european industrial pharmacy issue 28 (march 2016)

ISSUE 28 • MARCH 2016www.industrialpharmacy.eu

www.eipg.eu

features4 THE EU-FMD CLOCK IS TICKING!

This article examines key requirements of the“Safety Features” Delegated Regulation anddiscusses the implications for pharmamanufacturers and other participants in theEuropean pharma supply chain.by Christoph Krähenbühl

7 NEW PERSPECTIVES FOR GENE DETECTION The “ClickGene“ European Network (Horizon 2020) iscommitted to educating next generationresearchers in the assessment of new pathways forpersonalised medicine and innovative diagnosticapplications.by Birgit Oberleitner and Antonio Manetto

10 IMMUNO-ONCOLOGY: THE NEW WEAPONSFIGHTING CANCERRecent immuno-oncology developments in PD-1/PD-L1 checkpoint inhibitors, CAR-T therapies andcancer vaccines mean we appear to be on theverge of a treatment paradigm shift in medicalhistory.by Peter Murphy and Kelly Lambrinos

15 TRANSFORMING BIG PHARMA FORTUNESBY REPLACING PATENTS WITH PATIENTSAs Big Pharma is pummelled for staggeringly highdrug prices and poor R&D productivity, this articledigs deep to unearth the underlying cause of theissues—the crack of the patent gun. It thenproposes radically new ideas to transform thisindustry in crisis.by Hedley Rees

regulars3 EDITORIAL COMMENT19 NEWS FROM THE EIPG20 REGULATORY REVIEW23 BOTTLED BROWN24 EVENTS

europeanINDUSTRIALPHARMACY

2 european INDUSTRIAL PHARMACY March 2016 • Issue 28

europeanINDUSTRIALPHARMACY

March 2016ISSN 1759-202X

MANAGING EDITORSue Briggs

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldClaude FarrugiaMichael Gamlen

Linda HakesJohn Jolley

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europeanINDUSTRIALPHARMACYdiscussion group:

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european INDUSTRIAL PHARMACYis the official publication of the European IndustrialPharmacists Group (Groupement des Pharmaciens del’Industrie en Europe) www.eipg.eu

Cover photo: Pharmacist scanningmedicine pack (see The EU-FMD clock isticking! on page 4)

associate editors

Belgium: Philippe Bollen

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Janet Halliday

Greece: Giorgos Panoutsopoulos

Hungary: Sylvia Marton

Ireland: Stan O'Neill

Italy: Piero Iamartino

Latvia: Inta Saprovska, Anita Senberga

Malta: Claude Farrugia

Netherlands: Amon Wafelman

Norway: Quynh Li

Spain: Beatriz Artalejo

Switzerland: Valter Gianesello, Maurizio Battistini

EIPG: Energy,Inclusivity,Professionalism,GrowthEIPG is an active and vibrantorganisation representingindustrial pharmacists acrossEurope. This was the first thing Ilearned about EIPG when I joinedby working as a Finnish countrydelegate back in 2010 in Milan,where we had a wonderfulGeneral Assembly, my first one.Ever since, I have been honoured to representFinland as a country delegate and it has beenextremely rewarding at a personal level all theseyears. Thank you for that! In 2014, I was elected to the Bureau of EIPG as a

Vice-President for Education and Careers. In thisposition, my responsibility is to collaborate withstudents and promote self-education, work closelywith universities and other stakeholders providingcourses and training for self-improvement andcontinuous education. Learning should not stop witha degree in pharmacy. We all know that. To be “on-board”, one must develop and improve know-howconstantly. EIPG provides many good andcomprehensive channels for self-development!Scientific journals, active websites and social media,as well as close collaboration with universities andorganisations providing courses are some examplesto be mentioned. Last, but not least, we havelaunched webinars over a year ago and this new wayto learn from your home or your place of choicemakes learning and self-development easy and free-of-charge!Webinars, organised in conjunction with the

European Pharmaceutical Student Association (EPSA),have turned into a success story. We are very proudof this, and of our valuable and fruitful collaboration.EPSA represents students who study pharmacy inEurope. This collaboration brings students and

professionals together and, byestablishing these connections,facilitates and encourages knowledge-sharing and networking. Collaborationwith students is one of our core values.Of course, this is understandable asstudents are our future!What have I learned during these

years as a member of EIPG? There aremany potential points to bementioned but I will summarise a few Ihave valued the most. First, as amember of the Finnish PharmacistsAssociation (Suomen Farmasialiitto), Iam also a member of EIPG as our

national organisation is a member of EIPG. Thismeans that I have access to all the benefits EIPGoffers, for example, to this excellent journal you arereading at this very moment. This is a valuablemember benefit and an easy way to update yourself.Secondly, by being a part of the EIPG family, I havehad the opportunity to meet several, topprofessionals and have had the chance to engage infruitful talks and meetings with these people. You caneasily join our network by contacting us! Also, as amember of EIPG, you get the first seat to the hottestnews in the pharmaceutical industry. As this sector isconstantly evolving, staying on top of the latest newsis important! Thirdly, this organisation wants to do itsbest to ensure that we have this profession on-goingalso after 10, 20 and 50 years. Who knows, evenhundreds of years! This professional promotion thatEIPG undertakes for industrial pharmacists issomething to be much appreciated and treasured!EIPG is having its 50th anniversary this year! I invite

you to join our journey alongside us!

Anni SvalaVice-President Education and Careers

3european INDUSTRIAL PHARMACY March 2016 • Issue 28

editorial

The “Safety Features”Delegated RegulationOn 9 February 2016, the long-awaited European FalsifiedMedicines Directive (EU-FMD)“Safety Features” DelegatedRegulation was published in theOfficial Journal of the EuropeanUnion. This Delegated Regulationsets out the details of the “SafetyFeatures” provisions to beimplemented under the EU-FMD,such as the nature of the mandatorysafety features and how these are tobe used. The Delegated Regulationalso confirms the medicinalproducts that are in scope of theregulations and what theresponsibilities of the variousstakeholders are in this Europe-widemedicines verification process. Mostcritically, the formal publication ofthe Delegated Regulation marks thestart of the 3-year implementationtimeline to achieve compliance bythe early 2019 deadline that comesinto force across Europe. The key provisions of the

Directive and the DelegatedRegulation are well understood by

now, so a brief summary shouldsuffice. Key elements are, firstly, therequirement that in Europe allprescription drugs (with few, clearlydefined exceptions, see black-/white-list approach describedbelow) as well as some over-the-counter (OTC) products must carrysafety features consisting of a

Unique Identifier (UI) on each packcombined with anti-tamperingdevice (ATD). Secondly, thatmedicinal products will need to beverified routinely at the point-of-dispense as well as – risk-based – inthe supply chain (see Figure 1) and,thirdly, that a Europe-wideinfrastructure of “repositorysystems” will need to beestablished to support this end-to-end process.

EU-FMD scope: products,participants and countriesA few points are worth highlighting,first of all the products, participantsand countries that are in scope ofthis legislation. To start with, the EU-FMD covers

not just the 28 EU Member Statesbut also the three EuropeanEconomic Area (EEA) members,Iceland, Norway and Lichtenstein(Switzerland is likely to align aswell). There is the provision thatMember States that already applyserialisation to their packs, such asvignettes or Bollini in Belgium, Italyor Greece, might benefit from adeadline extended by 6 yearsalthough it is by no means certainthat all three of these MemberStates will choose to follow thislonger deadline, given thecomplications that would arise bythe common use of shared markedpacks.What is clear is that all

manufacturers of medicinal

european INDUSTRIAL PHARMACY March 2016 • Issue 28

THE EU-FMD CLOCK ISTICKING!by Christoph Krähenbühl

The publication of the “Safety Features” DelegatedRegulation on 9 February marked the start of the

3-year implementation countdown to the 2019 EuropeanFalsified Medicines Directive (EU-FMD 2011/62/EC)deadline. This article examines key requirements in detailand discusses the implications for pharma manufacturersand the other participants in the European pharmasupply chain.

Christoph Krähenbühl has been involved in serialisation projects since 2006, including asproject manager for the implementation of the global serialisation system forAstraZeneca, one of the early adopters and global leaders in pharma serialisation. In2012, Christoph founded 3C Integrity, specialising in consulting and training in pharmaserialisation, which joined forces on 1 January 2016 with Excellis Health Solutions to form3C Excellis Europe. 3C’s core business is to support pharma companies – brand owners,generic manufacturers, contract packers, from large enterprises that are active worldwideto small specialised companies – in shaping up, planning and delivering their serialisationprogrammes. Since 2009, Christoph has also been supporting EFPIA and the EMVO intheir work to prepare the industry stakeholder response to the EU-FMD requirements thatis now culminating in the roll-out of the EMVS at European level and across allparticipating Member States.

4

Figure 1: Point-of-dispense medicines verification process.

THE EU-FMD CLOCK IS TICKING! continued


products supplying the Europeanmarket are now tasked withupgrading their manufacturingcapabilities to apply the UI andATD, regardless of whether they arebrand owners, contractmanufacturers, generics companiesor repackagers/parallel traders. But manufacturers are not the

only participants in thepharmaceutical supply chain thatare affected: the requirement tocarry out risk-based verification inthe supply chain puts an obligationon wholesalers and distributors toverify and/or decommissionmedicinal products in situationswhere a higher risk is present, suchas returns or shipments not directlyreceived from the manufacturer orthe manufacturer’s direct distributor.In addition, the DelegatedRegulation describes a whole rangeof use cases where wholesalers mayneed to verify and decommissionpacks, for example, those that areexported from Europe, returns thatcannot be sold, products intendedfor destruction, etc.

