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features4 SCALE-UP OF SPRAY DRIED AMORPHOUS

SOLID DISPERSIONSTechnologies capable of addressing solubility issuesare needed in light of the many insoluble drugs indevelopment. The authors discuss the use ofstabilised amorphous solid dispersions preparedusing pharmaceutical spray drying.by José Luís Santos, Paula Cordeiro, Márcio Temtem

9 THE INNOVATIVE MEDICINES INITIATIVEOrBiTo PROJECT – DEVELOPING THE NEXTGENERATION OF PREDICTIVE TOOLS FORORAL BIOPHARMACEUTICSThe Innovative Medicines Initiative OrBiTo project is acollaboration between pharma, academia andspecialist technology companies to enhance ourunderstanding of absorption of orally-administereddrugs from the gastrointestinal tract and apply thisknowledge to predict the performance of oralformulations in patients.by Mark McAllister, Bertil Abrahamsson, Hans Lennernäs

12 FORMULATION TECHNOLOGY ENABLES THEDELIVERY OF HIV MEDICINESInnovative formulation technologies have beendeveloped to overcome drug delivery challenges oftreatments of HIV infection. This article describesproblems of solubility, pharmacokinetics andphysical material properties along with theirresolution in a series of case examples.by Peter Timmins, Jonathan Brown

18 TAKING STEPS TO IMPLEMENT THE FALSIFIEDMEDICINES DIRECTIVE AND COMBATCOUNTERFEITING IN EUROPE – THE EUROPEANSTAKEHOLDER MODELFalsified medicines present a public health threat atglobal level, with counterfeit goods threatening thehealth of patients in countries around the world. Thisarticle discusses measures to fight counterfeiting. by Richard Bergström

regulars3 EDITORIAL COMMENT20 REGULATORY REVIEW21 NEWS FROM THE EIPG22 EVENTS

2 european INDUSTRIAL PHARMACY December 2013 • Issue 19

europeanINDUSTRIALPHARMACYIssue 19 December 2013

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european INDUSTRIAL PHARMACY December 2013 • Issue 19 3

Dear ColleaguesWelcome to the December edition of theEuropean Industrial Pharmacy journal.Over the past 3 months, a number of actionshave been undertaken by members of theBureau and, in particular, I would like toemphasise the revamping of the website. Thishas been possible because of the tireless effortsof Dr Claude Farrugia, Vice-President,Communications, whom I would like to thankwarmly for his dedication and support in thisrespect.

Rather than describing the new features andadvantages of our website, I would like to inviteyou to pay it a visit at the following address:http://eipg.eu. The new website has beendesigned to raise the profile of the EIPG and itscommunications with its members and withpharmaceutical industry pharmacists in general,irrespective of whether they are employed withinthe European Union or outside it.

I consider it essential for the work of the EIPG– position papers, publications, presentations,

guides, codes, contributions to meetings withother European professional organisations andinstitutions – to be made rapidly available to all.By way of an example, I would like to invite youto check out our position papers: 'EIPGFeedback on Revision to Annex 16' and 'Jointcall for actions on medicines shortages fromEuropean pharmacist organisations'.

I also consider it essential that visitors to ourwebsite become frequent visitors and would liketo advise regular use of the site as a source ofnews and information for industrial pharmacists.

Lastly, in the context of strengthening theGPIE's partnerships with key stakeholders, I havethe pleasure of announcing that GPIE has beenaccepted as an observer in the USP Convention,since several opportunities for closecollaboration with the USP have been identified.

May I conclude by wishing you a very MerryChristmas and a Happy New Year.

Jean-Pierre PaccioniGPIE President

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european INDUSTRIAL PHARMACY December 2013 • Issue 194

Spray drying is a well-establishedunit operation, mostly owing tointense process optimisation in thefood industry where profit marginsare tighter. In pharmaceutical spraydrying, powder properties (e.g.particle size and bulk density) aretypically considered critical qualityattributes and because of this agood process understanding isfundamental to enabling a seamlesstransfer between spray dryingunits/scales with the smallestnumber of trials and a minimal useof API.

