully compliant with pharmaceutical industry regulations.

“The advantage of working with us is that we are not just a design office,” Zurkirch explains. “Our approach of working within the parameters set by our customers allows us to maximise the operational efficiency of the machine, which saves a lot of money.” Although Dividella’s designs are carefully customised, the company puts a premium on adaptability. Its machines can be easily retrofitted, giving them a much longer shelf life than competing products. In Zurkirch’s view, this is one of the company’s major advantages.

“If someone just buys on a price basis, then we are out of the equation,” he says. “Our savings are in raw material flow and transport flow, as well as in the asset protection offered by our machines. Sometimes a company will buy a machine for a product and the product isn’t approved or doesn’t take off as expected. We will retrofit it for them. In fact, 50% of our machines on the market don’t look the same as when we sold them.”

strength in innovationOver the medium term, Zurkirch sees South America and Russia, in which parenterals are already commonplace, as being potential growth markets. For now, though, Dividella will continue to consolidate in its main area of strength. The company already provides machinery for the majority of the 20 biggest pharmaceutical firms, and will try to bring the remainder onboard by placing innovation at the centre of its strategy.

“The requirements of the pharmaceutical industry are changing,” Zurkirch says. “We just want to keep up to date and always be one step ahead of the competition when it comes to innovation. We want to build business cases for our customers so they can say, ‘ok, this investment is well worth it’.” ■

on top of packagingMore pharmaceutical products are produced in parenteral form, which boosts demand for top-load packaging solutions. Dividella’s Manfred Zurkirch explains how the company produces strong, cost-effective packaging and extends the lifecycle of manufacturing machinery.

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WPF020_Dividella.indd 130 06/10/2011 08:03

WPF020_Dividella.indd 1 04/10/2011 14:56



mM Karton’s board qualities have a great reputation and are used for numerous applications and products. Now, one of its assets has become

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Hot foil stamping, spot varnishing, die-cutting, creasing and embossing – and perhaps adding Braille for blind and partially sighted consumers – are typical requirements for cartonboards used for pharmaceutical products. The legal framework against counterfeiting has also been tightened and there are calls for new packaging features. Apart from good rigidity and thickness, great printability is essential to fulfil these high expectations: MM Karton is ready for this.

Printing 2d matrix codesThe codes printed by an inkjet on packing lines must be dried and smear-resistant in less than half a second. This makes it ideal to fulfil the new legal regulations regarding 2D matrix codes and offers pharmaceutical companies the option to add additional information via smartphones, scanners or websites. Matrix codes also support better traceability.

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new quality ready for a sustainable futureTo second a further development in the digital world, MM Karton offers a new board grade: MM Digicarton. Customer friendly, sustainable and ahead of the competition, it is the worldwide first FBB quality that has been homologated for digital print.

In the same way that 2D matrix codes integrate the offline world closer to online media, MM Digicarton connects online closer to the print world. This quality creates a new base for personalised and differentiated products at high cost efficiency, without minimum order quantities or long preparation time. When it comes to the pharmaceutical

industry, it enables the convenient implementation of multiple languages and simplifies the application of relevant consumer information for clinical trials. Together with the matrix code, this could serve as an additional security tool against product piracy. MM Digicarton is available in the grammage range of 230g/m², 250g/m² and 275g/m².

Print-on-demand and just-in-time have become symbols of extremely efficient solutions. Short print-on-demand print runs bring – in addition to cost, time and stock savings – the advantage of high sustainability by reducing waste during the production process to almost nothing. With digital print, the preparation process can be reduced to three steps. Files can be modified, saved, and transferred directly to the printer. MM Digicarton has received a 100% top rating for its compatibility with Hewlett Packard’s HP Indigo WS6000 printing unit.

cartonboard packaging saves resourcesCartonboard is the only packaging solution that is recyclable and compostable, and it is made from renewable or recycled sources with low carbon dioxide emission values. MM Digicarton is FSC and PEFC-certified, just like all other MMK qualities.

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Board issuesTechnological advances and looming regulations mean that there has never been a better time for the pharmaceutical segment to embrace digital print for its packaging. MM Karton reveals how its products – established and new – are a boon for any drug maker.

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From securing a robust supply chain to encountering different comparator drug formulations, there are a swathe of variables to consider when conducting pharmaceutical research. But what is the best way to overcome such obstacles? Nic Paton asks H Lundbeck’s Dorthe Lerche Berg what strategies are needed to ensure a successful comparator drugs trial.

Insight > Clinical supplies & logistics

Best laidplans

dorthe lerche BergDorthe Lerche Berg is head of department, clinical supply coordination at H Lundbeck, with responsibility for managing clinical supply coordination, coordination of packaging activities, distribution and IVRS activities for clinical studies.

WPF020_021_Comparator and contrast.indd 135 06/10/2011 12:17



i n an increasingly tightly regulated pharmaceutical environment, it is only natural that everyone – the public, politicians, pharmaceutical firms, regulators and clinicians –

will want compelling evidence that new drugs coming off the production line compare favourably with existing drugs in terms of safety, efficacy and cost. To this end, comparative effectiveness trials are becoming an ever-more important part of the R&D mix for pharmaceutical firms when it comes to drug development.

With potentially billons of dollars of investment riding on the success or failure of new product streams, being able to demonstrate the value of new therapies and drugs, not to mention being able to make the strongest business case possible for their inclusion within hospital and government formularies, is absolutely paramount.

Yet sourcing and supplying comparator drug trials is not straightforward. It will normally require a lot of careful thought and strategic planning to get right, as well as to ensure it doesn’t end up costing a fortune, argues Dorthe Lerche Berg, head of department, clinical supply coordination, at pharmaceutical company H Lundbeck.

“The challenges, unfortunately, can be myriad,” she says. “Some of the most fundamental include the need to ensure you have obtained the necessary pedigree and product documentation for the comparator, the need to be 100% sure your supply chain is secure to guard against the introduction of possible counterfeit comparators and the need to look at issues around possible delays or interruptions in resupply throughout the course of the trial. Other issues that can be problematic include fluctuating patient enrolment, unexpected changes in the regulatory climate or a breakdown in supply chain or partnership relationships.”

And it is the strength and robustness of the partnerships or relationships you forge in this context that can often make the difference between success or expensive failure, stresses Berg, whether this is simply the relationships within your internal supply chain or, as with many smaller firms, the partnership struck with a specialised company to source and manage comparator studies.

“A big pharmaceutical company will probably have a dedicated department for sourcing comparators or finding companies that specialise in that area,” she adds. “For a smaller firm, it may make sense to take this process externally.”

crucial decisionsBerg stresses the importance of having the right relationship with a partnering company.

“It will be a close association with critical decisions to be made in areas such as the timing of supplies,” she says. “It is important you have a robust plan that can meet your timelines. You need to have access to specialised knowledge, whether in-house or through a partner. For example, in Europe the comparator is not that expensive compared to the US but lead times in the US for sourcing comparators are often much shorter than in Europe. So you have to decide what is most important for you, cost or lead time, for example?”

The issue of ‘pedigree’ – does the potential partner have the appropriate capacity, do they completely understand the documentation required, can they meet the regulatory requirements – will be another vital consideration.

“Within Europe, the EU Clinical Trials Directive established standardisation of research activity in clinical trials throughout the European Community,” says Berg. “But there will be different requirements in other countries.”

It is also vital to have strategies in place to mitigate risk. These will need to include looking at how to ensure the supply chain is robust and secure, how to guarantee that counterfeits will not enter the supply chain and how to minimise delays.

“You need to ensure that risk, within the context of what you are doing, has been absolutely defined and agreed with the stakeholders,” says Berg.

supply and demandAnother important question that will need to be addressed is that of central or local sourcing.

“It will very much depend on the strategic approach the company is taking,” says Berg. “One approach that is right for one company may not necessarily be right for another. So it is important to be having conversations with the different stakeholders within the internal supply chain. There has to be an agreement about costs and timelines, so it is important to define your strategy and then incorporate that into your sourcing of comparative studies.

In Europe, the comparator is not that expensive compared with the US but lead times in the US for sourcing comparators are often much shorter than in Europe. So you have to decide what is most important for you, cost or lead time?


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“Whether you follow a central or local approach will, again, often depend on your supply chain. For some companies, it might be better to have four or five local suppliers rather than one global one. And when setting the comparator sourcing strategy, it is very important to ensure that quality is paramount.”

Particularly in the current uncertain economic environment, it is imperative to have planned for the possibility that things may change unexpectedly, perhaps regarding the availability of the comparator, or fluctuations in patient enrolment, for example.

“This is something that needs to be discussed internally at an early phase,” explains Berg. “You need to be looking at any risks associated with running short of supplies, as things will often change.

“You have to build an element of flexibility into your plan, and you need to be in very close contact with the people on the clinical side and be up to speed with how the trial is designed, to ensure any changes or fluctuations are spotted as early as possible.”

This requires extensive planning and forecasting, and the ability to manage information from as early a stage as possible. Within this is the ability to source comparators at short notice.

“Right from the beginning you need to have a strategy in place that has contingencies for this sort of eventuality,” explains Berg. “You always need a plan B and alternatives. Things can always go in a different way to how you expect; suddenly the market and availability can change.

“So you can have a situation where, when you start the study, the availability of your comparator is one month delivery. But then suddenly availability goes up to three months for delivery.

“You cannot just sit on your hands because you already have the study running, so you need a plan B within your strategy. You have to have pre-planned what you might do in this eventuality or simply have a plan of where else you are going to go in the market.”




Key tips for designing comparator studies

nn Plan your options in advance, including the availability or limitations for sourcing the desired comparator.

nn Evaluate any regional variations of and requirements for comparators, including dosage form, strength and intra-country regulatory agreements, packaging, reformulation, blinding and any re-labelling needs.

nn When considering single sourcing, carefully weigh up the pros (one comparator source, a simplified supply chain, more consistency of data, greater flexibility) and cons (regulatory approval, country variability).

nn Assess required pedigree and product documentation of any potential partners.

nn Assess how you or your partners will mitigate risk (such as delays or counterfeits) and/or respond to the unexpected, such as fluctuating patient enrolment or the need to source comparators at short notice.

nn Ensure your strategy and approach is robust and flexible and always have a plan B.

single sourcingThere is also the issue of whether you intend to go down the single sourcing route or not. As with most things, there are both benefits and drawbacks, cautions Berg.

“If you opt for single sourcing, there will be many advantages,” she explains. “It will often cut your costs and reduce your administration. You may, for example, only need one batch with one expiry date.