Member States empoweredThe need to accommodate the richvariety of processes across theparticipating markets is reflected inthe regulation’s provisions that allowMember States to define additionalpoints in their national supplychains when the verification of thesafety features and thedecommissioning can be delegatedto wholesalers. This includes supplyto nursing homes, hospices, prisons,“universities and other highereducation establishments usingmedicinal products for the purposesof research and education”, “armedforces, police and othergovernmental institutionsmaintaining stocks of medicinalproducts for the purposes of civilprotection and disaster control”,emergency services, etc. HowMember States will interpret thisprovision is not yet clear but, giventhe primary aim of the EU-FMDlegislation to protect patients byclosing all loopholes through whichcounterfeit medicines mightinfiltrate the legal medicines supply

chain, it would be a safe assumptionthat national authorities will want tomaximise the powers granted themby the European legislation.Similarly, Member States are

entitled to refine the scope ofapplication of the UI or the ATDbeyond what has been defined bythe Europe-wide risk-basedapproach: by default all prescriptionmedicines are in scope (unless theyare white-listed) and OTCmedicines are out of scope (unlessthey are black-listed). The initialwhite- and black-lists that havebeen released along with theDelegated Regulation offer nosurprises: the list of prescriptionmedicines that are excludedcontains radionuclides, medicinalgases, intravenous solutions in ATC(Anatomical Therapeutic Chemical)therapeutic subgroup B05B “bloodsubstitutes and perfusionsolutions”, contrast media, as wellas homeopathic medicinal productsamongst others. The proposedblack-list of OTC products that willbe subject to the safety featuresrequirements is even shorter andcurrently consists of two strengthsof omeprazole capsules. Theinclusion of this product gives agood indication of how the risk-based approach will beadministered: this is not only aproduct that is OTC in somemarkets but prescription-only inother markets, but omeprazole wasalso subject of falsification alerts inretail pharmacies in April 2013 (inGermany). Member States, however, can

extend (but not reduce) the scopeof application of the UI or the ATDas follows. For the purpose ofreimbursement or pharmaco-vigilance, any medicinal productsubject to prescription orreimbursement can be included or –for the purpose of patient safety –the scope of application of the ATDcan be extended to any medicinalproduct. How this provision will playout in practice remains to be seen,although what is clear is that thiswill, in practice, affect mainly OTCproducts (given that prescriptiondrugs are by default already subject

to the Europe-wide UI/ATDrequirement).

Getting ready:manufacturers, wholesalers,pharmacistsThere are several areas of activity thatneed to be undertaken to ready thepharma supply chain into Europe.The first of these has already beenmentioned, the work that needs tobe completed by all pharmamanufacturers to establish their in-house capabilities to applyserialisation and ATD to theirproducts. Experience from earlyadopters has shown that it is not atrivial task to equip pharmaceuticalmanufacturing lines with thenecessary technology which is,moreover, only part of the picture:complying with the EU-FMD’s datareporting and data retentionrequirements means, in practice, thatevery manufacturer will be looking atestablishing a serialisation datarepository to manage this vital datasecurely and reliably. After all, oncethe EU-FMD has come into forceacross Europe, the definition ofquality product changesfundamentally – a pack in the marketwithout a corresponding “highquality” UI available for validation, forthe duration of its shelf-life, is nolonger a “good pack” and cannot besold.But manufacturers are not the only

participants in the pharma supplychain who will need to establishadditional technical capabilities. Therequirement on distributors andwholesalers that has beenmentioned before, in particular, willdemand investment in newtechnology and the introduction ofadditional process steps presentinga challenge that should not beunderestimated.Similarly, the key players at the

other end of the medicinal supplychain, the pharmacists, are nowtaken to task to scan every pack ofmedicines that is dispensed to thepublic. The role that comes first tomind is that of communitypharmacists where scanningtechnology and additional processsteps now come into play, but let us

not forget that there are a plethoraof other situations where similarsystem interactions will become partof daily operations.

Getting ready: Europe-wideinfrastructure of “repositoriessystems” All these process steps are linked tothe Europe-wide infrastructure of“repositories systems” required bythe FMD that will be needed tosupport the routine verification of allmedicinal products at the point-of-dispense. The bitter pill thatmanufacturers have had to swallowhas been the provision in theoriginal directive stating that it is thepharma manufacturers who have tofund the establishment and on-going operation of thisinfrastructure. The spoonful of sugarto help that particular medicine godown is the European Commission’ssupport of the approach embodiedby the European MedicinesVerification System (EMVS) which iscurrently being rolled-out acrossEurope by the European MedicinesVerification Organisation (EMVO)that was set up in February 2015 asa collaboration between theorganisations representing the mainstakeholders in the Europeanpharmaceutical supply chain – theEuropean Federation ofPharmaceutical Industries andAssociations (EFPIA), the Medicinesfor Europe (formerly the EuropeanGeneric Medicines Association), theEuropean Association of Euro-Pharmaceutical Companies, theGroupement International de laRepartition Pharmaceutique (theEuropean Healthcare DistributionAssociation) and the PharmaceuticalGroup of the European Union.The central piece of this

infrastructure, the European Hubthat the manufacturers will connectto in order to upload the UI data,was implemented in 2014 and isnow in ramp-up mode, connectingan increasing number of pharmamanufacturers via a standard

interface to the manufacturers’internal serialisation data repository(see Figure 2). The companion pieces, the

national repositories, are following,with the first national system –Germany’s SecurPharm – live since2014 and connected to theEuropean Hub since mid-2015. Inorder to help the remaining marketsmake the tough 2019 deadline – andto achieve consistency andinteroperability, as well as cost-efficiency – the EMVO has selectedthree providers of so-called‘blueprint’ systems (i.e. nationalsystem solutions that are fullycompliant with the EMVS userrequirements) that are stronglyrecommended to be selected as thebasis for the national systems.

EMVO and NMVOsSo who will choose, establish andoperate these national systems?This is the – formidable – task of theNational Medicines VerificationOrganisations (NMVOs) that willneed to be established in everyEuropean country. The process of setting up the

NMVOs has started across Europeand will gather pace through 2016.While the detailed steps and theprocess of how these NMVOs will be

set up will vary between countries toreflect their specific circumstances, itwill generally follow a similar course. The national representatives of

the key pharma supply chainstakeholders are coming together,supported by the EMVO and thepreparatory work that has beendone at European level over the lastfew years, to reach a commonunderstanding. In line with thelegislation, the NMVO – and laterthe national systems – will be set upand managed by the industrystakeholders, with NationalCompetent Authorities playing ahands-off supervisory role.Following the establishment of

the legal entity, a technical projectteam will be appointed that willengage with the vendors and selectthe most suitable technical solution.In parallel, the NMVO will need toset up an organisation to take overownership of the national system, tomanage the day-to-day operationand provide the support to theinvolved pharmacists, wholesalersand manufacturers who are going torely 100% on the functioning of thisinfrastructure of interoperablesystems that are going to beessential to the provision of safemedicines to each and everyEuropean citizen.


THE EU-FMD CLOCK IS TICKING! continued

Figure 2: The European Medicines Verification System (EMVS).

IntroductionClick chemistry was developed toprovide an easy method to join twoorganic molecules with high yieldsin mild conditions. Probably, thebest example among this class ofefficient chemical reactions is thecopper(I) catalysed [3+2] azide-alkyne cycloaddition (CuAAC)reaction (Figure 1).Since its discovery by M.P. Meldal

and K.B. Sharpless in 20021,2, theCuAAC forming 1,2,3-triazolesbecame the epitome of clickchemistry due to its reliability,specificity and biocompatibility.Click chemistry is largely used indifferent scientific areas, such asdrug discovery, bioconjugation,polymer and supramolecularchemistry3. The triazole ring formedby this reaction is more than just asimple linking unit: it has shown itspotential as a very importantpharmacophore, widely used inmedicinal chemistry4,5. Thisparticular Cu(I) catalysed

cycloaddition reaction has a greatimpact on, for example, chemicaltransformations as it allows theproduction of new classes ofmaterials and libraries of moleculeswith applications in biologicalsystems. Main advantages of theCuAAC over traditionalbioconjugation methods can befound in its unique properties.

• The functional alkyne and azidegroups are biorthogonal and,therefore, ensure pure, sideproduct-free conjugates inbiological environments.

• These regio- and stereospecificreactions are high yielded, veryfast and allow for mild workingconditions and tight control.

In addition, this chemicalmodification strategy can be usedto attach novel functionalities to thenucleic acid molecule opening theway to innovative studies ofunsolved biological questions. Such

applicationsinclude, but are notlimited to,moleculardiagnostics, forexample, thesynthesis of DNAmicroarrays6,

molecular probes7, antisenseoligonucleotides8,9, and short-interfering RNAs10. Furthermore,synthetically modified nucleic acidderivatives are constantly used asantiviral and anti-tumour agents,and for the regulation of geneexpression. In next-generation medicine,

gene therapy will play an importantrole by correcting the geneticcauses of disease, consequentlyfacilitating a personalised approach.Current gene therapy methods,such as viral vectors, often sufferfrom undesirable side effects,including insertional mutagenesis,toxicity, low efficiency and off-targetcutting11. Another unsolved issue isthe optimal method for deliveringnucleic acids into cells and tissues.The aim of these strategies is toachieve the stable expression oftransgenes in cells or tissues for theperiod required, in a specific region,without side effects, such as toxicityor carcinogenic transformation.

Click chemistry and theEuropean Commission The above described limitations willbe thoroughly studied within theunique and innovative approach ofthe European training networkClickGene, a research project in thefield of click chemistry and genetherapy. The modification,activation, modulation andrepression of DNA functionaldomains holds an immensepotential for human healthapplications. The main researchfocus of this network is to developnew knowledge and methods forgenetic engineering while training anew class of young scientists in thisfield. To reach these ambitiousgoals, ClickGene bases its researchon three different pillars.