Dobry et al.1 proposed a scale-upmethodology for developing SDDformulations with minimum API.Their approach is based on a

scientific understanding of the spraydrying process and critical materialattributes that need to beconsidered: amorphous stability,chemical stability to hightemperatures, thermodynamicspaces of the different spray dryerunits, atomisation assessment anddroplet size measurement, dryingkinetics in the drying chamber andexperimental confirmatory runs.Such work, however, does notinclude detailed information on theimpact of raw materials and processconditions on the SDD criticalquality attributes.

In a review paper by Vehring2, atheoretical framework wasestablished for determining the

mechanisms of particle formation.Despite not considering localinteractions with the drying gas flow,such simple approach can providean understanding of what can bethe structure and morphology of thespray dried particles. Nevertheless,due to the characteristics of the API,each formulation is unique, posinggreat challenges in the accurateprediction of final powderproperties. A recent contribution byPaudel et al.3 reviews the state-of-the-art, from an academicperspective, including severalexamples of the impact of rawmaterials and process conditions onthe SDD properties. This is,however, limited to laboratory- andpilot-scale equipment, and does notinclude industry-relevant casestudies – the authors are clear instating that the literature is scarce inthat respect.

A recent work from Ullum et al.proposed the use of computationalfluid dynamics (CFD) through theinvestigation of the flow profile ofthe drying gas in a spray dryercoupled with droplet drying4.Additionally, recent advances in themodelling of spray drying by CFDhave been discussed5, including itsuse for pharmaceuticalapplications6. The complexity of thespray drying process, wherephenomena occur on vastly differenttime and spatial scales, suggeststhat the computational power stillneeds to evolve substantially beforethe particle formation process canbe adequately predicted within aplant-scale CFD simulation.

In this current paper, the authorsaim to discuss the differentchallenges and perspectives of thescale-up of SDDs based on theirexperience with a large number ofprojects spanning from thelaboratory up to the largepharmaceutical commercial scale. Itis the authors’ intention to shareindustry-relevant information andopinion on what needs to beconsidered in the scale-up of SDDs,hoping that it can contribute toimprove the scientific and technicalunderstanding of the relation ofSDD quality attributes with both rawmaterial attributes and processconditions.

SCALE-UP OF SPRAY DRIEDAMORPHOUS SOLIDDISPERSIONSby José Luís Santos, Paula Cordeiro, Márcio Temtem

With an increasing number of relatively insoluble drugsin development today, there is a need to develop

and use platform technologies capable of addressingsolubility issues. Among the different alternatives, the useof stabilised amorphous solid dispersions is becomingincreasingly popular, with pharmaceutical spray dryingbeing one of the key technologies used in theirpreparation. In spray dried dispersions (SDD), the activepharmaceutical ingredient (API) is molecularly dispersed ina polymeric matrix. The polymer is used to stabilise theamorphous, metastable form of the drug and sustainsupersaturation of the API in solution/biological fluids,thereby increasing bioavailability.

José Luís Santos is a Drug Product Development Scientist at Hovione. He joined thecompany in 2011 and has worked on many projects involving development of spraydried dispersions, manufacture of micro and nanoparticles using integrated milling andmembrane technologies, and implementation of scale-up and modellingmethodologies. (email: [email protected])

Paula Cordeiro is a Drug Product Development Scientist at Hovione. She joined thecompany in 2011 and has worked on many projects involving development of spraydrying processes with the use of scale-up and modelling methodologies, spraycongealing processes and milling technologies.

Márcio Temtem is Group Leader and Senior Scientist in the Drug Product Developmentteam at Hovione. He joined the company in 2008 and has been technically involved indevelopment of spray drying processes, amorphous solid dispersions, millingtechnologies, biodegradable release systems and oral final dosage forms.


SCALE-UP OF SPRAY DRIED AMORPHOUS SOLID DISPERSIONS continued

Stability of amorphous soliddispersionsOne of the most important attributesof an amorphous solid dispersion isits glass transition temperature (Tg),which is intrinsically related to theAPI molecular mobility and is one ofthe characteristics that dictateswhether an SDD formulation isstable enough not to changesignificantly over the shelf-life of theproduct. To reduce the molecularmobility, a typical rule of thumb usedduring formulation development isto target a single Tg (true solidsolution) of at least 50ºC higher thanroom temperature7, i.e. a single Tgabove 75ºC is ideal from a productshelf-life perspective. Phaseseparation, as shown by multipleTgs, is typically associated with thepresence of clusters (API or polymer-rich phases) in the matrix and,therefore, the material presents ahigher potential for recrystallisation.Both polymer/excipients and APIcontribute to the Tg of theformulation, which can be estimatedby simple equations that weight theindividual Tgs of the API, polymerand solvent, e.g. the Fox orGordon–Taylor equations8.