“So, it can be a much more efficient way to manage things. However, some countries will not approve single-sourced

comparator studies because their requirements are different, or you may be required to use a product from a specific country as a comparator, or there may not be exactly the same formulation in different countries, so you may have to do studies to show that the formulation meets the requirement of that market, which can cause some challenges.” ■

You need to be 100% sure your supply chain is secure to guard against the introduction of possible counterfeit comparators and you need to look at issues around possible delays or interruptions in resupply throughout the trial.

Are you sharing your copy of World Pharmaceutical Frontiers with a colleague?As you read this, we at World Pharmaceutical Frontiers are busy working on the next issue, analysing and researching trends, opinions and developments to provide you with the most up to date information.

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Company insight > Clinical supplies & logistics


t raditionally, pharmaceutical and biotechnology companies have incorporated comparators within their clinical trials to demonstrate the safety, effectiveness

and worth of their new drug products or an existing drug product’s new indication. Comparative effectiveness is determined by a clear evaluation or the impact of different options available for treating a given medical condition for a particular set of patients. Generally, comparative effectiveness looks at the following areas:

■ comparing similar treatments or competing drugs ■ analysing different approaches, for example, surgery

or drug therapy ■ assessing the benefit/risk options and/or cost.

As such, sponsor organisations conduct global clinical trials using comparators to facilitate the evaluation of their comparative effectiveness. Comparators are commercial products or placebos used as references in clinical trials. They are also referred to as investigational medicinal products when the drugs are intended to be further manufactured, repackaged or used outside of their registered indications.

comparator sourcingSourcing authentic comparators becomes more complicated when trying to secure material based on the clinical trial’s requirements, which can vary from needing multiple lots, short and long-dated inventory, and small and large quantities. Having access to information is one of the most critical strategy components needed and the following should be considered: determine the complexity of comparator sourcing in the clinical trial, develop an executable yet flexible strategy, and select a sourcing option that best suits the clinical trial.

Although comparator sourcing is a small part of the overall clinical trial supply chain, it can be complex. Determining the complexity of the trial is arguably the biggest initial stumbling block. Thus, it is worth considering the following:

■ identify which product is available in each region where the trial will be conducted

■ assess the availability of the comparator and the forecasted quantities needed in each region

■ confirm product lead times and expiry dates ■ understand the availability of and access to the necessary

supporting documentation ■ research the requirements needed for further manufacturing

of the comparator ■ recognise the source of the comparator ■ strategically identify practical alternatives for any potential

restrictions to supply.

Teams typically approach comparator sourcing by finding out what is available, seeking consultation to plan the best ways to secure the product, sourcing the material and managing the delivery of the comparator through the appropriate supply chain.

sourcing decisionsSourcing the comparator can be managed internally, outsourced or a combination of the two. Many teams source internally through on-site resources or through their trial sites, while others outsource the procurement of the comparator and associated activities to specialised comparator providers. But if the sourcing is not being managed within the sponsoring organisation, a bit of control and disclosure of trial information will have to be relinquished in order to take full advantage of using a comparator provider.

When deciding who will source the comparator, first determine in-house capabilities and then evaluate core business functions and see if the team is willing to take on the task of sourcing the comparator and its associated activities. After evaluating these two items, inquire about accessibility to information to facilitate the sourcing of the comparator, and consider how the project and time management of the comparator and its associated activities will affect the overall clinical trial timeline.

The goal is to ensure that clinical trials are effectively executed with sound delivery of the comparator product and its associated requirements. This will lead to a successful clinical trial outcome. Thus, after completing the comparator need assessment, ensuring that authentic material can be obtained, and using a secure, direct, safe and efficient supply chain, then the ultimate goal of supporting the comparator supply chain from receipt to reconciliation can be attained. ■

comparative studiesDefining and securing a comparator for clinical drug trials is an essential component for a successful operational outcome. Multipharma outlines the principles involved.

Further informationMultipharmawww.multipharma.com

A comparator provides a clear evaluation of the impact of different options available for treating a given medical condition for a particular set of patients.

The comparator:

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Complex logistics and distribution

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WPF020_Multipharma.indd 141 06/10/2011 08:10



l ogistics management is vital to the pharmaceutical industry, with study drugs, clinical supplies and biological substances requiring careful handling to

ensure they remain intact and safe to use. For this reason, pharmaceutical companies benefit greatly from services that are customised according to their individual needs.

SafeLab & Logistics is one of the most respected logistics solutions companies operating in Brazil. SafeLab was founded in 2002 and is a member of the CSW Group, which has over 20 years’ experience in the courier express sector. It combines the logistics know-how of its parent company with a finely honed focus on clinical trials.

SafeLab’s services have been carefully developed to fulfil the needs of central labs, hospitals and other companies that develop clinical studies. Specifically, it concentrates on the storage and distribution of study drugs, health products and clinical trial supplies. It also transports biological material samples throughout Brazil across a network of more than 50 cities.

the right stuffSafeLab’s guiding tenets are respect, sustainability and innovation. Underlying every relationship with its collaborators and clients is a focus on ethics and transparency – SafeLab aims to do the right thing, in the right way, at the right time.

These principles apply across all areas of the company’s operations. The first of these is the specialised transportation of biological samples, including diagnostic specimens (UN3373) and infectious substances affecting humans (UN2814). Each material is packaged appropriately, and comes supplied with dry ice and gel packs, when applicable.

With highly skilled professional staff and nationwide pick-ups and deliveries, SafeLab offers automatic proof of delivery and strong regulatory support. From the moment a product is picked up until its final delivery into the hands of the consignee, the process is monitored rigorously, with satellite tracking and a risk management system incorporated into the vehicle fleet. Safety and legal

compliance are assured, and clients also benefit from an on-demand service at weekends or after hours.

The same standards apply to the transportation of study drugs or clinical supplies. With ambient (15-25°C), refrigerated (2-8°C) or frozen (-70°C) shipments, SafeLab takes the cold chain management process extremely seriously and uses data loggers to monitor the product’s temperature and ensure it remains within its optimal range.

storage and safetyTransportation is just one part of the logistics process; SafeLab also provides clients with intelligent storage solutions. The company closely monitors all products, controlling variables such as temperature and providing a 24 hours a day, 365 days a year safety system with cameras, and smoke and motion detectors. Products are painstakingly stored – personnel are issued with individual passwords monitoring their entrance and exit to the storage area.

Each product’s information is submitted into a computerised inventory, including the expiry date. SafeLab also offers reverse logistics by incinerating obsolete materials and issuing a destruction certificate. All equipment is calibrated and the storage areas are validated.

a quality approachAt the heart of all its operations lies a focus on sustainability. As evidence of its commitment, professionalism and focus on quality standards, SafeLab is ISO-certified for 9001 Quality Assurance system standards.

The company is convinced that believing in the future is equal to investing in the present, and each day it seeks new ways of protecting the environment, society and the community. Working in collaboration with clients, partners and suppliers, SafeLab knows that simple actions will produce effective results.

Truly a logistics management company for the 21st century, SafeLab is fully equipped to meet the needs of the Brazilian clinical trials market. ■

Professional clinical trials for emerging marketsSafeLab & Logistics is a logistics management company offering specialised services for the Brazilian pharmaceutical industry. With end-to-end logistic solutions, including the transportation and storage of pharmaceutical products, the company has built its success around the guiding tenets of respect, sustainability and innovation.

Safety and legal compliance are assured, and clients also benefit from an on-demand service on weekends or after hours.

Further informationSafeLab & Logistics www.safelab.com.br

WPF020_SafeLab.indd 142 06/10/2011 08:13

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s o, the decision has been made and your clinical trial is going to Russia, Ukraine or Belarus. Your contract research organisation has a good

reputation, the central lab is set up and the best dates for the investigator meeting have been selected. Everything seems to be coming together nicely and then you break a cold sweat: How will the study drug be imported into the country? Where will it be stored? How will it get to the remote locations of the trial sites? How can you ensure that there will be no temperature deviations on the way? What happens to the unused drug supply? The questions are piling up and you need answers.

regulatory processes and customs clearanceThe first key to success is to have a clear understanding of the regulatory processes in these countries to avoid unnecessary delays with your drug shipments and customs clearance. While the governing legislation is still being refined, these countries already have procedures in place for obtaining clinical trial approvals, issuance of import/export licences and customs clearance of investigational drugs and study materials; however, it is not easy to navigate the specific regulatory requirements, let alone keep track of ongoing changes and developments in legislation.

Russia passed a law effective from 1 September 2010 that, among other changes in the circulation of medicines, revamped the regulatory aspect of clinical trials with the intention of simplifying the process. The law has since been amended four times to correct the deficiencies of the original version; for example, the Russian Ministry of Health and Social Development (MoH) stopped issuing import licences for commercial comparators because the new law did not directly give the MoH the authority to issue such licences. Although the overarching Customs Union legislation provided for such authority, the MoH took a cautious approach and put a hold on issuing import licences until the problem was cleared many months after the new law came into effect.

While Ukraine provides more stability in terms of the regulatory processes, it appears to be more challenging on the customs clearance side. Customs posts have the authority to assess tariffs on commercial drugs imported for clinical trial purposes based on the market price as listed in the customs authority databases. If the drug is not registered in Ukraine, customs will do a web search for a similar product and assess the tariffs based on the market price of a similar drug. This creates unpredictability in calculating customs clearance costs, because each customs post uses its own sources/databases as a basis for tariff assessment.

Belarus, while having straightforward regulatory and customs clearance processes, requires individual import licences for each shipment of drug and/or clinical trial supplies, thus creating a need to constantly submit applications for such licences to its health authorities.

Warehousing facilitiesThe second key to success is the assurance that the warehouse you selected has all the processes and procedures in place for the proper storage and distribution of the investigative drug and clinical trial supplies. Your QA department can help by auditing the provider’s facilities, checking standard operating procedures and assessing the quality of the provider’s operations.

The best solution is to choose a provider that has sufficient storage capacities with the potential for expansion, operates out of a modern warehousing facility and has dedicated departments for each area of operations, be that quality assurance, regulatory or logistics.

Five keys to successful cold-chain logistics in russia, ukraine and BelarusOperating in the geographical region of Russia, Ukraine and Belarus is not an easy task; but, according to Leon Dzivinsky, VP and General Counsel of ClinStar/IMP Logistics, it is manageable through the first-hand knowledge of local specifics or the use of a capable partner.

Conducting a clinical trial in Russia, Ukraine (above) and Belarus requires in-depth knowledge of local customs and regulations.