• Unique gene silencing toolsthat interact with DNA in afundamentally different waycompared to state-of-the-arttechnology.

• New liposomal nanoparticles asdrug delivery agents.

• Novel fluorogenic probes forepigenetic base detection inhigh-throughput polymerasechain reaction (PCR) assays.


NEW PERSPECTIVES FORGENE DETECTIONby Birgit Oberleitner and Antonio Manetto

The term click chemistry, introduced by the nobellaureate K.B. Sharpless in 2001, refers to the

possibility to synthesise complex molecules in a simpleand rapid way. The copper(I) catalysed azide-alkynecycloaddition (CuAAC) is the most prominent example ofthis group of reactions. baseclick GmbH, a member of theEuropean training network “ClickGene” (Horizon 2020),set out to develop a new click chemistry-based assay toimprove current gene detection approaches.

Dr. Birgit Oberleitner is the Head of Business Development and Marketing at baseclickGmbH, Neuried, Germany (www.baseclick.eu).

Dr. Antonio Manetto is the company’s Chief Scientific Officer and PhD supervisor in theClickGene program.

Figure 1: Schematic representation of CuAACreactions.

NEW PERSPECTIVES FOR GENE DETECTION continued

What baseclick will add tothis programAlready awarded with aninternational EU Initial TrainingNetwork grant in 2013 that isfocused on the application of DNAnanotechnology in life sciences andbiomedicine (EScoDNA), baseclick isagain a full partner in such aprivileged network, the Horizon2020 Innovative Training Network.The so-called ClickGene consortiumbrings together leading scientists inthe field of click chemistry and genetherapy. baseclick fits perfectly inthis list of outstanding members, asits core technology is the clickreaction, and it holds an exclusiveworldwide license for the use of thisclick chemistry technology in thefield of nucleic acids. Gene therapy and molecular

diagnostics are nowadays regardedas revolutionary tools inpersonalised medicine. The cells in all organisms regulate

gene expression by adjusting thegene transcripts (messenger RNA(mRNA)): the level of geneexpression in a cell can be

measured by the number of copiesof mRNA transcript of that genepresent in a sample. To detect andquantify gene expression from smallamounts of RNA, an amplification ofthe gene transcript is usuallyneeded. The PCR is a commonmethod for amplifying DNA; formRNA-based PCR the RNA sampleis first transcribed into cDNA withreverse transcriptase. baseclickGmbH aims to develop a new clickchemistry-based assay capable offacilitating, speeding up andimproving the sensitivity of thedetection of gene/transgenes intissue. Such new methods couldeventually allow the development ofpoint-of-care methods or devices forrapid, reliable and easy detection of(trans-)genes. The main approachesfollowed at baseclick include thefollowing.

Gene/transgene detectionvia fluorescence in situhybridisation (FISH) assay Active genes/transgenes areexpressed through the transcriptionof the DNA sequence into mRNA.

These mRNA strands can beselected by their complementaryDNA (e.g. PCR products or syntheticoligonucleotides), which are labelledgenerally with fluorescent dyes,biotin and others. Using thisfluorescence in situ hybridisation(FISH) technique, it is possible tovisualise mRNA synthesis within cellsby fluorescent microscopy,fluorescence-activated cell sorting,fluorescent reader, etc. However, thistechnique still lacks from lowlabelling rates, low sensitivity andlow selectivity of the probes.baseclick GmbH will investigate theuse of multi-labelledoligonucleotides prepared by clickchemistry as efficient FISH probes.Using these probes, RNA moleculeswill be simultaneously detected,localised and quantified at the sub-cellular level in fixed samples, usingwide field fluorescence microscopy.In a first approach, a pool of multi-fluorescent-labelled oligonucleotideswill be designed as complementarystrands of the target sequence. Theywill then be used in a standard FISHexperiment in target cells followed


Figure 2: ELISA-like assay using click chemistry at baseclick GmbH.

by fluorescence microscopy. Efficientand cost-effective sample synthesispaired with high labelling rates andthus decreased probe quantityrequirements makes this a superiorapproach compared to the state-of-the-art techniques. The setup caneventually be applied to the directdetection of non-purified/isolatedmRNA in more complex samples.

Gene/transgene signal-amplification/detection viachromogenic in situhybridisation (FISH) assayIn a second approach, the detectionof gene activity will be achieved bysimple signal amplification. Herein,a pool of multi-labelledoligonucleotides will be hybridisedto their target (mRNA) before theclick reaction will be performed.The signal amplification will be aresult of azide derivatives ofenzymes (such as peroxidase,alkaline phosphatase or horseradishperoxidase), undergoing a colourchange by the addition of itssubstrate (ELISA-like assay),

visualised under a standard bright-field microscope or ELISA reader(Figure 2).The project ClickGene officially

started in January 2015 and willcontinue until the end of 2018. Itgave 14 Masters students theopportunity to perform their PhDthesis in another EU country. SinceAugust 2015, a Masters studentfrom the University of Rome TorVergata, Stefano Croce has beenconducting his PhD project atbaseclick, working on exploring theoptions mentioned above.

References 1 Rostovtsev VV, Green LG, Fokin VV,

Sharpless KB. A stepwise huisgencycloaddition process: copper(I)-catalyzedregioselective “ligation” of azides andterminal alkynes. Angew Chem Int Ed2002;41:2596–2599.

2 Tornøe CW, Christensen C, Meldal M.Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions ofterminal alkynes to azides. J Org Chem2002;67:3057–3064.

3 Hein JE, Fokin VV. Copper-catalyzedazide-alkyne cycloaddition (CuAAC) andbeyond: new reactivity of copper(I)

acetylides. Chem Soc Rev2010;39:1302–1315.

4 Thirumurugan P, Matosiuk D, Jozwiak K.Click chemistry for drug developmentand diverse chemical-biologyapplications. Chem Rev2013;113:4905–4979.

5 Agalave SG, Maujan SR, Pore VS. Clickchemistry: 1,2,3-triazoles aspharmacophores. Chem Asian J2011;6:2696–2718.

6 Miller MB, Tang YW. Basic concepts ofmicroarrays and potential applications inclinical microbiology. Clin Microbiol Rev2009;22:611–633.

7 Seo TS, Bai XP, Ruparel H, et al.Photocleavable fluorescent nucleotidesfor DNA sequencing on a chipconstructed by site-specific couplingchemistry. Proc Natl Acad Sci USA2004;101:5488–5493.

8 Izant JG, Weintraub H. Inhibition ofthymidine kinase gene expression by anti-sense RNA: a molecular approach togenetic analysis. Cell 1984;36:1007–1016.

9 Uhlmann E, Peyman A. Antisenseoligonucleotides: a new therapeuticprinciple. Chem Rev 1990;90:543–584.

10 Bumcrot D, Manoharan M, Koteliansky V,Sah DWY. RNAi therapeutics: a potentialnew class of pharmaceutical drugs. NatChem Biol 2006;2:711–719.

11 Gardlik R, Pàllfy R, Hodosy J, et al.Vectors and delivery systems in genetherapy. Med Sci Monit 2005;11:110–121.

european INDUSTRIAL PHARMACY March 2016 • Issue 28 9

NEW PERSPECTIVES FOR GENE DETECTION continued

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PD1/PD-L1 Anti-programmed death (PD-1)inhibitors and anti-programmeddeath ligand 1 (PD-L1) inhibitors areimmunomodulators designed toinhibit the interaction between PD-L1, found on the surface of tumouror antigen-presenting cells, and PD-1, found on the surface of activatedlymphocytes. This interaction blocksthe negative regulation of T-cellactivation and allows the immunesystem to attack the cancerouscells. In 2014, Bristol-Myer’s Squibb

(BMS) saw the approval of itsmetastatic melanoma drug, Yervoy(ipilimumab), the first checkpointinhibitor to receive US Food and

Drug Administration approval. Thiswas followed by the approval ofanother BMS drug Opdivo(nivolumab), again for metastaticmelanoma and then later for non-small cell lung cancer (NSCLC). It iswidely regarded the largelyunrivalled treatment effects seen inmelanoma and lung cancer so farcould be just the tip of the iceberg.The push is to not only findeffective treatments for cancers withno current therapeutic options butto continually improve on thosecancers already benefitting fromhaving PD-1/PD-L1 checkpointinhibitors on the market.PD-1/PD-L1 inhibitors in

combination with platinum doublet

chemotherapy have oncologistsencouraged for future potential infirst-line NSCLC. One oncologistsaid the combination may offer apotential route for “PD-L1negative” patients to receive first-line treatment with checkpointinhibitors. Both Roche and Merckpresented Phase I data for their PD-1 and PD-L1 inhibitors, MPDL3280Aand Keytruda (pembrolizumab),respectively, in combination withplatinum doublet chemotherapy atlast year’s American Society ofClinical Oncology (ASCO). BMS’sOpdivo, a PD-1 inhibitor, did notshow overly impressive data incombination with platinum doubletchemotherapy. Both Roche andMerck have been using PD-L1expression to enrich clinical trials aspatients with higher PD-L1expressions are more likely torespond to these drugs, said oneinvestigator in the ongoingMPDL3280A trial. One oncologistnoted future patients considered“positive” for PD-L1 expression, arelikely to get single agent PD-1/PD-L1 inhibitors in the first-line setting.For low expressers of PD-L1, PD-1/PD-L1 inhibitors in combinationwith chemotherapy may benecessary for the cancerimmunotherapy to be used in thefirst-line setting.Checkpoint inhibitors in

combination with radiotherapy haveoncologists feeling encouragedabout future lung cancer treatmentpotential. Oncologists noted thecomplimentary mechanisms hadpotential to improve upon currentefficacy standards. As radiotherapyhas an immuno-modulatory effect,other types of cancerimmunotherapy could also havepotential in combination withradiotherapy. Experts told BioPharmInsight, the hypoxic niche, i.e. thetumour environment, suppressesthe immune system, however,irradiating the tumour stimulatesthe immune system against thetumour by increasing dendritic cellproduction. By destroying lesions,radiotherapy is able to increase theexpression of antigens, which inturn is likely to enhance the efficacyof the immune checkpointinhibitors.

european INDUSTRIAL PHARMACY March 2016 • Issue 2810

IMMUNO-ONCOLOGY: THENEW WEAPONS FIGHTINGCANCERby Peter Murphy and Kelly Lambrinos

There has seldom been a word used in thebiotechnology space that has generated quite as much

excitement as the word immuno-oncology (IO). Recentdevelopments in anti-programmed death (PD-1)/anti-programmed death ligand 1 (PD-L1) checkpoint inhibitors,chimeric antigen receptor T cell (CAR-T) therapies andcancer vaccines have given oncologists more weapons intheir often underpowered arsenal. It is apparent we couldbe on the verge of a treatment paradigm shift in medicalhistory as new innovations hone the ability to harness thepower of the body’s own immune system. Investigatingthe current developments in the field, we talk to expertsin IO to give a brief overview of the current drugcandidates in developments.