Deviations to these predictions aretypically attributed to interactionsbetween the different ingredientsand should be considered aspositive events from a stabilityperspective. The inherent use ofsolvents in spray drying processesalso contributes to lowering the Tgof the SDD through a plasticistioneffect attributed to the solvent andthis should be considered duringprocess development and scale-up.

In addition to the supersaturation/bioavailability considerations thatare not covered in this paper,laboratory-scale SDD developmentprimarily focuses on achieving highand single glass transition materials,so that the formulation is stable andthe process can be developed witha good yield. To prepare the scale-up and account for the operation inclosed loop units (i.e. with nitrogenrecycle), a few trials are executedwith varying drying conditions togenerate SDD materials with distinctresidual solvent contents. The Tg of

those materials is then assessed bymodulated Differential ScanningCalorimetry (mDSC) in a closed panto assess the plasticisation effect ofthe solvent. A useful illustration ofthese results is presented in Figure 1,where the drying conditions,expressed as the relative saturationof the solvent in the drying gas(RS¬_out), and Tg are plotted as afunction of the residual solventcontent in the SDD. Theplasticisation effect is scale-independent and is used to supportthe selection of the most suitabledrying condition. Included in Figure 1are laboratory and large-scale trialsthat can be taken as representativeof the majority of SDDformulations. Conversely, therelation between relative saturationin the gas stream and powdersolvent content is scale-dependentas it is related to residence timeand droplet/particle size.

In particular cases, the trends ofboth spray drying scales arecoincident as illustrated in Figure 1,which indicates that the datagenerated on amorphous stability inthe laboratory with a small quantityof API can aid the preparation of thescale-up for commercially readyspray drying units. Figure 2illustrates one such case, where thematerial from the larger-scale spraydryer matched perfectly the Tg andX-ray powder diffraction (XRPD)

profile of the SDD produced in thelaboratory. Furthermore, the datafrom laboratory-scale trials cangenerally be regarded as a worst-case scenario since the particles’residence time in the dryingchamber is lower than in larger-scalespray dryers, causing the solventcontent of laboratory-generatedSDD to be typically higher.

The secondary drying of wet SDDmaterials is another commonoperation in the manufacturing ofamorphous solid dispersions. Toachieve the International Conferenceon Harmonization limits for theresidual solvents, tray dryers, double-cone dryers or static agitated dryersare most widely used. The same setof data shown in Figure 1 can alsobe used in the optimisation anddevelopment of a secondary dryingstrategy. Figure 3 shows secondarydrying data, where the Tg of thepowder is increasing with a decreasein residual solvent content. Aconservative approach is to alwaysuse drying temperatures below theSDD Tg, which can be adjustedincrementally during the operationas illustrated in Figure 3 to decreasethe secondary drying cycle time.

SDD downstreamprocessability andperformanceThe downstream performance of aspray dried material may be

Figure 1: Tg and relative saturation of the solvent in the drying gas(RS_out) as a function of residual solvent content in the SDD (circles:laboratory scale spray dryer; squares: large scale spray dryer).


discussed from two differentperspectives: processability andproduct performance. Typicaldownstream operations includeblending, roller compaction andtableting. The ability for an SDDmaterial to flow and be processedin the downstream equipment withno major operational difficulties isclosely related to powderproperties, namely particle size,density and cohesive–adhesivebalance between the ingredients9.Rule-of-thumb strategies forimproving flow indicate that bothparticle size and density should be

as large aspossible. In abest-casescenario, thepowder wouldalso have thenecessarycompressibility