WPF020_IMP.indd 144 06/10/2011 08:05



Further informationIMP Logistics Russiawww.imp-log.com

courier selectionSelection of a proper transportation company is the third key. The courier must be experienced in deliveries to remote locations within Russia, Ukraine or Belarus, and must ensure that the drug is delivered to participating sites in time for patients’ visits. The easiest way, of course, is to select a global courier company; however, can this particular courier ensure deliveries without temperature deviations from the warehouse located in, say, Moscow to the northern city of Novosibirsk during cold winters or from a Kiev warehouse to the southern city of Odessa, Ukraine, during a hot summer? Will the package be delivered directly to the investigator conducting the trial or will it be left at the hospital’s front desk, waiting for hours to be picked up by the proper recipient?

To ensure the smooth delivery of shipments and to address all of these concerns, input from the local warehousing and logistics partner about its experience with courier companies in this region will prove invaluable.

Pharmaceutical licence/comparator purchasingA back-up plan for the import of your comparators is important. After the new regulatory changes came into effect in Russia and the MoH temporarily stopped issuing import licences, study sponsors were forced to rethink their drug supply strategies and seek alternative methods to supply comparators in the country.

In Russia, Ukraine and Belarus, it is possible to buy comparators locally only with a pharmaceutical licence that allows wholesale drug purchasing and distribution. Make sure your warehousing and logistics provider holds pharmaceutical licences in the countries where the clinical trial will be conducted so that commercially available comparators can be bought from authorised local distributors, should it become necessary.

Key performance indicatorsThe most important key to success is ensuring that the local warehousing and logistics provider has a system of tracking key performance indicators to consistently deliver positive results on all projects. Request KPIs with a two-year history to view the provider’s record of timely handling of incoming and outgoing shipments, its picking and packing accuracy, and its ability to avoid shipment losses and temperature deviations and arrange the destruction of returned products.

The selection of a proper warehousing and logistics provider within Russia, Ukraine and Belarus can save undue stress and ensure a successful cold chain logistics process for your clinical trial. ■

WPF020_IMP.indd 145 06/10/2011 08:05

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c emelog Zrt is an independently owned Hungarian logistical services provider that has been

helping its partners in the pharmaceutical industry for almost 15 years, specifically in the Hungarian market and in Central and Eastern Europe (CEE). The company was established to fulfil the pharmaceutical industry’s logistical needs. Its professional application of good manufacturing practices and good distribution practices is unparalleled throughout the region.

During the course of its history, Cemelog has experienced dynamic growth, especially in the last few years. This growth applies not only to turnover, but also to the number of clients and the amount of pallets stored and transported.

Cemelog provides its clients with comprehensive logistics services, covering the entire value chain from warehousing to secondary packaging and international transport. Its many multinational clients, which include GlaxoSmithKline, Pfizer, AstraZeneca and Janssen-Cilag, have been satisfied with its services, which is proven partly by the increasing number of services Cemelog provides and by the long-standing partnerships it has with the majority of its clients.

Cemelog works continuously to earn this trust by providing made-to-measure solutions and a high level of customer service. The company’s professional qualification is supported by it being regularly awarded tenders from existing as well as new clients.

Why regionality?Many leading pharmaceutical companies have realised that a transition is necessary from the ‘one market, one warehouse’ model to a ‘several markets per warehouse’ model, so that one warehouse should be suitable for the provision of several markets. GlaxoSmithKline’s consumer branch has used this model in the CEE region for over ten years. Other pharmaceutical manufacturers have also moved their central warehouses from countries in Western Europe to Hungary, because they have recognised that the CEE’s markets are being serviced in a way that is more economic.

Benefits of a regional warehouse The main benefits of having a regional warehouse in the CEE is customer service improvement and shortening the ordering deadline. The regional warehouse is closer to the destination market and consumers, which means that reactions to market needs can be carried out faster.

In addition to traditional warehousing functions, there is an opportunity to store ‘semi-finished’ products (for example, in the form of blister packages) and final packaging can take place based on market needs. If such a solution is possible, it provides additional tangible

benefits such as lower product manufacturing costs and, as a result of flexible inventory management, less out of stock and lower levels of over stocking.

Cemelog, the CEE region’s specialist in pharmaceutical industry logistics, supports its clients in implementing the regional concept with the application of its professional expertise, a wide array of experience and innovative solutions. ■

Pharmaceutical logistics dedicated to the cee Providing customised solutions and high levels of service has been the backbone of success for logistical services provider Cemelog. Its warehouse in Hungary has provided its clients in Central and Eastern Europe with improved customer service and a shorter ordering deadline.

The regional warehouse is closer to the destination, which means that reactions to market needs can be carried out faster.

Further informationCemelogwww.cemelog.eu

In addition to traditional warehousing functions, there is an opportunity to store ‘semi-finished’ products at Cemelog’s regional warehouse.

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O ver the past ten years, enormous amounts of money and energy have been injected into the development of new, life-saving vaccines. Current vaccination

programmes save three million lives each year, and this is likely to increase as more innovative products move into development. But are the supply chain systems that support the delivery of these ground-breaking vaccines as innovative as the products themselves?

Bill and Melinda Gates have christened the next ten years ‘the decade of vaccines’, promising that their foundation will commit $10 billion to help research, develop and deliver vaccines for the world’s poorest countries, with ‘deliver’ being the operative word. The sad fact is that because the logistics and distribution systems are not yet up to scratch in these countries, vaccines are often either rendered useless by the time they reach their destination or are not being delivered at all.

The multi-billionaire philanthropists are involved in a programme known as Project Optimize, a collaboration between the World Health Organization (WHO) and PATH, an international non-profit organisation dedicated to improving global health. The project aims to improve the logistics and distribution systems in resource-poor countries by encouraging the various stakeholders involved in immunisation to put their heads together and implement the changes needed to get the systems up to modern standards.

“It’s quite an unusual project in that it’s all about a vision of the future,” says John Lloyd, senior technical advisor for the PATH/WHO Optimize project, which aims to implement effective supply chain solutions in developing countries on a large scale by 2020.

“We’re looking outside immunisation to the public health field, and further than that, looking outside public health programmes to the private sector to determine what standards they are using and which developments they are pursuing.”

coolLogistics systems in the developed world continue to evolve at breakneck speed, but their counterparts in emerging nations are lagging behind, meaning drugs and vaccines are not being delivered in optimum condition or in the correct quantities. Elly Earls talks to John Lloyd of Project Optimize about the initiatives underway to change this.

Insight > Cold chain

The PATH/WHO Optimize project aims to implement effective supply chain solutions in developing countries on a large scale by 2020.

WOrldPharmaceuticalFrOntiers | www.worldpharmaceuticals.net 149

John lloydJohn Lloyd is a senior technical advisor for PATH. He is currently working on the development and introduction of a software application to plan for future equipment needs in cold chain systems.

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There are three arms to the project, which Lloyd terms ‘a suitcase of changes’.

■■ Demonstration: Project Optimize is demonstrating new supply chain systems and technologies in pilots across four developing countries – Vietnam, Albania, Tunisia and Senegal.

■■ Enabling change: Working closely with organisations such as the WHO and UNICEF, the team at Project Optimize is working on developing the systems that enable change and result in recommendations for countries. How can these countries actually achieve changes in policy and technology?

■■ Getting the message out: This sector of Project Optimize is about encouraging the stakeholders of immunisation to participate and start aligning themselves in favour of certain changes.

Beyond the cold chainAt present, all vaccine manufacturers require their products to be stored within the cold chain, even if they are heat stable – a heat-stable vaccine can be stored safely within a temperature range outside the cold chain parameters of 2-8ºC and has heat-exposure indicators attached to it. Yet some of these vaccines are already being taken beyond the cold chain at the field level in order to enable immunisation in remote areas.

“We don’t think this is sustainable because it is not accepted by the manufacturers,” says Lloyd. “It’s not a long-term position.”

Project Optimize is working on bringing four vaccines out of the cold chain: hepatitis B, yellow fever, pnemococcal and meningitis. For Lloyd, meningitis is the most likely to come out of the cold chain first because its manufacturers are behind the idea.

One of the main challenges to ensuring that the other vaccines get to the position where they can be relabelled as heat stable is that their manufacturers are demanding clinical studies to demonstrate their stability outside of the cold chain. This is certainly one of the slower-moving concepts within Project Optimize, but its impact could be wide-ranging, according to Lloyd.

“The broader picture is that if we are able to get some of the vaccines out of the refrigerated cold chain by 2020, we’ll be taking them into the controlled temperature chain,” he explains. “We’d then be keeping them at room temperature, but in a controlled fashion, something that is less demanding than keeping them refrigerated.”

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Project Optimize is working on bringing four vaccines out of the cold chain: hepatitis B, yellow fever, pnemococcal and meningitis, of which meningitis is likely to be the first.




here comes the sun Historically, developing nations with unreliable electricity supplies have used kerosene and gas-fuelled absorption refrigerators to store their vaccines. But these devices are rife with problems: kerosene-fuelled fridges are incapable of operating a thermostat, and therefore controlling the temperature of the vaccines, while their gas-fuelled counterparts suffer from extreme unreliability in terms of both supplies and distribution networks.

“We’ve learned to live with absorption refrigerators, but solar refrigerators are the likely future where there is no good supply of electricity,” Lloyd says.

Solar-powered refrigerators are better controlled than absorption refrigerators, which use huge amounts of fuel and are inefficient.

“Electrical compression refrigeration is much more efficient, uses less energy and is less expensive,” he adds. “The other enormous advantage is that you don’t have to pay for fuel. The maintenance intervals (every 36 months for major maintenance and every 12 months for minor maintenance) are also dramatically different from absorption refrigerators that need attention every day.”

Sounds like a win-win situation; however, the batteries needed for solar refrigeration have not reached the level of reliability or long life that makes them feasible in countries where electricity is not available in all areas of rural infrastructure. They’re also prohibitively expensive.

Optimize has been working on a project called Solar Chill, a multilateral programme with members including the World Bank, to develop battery-free solar cooling technology to replace the battery-powered options.

“We’ve now got three solar battery-free refrigerator options,” says Lloyd, adding that there is one problem. “The process of installation is crucial; it’s got to be done properly or health workers don’t understand how to use the solar equipment and they fill it up with bottles of water or try to freeze vaccines when they shouldn’t.”

With installation a challenge that can certainly be overcome, solar refrigeration is emerging as the preferred option for areas with unreliable supplies of electricity.

With more than a third of the pharmaceuticals being used in Optimize’s demonstration projects supposed to be protected at room temperature anyway, resource-poor countries need to be developing technology to support the controlled temperature chain.