Peter Murphy is a senior healthcare analyst at BioPharm Insight, and is based in London.He has a first-class honours BSc degree in chemistry from Newcastle University, UK. Healso undertook 3 years of medical school training before joining the BioPharm Insighthealthcare analyst team. Peter has obtained the CFA Society’s Investment ManagementCertificate and is an associate member of the Chartered Institute for Securities andInvestment.

Kelly Lambrinos is a healthcare analyst at BioPharm Insight and is based in New York. Priorto joining BioPharm Insight, Kelly held a researcher position at Innovative ScienceSolutions, a full-service scientific and strategic regulatory consulting firm. Kelly has a BSc inbiology from the University of Athens, Greece and earned a Master’s degree inbiotechnology from Columbia University. Her Master’s thesis focused on comparing theestablished guidelines, approval rates and length of the approval process for biologicsbetween the US and EU.

IMMUNO-ONCOLOGY: THE NEW WEAPONS FIGHTING CANCER continued


Strong efficacy data backing IOdrugs has oncologists excited forfuture clinical potential in small-celllung cancer (SCLC). However,according to some, considerabletoxicities observed withcombination IO therapies couldlimit their applicability in frailerpatients. The combination appearsto increase response rates as Yervoyprimes T-cells, allowing them toinfiltrate the tumour moreeffectively and generate the

inflammatory phenotype that makesOpdivo more active. There isparticular concern about thecombination’s synergistic toxicities,particularly for patients who areperformance status 2 or 3, said oneexpert. Whilst in melanoma it maybe tolerable, the SCLC patientpopulation is older and tend to beheavier smokers so are unlikely totolerate the combination. Despite some early efficacy

potential in NSCLC, Merck and

AstraZeneca’s IO combinations facesignificant tolerability issues.Autoimmune toxicities in both trialsmade oncologists hesitant aboutthese combinations. While therehave been no fatal toxicities withKeytruda/Yervoy, theaforementioned autoimmunetoxicities for both combinationswould be challenging to manage.MEDI4736/tremelimumab hadslightly better tolerability but not adramatic improvement, experts

Table 1: BioPharm Insight’s top five anti-PD-1/PD-L1 therapies on the market and in developmentDrug Company Indications Stage of Data expected/

development NDA* filing date

Opdivo (nivolumab) BMS – Pre-treated NSCLC Approved N/A

– First-line NSCLC Phase III November 2016

– Advanced metastatic melanoma Approved N/A

– Advanced gastric cancer Phase III August 2017

– Renal cell carcinoma Approved N/A

– Follicular lymphoma Phase II December 2016

– Diffuse large B-cell lymphoma Phase II February 2016

– Squamous cell carcinoma of the head and neck Phase III October 2016

– Metastatic triple negative breast cancer Phase II August 2019

– Advanced urothelial cancer Phase II April 2016 (start)

– Classical Hodgkin’s lymphoma Phase II August 2016

Keytruda Merck – Pre-treated NSCLC Approved N/A(pembrolizumab) – First-line NSCLC Phase III June 2016

– Advanced metastatic melanoma Approved N/A

– Advanced gastric cancer Phase III May 2018

– Diffuse large B-cell lymphoma Phase II July 2018

– Squamous cell carcinoma of the head and neck Phase II May 2016 (start)

– Metastatic triple negative breast cancer Phase III May 2017

– Advanced urothelial cancer Phase III January 2017

– Classical Hodgkin’s lymphoma Phase II July 2018

Atezolizumab Roche – Pre-treated NSCLC Filing NDA First quarter 2016

– First-line NSCLC Phase II January 2017

– Renal cell carcinoma Phase II December 2017

– Metastatic triple negative breast cancer Phase III May 2019

– Advanced urothelial cancer Filing NDA First quarter 2016

Durvalumab AstraZeneca – Pre-treated NSCLC Filing Second quarter 2016

– First-line NSCLC Phase III March 2017

– Squamous cell carcinoma of the head and neck Filing NDA 2016

– Metastatic triple negative breast cancer Phase II June 2017

– Advanced urothelial cancer Phase III November 2017

Avelumab Pfizer – Pre-treated NSCLC Phase III October 2021

– First-line NSCLC Phase III February 2018

– Advanced gastric cancer Phase III November 2018

– Ovarian cancer Phase III February 2018

* NDA: new drug application; Source: BioPharm Insight

added. As these trials have verysmall, carefully selected groups ofpatients, tolerability could even beworse in the general population,one oncologist noted.Prior to the unprecedented fast

approval of Opdivo in second-lineNSCLC, BioPharm Insight reportedthe approval of Opdivo could spellthe end for docetaxel in thesecond-line setting and hamperuptake of Eli Lilly’s Cyramza.Although Cyramza is unlikely to beused in patients that have receivedfirst-line Avastin due to thesimilarities in mechanisms, there isno doubt that Cyramza improvesupon the efficacy of docetaxel whenused in combination. However,there is only a marginal efficacyincrease, noted one oncologist. Bycomparison, Opdivo greatlyimproves upon the efficacy ofdocetaxel, all experts noted. BMS’s Phase III Checkmate 214

trial of Opdivo with Yervoy hasgood chances of showingsignificant improvement inprogression-free survival in renal cellcarcinoma, experts told BioPharmInsight. Yet, demonstrating anoverall survival benefit will bedifficult, they added. The trueimpact of the combination of thesecheckpoint inhibitors is seen in thelonger response observed in asmaller proportion of patients,experts noted. Median overallsurvival will not be as impressive, if

this subset is the minority ofpatients. The field for PD-1 and PD-L1

inhibitors in ovarian cancer is stillnascent, experts told BioPharmInsight. Despite this, Merck’s KGaAand Pfizer’s PD-L1 inhibitoravelumab has experts cautiouslyoptimistic about immunecheckpoint inhibitors in ovariancancer, with the hope thatcombinations might increaseresponse rates. Better responses inless heavily pre-treated patientsindicate that the PD-L1 inhibitormay be more efficacious earlier inthe treatment process. Therelatively good side-effect profile ofthe drug also offersencouragement, experts noted.Table 1 gives a breakdown of

various anti-PD-1/PD-L1 therapiesand details the indications in whichthe therapies are being trialled. Thestage of development and the datethe results of each trial areexpected are also given.

CAR-T Chimeric antigen receptor T cells(CAR-Ts) are genetically engineeredT-cell receptors that redirectspecificity and enhance T-cellfunction. T-cells are extracted fromthe patient, modified and grown inthe laboratory until there is asufficient number for reinfusion.These CAR-T cells bind to specificsurface antigens on the patient’s

own cancerous cells and multiply innumber to mount an immuneresponse.Data from several studies of the

eagerly anticipated CAR-T therapiesin haematological malignancieswere presented at ASCO 2015. Datafrom a Phase I study of JunoTherapeutics’ JCAR015 inrelapsed/refractory acutelymphoblastic leukaemia and innon-Hodgkin’s lymphoma, waspresented, as well as JCAR014 inacute lymphoblastic leukaemia,non-Hodgkin’s lymphoma andchronic lymphoblastic leukaemia.Novartis presented CTL019 data onnon-Hodgkin’s lymphoma andmultiple myeloma, while KitePharma presented data on KTE-C19in patients with diverse B-celltumours. Despite very promisingearly stage efficacy signals, thesentiment from experts is that CAR-T therapies have become morepredictable in terms of toxicity, butchallenges still remain. There aresome toxicity predictors, such asmore cytokines, to which physicianscan respond by giving patientsprophylaxis, for example withsteroids. However, while steroidscan be used to mitigate some ofthe toxicity, they can also reducethe CAR-Ts’ activity because theykill T-cells. Experts highlightedcytokine release syndrome (CRS) asbeing the main toxicity that worriesphysicians, and the various



Table 2: BioPharm Insight’s top five CAR-T cell therapies in developmentDrug Company Indications Stage of Data expected/


CTL019 Novartis – Adult acute lymphoblastic leukaemia Phase II June 2017

– Paediatric acute lymphoblastic leukaemia Phase II November 2017

– Diffuse large B-cell lymphoma Phase II October 2021

– Multiple myeloma Phase I 2016

JCAR015 Juno – Acute lymphoblastic leukaemia Phase II December 2016Therapeutics – Adult non-Hodgkin’s lymphoma Phase I April 2016