(indicated by the differences in bulkand tap density) to enable a directcompression approach9. Theconcern for product performance isthat as SDDs are mostly developedwith BCS class II APIs (goodpermeability, poor solubility), thedrug product bioavailabilitychallenge is more related toimproving solubility. Solubilityenhancement may be achieved byincreasing the maximum APIconcentration in solution (BSC classIIb) – here the polymer used in anSDD may play an important role asit may promote supersaturation –

and/or by improving the APIdissolution kinetics (BCS class IIa).Where dissolution kinetics are keyto achieving bioavailability, theSDD properties, namely particlesize, can play an important role inthe dissolution profile of the drugproduct, in the same way as tabletdisintegration due to the erosion ofthe small SDD granules. Particlesize dictates the specific areaavailable for mass transfer of theAPI in the dissolution medium (thesmaller the particle size the largerthe specific area).

Bioavailability can also be limitedby the supersaturation potential ofthe amorphous solid dispersionrather than the dissolution kinetics,and in those cases particle size ofthe SDD is not as critical. Hence, atight control over particle sizeshould be on the list of priorities ofevery spray drying scientist whendeveloping an SDD.

In the scale-up process from thelaboratory to a commercial-scalespray dryer, distinct points should beconsidered. In the laboratory scale,the bottleneck is usually related tothe powder properties that can beattained. Due to the reduced size ofthe drying chamber, laboratory-scaleunits typically use external mixingtwo-fluid nozzles. Such atomisationtends to produce particles with aDv50 (mean particle size in volume)below 10µm and a bulk densitybelow 0.15g/mL, which are notadequate for downstreamprocessing, primarily due to very


Figure 2: DSC (top left/right) and XRPD (left) for SDDproduced at both scales (blue lines: laboratory; red lines:large scale).

Figure 3: Secondary drying strategy for an SDD (green points: SDD Tg; redline: drying temperature).


poor flow properties. Although acertain degree of flexibility exists inthe blending step, and despite ajudicious selection of the excipientsand their relative amounts, it is veryunlikely, particularly for large-dosedrug products, that a goodformulation candidate can bedeveloped without an additionalgranulation step. In larger-scale spraydryers, an enhanced flexibility existsto improve the SDD properties sincethe range of atomisation mechanismsis broad, allowing the production of alarge spectrum of droplet sizes andconsequently products with particlesize distributions more suited fordownstream processing. During pre-clinical and formulation screening,with processes being developed on asmaller scale and clinical trialsbatches being produced with limitedpowder properties (e.g. small particlesize and low bulk density), theadvancing of the drug candidates tolate-phase stages can posesignificant challenges for the spraydrying process development. One ofthese situations may be when anSDD process is locked with a smallparticle size.

An ideal approach would be tohave the exact same powderproperties across scales, targetingthose to be used in late-phase andcommercial stages. One suchapproach involves the use of alaboratory unit with an ultrasonicnozzle atomisation and optimiseddrying gas flow rate and dryingchamber configuration10. The use ofultrasonic atomisation enables thegeneration of droplets of similardimensions to those in larger-scale

spray dryers, which coupled with thecorrect thermal and residence timeconditions can meet the objective ofmatching the larger-scale powderproperties in the laboratory. Figure 4illustrates the morphology of spraydried materials produced in thelaboratory and in a larger-scale spraydryer, where particle size and densitycould be maintained across scales.

Droplet sizeExperience shows that the mostdeterminant parameter to adjustSDD particle size in spray drying isdroplet size. Droplets can begenerated through differentatomisation mechanisms. The mostwidely used atomisation mechanismsin pharmaceutical spray dryingapplications are pressure nozzles andtwo-fluid nozzles. For the productionof SDDs, pressure nozzles aretypically preferred due to theirflexibility in adjusting droplet size

(although two-fluid nozzles can bemore efficient in this respect), andfor enabling the production ofpowders with relatively larger bulkdensities than with two-fluid nozzles.Droplet size can be estimatedthrough the use of correlationsavailable in the literature. Thesecorrelations are typically developedfor water spraying, and conversionfor specific solvents can beaccomplished by considering theirsurface tension and viscosity11. Whilesuch equations from the literaturecan be applied successfully forspecific geometries (e.g. as forexternal mixture two-fluid nozzleswhich have a simpler geometry),their application for vendor-specificpressure nozzle geometries may beless adequate given theparticularities of the differentnozzles. For such cases, thedevelopment of droplet sizeempirical correlations is one of themost straightforward approaches,provided that droplet sizemeasurements are available.