And with both vaccines and drugs set to require these systems, the long-term pointer will be to integrate the storage of the two.

Unfortunately this is easier said than done. While it could be achieved in some countries through some simple architectural amendments, such as increased insulation and ventilation, the buildings are sufficiently sub-standard in other regions to mean that additional equipment is also necessary.

“We’re looking at both the energy and cost aspects of this,” Lloyd notes.

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continuous stable running and the cooling is passive most of the time.”

Unfortunately, this cooling equipment is mainly produced in the developed world and is expensive compared with the domestic refrigerators that many healthcare facilities are making do with.

From zero to hero The concept of net zero energy means that taking into account the energy generated and the energy used, zero energy is actually consumed, and a question increasingly being asked by Project Optimize is: “Can we pay for the electricity in the stores, including refrigerators, computers and lighting, as well as the energy used for transporting vaccines, through the use of solar energy?”


Passive cooling Passive cooling technologies are developing rapidly in four areas: 90-day cold-life containers, mobile passive cooling, super-long life ice-lined refrigerators and phase change materials.

“Passive cooling containers are pretty exciting,” Lloyd says. “There is one fairly revolutionary technology that has a 90-day cold life, which is excellent for small, remote health centres.”

As this technology has the full backing of the Bill & Melinda Gates Foundation, it is not facing any resource shortages and will be tested throughout 2012 in Senegal.

In a related development, mobile passive cooling rolling containers can now store 100-1,000l of vaccines, as opposed to the 19l boxes that had been commonly used.

“They’re much more compact for large quantities of vaccines than the small boxes, which means they allow more additional supplies such as drugs to travel with the vaccines,” says Lloyd. “This is an example of a technology that isn’t new – it’s been used for cooling fruit and keeping meals hot in factories.”

Optimize is also looking at moving vaccines at a local level with the use of phase-change materials in transport containers.

“These are very much the future of passive cooling in the cold chain,” Lloyd notes. “They change at 5°C so they’re not capable of freezing vaccines, which is excellent. We’re also looking at the possibility of using these packs to stabilise the temperature in domestic fridges, which are widely used in developing countries to store vaccines.”

Lloyd is keen to mention super-long life ice-lined refrigerators. “This is going to be a tremendous technology,” he says. “The latest development in ice-lined refrigerators can survive on just four hours of electricity in 24. It has

Project Optimize has been working on a project called Solar Chill, a multilateral programme with members including the World Bank, to develop battery-free solar cooling technology.


Fuel-guzzling four-wheel drives and diesel vehicles are widely used to distribute vaccines across developing countries, so the team at Project Optimize decided to replace 82% of these with the best of the electric delivery vehicles coming off the European production lines.

“It’s an exciting idea, but it’s a little bit compromised in two areas: the state of development of electric vehicles and the state of the buildings in the countries,” says Lloyd. “We’re crossing our fingers that the vehicles are big enough for our purpose and we’re aiming to eventually have architecturally designed standardised stores to minimise the amount of energy used in the buildings. We will then be able to achieve some quite important economies.”

Getting the word outEach technology or system covered here is years away from widespread implementation. This is for two key reasons, according to Lloyd. One – there is no global database describing the market for cold chain equipment, meaning it is difficult to access venture capital funding. And two – managers in developing countries are not educated enough to navigate between the many options available. These barriers need to be overcome if any of the programmes mentioned in this article are to be successfully scaled up.

“We’re partly involved in this [with the project’s ‘getting the message out’ set of activities], but we’re also planning to set up a grant system within the Gates Foundation in the US to tackle some of the things we haven’t been able to tackle directly within the Optimize project,” he explains. “It’s one thing to have a vision and it’s another thing to have an innovative idea. But it’s quite another thing altogether to have a vision, an innovative idea and an idea of how the vision can be realised.”

With the vision such a valuable one, the important thing at this point is to get as many stakeholders on board as possible, so that the delivery systems associated with vaccines can reach the standards of the vaccines themselves and increase global immunisation rates to a level the industry can be proud of. ■

Solar refrigeration is emerging as the preferred option for areas with

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Company insight > Cold chain


c old-chain management is of vital importance when it comes to maintaining the quality of pharmaceutical products. If such items are exposed to suboptimal

temperatures during shipment – either too high or too low – there is a risk that they will be damaged and their efficacy reduced. For this reason, Temperature Sensitive Solutions (TSS) has developed a cold chain information system (CCIS), a web-based program designed to monitor and analyse temperatures at every step of the transportation chain.

Pharma-attuned serviceBased in Stockholm, Sweden, TSS has been supplying temperature monitoring solutions since 1992. As one of the leading providers of such services, the company designed CCIS in conjunction with its partners in the pharmaceutical industry. As such, it is highly attuned to its customers’ specific needs.

The key benefit of CCIS is that it offers automated data processing with a global approach, supporting corporate SOPs for temperature control. Created with a view to minimising human error, the system ensures that cold-chain management remains straightforward. It is ERP-integrated, which leads to streamlined, efficient processes and reduces workload across an organisation. This, in turn, means saving time and, importantly, cutting costs.

The decision on product temperature profile and data logger configuration is controlled by qualified people, as it is the logistics experts who set up the shipment rules in an ERP system. At the product dispatching site, the ERP system provides the warehouse operators with instructions for issues such as packaging solutions, quantity and the location of temperature data loggers. This information, along with data logger temperature intervals, are applied to the data logger using a 2D barcode. This enables a leaner process in the warehouse, where the data logger is started in the online application without any manual input of information.

The information carrier, known as the TempTracer data logger, is sourced from Maxim Integrated Products. The unique iButton data logger technology is robust, resilient and reliable, it has been rigorously tested for accuracy and each unit is calibrated separately. The TempTracer comes in single or multiple-use formats and its temperature intervals are configured by the customer. There is no need to keep data loggers of independent intervals in stock as a multiple-use TempTracer data logger can be configured for one type of product on one trip and go with a completely different product on its next trip.

When a shipment arrives at its destination, the data is secured in the global web database and automatic notifications are sent if the shipment is out of the temperature range. The control over product quality and release is with the qualified experts as the temperature result of a shipment is not displayed until it is downloaded online.

As well as considering temperature data from an excursion perspective, CCIS assesses shipments in terms of risk. The CCIS supplies quality managers with key data helping them make decisions and adapt risk management processes. Data can be compared from different products, packaging solutions and regions, while suppliers are appraised against agreed key performance indicators. Freight forwarder milestone data is integrated with the CCIS temperature data, outlining the exact position in the supply chain where goods are at risk.

high-quality data, high-quality decisionsThe overriding advantage for pharmaceutical companies is that CCIS provides a detailed overview of the complete supply chain. High-quality data is secured online, using automated processes for the launch and download of data loggers with superior reliability. Keeping track of suppliers’ KPIs, identifying risk lanes in the supply chain or creating thermal profiles for packaging solutions, the data is already available in CCIS, where reports generated to the user’s specification translates the data into a core business decision.

TSS’s temperature monitoring system provides flexibility, simplicity, reliability and, above all, full visibility. It helps pharmaceutical companies gain insight into the modern cold chain and develop an all-encompassing corporate strategy for fast and intelligent temperature management. ■

Keeping the cold chain on the levelMaintaining an optimal temperature is vital during the transit of pharmaceutical products. The data captured as evidence of product conditions must be of the highest possible quality or the entire cold chain is put at risk. Temperature monitoring services provider TSS’s cold chain information system offers shipment analysis from a risk management perspective.

Further informationTSSwww.tss.se

The CCIS supplies quality managers with key data, helping them make decisions and adapt risk management processes.

WPF020_TSS.indd 156 06/10/2011 08:13

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Designed to move consignments within a single country, this is primarilybut not exclusively based upon road transportation.

Contact us through our websitewww.biocair.com or email us at

[email protected]

WPF020_Biocair.indd 1 04/10/2011 15:02



t here is no mistaking that the pharmaceutical industry has faced turbulent times over the past few years and this shows no signs of stopping.

Companies are making cutbacks everywhere – taking a good look at their expenditures and trying to shave costs wherever possible. Some easy targets are contracts for services that they use regularly, scrutinising the invoice for the little extras that have been happily paid each month: will anyone really notice the difference between a luxury and not-so-luxury bathroom soap?

For the pharmaceutical industry, logistics is a big part of daily life. But unfortunately, due to the nature of its shipments, it can’t just be ‘thrown in the post’. The majority of pharmaceutical shipments require licences and specialist attention and therefore need to be couriered by a specialist. This raises the question, “Why ship with a specialist courier, rather than an integrator service?”

The obvious answer would be to benefit from the specialist’s knowledge and expertise – it can do things an integrator cannot. But this can come at a price and the value of this service is often difficult to demonstrate to the people paying for it.

It has always been a challenge for pharmaceutical companies to get the balance right between service and cost in terms of logistics. This is demonstrated by the internal struggle between the scientific community and purchasing teams. The scientist is looking for high levels of quality, compliance and capability, but the purchasing department is seeking a cost-effective service provision.

If we tip the balance too far towards the scientists’ requirements, the specialist courier service they are looking for can be seen as too expensive. Too far towards the purchasers and the scientists aren’t getting the peace of mind they need in terms of care and compliance.

how to get the balance rightThe strengths and weaknesses of both service offerings need to be identified to ensure that the most appropriate solution is chosen for the specific logistical and compliance requirements. This is particularly important when dealing with a clinical trial.

The scientists are looking for reassurance that their hard work is being looked after throughout its journey. A specialist courier can provide processes that avoid risk and offer high levels of customer care. Their industry expertise allows them to offer services such as product classification, sophisticated packing technology and experienced staff holding relevant, industry-recognised degrees. But we need

that integrator cost saving to get past the purchasing teams. We want the best of both worlds, so the obvious answer is to combine the two – a hybrid.

The hybrid service combines the pick and pack skills of the specialist courier with an integrator network and its worldwide footprint, allowing the customer to choose the level of care that is relevant for them: specialist pick up, combined with the cost-effective city-to-city service of an integrator. The key element of this service is demonstrating honesty, integrity and transparency. Providing this service means sharing the cost saving with the customer to the benefit of:

■ patients ■ scientists and investigators ■ purchasing teams ■ chosen logistics partners.

Wisdom of the middle way This type of service initiative would give an ideal compromise, rather than an ‘either/or’ scenario, to the benefit of the pharmaceutical industry. In a logical world, big pharmaceutical companies could reduce costs while maintaining a high level of regulatory compliance – and smaller research organisations could afford to employ the skills of a specialist, without spending their entire research budget on logistics.