KTE-C19 Kite Pharma – Diffuse large B-cell lymphoma Phase II March 2017

– Mantle cell lymphoma Phase II September 2017

– Acute lymphoblastic leukaemia Phase I/II March 2017

– Chronic lymphocytic leukaemia Preclinical March 2016 (start)

bb2121 bluebird bio – Relapsed/refractory multiple myeloma Phase I December 2016

BPX-601 Bellicum – Prostate cancer Phase I June 2016 (start)

* NDA: new drug application; Source: BioPharm Insight


therapies appear pretty similar inthat regard except for when CRSbegins. CRS starts early with CD28CAR-Ts like Kite’s KTE-C19 andJuno’s JCAR015, whereas CRS startslater with 4-1BB-based therapiessuch as Novartis’ CTL019 and Juno’sJCAR014. In addition, 4-1BB CAR-Ts’ greater persistence can lead toB-cell aplasias, which in turn leavesuncertainty as to whether patientswill become more susceptible toinfections, experts noted. CAR-T toxicity concerns are

prompting expert discussion ontheir potential use in the treatmentof glioblastoma mulitforme (GBM).One expert told BioPharm Insight,the 4-1BB co-stimulatory domainproduces lower cytokine productionthan the CD28 co-stimulatorydomain, while another said the lackof CRS or other major toxicitynevertheless seen with CD28 CAR-Ts in GBM could be due to the cellshaving less room to grow andmultiply than they do in bloodcancers like acute lymphoblasticleukaemia, given the ample spaceand abundance of B-cells for themto attack. Aurora Biopharma of Cambridge,

Massachusetts, is thecommercialisation partner for onestudy of “living drug” CAR-T agentAU-105 taking place at the BaylorCollege of Medicine, while City ofHope in Duarte, California, issponsoring another study of

IL13Ra2-specific CAR. FortressBiotech division Mustang Bio is thepartner for the City of Hopeprogram.Table 2 gives a breakdown of

various CAR-T cell therapies anddetails the indications in which thetherapies are being trialled. Thestage of development and the datethe results of each trial areexpected are also given.

VaccinesCancer vaccines are intended topromote tumour antigen specificimmune responses amongst thepatient’s own T-cell population.Many vaccine strategies are beingtested, including autologous andallogeneic tumour cell vaccines,protein/peptide-based cancervaccines and genetic vaccines.The Phase II overall survival

benefit observed with Celldex’sRintega in EGFRVIII-mutatedglioblastoma (EGVRvIII+ GBM), hasexperts believing it maydemonstrate similar Phase IIIefficacy. However, the heterogeneityof glioblastoma raises scepticismregarding the effect magnitude,since the vaccine only targetscancer cells expressing the EGFRvIIIantigen thus leaving behind aportion of the tumour without themutation. Experts told BioPharmInsight, use of the vaccine in thefrontline – when tumours aregenerally more homogenous before

extensive genetic modifications –has a good chance of improvingoverall survival. Bavarian Nordic’s vector-based

vaccine for metastatic castrate-resistant prostate cancer (mCRPC)patients has triggered restrainedoptimism regarding the success ofthe Phase III trial. Expert confidencewas largely based on theencouraging Phase II Prostvacefficacy and safety outcome inwhich the overall survival benefitwas significant and on par withapproved therapies. Nonetheless,they highlighted the need forappropriate biomarkers – currentlylacking in mCRPC immunotherapystudies – which would enableassessing the improvement inprogression-free survival. Oneexpert also explained prior patientexposure to recently approved anti-androgen drugs in the Phase IIIstudy could improve overall survivalfor both treatment and placebogroups and subsequently decreasethe Phase III overall survivaladvantage compared to Phase II. VentiRx Pharmaceuticals’ toll-like

receptor (TLR) agonist VTX-2337(motolimod) which targets TLRs, orTLR8 in particular, has a scientificrationale to demonstrate beneficialsynergistic anti-tumour effects whencombined with pegylated liposomaldoxorubicin in platinum-resistantovarian cancer, according tooncologists. While they agreed it


Table 3: BioPharm Insight’s top five cancer vaccines in developmentDrug Company Indications Stage of Data expected/


Rintega Celldex – EGFRvIII-positive glioblastoma Phase III March 2016(rindopepimut) Therapeutics

Prostvac Bavarian – Asymptomatic or minimally symptomatic Phase III January/February (Rilimogene Nordic mCRPC 2017Glafolivec)

GVAX Pancreas Aduro Biotech – Metastatic adenocarcinoma of the pancreas Phase II First half 2016+ CRS-207

Axalimogene Advaxis – Recurrent/refractory cervical cancer Phase II First half 2017Filolisbac – HPV†-associated squamous cell carcinomas Phase I/II First half 2016

of the head and neck– HPV-associated anal cancer Phase I/II Second half 2016

INO-3112 Inovio – HPV-associated cervical cancer Phase I/II April 2019Pharmaceuticals/ – HPV-associated squamous cell carcinomas of Phase I/II December 2017MedImmune the head and neck

* NDA: new drug application; † HPV: human papilloma virus; Source: BioPharm Insight

was too early to comment on thePhase II efficacy outcome, they seethe trial sufficiently powered toshow a clinically meaningful overallsurvival improvement, and the side-effect profile seen so far ismanageable.Combining vaccines with a PD-1

checkpoint inhibitor reflects a soundscientific rationale which canaugment the vaccine’s immunestimulatory potential in variouscancers, according to experts. Theconcept of pairing Agenus’Prophage vaccine with a PD-1checkpoint inhibitor has triggeredexpert interest who characterisedthe combo as a “double-killer” withpotential to improve overall survivalin glioblastoma. While patients withlow PD-L1 expression seemed tobenefit the most from the vaccine inan investigator-sponsored Phase IIstudy, experts believe the combocan provide benefits to patients withhigh PD-L1 expression as well.

Despite some concerns that the duocan lead to an immune overreactionand subsequent autoimmune-related side effects, the Phase III trialshould demonstrate animprovement in overall survival. Combining Inovio

Pharmaceuticals and MedImmune’sINO-3112 vaccine with a PD-1checkpoint inhibitor can enhancethe immune system in humanpapilloma virus-causing cancers,according to oncologists. Pastvaccine monotherapy studies havenot demonstrated adequatelystrong immune responses. Thecombination with PD-1 checkpointinhibitors – which allow theinduction of prolonged T-cellproliferation – could potentiallychange that, one expert added.However, he stressed theimportance of establishing thevaccine’s effectiveness as amonotherapy prior to examining itspotential in combination with

another agent. According toanother expert, administering INO-3112 following chemoradiationcould trigger a subsequent immunereaction which the vaccine wouldfurther reinforce. Table 3 gives a breakdown of

various cancer vaccines and detailsthe indications in which thetherapies are being trialled. Thestage of development and the datethe results of each trial are expectedare also given. This analysis wasbased on investigative news articlesby Hamish McDougall in Londonand Manasi Vaidya and AlaricDeArment in New York.

Further readingBioPharm Insight. Immuno-OncologyReport – December 2015. London,UK: BioPharm Insight; 18 December2015. Available at:http://www.biopharminsight.com/immuno-oncology-report-december-2015



How is it looking for BigPharma these days?Big Pharma is not in good shape,neither by reputation nor in thebusiness sense, if you listen to themedia. Even taking much of it withthe customary pinch of salt, thebalance of evidence, certainly from apatient perspective, seems tosupport a damning picture.The recent much criticised Big

Pharma advertisement for opioid-induced constipation, during theSuper Bowl, is a recent example ofhow Big Pharma companies arebeing vilified. Many saw theadvertisement as an attempt to

capitalise on the opioid epidemicthat is plaguing the United States –apparently fuelled by the industryitself.This is just one of many examples.

Recent eye-watering prices beingcharged for new drugs, such as theGilead hepatitis C drug, hasreceived broad criticism frompatient groups and governmentsalike. A search engine trawl of thepharma press will list numbers ofother drugs, often for orphanindications, with hefty price tags.US legislation is now pushing for a

breakdown of the cost to developdrugs, as reported in the Los

Angeles Times1. The articlehighlights a crucial policy idea inPresident Obama’s $4 trillion budgetplan, labelled "EstablishTransparency and ReportingRequirements in PharmaceuticalDrug Pricing", which the reportsuggests is a bureaucratic way ofsaying that drug companies shouldhave to justify their high prices. Thereport concludes that certain drugs“cost a small fortune because drugcompanies can get away withcharging that much”.Less obvious, but still of great

concern, are the unscrupulousbusinessmen, such as Martin Shkreli,CEO of Turing Pharmaceuticals andJ. Michael Pearson, CEO at ValeantPharmaceuticals, who have beensnapping up out-of-patent productsdiscarded by Big Pharma andramping up the prices byastronomic proportions.If we add to this the fact that

estimates suggest ever-decreasingreturns on investment on researchand development in thepharmaceutical industry2, thensomething must have gone wrongsomewhere, mustn’t it?

What is behind it all?Figure 1 overleaf, reveals some starkfacts. The US GovernmentAccountability Office diagramdepicts the sickening attrition ratesin drug development – for every 250compounds entering thedevelopment pipeline, only onemakes it to market. Overlaid on thediagram is the underlying cause ofsuch a failure rate – the crack of thepatent gun.Once a new molecular entity

enters the development pipeline,with a robust patent lasting up to 20years behind it, the skids are putunder it. Figure 2 overleaf, is acartoon (courtesy of Dr GrahamCox, expert witness in Find It, FileIt, Flog It: Pharma’s CripplingAddiction and How to Cure It 3),somewhat tongue in cheek, butillustrating the principle.This haste to gain a regulatory

approval to market results in thedevastating failure rates. I haveresorted to calling this the ‘File It’stage of drug development, part ofthe industry’s overall approach to


TRANSFORMING BIGPHARMA FORTUNES BYREPLACING PATENTS WITHPATIENTSby Hedley Rees

Big Pharma is receiving unprecedented attention fromgovernments, regulators, payers and patient

advocacy, over such issues as sky rocketing drug prices,poor levels of research and development productivity,shortages of life-saving drugs and a general lack ofconsideration for the patient. This paper cuts to thechase by homing in on the underlying cause – the crackof the patent gun. The contention is that an unyieldingfocus on conserving remaining patent life has led tobehaviours that have undermined Big Pharma’s ability todevelop properly differentiated drugs.As an alternative, the paper proposes a new model for

product development, based on tried and testedmethods adopted by sectors that have made massivetransformations. Finally, suggestions are made as to howeach key stakeholder in the industry can contribute tomeaningful change for the better.