Figure 5 shows droplet sizepredictions for three differentpressure nozzles for atomisation flowrate, using a correlation developedfor one such vendor-specific nozzlegeometries. This predicts the impactof changing the nozzle on dropletsize for a fixed feed flow rate. One ofthe state-of-the-art methods fordroplet size data generation is theuse of Phase Doppler analysers.These, however, have limitations for


Figure 5: Droplet size estimation for three different pressure nozzles as afunction of feed flow rate.

Figure 4: Scanning electron microscopy images comparing powdersproduced in a commercial scale pharmaceutical spray dryer and anoptimised laboratory scale unit with an ultrasonic nozzle.


commercial-scale spray dryers due tothe very high density of the sprayplume (given the very high feed flowrates) which makes the penetrationof the laser and adequatemeasurements of droplet sizedifficult. In these cases, extrapolationof available correlations may be theonly option to make an estimation ofdroplet size.

Macroscopic heat and massbalanceIn a macroscopic evaluation of aspray drying process, typically acombined heat and mass balanceneeds to be considered. In a spraydrying process, a solution is fed tothe top of a drying chamber where itis atomised into small droplets,being heated and vaporised uponcontact with hot drying nitrogen.Solid particles are formed veryrapidly, typically within seconds, andthen separated from the gas in acyclone and filter bag; the solventwithin is later removed in acondenser, closing the mass balancein terms of solvents and solids. Forheat balance closure, the onlyunknown is the heat transfercoefficient of the drying chamberwalls that dictates the amount ofheat lost to the surrounding room.As the walls are thermally insulated,the global heat transfer coefficientfor the walls is a combination of thatof stainless steel and of the

insulation material. As such, theglobal wall heat transfer coefficientfor a spray dryer is not easilyestimated and needs to beestablished using actualexperimental data in a macroscopicheat and mass balance model. Theuse of such macroscopic modelsenables an accurate estimation ofthe drying conditions that are to beexpected (e.g. in terms of relativesaturation of the solvent in thedrying gas), which coupled with thedata generated in the laboratory inFigure 1, can provide an estimate ofthe SDD Tg in larger-scale spraydryers as illustrated in Figure 6.

Final remarksThe future strategies for the scaling-up of SDDs should include the useof advanced computational methodssuch as CFD that can betteranticipate spray-related challenges,e.g. the sticking of materials with lowTg to the walls of the spray dryer. Asfor the impact of SDD powderproperties downstream, keyattributes that can affect powderflow (and consequently itsprocessing by blending, rollercompaction and tableting) and theSDD dissolution performance needto be better understood so that thespray drying process can beoptimised to produce material thatmeets all downstream requirements.The use of advanced analytical

equipment, such as powderrheometers and compactionsimulation apparatuses, should assistin meeting such objectives throughthe establishment of quantitativerelationships between SDDproperties (even with smallquantities of powder) anddownstream performance. Clearly,the possibility of producing SDD inthe laboratory with comparableproperties to that of larger-scalespray dryers can help to simplify andstreamline the process developmentworkflow (from the spray driedpowder to the final tablet dissolutionperformance). The use of specialatomisation mechanisms inlaboratory-scale spray dryers (such asultrasonic nozzles) needs to befurther investigated to enable animproved match of particle size anddensity across scales, therebyreducing the time for an SDDformulation to reach the market.

References1 Dobry DE, et al. A model-basedmethodology for spray-drying processdevelopment. J Pharm Innov2009;4:133–142.

2 Vehring R. Pharmaceutical particleengineering via spray drying. Pharm Res2008;25:999–1022.

3 Paudel A, et al. Manufacturing of soliddispersions of poorly water soluble drugsby spray drying: formulation and processconsiderations. Int J Pharm2013;453:253–284.

4 Ullum T, et al. Predicting spray dryerdeposits by CFD and an empirical dryingmodel. Drying Technol 2010;28:723–729.

5 Fletcher DF, et al. What is important in thesimulation of spray dryer performance andhow do current CFD models perform?Appl Math Model 2006;30:1281–1292.