■ Scenario one: a Big Pharma company has a large budget, so has a decent budget to spend on logistics, but is still struggling to justify the expense of a specialist courier with purchasing. It does not want to sacrifice services such as dry-ice replenishment, shipping paperwork, licences and compliance.

■ Scenario two: a small biotech firm has a limited budget and can’t afford to send all of its precious shipments by specialist, but feels cautious about using an integrator. It can send most of the shipments with an integrator, but the occasional shipment would benefit from the ‘icing on the cake’ services that only a specialist can offer.

The answer to both is a hybrid courier service, using the skills and expertise of a specialist to pick and pack their items to industry standards. ■

logical logistics Compromise isn’t always a bad thing when it comes to logistics. Biocair explains how hybrid courier services offer a happy middle ground between the care and compliance demands of scientists and the frugal mindset of purchasing teams.

Further informationBiocairwww.biocair.com

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t he primary challenge of companies in the healthcare industry is to maintain compliance, product integrity and security along their supply chain; however, this

has led to rising logistical and transport costs. To combat this problem, Panalpina approached a US

company that develops medical technology and services. The firm has operations and manufacturing facilities across the world and sells products for the treatment of cardiac and neurological pain patients in more than 100 countries. Panalpina analysed the company’s complete supply chain, identified the key challenges and presented a tailored solution.

multiple challengesThe main challenge was reducing overall transportation costs and making the supply chain leaner and more transparent, while maintaining controlled temperature conditions throughout the transportation of sensitive products.

When Panalpina approached the company, it was shipping freight from Latin America (production) via two different locations in the US (sterilisation and preparations for export) to Europe using commercial carriers. This made the supply chain very complex, visibility was poor, logistics costs were high and flexibility was low.

tailored solution Panalpina successfully demonstrated how the supply chain could be greatly improved. Its solution took the complexity out of the supply chain, made it more visible (order forecast) and guaranteed controlled temperature conditions. Panalpina could

shorten the supply chain by offering its own controlled ‘cool plane’: the Dixie Jet.

The Dixie Jet was launched in 1990 and is one of the longest existing, single transatlantic cargo connections. Thanks to this unique service between Huntsville, Alabama, and Luxembourg, one air freight leg in the US could be eliminated. With five eastbound flights per week (four westbound) the service offers sufficient capacity, high flexibility, a stable supply chain and 100% visibility: every flight is fully controlled by Panalpina.

true temperature-controlled environmentThe Boeing 747-400F planes used for the Dixie Jet provide a true temperature-controlled environment, because the temperature in a designated cargo area of the plane can be controlled and monitored from the cockpit.

Temperature control could therefore be changed from an active to a passive and more cost-effective solution with thermo blankets. These blankets protect the goods by covering the complete unit load device. The temperature is not only monitored onboard the plane, but also throughout the whole transport system, from door to door. This is achieved through an end-to-end, proactive temperature monitoring and control set-up based on radio-frequency identification.

Various benefitsThe customer benefits from Panalpina’s proactive approach and the implemented solution in the following ways:

■ lean, smooth and stable supply chain ■ full supply chain visibility ■ own-controlled air freight service guaranteeing sufficient

capacity and flexibility ■ controlled product temperature ruling out temperature

excursions and damages ■ reduced logistics costs ■ reduced total lead time and a shorter order-to-cash cycle ■ improved CO2 footprint (estimated reduction of 172t of

CO2 per year). ■

take full control of cold-chain management The Dixie Jet by Panalpina provides a true temperature-controlled environment that is perfect for the reliable, cost-effective and fast transport of sensitive pharmaceutical and medical technology products. In a proactive approach, the company’s healthcare experts showed a medical technology company how it could improve its supply chain.

Further informationPanalpinawww.panalpina.com

Panalpina shortens the supply chain through the Dixie Jet, its own controlled cool plane.

WPF020_Panalpina.indd 160 06/10/2011 08:11

Directory > Product showcase


Product showcaseefficient connections via russia

AirBridgeCargo Airlines is an integrated provider of air cargo transportation. Established in 2004, ABC offers complex solutions for cargo deliveries that link the world’s largest manufacturers with consumers and business partners worldwide.

The ABC network in Europe covers major import markets, including Amsterdam, Frankfurt, Maastricht, Milan, Paris and Zaragoza. The company operates its scheduled flights from Europe to Asia's biggest cities: Beijing, Hong Kong, Seoul, Shanghai and Tokyo. In April 2011, ABC introduced its first flight to the US (Chicago), linking the markets of Europe and Russia with the most lucrative market in the world. All flights are operated via hubs in Moscow's Sheremetyevo and Domodedovo airports.

ABC’s fleet of Boeing 747 freighters offers the capacity to carry up to 110t on a single flight and complies with all transportation standards for the delivery of all cargoes, including shipments that require special handling and temperature-controlled conditions.

The firm’s general cargo is less general than it sounds. In addition to shipments without any particular specifications, it handles special cargo products that embrace all items for which IATA issues special transport regulations, including dangerous goods, perishables, live animals, vulnerable, bulk and heavy items.

Russia’s geographical position and the development of Moscow as its network hub allow ABC to connect markets in the most efficient way; for example, the company offers the shortest connections between China, Europe and North America via Russia.

Combining high-quality service and competitive products, ABC continues to develop its route network by adding new flight frequencies to meet growing demand, backed by solid business relations with major global and regional logistics companies.

Further informationAirBridgeCargowww.airbridgecargo.com

a superior saltAkzoNobel Sanal Salt has been awarded the Certificate of Suitability, complying with the monograph of the European Pharmacopoeia (CEP). The company is only the third manufacturer worldwide to receive the CEP for its Sanal® Sodium Chloride Pharmaceutical Quality products – salt in its purest form. The salt is produced at the company’s site in Mariager, Denmark.

Highly pure sodium chloride free from additives and bacterial endotoxins plays an essential role in the pharmaceutical industry and in the manufacture of medical and pharmaceutical products. The CEP, awarded by the European Directorate for the Quality of Medicines, indicates that the Sanal products comply with the monographs of the latest European Pharmacopoeia. In March 2006 the site was approved by the Food and Drug Agency as an “active pharmaceutical salt ingredient manufacturing facility” and at the beginning of 2008 the

Mariager site won the GMP Certificate on ICHQ7 (API).

AkzoNobel Sanal Salt is salt in its purest form for use in the pharmaceutical industry, medicine, cosmetic and health products. Its manufacture is subject to strict quality controls at all stages of processing in accordance with the guidelines for the manufacture of pharmaceutical agents (GMP-ICHQ7).

Sanal Sodium Chloride Pharmaceutical Quality is an active ingredient in parenteral and peritoneal solutions and a base material for haemodialysis and haemofiltration solutions, as well as other pharmaceutical applications.

As well as the above uses, Sanal SQ is suitable for use as a fine chemical pursuant to American Chemical Society requirements, in microelectronics and microgalvanic processes.

Further informationAkzoNobel Saltwww.akzonobelsalt.com

medicinal aerosols at the highest standardAVEFLOR has produced liquid and powdered aerosols since its foundation in 1995. The firm specialises in the production and marketing of its own products as well as those of its contract manufacturing clients. All products are manufactured in clean premises with strict controls on air quality, and comply with cleanroom standard grade 7 and grade 8 for background environment according to ISO 14644.

The company provides complex services such as product development, raw materials purchasing, production, product testing and packaging. Its main advantages are its flexibility and

its wide range of bulk products that can be used for filling.

AVEFLOR produces liquids, powders, gels and emulsions in aerosol form, BOV aerosols or classical forms in plastic tubes or glass and plastic bottles. Its products are sold throughout Europe as well as in some non-European countries.

Pharmaceutical production is performed at AVEFLOR's production site on the basis of the following manufacturing authorisations:

■ medicinal products for human use: these are designed to come into direct contact with human organisms

■ medicinal products for veterinary use: preparations and technical devices

■ development and manufacturing of medical device in sprays, liquid and semi-solid forms to be applied to intact and wounded skin, mucosa and teeth.

Non-pharmaceutical manufacturing performed at the site include cosmetic products, medical and sanitary products, biocides and technical devices. There are no antibiotics, hormones or cytostatics involved in AVEFLOR's production.

Further informationAVEFLORwww.aveflor.com

ensuring low migration to meet high standards The new generation of drug containers and delivery systems face challenges that are not an issue for glass containers. Plastics such as low density polyethylene (LDPE), high DPE and polypropylene (PP) are convenient, paticularly for small packages and where squeezing is

The AirBridgeCargo fleet offers temperature-controlled conditions.

WPF020_Product Showcases.indd 161 06/10/2011 12:50



required. They also offer higher efficiency, reduced breakage and lower costs; however, plastic containers make the choice of label material far more critical.

Components in inks, lacquers, top coats, adhesives, papers and films can leach through the container wall and contaminate the medicine inside. The container itself also needs careful selection to avoid leaching from the plastic wall.

The highest migration threat comes from solvent-based inks, UV inks, top coats and lacquers. There are strict regulations on the migration of contaminants from packaging and Avery Dennison has made compliance a priority. Its adhesive Fasson® S692NP™ has been developed to perform well in applications with a high migration risk, such as fluid-filled linear LDPE containers.

S692NP is a clear, permanent adhesive that adheres well to many tightly curved substrates including glass, polyethylene and PP. UV resistance and weatherability is also excellent. Extraction studies comparing a range of adhesives show that S692NP gives the lowest risk of migration; for example, one international pharmaceutical company abandoned qualification testing of alternative adhesives after finding that S692NP gave outstanding results.

Experience, expertise and global reach are important when producing compliant and reliable pharma labels. With divisions around the world, Avery Dennison offers a guaranteed product

portfolio of dedicated pharmaceutical label materials, together with adhesives that meet the highest regulatory and compliance requirements.

Further informationAvery Dennisonwww.europe.fasson.com/[email protected]

Virtual biobanking

Netherlands-based Cryo Store is a full service logistical partner for the pharmaceutical, biotech and medical industries. Packaging, storage and distribution of temperature-sensitive goods has been its core business for over 12 years. The company's unique ability in providing specialist services in the storage of biological materials as well as in the packaging of temperature-sensitive products has proven to be a valuable resource for many pharmaceutical, medical and life science companies.

Firms considering having their own warehouse in Europe or looking to outsource their long-term storage need look no further than Cryo Store's Virtual Biobanking and Warehousing service. Working from a virtual office is becoming more common and brings companies significant savings due to reduced office space and travel costs.