Hedley Rees is author of “FIND IT, FILE IT, FLOG IT: Pharma’s Crippling Addiction andHow to Cure It” (December 2015) and "Supply Chain Management in the Drug Industry:Delivering Patient Value for Pharmaceuticals and Biologics" (February 2011). He holds adegree in production engineering from the University of Wales and an executive MBAfrom the Cranfield University School of Management.

After working as an industrial engineer, Hedley held senior positions at Bayer UK,British Biotech, Vernalis, Ortho-Clinical Diagnostics and OSI Pharmaceuticals beforebecoming the managing consultant at Biotech PharmaFlow Limited, a UK-basedconsultancy specialising in operations and supply chain management in the life sciencesector.

TRANSFORMING BIG PHARMA FORTUNES BY REPLACING PATENTS WITH PATIENTS continued


development of medicines I havechristened “Find It, File It, Flog It”.This approach involves finding a

promising patented compound(Find It), placing it into adevelopment pipeline intended forregulatory approval to market (FileIt), and then marketing theapproved product with the utmostverve and vigour (Flog It). Inmathematical terms, we have:

F1 + F2 + F3 = $$$.

Where:

F1 = Drug discovery (Find It)F2 = Regulatory review andapproval (File It)F3 = Marketing (Flog It)$$$ = Megabucks

This is the equation that hasdriven the industry ever since thebattle of the stomach ulcer drugsTagament and Zantac, in the 1980s,where superior marketing musclewas reported to have won the dayfor Glaxo’s Zantac over SmithKlineFrench’s Tagamet.

So how does this relate tothe issues we see today?This modus operandi has resulted ina very clear chain of events. Therush to register a pipeline ofproducts for market, maximisingremaining patent life, results in what

we now know as the valley of death.That has spawned the patent cliff,whereby significant revenues are lostonce the patent runs out.This, sadly, is not the end of it.

Dependence on the crack of thepatent gun has also driven twocrippling behaviours that have beenendemic in Big Pharma for overthree decades; dropping out-of-patent products and outsourcingcritical assets, both people andfacilities.The former has resulted in eighty

percent plus of products sold todayresting in the hands of genericcompanies, which have beengrowing like topsy. The large,research and development-basedpharma companies are now havingto target increasingly shrinkingpatient populations, chargingswinging prices in an attempt tomaintain blockbuster returns. Hence,we have the commotion from USpoliticians and many other industrystakeholders.This would not have been so

damaging if the Big Pharmacompanies had held onto thepeople and facilities involved indeveloping new products formarket; but that hasn’t been thecase. Fuelled by blind optimismover the power of the patent, thesecritical assets were allowed to goand the consequence, Big Pharma

companies now have to dependheavily on third parties to developtheir products. Professional as thesethird parties are, they do not havethe skin in the game that clinical trialsponsors and product licenseholders have.Some readers may be thinking at

this point that other sectors havesuccessfully used an outsourcedapproach with good results; but inthe words of that well-known song“it ain’t what you do, it’s the waythat you do it”; and pharma hasn’tdone it very well.This is what Professor Andrew

Cox, world renowned expert inprocurement and outsourcing bestpractice, has to say on the matter.

“Unfortunately for the majorPharmaceutical companies thatused to be the ‘channel captains’,who controlled the industry and allof its major supply chains through ajudicious control internally of criticalassets, there has been considerableevidence of very poor practice inoutsourcing in recent years.”

We also have the example ofBoeing, which dabbled withincreased levels of outsourceddevelopment for the Dreamliner andsuffered a reported 18-month delay,as well as much pain and suffering,for its troubles. This is what Peter

Figure 1: Attrition and the crack of the patent gun.



Cohan, author of “You Can’t OrderChange: Lessons from JimMcNerney’s Turnaround at Boeing”4

had to say in his book.

“But by outsourcing both thedesign and the manufacturing,Boeing lost control of thedevelopment process.”

At this point, I am drawing theconclusion that for Big Pharma toreverse its fortunes, massive changeis required.

What should change looklike?We must turn product developmenton its head, as other sectors did verysuccessfully in the 1950s and 1960s.They had similarly been throwingtheir products ‘over the wall’ intothe system consuming their goods,until the Japanese revolution tookplace. Companies, such as Toyota,Honda Nissan and Matsushita ledthe charge to place end-user valueat the forefront of their missions inlife. The results were startling as weall now know.The same has to happen in Big

Pharma, the alpha male of theindustry. Healthcare professionalsand the patients they serve have tobecome the central focus ofdevelopment activites – they mustbe deeply involved and consulted onthe indication under consideration,at the earliest stage, even beforepre-clinical assessment takes place.It is not sufficient to involve only asmall number of investigators,appointed by the pharma company,in trialling drugs; attrition rates in theindustry prove that.Once this engagment takes place

and the value propositionestablished, prototypes must bebuilt and pressure tested beforeprogressing into commercialdevelopment. Maximum use ofpredictive technologies must beemployed, using in silico and ex vivotechnologies. These methods havemoved on unrecognisably in recentyears, but the industry is reluctant toapply them in any meaningful way.To achieve the above, discovery

research scientists need to stay and

help develop the prototypes, ratherthan move on to ‘discover’ newcompounds, oblivious to any issuesarising from their previouslyorphaned offspring. Only thoseprototypes passing muster under thescrutiny of a multi-disciplinary reviewteam (including the healthcareprofessionals), would move forwardinto development for end-usermarkets. Figure 3 overleaf, shows aschematic comparing the currentand proposed new approach3.Readers will notice the iterativenature of the proposed approach,whereby candidate compounds aredesigned, tested and optimised andthen subjected to clinical validationusing predictive technologies. Thepower of this approach is the depthof scrutiny each compound receives,weeding out potential failures at thestarting gate.Once on the road to development

for commercial markets, a‘production system’ approach mustbe taken, whereby the targetdestination is a product in end-users’ hands, not the statistical end-point of a clinical trial, as it is today. This means that a much broader

range of skills, including thosederived from the world ofengineering, must be recruited andapplied; also leadership in takingthe product to market will be asingle continuum, rather than a two-tier approach as it is currently.This severely challenges the

industry’s historic tendency towithhold allocation of resources untilthe later stages of clinical trials.However, this has only come aboutbecause attrition rates are so high.The solution is to reduce theattrition, as suggested here, ratherthan withdraw the resources.

What can stakeholders do tohelp?It would be naïve to think this levelof change would be easy; itcertainly was not for the othersectors discussed above. There isalso no sign of one such as Toyota’sTaiichi Ohno emerging from theranks of Pharma CEOs. We,therefore, contend that it isincumbent upon key stakeholdersto catalyse the change. Below aresome suggestions, radical in part,that may be considered as a usefulstarting point.

GovernmentsThe underlying root cause of theissues lay in patent laws, as appliedin pharma. Patenting a moleculewith no evidence that it can beconverted into a medicine isridiculous. Along with changingthese laws to require more evidencefor patent registration, governmentsshould also seek post mortems onfailed drugs to prevent predictable‘no hopers’ being pursued. TheItalian Medicines Agency is alreadyshowing innovative thinking by

Figure 2: The skids are under drug development (courtesy of Dr GrahamCox3).

focusing on success in drugdevelopment, by asking for itsmoney back if drugs do not meetthe potential claimed, as reported inBloombergBusiness5.If these things were developed, it

would encourage drug developersto collaborate with healthcareprofessionals to gather the necessaryevidence and avoid the failures.

Regulatory authoritiesRegulation is vitally important topatient safety, but there is a risk thatit can sometimes confuse theinterface between healthcareprofessionals and those developingdrugs. We should bear in mind thata ‘highway code’ for medicines isessential, but it does notautomatically lead to safe drivers.Regulators should increasinglybecome facilitators of interaction,rather than enforcers of rules.

Healthcare professionalsHealthcare professionals must beginto view themselves as the ones incontrol and start with a proactiverejection of sales representatives atthe door, if they have not alreadydone so. They must ceasedependence on pharma-derived

statistical evidence supporting one-sided marketing claims, andanything else that detracts from thepatient/provider interface. Theyshould then push for earlyinvolvement in development of thedrugs they prescribe, if notthemselves personally, then theirprofessional bodies.

PatientsPatients should ask their doctors thedumb questions and expectsensible answers. If the answersdon’t work, they should keep onwith the questions. As is often said,there is no such thing as a stupidquestion and the few minutes ofembarrassment in asking thequestion could avoid decades ofsuffering by remaining silent. Theyshould also support their healthcareprofessionals in pushing back onpharma sales speak.

Pharma CEOsThe final message is for CEOs of BigPharma companies. Yourpredecessors discovered a wonderfulway to build businesses, which couldnot be summed up better than byrepeating the words of George W.Merck, founder of Merck:

“We try never to forget thatmedicine is for the people. It is notfor the profits. The profits follow,and if we have remembered that,they have never failed to appear.The better we have remembered it,the larger they have been!”

References1 Lazarus D. Obama’s budget includes

healthcare proposals that could changeeverything for consumers. Los AngelesTimes 16 February 2016.http://www.latimes.com/business/la-fi-lazarus-20160216-column.html

2 Deloitte LLP. Measuring the Return fromPharmaceutical Innovation 2013 –Weathering the Storm? London, UK:Deloitte LLP; December 2013.http://www2.deloitte.com/uk/en/pages/life-sciences-and-healthcare/articles/measuring-the-return-from-pharmaceutical-innovation-2013.html

3 Rees H. FIND IT, FILE IT, FLOG IT:Pharma’s Crippling Addiction and How toCure It. CreateSpace IndependentPublishing Platform; December 2015.

4 Cohan PS. You Can’t Order Change:Lessons from Jim McNerney’s Turnaroundat Boeing. London, UK: PortfolioPublishing; 2008.

5 Kitamura M, Koch J. When new cancertreatments fail, Italy wants its money back.Bloomberg Business, 15 January 2016.http://www.bloomberg.com/news/articles/2016-01-15/when-new-cancer-treatments-fail-italy-wants-its-money-back



Figure 3: Alternate stages in the drug development process (courtesy of Dr Jesús Zurdo, Lonza Biologics3).


January Bureau meeting The arrangements for the 50thAnniversary General Assembly werediscussed. The meetings will beheld in the headquarters of theOrdre National des Pharmaciens. AFriday Symposium will be held withthe title “1965–2015 – Howmedicines have changed over 50years”. Working groups at theGeneral Assembly will discuss: “Theimpact of the Delegated Act onFalsified Medicines on QualitySystems in the PharmaceuticalSupply Chain” and “The job of theindustrial pharmacist in 2026”.

Implementation of theDelegated Act on FalsifiedMedicinesMaurizio Battistini (EIPG VicePresident European Affairs) andFrank Peeters (President UPIP-VAPI)represented EIPG at a stakeholdermeeting organised by the EuropeanCommission to discuss theCommission Delegated RegulationNo 2016/161 published in theOfficial Journal on 9 February. Themain speaker was Dr Patrizia Tosetti,the Policy Officer of Unit B4 inDirectorate General for Health andFood Safety. The document sets outthe characteristics and technicalspecifications for the uniqueidentifier to be applied bymanufacturers and re- packagersand its verification bypharmacies/retailers and wholesaledistributors. The unique identifier,the tamper evident devices, therepository system to be used bystakeholders and the use of the barcode scanners that will trace andidentify each pack of medicinal

product released into the Europeanmarket were discussed. Hospital andcommunity pharmacies will have theobligation to decommission packson the repository system at the timeof dispensing. The safety featureswill be mandatory for products listedin Annex I and II of the Regulation,effectively all prescription productsand omeprazole but excludingsome hospital only products.In response to a question from

EIPG, the European MedicinesVerification Organisation confirmedthat the repository system willautomatically block each batch at itsexpiration date. The EuropeanHospital Pharmacists Associationindicated their concern over theamount of time that will be involvedwith decommissioning, which willsignificantly impact work practice. Inresponse to a question on how theRegulation will be applied tomedicinal products considered“over the counter” in somecountries and “prescription only” inothers, the reply was that the lawregulating the product in individualMember States will be applied. The provisions apply to all

Member States from 9 February2019 except Belgium, Italy andGreece (where there are existingmeasures applied to medicinalproducts) who must comply by 9February 2025.A link to the slides presented at

the stakeholder meeting is given onthe EIPG website under News –From the Bureau.Claude Farrugia (EIPG Vice-

President Communications)presented an EIPG perspective onthe Verification of Medicinal

Products in Europe at the UPIP-VAPISeminar on the Implementation ofthe Act on Falsified Medicines. Hiscomprehensive slides are publishedon the EIPG website under MediaLibrary – Presentations.

Moglynet (European jointdoctorate project)The student recruitment phase ofthis 3-year project has beencompleted and twelve PhD studentshave been selected and enrolled intheir home institutions from 1February. The summer school time-table

and potential speakers have beendiscussed. Anni Svala, EIPG Vice-President Education and Training, isa member of the project’ssupervisory board and is advising onthe industrial expectations ofstudents and the dissemination ofthe project results. Anyoneinterested in assisting with thisproject, for example by lecturing tothe postgraduate students at asummer school, should contact AnniSvala ([email protected]).

February joint webinarEIPG/European PharmacyStudents’ AssociationMinna Matikainen, GSK’sCommercial Manager forRespiratory Business Unit in Finland,and Marien Rouchon, MSD’s formerProduct Manager for Oncology inFrance, discussed marketing in thepharmaceutical industry. Seventyparticipants were on-line fromvarious European countries.

Jane Nicholson, Executive DirectorEIPG [email protected]

news from the EIPG

Visit the website: www.industrialpharmacy.eu for PharmaTV and Qualityby Design videos, Regulatory Review, Financial Pharma News and other

current items concerning Industrial Pharmacy

www.industrialpharmacy.eu


regulatory reviewThe current review periodhas seen a number ofchanges in the regulation ofmedicines and regulatoryguidance in the EU,International markets andthe USA

USAFormal Meetings Between theFDA and Biosimilar BiologicalProduct Sponsors orApplicants – Guidance forIndustryThis final guidance reflects a unifiedapproach to all formal meetingsbetween sponsors or applicantsand the Food and DrugAdministration (FDA) for biosimilarbiological products. This guidanceis intended to assist sponsors orapplicants in generating andsubmitting a meeting request andthe associated meeting package tothe FDA for biosimilar biologicalproducts.

Advancement of EmergingTechnology Applications toModernize the PharmaceuticalManufacturing BaseThis draft guidance providesrecommendations topharmaceutical companiesinterested in participating in aprogram involving the submissionof chemistry, manufacturing andcontrols (CMC) informationcontaining emerging manufacturingtechnology to the FDA. While the implementation of

emerging technology is critical tomodernising pharmaceuticalmanufacturing and improvingquality, the FDA also recognisesthat innovative approaches tomanufacturing may representchallenges to industry and theAgency.Companies may have concerns

that using innovative technologiescould result in delays while FDAreviewers familiarise themselves withthe new technologies. The FDA’sEmerging Technology Team willfacilitate the review of submissionsinvolving manufacturing

technologies likely to improveproduct safety, identity, strength,quality and purity.

New Requirement forElectronic Submission of DrugMaster Files (DMFs)This requirement was first publishedon 5 May 2015 and comes into forceon 5 May 2017. The following shouldbe noted.

• There is no requirement toresubmit anything that hasalready been submitted inpaper.

• If you choose to resubmit yourentire DMF upon conversion toan electronic common technicaldocument (eCTD), this isacceptable but it is notrequired.

• You may choose to use eitherversion of eCTD Module 1 (DTDversion 2.3 or 3.3).

EuropeSafer use of medicines bypreventing medication errorsMedication errors can occur formany reasons at the time ofprescribing, dispensing, storing,preparation or administration of amedicine. It is estimated that amonghospitalised patients, 18.7% to 56%of adverse events are caused bymedication errors.This good practice guide on

medication errors complementsother existing guidelines publishedby the European Medicines Agency(EMA). It consists of two parts.

• How suspected adversereactions that are caused bymedication errors should berecorded, coded, reported andassessed. The goal is to improvereporting and to learn frommedication errors for the benefitof public health.

• Key principles of riskmanagement planning inrelation to medication errors. Itdescribes the main sources andtypes of medication errors andproposes options to minimise

the risk of medication errorsthroughout the lifespan of amedicine.

In parallel, the EMA has launched awebpage highlighting measuresrecommended by the Agency toprevent medication errors forspecific medicines.

New strategy to fightantimicrobial resistanceThe EMA has released for publicconsultation a new strategy onantimicrobials which has beenadopted by its Committee forVeterinary Medicinal Products.Antimicrobial resistance is a globalproblem affecting both animal andhuman health. This strategy setsclear objectives to help combat thethreat of resistance which may arisefrom the use of antimicrobials inanimals.

Guidelines for using the test forbacterial endotoxinsThe European Directorate for theQuality of Medicines (EDQM) haspublished a document CommentsConcerning Revised Texts Publishedin Supplement 8.8 to the EuropeanPharmacopoeia.The general chapter on bacterial

endotoxin has undergone a generalrevision with the following scope.

• A section has been added toinclude aspects to beconsidered when establishingan endotoxin limit for a specificsubstance or product.

• Reference to General Chapter2.6.30. Monocyte-Activation Testas an alternative to the rabbitpyrogen test.

• Reference to the use ofalternative reagents to thelimulus amoebocyte lysate, suchas recombinant factor C (thispractice avoids the use ofanimal species).

A number of additional specificpoints have been included and thestructure of the general chapter hasbeen modified to improve its clarity.


Raw materials of biologicalorigin for the production ofcell-based and gene therapymedicinal products This new chapter will be publishedin the 9th Edition of the EuropeanPharmacopoeia and will becomeeffective on 1 January 2017. Thechapter is, however, for informationonly and is not legally binding. Itincludes sections on the risk, origin,production of and qualityrequirements for raw materials ofbiological origin used for theproduction of cell-based and genetherapy medicinal products forhuman use.

Changes in contact details tobe notified to EDQMIt is important to keep the details ofthe official contact person up-to-date. It is the responsibility ofapplicants and holders of certificatesof suitability (CEPs) to ensure thatthis is done. The EDQM communicates only

with the official contact personappointed in a CEP application and,to protect confidentiality, does notshare information with other people.Not receiving communication fromthe EDQM may lead to the closureof an application or to thecancellation of a CEP.

Optimising the presentation ofmedicines for Alzheimer'sdiseaseThe Medicines and HealthcareProducts Regulatory Agency isworking with the pharmaceuticalindustry to optimise the waymedicines for the treatment ofAlzheimer’s disease are presented.All these medicines will include thedays of the week clearly on theblister packs. This may enablepatients to retain independence intaking their medicines.