When outsourcing storage and distribution, there is no need for companies to invest in a secured

storage area, storage facilities and security: the storage and shipping of materials, samples and products can be carried out in their own 'virtual warehouse' from their home office or even from another continent.

Clients can be reassured that their clinical samples, production batches or other biological products will be kept in the safest place. Cryo Store's systems are all about safety and maintaining the right environment, and are equipped with all the required back-up systems and data management. It stores samples from -196°C to room temperature and its storage facilities are only accessible for trained employees.

As a packaging specialist, Cryo Store knows how to pack and ship valuable samples at the right temperatures. For years, the firm has developed packaging solutions for clinical trial programmes or the shipment of pharmaceutical products and medications. Many national and international companies in the pharma, biotech, healthcare and food industries have found Cryo Store to be a trusted partner.

Further informationCryo Storewww.cryostore.com [email protected]

streamlined compound acquisition

Chemonaut, which is located in the Netherlands, offers a comprehensive outsourcing solution for obtaining high-quality screening compounds and building blocks in a cost-efficient

way. The company focuses on the increasing need within pharmaceutical and biotech companies to streamline their R&D supporting processes. Chemonaut directly addresses the issues related to the selection and acquisition process of research compounds and offers a complete procurement solution.

The Chemonaut application is a web-based compound-sourcing platform that enables its users to search and acquire screening compounds and building blocks from the combined compound stocks of 60 high-quality suppliers from around the world. By allowing only in-stock compounds into the Chemonaut database, the firm can ensure high availability and delivery rates after the compound selection has been done.

In addition to a catalogue of screening compounds and building blocks, Chemonaut offers a range of unique high-quality special libraries from reputable and innovative compound vendors worldwide. The online Chemonaut application offers all the functionality needed in the compound selection process, from substructure search and chemical property filtering to the preferred delivery format of the selected compounds. Due to import and export possibilities, the platform is ideal for integrating into an existing IT infrastructure.

The database is available by means of a subscription. Subscribers receive monthly database updates for use with their own in-house compound-selection tools. Chemonaut also provides procurement and ‘single-point of purchase’ services for compounds sourced from all vendors included in the database. Compounds may be ordered as solid and neat samples in vials or plated in any format.

Pharmaceutical packaging must meet the highest industry standards.

Chemonaut offers access to a catalogue of screening compounds.

Packaging solutions dedicated to the pharmaceutical industry.




Chemonaut provides an excellent combination of flexible compound searching and reliable compound logistics, which results in great efficiency gains for any compound acquisition process.

Further informationChemonautwww.chemonaut.com [email protected]

PdF logger for cold chain monitoringSwitzerland-based ELPRO-Buchs is dedicated to supporting pharmaceutical and biopharma companies in cold chain monitoring. LIBERO, its PDF Datalogger®, provides the user with speed, ease of use, higher accuracy, six alarm limits, validation documents and faster data access. Its unique features and its low price for high quantities are also appealing to pharmaceutical companies and clinical trial organisations worldwide.

No software is needed at the destination – a complete evaluation report is available within 10s. The PDF Logger measures and stores temperature during cold chain transportation. At the destination, LIBERO can be simply plugged into a USB port of any computer (Windows, MAC or Linux). It automatically creates a PDF/A (ISO standard for long-term archiving of electronic documents) report with text, alarm information, statistics and a graphical line chart. It acts as a USB memory stick and the computer will

automatically show the file as a new-found drive. The evaluation report can now be viewed by Acrobat Reader, printed or directly sent by email.

Further informationELPRO-BUCHS AG www.pdf-datalogger.com

on the right wavelength

Escort’s latest radio frequency identification (RFID) technology allows online visibility of a shipment’s temperature and humidity at inspection points via a track-and-trace, web-based platform. The system alerts the shipper or recipient when conditions are unsatisfactory.

This affordable yet efficient RFID logging solution with semi-passive technology allows the temperature and humidity loggers to be transported by aircraft and is compliant with EPC Class 1 Gen 2/ISO 18000-6C. With a simple adjustment any standard UFH RFID reader can read Escort RFID temperature and humidity loggers.

Whether a client wants to monitor the temperature of its shipments systematically to integrate supply chain and cold chain management or take its supply chain system to the next level, this technology could be the answer. Escort RFID loggers and tracking system give clients the ability to:

■ programme and download a large number of loggers simultaneously

■ read temperature, humidity and other data from long distances

■ read temperature information inside boxes or pallets without opening them or breaking the cold chain

■ download data via portals without the intervention of an operator

■ track and trace the shipment at inspection points and up to the final destination

■ send email or text alarms when the conditions of the shipment are not satisfactory at an inspection point

■ have automatic identification integration of the temperature data logger with identification technologies, such as GEN2

■ combine automatic identification and temperature measurement in the same device.

The RFID loggers and tracking system also provides clients with data such as a Certificate of Analysis, import documents and compliance literature, which are useful for shipment and export with the product on the RFID logger, and gives them the ability to add information on a tag or database at an inspection point.

Further informationEscort Data Loggerswww.escortcoldchain.com

italy’s finest chemicalsFabbrica Italiana Sintetici (FIS) is one of the larger producers of fine chemicals in Europe, with a total cGMP reaction volume of more than 2,100m³ across two sites in Italy. The company’s diversified contract manufacturing product portfolio has seen a sharp increase

over the past five years, accounting for 80% of its business, with generic APIs making up the remainder.

FIS’s main objective is to continue advancing its position as a 'powerhouse for API solutions'. To do so, it works as a partner for API development, from the bench scale through to commercial launch in full-scale production units.

FIS has the capacity to supply large quantities of APIs and advanced intermediates, while retaining the appropriate resources to manage small to intermediate-scale commercial volumes. FIS is 100% privately owned and in 2010 achieved net sales of €177.9 million, an all-time company record. The increase in revenue enables the firm to invest in state-of-the-art assets and provide new technologies.

FIS has for a long time been autonomous in waste management, using incinerators for solid, liquid and gaseous waste. In 2010, it invested more than €10 million in increasing its incineration capacity and recovering heat from the incineration process. A stainless steel 316l API lyophiliser, which enables FIS to treat industrial quantities of APIs requiring lyophilisation, came onstream in 2010, adding another technological edge to the business’s production sites.

FIS’s R&D is extending the company’s know-how in the biocatalysis field, while research in continuous reaction technology via microreactors is broadening its technology dimensions. Organisational improvements in the field of lean manufacturing are ongoing.

FIS is collaborating with renowned universities in north-east Italy, namely the chemical and biological faculties of the University of

With the PDF/A, no software is required at the destination.

FIS has two production sites in Italy: Montecchio (above) and Termoli.

Escort’s RFID technology sends alerts when shipment conditions are not satisfactory.




Padova and the University of Venice. Outside of the country, the company has established platforms in China through a purchasing office in Shanghai and a joint venture for early-stage process R&D and market intelligence. FIS believes that emerging markets will gain and perhaps overtake the growth in the triad markets of the US, Europe and Japan.

FIS has been FDA-inspected since 1964 and holds more than 600 drug master files worldwide. The company’s regulatory experience is unparalleled in the API custom-manufacturing field. Looking ahead, FIS will continue its efforts to stay ahead of its competitors and be fully competitive in global terms by offering more value for its products and services, and by being more innovative.

Further informationFabbrica Italiana Sintetici SpAwww.fisvi.com

technology meets designHaselmeier is a leading designer and manufacturer of pens and auto-injectors for injectable pharmaceuticals. For 40 years the company has combined experience and innovation to produce disposable and reusable self-injection systems, many featuring a hidden needle design.

Haselmeier’s injection devices are designed to meet client requirements. Its Axis Pen System is a variable-dose injection device for manual injection and is available in a disposable or reusable format. Its unique technical function features include:

■ dose adjustment 0.01-0.6ml per injection

■ minimal or no priming ■ easy and safe

dose correction ■ accurate dose reading

with sliding window

■ no rotating outer components

■ protected dose scale.

The i-Pen is a reusable variable-dose injection device for use with a 3ml cartridge. It is available as a standard design or can be customised. Its features include:

■ dose adjustment of 0.01-0.6ml per injection

■ easy handling and portability due to its compact size

■ a large, easy-to-read dose indicator.

The Softpen is a fully automatic reusable injection device featuring Haselmeier’s patented hidden needle design. On depressing the pen’s clip, the needle automatically enters the subcutaneous tissue, then the device injects the solution. Its features include:

■ fully automatic needle insertion and injection

■ a needle that is hidden prior to injection

■ multiple injection from a single 3ml cartridge.

The Haselmeier disposable Penlet is a fully automatic, fixed-dose injection device designed for use with a 3ml cartridge and disposable pen needle. Delivery of the solution is as for the Softpen. Its features are:

■ ready for use by the patient with no dose adjustment required

■ fully automatic needle insertion and injection

■ a needle that is hidden prior to injection.

Further informationHaselmeier GmbHwww.haselmeier.com

regulating child-resistant packagingChild-resistant packaging originated in the US in 1970 when the Poisons Prevention

Packaging Act (PPPA) stated that products that could be harmful to children must be packaged in a child-resistant way. A number of accidents involving household and automotive chemicals, as well as accidents with drugs and other hazardous substances, initiated the process of legislation. These incidents had severe consequences for children and parents, and because of this more products are being sold in child-resistant packaging today.

Under the PPPA, standardised testing procedures for child-safe packaging were fixed in order to guarantee their functional reliability. During these tests, 200 children aged from 42 to 51 months had to try and open a package. If 80% were not able to perform the task, the package could be considered child-resistant. It was equally important that adults, especially the elderly, were able to open and reseal the package.

Other countries established similar standards that differed only in the size and composition of the test groups, in the length of the tests and in the analysis procedure. Today, next to other legal guidelines, two central regulations lay down the pharmaceutical use of child-resistant packaging:

■ ISO 8317 (2003), which is equivalent to DIN EN ISO 8317 (2004) – is one of the most important international standards for reclosable child-resistant packaging, especially child-resistant closures. It applies to

pharmaceutical as well as to chemical-technical products. Only packaging that has been considered child-resistant in tests with infants while being convenient for elderly people meet this standard.

■ EN 14375 (2003),which is equivalent to DIN EN 14375 (2004), is the international standard for non-reclosable child-resistant packaging for pharmaceutical products. This standard is particularly relevant for blister packs, stick packs and granule bags.

Further informationHeinlein Plastik – Technikwww.heinlein-plastik.de

driving healthcare via the cold chainGuaranteed quality is essential to the role the cold chain plays in medicine transportation. Integra2 offers an exclusive transport service, dedicated to the needs of wholesalers, hospitals, health centres and pharmacies. The company's unique, temperature-controlled capillary network is supported by over 20 years' experience in cold chain management and more than 30 years in distribution.

Integra2 is a collaborating member of the AEFI (Spanish Pharmacists Association) and AESEG (Spanish Generics Association) and actively participates in pharmaceutical logistics and cold chain forums.

From 2006 to 2010, Integra2 saw a growth of 38% in temperature-controlled expeditions and in September and October of each year it played a key role in the distribution of the flu vaccine in Spain. The vaccine is a thermolabile product that must be kept at an average temperature of +5ºC, with a maximum variation of ±3ºC

Opening drug packaging must be easy for adults, but hard for children.


MMI028_Global Vision (PS).indd 1 04/10/2011 14:55



while assuring the product does not freeze.

Maintaining the appropriate temperature is a key factor in transporting vaccines, given that any failure in the cold chain could lead to the vaccine losing its properties. Integra2 complies with the requirements of vaccine transportation through its specialised service FríoFarma, which guarantees that medicines are transported at a controlled temperature of between +2 and +8ºC.

This is the aim of the cold chain: to maintain a constant and adequate temperature throughout the supply system to assure the perfect conservation of the components that make up the products. This kind of service is particularly important in a country such as Spain, which has a varied climate map and where, for six months of the year, the weather is considered hot.

Integra2 has all the equipment required to maintain the cold chain, including temperature-controlled vehicles, refrigerated storage and pre-storage areas, insulated loading bay docks, insulated and distributed refrigeration systems, checked and authorised vehicles with side doors, temperature separation, air recirculation ducts, loading protocols, double evaporators, management systems and a temperature-control culture.

In 2010, more than 12,500 hours were invested in cold chain improvement projects, 464 RFID data loggers, black boxes with GPS and dual temperature trailers were installed, allowing more than

100 million temperatures to be registered per year.

In addition to giving special attention to the cold chain by means of an internal team of auditors and process controllers, Integra2 has noted an increase in the number of audits carried out by laboratories each year. Its cold chain has received the Cold Chain Quality Indicator standard accreditation and its FríoFarma service was certified by Qualipharma.

Further informationIntegra2www.integra2.es

one turn and fill

Medisize's two-part dosing system has been developed for pharmaceutical liquids that are used in connection with oral remedies/liquid medications, as well as mouthwashes and liquid foodstuffs that must be administered in precise dosages. The two principal components (apart from the container and dip tube) are the dosing head and closure.

Handling of the Medisize two-part dosing system could not be easier. At the closure opening point the precisely measured liquid reaches the dosing head to an accuracy of +/-5%. When developing the system, it was Medisize's aim to dispense with awkward and imprecise administration implements such as spoons, measuring cups and bottle caps. By simply turning the screw closure of the new system, the dosage head is filled with exact precision: one turn and filling is perfect.

Depending on customer specifications, the dosing head can be adapted to dosage volumes of between 1ml and 20ml. Child safety locking, TE original closure and special geometries are available as optional extras.

Bottle and container sizes correspond to the system and can contain volumes of up to 750ml. Depending on the application, Medisize can produce the relevant screw closures and dosing heads, injection-moulded in either HDPE or PP. The bottle and containers can be blow-moulded in PET, LDPE or HDPE, and the moulds are applied using hot runner technology with up to 32 cavities

Further informationMedisizewww.medisize.com

Flexible tubes for parenteral packaging Neopac, the Swiss-based provider and inventor of high-barrier tubes for the cosmetics and pharma industries, in collaboration with Harro Höfliger, has introduced Fleximed™, a range of transparent, flexible, medical tubes that serve as a smart and unique alternative to glass for parenteral packaging. They offer significant advantages in terms of ease, reliability and medical administration safety.

Fleximed Luer Lock, when fitted with a male Luer Lock, eliminates the need for syringes to release medication from the vial. Instead, by removing the seal, medical staff can quickly and accurately pour the medicinal product directly from the medical tube into the catheter or IV bag.

Alternatively, with Fleximed Vial, the tube can be directly connected to a syringe for immediate and seamless

distribution of medication, so there is no need to change needles. Additionally, in response to the need to be able to easily mix two or more components just before application, Neopac created Fleximed Easymix, a tube with two or more chambers to mix different dry/liquid or liquid/liquid components. The new Fleximed tubes are engineered with materials that satisfy the strict requirements of the pharmaceutical industry. Their silicon and tungsten-free primary packaging materials were made specifically for this market and the tubes can be sterilised using radiation.

In addition, the tubes are lined with a high-barrier transparent laminate. They are produced in Switzerland under fully qualified cleanroom conditions.

Further informationNeopacwww.neopac.com

Premium stearates for pharmaOleochemical additives are the most important excipients in the pharmaceutical industry and the Peter Greven production plant in Venlo, Netherlands, is dedicated to the

Fleximed tubes are used instead of glass for parenteral packaging.

Peter Greven specialises in high-quality vegetable stearates.

Integra2 ensures the successful transportation of cold-chain medicines.

Medisize's two-part system requires just one turn for precise dosing.




production of high quality vegetable stearates specifically for pharmaceutical applications.

The complexity of this application field requires constant improvements, modifications and developments. Peter Greven rose to this challenge and is now the European marked leader for pharmaceutical stearates with its LIGAMED® product line.

This LIGAMED product line includes high quality magnesium stearates with the brand names LIGAMED MF-2-V, LIGAMED MF-3-V and LIGAMED MF-2-V PREMIUM. Furthermore, calcium stearates are offered under the brand name LIGAMED CPR-2-V and different types of stearic acids are available as LIGAMED SA-1-V and LIGAMED SA-2-V.

As well as their physical and chemical characteristics, the toxicological and physiological properties make these products ideal for the selection of excipients in the pharmaceutical industry. This is founded on vegetable raw materials' natural ability to be metabolised within the organism without any adverse reaction. LIGAMED includes the following features and advantages:

■ production carried out according to GMP regulations of vegetable raw materials

■ meets PH.Eur, USP/NF, BP, JP, DAB standards

■ available as kosher and halal-certified grades

■ a high-specific surface that enables high efficiency despite low dosage

■ extraordinary lubrication and excellent release effect

■ dedicated production lines ■ exclusively high quality

vegetable raw materials are used during production

■ Peter Greven is a member of the Roundtable on Sustainable Palm Oil

■ batch consistency guaranteed by constant controls during the production process

■ remarkable high quality and purity.

Further informationPeter Grevenwww.peter-greven.com

the miniature revolution continues

pSivida Corp, of Watertown, MA, US, is a leading provider of miniaturised drug delivery systems. The firm has developed two of the only three FDA-approved, sustained-release back-of-the-eye treatments for chronic eye diseases. Vitrasert and Retisert, which are licensed to Bausch & Lomb, are surgical implants that treat CMV retinitis and posterior uveitis, respectively.

pSivida has two platform technologies: Durasert and Biosilicon. The company improved the initial technology to develop Durasert™, a third-generation system that can provide drug release for up to three years after a single injection (performed during an office visit). This technology has been licensed to Alimera Sciences and Alimera’s product candidate is ILUVIEN®, which delivers a steroid fluocinolone acetonide for diabetic macular oedema, one of the leading causes of blindness. Alimera has filed an NDA with the US FDA and a decision is expected in November 2011.

The Durasert technology is also being used in two early stage clinical programmes:

■ Bio-erodible Duraset for glaucoma: pSivida is developing a subconjunctival sustained release insert for latanoprost for glaucoma. This product is the subject of a research agreement with Pfizer and is presently in an investigator-sponsored phase I/II clinical trial.

■ An investigational new drug is now open for pSivida’s Durasert device for the treatment of posterior uveitis. This is the same delivery device that was licensed to Alimera, although Alimera does not have the rights to uveitis.

pSivida’s Biosilicon technology is promising. The first application, Tethadur, is a nanostructured delivery system that has the potential to deliver proteins, peptides, antibodies and biosimilars for extended controlled release for up to six months after a single injection.

Initial efforts are focusing on its use in the eye, but it also has the potential to be used in other drug delivery areas.

Further informationpSivida Corpwww.psivida.com

customised quality control seraRandox understands the importance of good laboratory quality control in any drug development programme or clinical trial, and ensures that pharmaceutical, central laboratory and CRO clients receive exactly what they need when it comes to sera.

Randox supplies quality control products including customised sera to more than 60,000 laboratories worldwide. The company’s customised quality control service is designed to provide a cost-effective, tailor-made product

to meet individual trial specifications without compromising performance. This customisation includes not just a selection of desired analytes, but also a specification of the levels to suit any clinical or therapeutic application.

As with Randox’s traditional off-the-shelf control products, customised controls offer superior performance and reliability. All controls are made from the highest-quality materials and are free from interfering preservatives or stabilisers.

Randox controls have unrivalled stability, with most controls not only meeting but often exceeding the stability claims on the label. Many controls have a four-year shelf life, making them ideal for use in long-term clinical studies. In addition, all controls designed for use with antibody-based methods are manufactured from 100% human materials ensuring accurate results: Randox is the only manufacturer that excludes animal components from its immunological controls.

All controls are manufactured at the company’s state-of-the-art, FDA-inspected manufacturing plant in the UK and conform to international standards. This commitment to quality is supported by ISO 13485 accreditation for the development and manufacture of diagnostic test kits. Randox controls can be single or multi-

Randox's quality control products ensure accurate clinical trial analysis.

ILUVIEN is able to deliver medication to treat diabetic macular oedema.




analyte, liquid or lyophilised. The company's comprehensive range of more than 300 routine and esoteric analyte options cover everything from routine chemistries, immunoassays, immunology/proteins, toxicology, cardiology and lipids to more specialised analytes such as tumour markers, antioxidants and cytokines.

Further informationRandox Pharma Serviceswww.randoxpharmaservices.com

custom synthesis for a full product lifecycleSaltigo is a leading supplier in the field of custom synthesis, providing services for full product lifecycle requirements. The company is part of speciality chemicals group LANXESS Corporation as part of its advanced intermediates segment, which achieved total sales of €1.321 billion in 2010.

Saltigo, which is based in Langenfeld, Germany, and has FDA-approved production facilities in Leverkusen, employs approximately 1,400 staff worldwide. LANXESS also operates a further site for Saltigo at Redmond in Washington, US.

The company has a strong heritage in chemistry and engineering with unique expertise in asymmetric synthesis, chiral separations and proprietary catalysed coupling reactions. This is complemented by a wide range of traditional chemistries including low temperature and high pressure reactions.