InternationalJapanData IntegrityFollowing the discovery in late 2015that Chemo-Sero-TherapeuticResearch Institute (Kaketsuken), amanufacturer of blood products andvaccines, had been addingunauthorised ingredients to itsproducts and falsifying data, aninvestigative panel found that theinstitute had been doing so formore than 40 years. As a result,Japan’s Ministry of Health Labourand Welfare (MHLW) has issued ademand to marketing authorisationholders for them to confirm that thecurrent actual manufacturing

process complies with the approvedregulatory files in Japan. All manufacturers (drug products,

active pharmaceutical ingredients,intermediates) listed in theregulatory files in Japan are inscope.Confirmation should be

completed by reviewingmanufacturing batch records andinterviewing operators, etc. Thisreview should be made by anindependent department frommanufacturing, such as a qualityunit.Confirmation at domestic

manufacturing sites should havebeen completed by 18 February2016 and should be completed by22 March 2016 at foreignmanufacturing sites. If there areclear reasons, the due date may beextended subject to MHLWagreement.

For further information on theseand other topics, we suggest yourefer to the websites of relevantregulatory bodies and to currentand past editions of “GMP ReviewNews” published by EuromedCommunications. To subscribe tothis monthly news service [email protected]

REGULATORY REVIEW continued

CALL FOR ARTICLESDear ColleagueWe hope you enjoy the European Industrial Pharmacy and find it both usefuland informative. We are currently seeking new articles for future issues of the journal and wouldlike to invite you to contribute an article or review paper on any aspect ofindustrial pharmacy to the journal. All issues of European Industrial Pharmacyare indexed by both Scopus and Embase and thus are available through thelistings for any other industrial pharmacist internationally.Please contact the Managing Editor, Sue Briggs ([email protected]) forfurther information or submissions.

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Cheering onqualified persons Qualified persons (QPs) enjoy highstatus and salaries. The demand forQPs is urgent; more QPs are retiringthan are qualifying.Of course, being an industrial QP

is not every pharmacist’s cup of tea.But other roles have theirdisenchantments: the same fourwalls surrounding a communitypharmacy, “frozen” hospital salaries,company regulations, diabolicallylow fees as an independentcommunity locum or “heart-sink”patients. Would they prefer morevariety and global travel as,effectively, an EU “quasi-governmental” official? Beforeretiring, my colourful portfolioincluded medicines for Atlanticsalmon, sheep, goats, rabbits,chemical manufacturing and humanlyophilised antibiotics andinvestigational medicinal products.Would such variety compensatepharmacists for reduction in face-to-face patient contact, prescribing,injecting ‘flu’ vaccines and so on?After, say, a decade’s

employment, industrial pharmacistscould consider going intoconsultancy: being their own bosses– or become “poachers turnedgamekeepers”, working for theMedicines and Healthcare ProductsRegulatory Agency or the VeterinaryMedicines Directorate. As medicineinspectors, they would gainpensions, security and sufficientclout to close factories. Being sentall over the world, all expensespaid, is probably not a problem, onbalance.

I am puzzled why, especially withso many more MPharm graduates,more pharmacists do not becomeQPs. That possibility remains theirbirth right. Good quality medicinesare any pharmacist’s raison d’être.The QP viva has assessors from

the Royal Pharmaceutical Society,Royal Society of Chemistry and theSociety of Biology. The applicationfee is £600; pass rate is about 70%.Pharmacists gain a certificate andjoin the eligibility list of the RoyalPharmaceutical Society.

The door is openYou will know that pharmacists onlyneed 1 year of practical industrialexperience; chemists and biologistsneed 2. Chemists and biologists, ofcourse, make splendid QPs. Indeed,there is much mutual collegialrespect and positive synergy fromhaving somewhat differentbackground strengths. A pharmacistQP, for example, reviewing theefficacy of cleaning between batchesand possible cross-contamination,will instantly spot activepharmaceutical ingredients that, forexample, have low therapeutic dosesor are teratogenic. His or herantennae will quiver.Experience in hospitals (even in a

specials manufacturing unit) seldomcounts. Pharmacists must practise ata site that requires a marketingauthorisation for at least onemedicine. However, the pharmaceutical

industry is difficult to enter. Oneentrance route is to first work inNational Health Service hospitalproduction (including aseptic)

and/or (non-clinical) qualitycontrol/quality assurance for, say, 5years. That will turbo-boost chancesof success.

Use it or lose itBut one statistic astonishes me andeven leaves me a little sad. Only 6%of viva candidates are pharmacists.Wait much longer and actuallyapproving medicine batches willbecome something that pharmacistsjust no longer do; biologists andchemists certify instead. An analogyis that some Australian aboriginaltribes are reluctant to “gowalkabout” in their desert. Theirreason is that they have not, ascaretakers, looked after their landwell enough and the spirits – whichare real to the tribe – have becomestronger. Some spirits may killtravellers.My fear is that industrial

knowledge among pharmacists isbecoming so rare that pharmacistsmay lose their confidence to followa career in the pharmaceuticalindustry, let alone become QPs.Another threat looms. A

referendum about whether the UKshould remain a member of the EUor leave the EU is scheduled for 23June 2016. Suppose the vote wereto leave. Although, presumably, exitwould take quite some time toaffect British QPs and negotiationswould be detailed, my hunch is that,sooner or later, British QPs could,effectively, cease to exist. That isperhaps worth bearing in mindwhen you cast your vote.

Malcolm E Brown

bottled brown


eventsAPRIL4–7 April 2016 – Glasgow, UK10th World Meeting onPharmaceutics,Biopharmaceutics andPharmaceutical Technologywww.worldmeeting.org

11–12 April 2016 – Ware, UKAPS Industrial Insights 2016www.apsgb.co.uk

12–13 April 2016 – Venice, ItalyParenteral Packagingwww.pda.org

12–13 April 2016 – Dusseldorf,Germany2016 Pharma Congress:Production and Technologywww.pharma-kongress.com

17–21 April 2016 – Phoenix, AZ, USARDD 2016www.rddonline.com

19–20 April 2016 – Chicago, IL, USA12th Annual Medical DeviceCompliance Congress www.cbinet.com

20–21 April 2016 – Chicago, IL, USAWorld Drug Safety Americas 2016www.healthnetworkcommunications.com

20–22 April 2016 – Washington DC,USA7th Annual The Global OrphanDrug Conference & Expo USA www.allcongress.com/medical-congress/7th-annual-the-global-orphan-drug-conference-expo-usa

22–23 April 2016 – London, UKThe Clinical Pharmacy Congress –The Future of Clinical Pharmacywww.pharmacycongress.co.uk

MAY2–5 May 2016 – Athens, Greece3rd Annual InternationalConference on PharmaceuticalScienceswww.atiner.gr/pharmako

12 May 2016 – London, UKSterility assurance best practicefor aseptically manufacturedproductswww.jpag.org

17–19 May 2016 – Amsterdam,The Netherlands6th Cold Chain and ProductHandling: TemperatureControlled Logisticshttp://fleming.events

18–19 May 2016 – London, UKWorld Precision MedicineCongress 2016 www.terrapinn.com

19–20 May 2016 – San Diego, CA,USAWorld Biosimilar Congress USA2016 www.terrapinn.com

23–24 May 2016 – London, UKADC Summit 2016http://www.smi-online.co.uk/pharmaceuticals/uk/conference/adc-summit

23–24 May 2016 – Loughborough,UKAPS Excipients – Selection,Control, Application and Suitabilitywww.apsgb.co.uk

JUNE1 June 2016 – Leeds, UKSymposium of Digital Design ofDrug Products - Joint meetingwith the British Association ofCrystal Growthwww.apsgb.co.uk

1–2 June 2016 – Vienna, ItalyWorld Pharma MES Congress2016www.healthnetworkcommunications.com

5–6 June 2016 – Bethesda, MD,USA2016 ISPE Quality MetricsConference www.ispe.org

6–8 June 2016 – Bethesda, MD,USA2016 ISPE QualityManufacturing Conference www.ispe.org

7–8 June 2016 – Berlin, GermanyAdvanced Therapy MedicinalProductswww.pda.org

13–15 June 2016 – Istanbul, TurkeyEUFEPS Annual Meeting 2016www.eufeps.org

14–17 June 2016 – Boston, MA,USA15th Annual World PreclinicalCongresswww.worldpreclinicalcongress.com

20–21 June 2016 – Baltimore, MD,USA2016 PDA Biosimilars Conferencewww.pda.org

22–23 June 2016 – Basel,SwitzerlandPharmaceutical Packaging andLabelling Summitwww.pharmapackaginglabelling.com

23 June 2016 – London, UKPractical implementation of ICHQ3D; challenges and solutionswww.jpag.org

27–29 June 2016 – Valencia, Spain5th European BiosimilarsCongresshttp://biosimilars-biologics.pharmaceuticalconferences.com/europe

28–29 June 2016 – Berlin, Germany1st PDA Europe Annual Meetingwww.pda.org

JULY18–20 July 2016 – Berlin, Germany5th Annual European PharmaCongresshttp://europe.pharmaceuticalconferences.com

AUGUST4–6 August 2016 – Manchester, UK2nd World Congress onBiopolymershttp://biopolymers.conferenceseries.com

15–16 August 2016 – Toronto,Ontario, Canada5th International Summit onGMP, GCP & Quality Controlhttp://gmp-gcp-quality-control.pharmaceuticalconferences.com

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GROW WITH US

OF ENDOTOXINDETECTION

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Associates of Cape Cod, Int’l.Deacon Park, Moorgate Road Knowsley, Liverpool L33 7RX, UK

(44) 151.547.7444 [email protected] WWW.ACCIUK.CO.UK

european industrial pharmacy issue 28 (march 2016)

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