Saltigo serves emerging to Big Pharma companies supporting the development and manufacture of APIs and intermediates from laboratory to commercial scale under ISO, cGMP and FDA quality standards.

Further informationSaltigo GmbHwww.saltigo.com

chill out with Frizbox

The field of thermo-sensitive treatment is changing to keep pace with developments in treating particular pathologies and to protect populations against epidemics. These products have to be transported quickly and efficiently to sites throughout the world. Accordingly, one of the largest laboratories has asked Sofrigam to design and produce refrigerant boxes much larger than those commonly used.

The Pallet Shipper Frizbox® XXL is a box that can transport 1,500l of health products. It is made of polyurethane panels and is packed in cartons. The refrigerating components are made from packs of non-toxic gel. These containers can preserve products for more than 96 hours at a controlled temperature (2°C-8°C). They come in standardised sizes, which makes transportation easy.

It is now possible to forward thermo-sensitive products safely from the production plant to any destination. The product has been tested and verified in Ater Métrologie Laboratory, a Sofrigam partner. Thanks to metrology, clients can measure the ability of their packaging to store products within a fixed temperature range during transfer. These tests make it possible to reproduce the real conditions of transportation and to verify that the required temperature is maintained within the packaging. These tests can:

■ guarantee the integrity of the products during transportation

■ increase client confidence ■ respect legislation

through the submission of a test report or qualification file (according to request), the results of which are reproducible and enforceable (evidence in the event of a dispute).

Further informationSofrigam www.en.sofrigam.com

digital dispensingTecan is a leading global provider of laboratory instruments and solutions in biopharmaceuticals, forensics and clinical diagnostics. The company specialises in the development, production and distribution of instruments and automated workflow solutions for laboratories in the life sciences sector.

Tecan's new HP D300 Digital Dispenser is a simple, standalone instrument that uses HP Direct Digital Dispensing technology to rapidly deliver picolitre to microlitre volumes of drug compounds. Available exclusively through Tecan, this innovative device can cut titration times to mere minutes.

The HP D300 uses HP inkjet technology to provide fast and reliable performance across a large dynamic range, thereby

eliminating the need for slow, error-prone and wasteful serial dilutions. The instrument offers non-contact digital dispensing from 13pl to 5μl, using disposable dispense heads to help avoid cross-contamination, and can deliver any dose to any well while almost eliminating wasting valuable compounds. It combines walk-up convenience, ready-to-run performance and flexible experiment design software to increase reliability of results and the speed of drug discovery workflows.

As an original equipment manufacturer, Tecan is also a leader in developing and manufacturing OEM instruments and components that are then distributed by partner companies. Founded in Switzerland in 1980, the company has manufacturing, research and development sites in Europe and North America and maintains a sales and service network in 52 countries.

Further informationTecan Tradingwww.tecan.com [email protected]

simplicity and security equals valueUnivar Pharma Ingredients does not just produce a broad range of effective ingredients essential to the pharmaceutical industry; building on the global reach of the Univar network, it also offers its pharmaceutical clients access to products and innovative concepts from across the world in the simplest way possible.

Through its global sourcing capability, Univar builds simplicity into the supply chain, removing cost and complexity for its partners and assuring the delivery of safe and secure components vital to

The Pallet Shipper Frizbox XXL guarantees product integrity.

The HP D300 Digital Dispenser cuts titration times to just minutes.


Directory > Product showcase & suppliers guide


ABB Engineering Services ..............30www.abb.com/consulting

Air Canada Cargo ...........................148www.aircanadacargo.com

AirBridgeCargo Airlines ................139www.airbridgecargo.com

AkzoNobel Salt ..................................76www.sanalsalt.com

Alfa Wassermann SpA ...................106www.alfawassermannmanufacturing.it

Alkaloid Skopje ...............................112www.alkaloid.com.mk

AndersonBrecon .............................134www.andersonbrecon.com

Antares Vision ................................124www.antaresvision.com

AVEFLOR AS ...................................115 www.aveflor.cz

Avery Dennison ..............................123www.europe.fasson.com/pharma

Biocair ..............................................158www.biocair.com

Bobst Group ....................................127www.bobstgroup.com

Boehringer Ingelheim ....................103www.boehringer-ingelheim.com

BÜCHI Labortechnik AG .................27www.buchi.com

Burkert Fluid Control Systems .......33www.burkert.com

CAFOSA .............................................57www.healthingum.com

Cemelog ...........................................146www.cemelog.eu

Chemonaut ........................................69www.chemonaut.com

the pharmaceutical industry. It boasts over 170 distribution centres across the world, ensuring its global sourcing reach makes effective local delivery. It combines excellence in operations with an absolute commitment to:

■ safety – ensuring the safety of employees and neighbours

■ environment – reducing the impact of its operations on the environment and reducing its carbon footprint

■ growth – supporting the growth of customers and suppliers by providing sustainable solutions and ensuring the safe

stewardship of the products that it offers

■ compliance – ensuring that its products and services meet the most stringent of ethical and quality standards.

Through its unique industry focus, Univar is the distribution partner of choice for the pharmaceutical industry, offering its customers excipients, APIs, solvents, colours and process chemicals, all specifically packaged to meet their needs.

Further informationUnivarwww.univar.com

track recordZenatek is a company with extensive management experience in the civil and military logistical fields and in the development of software programming, particularly custom and commercial software. Its main product, the Zenatek Tracking System (ZTS), introduces a new level of performance in the tracking, monitoring and reporting of goods in transit.

ZTS is a smart technology that allows logistics operators to manage and monitor events in the supply chain in real time, 24/7, eliminating all uncertainty about the goods being transported in either dry or reefer containers and providing stakeholders with enough timely information to reroute shipments if necessary.

These capabilities improve the efficiency of the supply chain, providing high returns by reducing the misuse of containers, avoiding rejected loads due to temperature excursions beyond a pre-established range, and providing, other benefits, including correct demurrage timings.

The ZTS is based on Zenatek’s small and sturdy Container Tracking Device

(CTD), which is engineered using GPS and GSM technologies and can be easily installed in the middle of the container doors. It is configured on a web portal where clients can connect via the internet using an exclusive encrypted code, enabling them to see the information about the transportation of their containers at any time.

The CTD comes with simple specifications and an even simpler foolproof installation, and has been tested under EC and FCC standards. Remote configuration of temperature thresholds and transmission intervals to the data centre are additional features.

The ZTS does not require any additional investment in fixed infrastructure such as porticos, readers and repeaters. There is also no need to recover the unit and send it back to the client, which eliminates all costs associated with these tasks such as recovery personnel, forwarding, reconfiguration, and restocking.

Further informationZenatekwww.zenatek.eu

Clients can access information about their containers during transportation.

suppliers guide

Univar's products and services meet ethical and quality standards.


Directory > Product showcase & suppliers guide


Corning ..............................................46www.corning.com/reactors

CPhI Worldwide ..............................140www.cphi.com/visit

Cryo Store ........................................151www.cryostore.com

Deutsche Post DHL ........................150www.dhl.com/smartsensor

DIA ......................................................99www.diaeurope.org/euromeeting2012

Dividella AG ....................................131www.dividella.com

DSM Pharmaceutical Products .....110www.dsm.com

ELPRO-BUCHS AG .........................137www.elpro.com

Emirates SkyCargo .......................OBCwww.skycargo.com

Escort Data Loggers Inc ................139www.escortdls.com

Exam Packaging .............................150www.exampackaging.be

FIS-Fabbrica Italiana Sintetici .........89www.fisvi.com

Flavine Europe GmbH .....................76www.flavine.com

FPS Food & Pharma Systems..........40www.foodpharmasystems.com

Gerresheimer AG .............................63www.gerresheimer.com

Global Vision Solutions .....9, 128, 165www.globalvisioninc.com

Haselmeier GmbH ............................48www.haselmeier.com

Heinlein Plastik-Technik GmbH ...123www.heinlein-plastik.de

ICSE ..................................................105www.icsexpo.com

IMP-Logistics...................................145www.imp-log.com

Integra2 ............................................154www.integra2.es

IPO ....................................................118www.ipo-pszczyna.pl

Kelly Services ....................................96www.kellyscientific.com

Laboratoria Smeets ..........................55www.labosmeets.com

Linde North America Inc .................39www.lindeus.com

LOG GmbH ......................................122www.logpac.com

LTS Lohmann Therapie-Systeme ...51www.ltslohmann.com

Medisize .............................................48www.medisize.com

Merck Millipore .................................91www.merck4pharma.com

Mettler Toledo ...................................44www.mt.com/quantos

MM Karton ......................................133www.mm-karton.com

MPI Research ....................................74www.mpiresearch.com

Multipharma ........................................4www.multipharma.com

NETZSCH ...........................................43www.netzsch-grinding.com/pharma

Nirvention BV ...................................40www.nirvention.com

Owen Mumford Ltd .........................53www.omdrugdelivery.com

Panalpina Management ................IFCwww.panalpina.com

Patheon Inc ......................................109www.patheon.com

Peter Greven GmbH .........................89www.peter-greven.com

pSivida Corp ......................................52www.psivida.com

Randox Pharma Services .................68www.randoxpharmaservices.com

RAUMEDIC AG .................................59www.raumedic.com

Red Cube .........................................120www.redcube.ch

Richter-Helm BioTec ......................100www.richter-helm.eu

Roquette Group ................................82www.roquettepharma.com

SafeLab & Logistics ........................143www.safelab.com.br

Saltigo GmbH ....................................80www.saltigo.com

Sandoz Biopharmaceuticals ..........104www.sandoz.com

Sasol Wax GmbH ..............................84www.sasolwax.com

SGS Life Science Services ..................7www.sgs.com/pharmaqc

Sofrigam SA .....................................152www.sofrigam.com

SOTAX AG .......................................116www.sotax.com

TECAN ...............................................73www.tecan.com/digitaltitration

TAPI ..................................................171www.tapi.com

Titan ArcticStore .............................155www.arcticstore.co.uk

TSS ....................................................157www.tss.se

Unilife .................................................60www.unilife.com

Univar Inc ..........................................87www.univar.com

Usource ..............................................34www.usourceonline.com

Willis Ltd ............................................18www.willis.com

Zenatek ............................................153www.zenatek.eu


here’s to cooperation. tojoining forces. here’s totwo are better than one.here’s to all that’s ever beenaccomplished by puttingdifferences aside and findingcommon goals.here’s to what makespartnerships worth the trip.

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World Pharma 2011 Vol. 2

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Transcript of World Pharma 2011 Vol. 2