6 Santos J, Temtem M. Fluid Motion. PharmManuf Pack Sourcer 2013; May:74–79.

7 Rong L. Water insoluble drug formulation.London: Taylor & Francis; 2008.

8 Kalogeras I. A novel approach foranalyzing glass-transition temperature vs.composition patterns: application topharmaceutical compound + polymersystems. Eur J Pharm Sci2011;42:470–483.

9 Qiu Y, et al. Developing solid oral dosageforms. Amsterdam: Elsevier Inc.; 2009.

10 Vanwesenbeeck J, et al. Spray dryingscale-up from mg to kg scale with ahydroxypropyl methylcellulose acetatesuccinate (HPMC-AS) solution. AAPS2010, poster W5491.

11 Perry RH, Green DW. Perry's chemicalengineers' handbook. New York: McGraw-Hill; 2008.


Figure 6: Thermodynamic space for a large scale spray dryer. The contourcolours represent the temperature of the drying gas at the outlet of thedrying chamber, while the contour lines are the simulated SDD Tg.


IntroductionThe IMI is a new model forpublic–private collaboration whichaims to support open innovation inpre-competitive research andaccelerate the development ofsafer and more effective medicinesfor patients. With a €2 billionbudget, IMI is the world’s largestpublic–private partnership in healthresearch and development. IMI is ajoint undertaking between theEuropean Union (EU) and theEuropean Federation ofPharmaceutical Industries andAssociations (EFPIA), who eachcontribute €1 billion to IMI in cash(EU) and by in-kind contribution(EFPIA; Figure 1). From the firstthree IMI calls for projects(spanning 2008–2010), 23 projectswere approved for fundinginvolving 221 R&D teams fromEFPIA companies, 298 academicinstitutions, 47 small- and medium-

sized enterprises (SMEs), 11 patientorganisations and 7 regulatoryagencies.

The OrBiTo project wassubmitted as part of the IMI 4th callfor projects in 2011 and, followingapproval of funding, started in

October 2012 and will run for a 5-year period with an overall budgetof just over €24 million.

The OrBiTo project andconsortiumOur understanding of the GIenvironment and prediction offormulation performance hasadvanced significantly over the last15–20 years with theimplementation of tools such as invitro permeability models,biorelevant dissolution media, thebiopharmaceutical classificationscheme and in silico physiology-based pharmacokinetic (PBPK)models for the prediction of GIdrug absorption. However,significant gaps in ourunderstanding of oralbiopharmaceutics still limit ourability to select drug moleculesand/or formulation approacheswhich are truly optimised for theoral delivery route1. The impact onpreclinical and clinical drugdevelopment is often manifested indelays at key decision points due tothe need to repeat in vivo trials toconfirm formulation or drug productperformance. The OrBiTo vision isto transform our ability to predictthe in vivo performance of oral drugproducts across all stages of drugdevelopment. This will happenthrough partnership, collaborationand data sharing, developing ourfundamental knowledge of the GIconditions to deliver innovativebiopharmaceutics tools which willaccurately predict productperformance over a range of

THE INNOVATIVE MEDICINESINITIATIVE OrBiTo PROJECT –DEVELOPING THE NEXTGENERATION OFPREDICTIVE TOOLS FORORAL BIOPHARMACEUTICSby Mark McAllister, Bertil Abrahamsson, Hans Lennernäs

The Innovative Medicines Initiative (IMI) OrBiTo projectis pre-competitive collaboration between pharma,

academia and specialist technology companies whichaims to enhance our understanding of how orally-administered drugs are absorbed from thegastrointestinal (GI) tract and apply this knowledge todevelop new in vitro tests and in silico models that willbetter predict the performance of oral formulations inpatients.

Dr Mark McAllister is a research fellow in the Drug Product Design Group,Pharmaceutical Sciences, Pfizer, located in Sandwich, UK. Mark currently leads theUK Academy of Pharmaceutical Scientists Biopharmaceutics focus group and isDeputy Scientific Coordinator for the Innovative Medicines Initiative ‘OrBiTo’ project.

Figure 1: Overview of the IMI.


THE INNOVATIVE MEDICINES INITIATIVE OrBiTo PROJECT continued

clinically relevant conditions. Theintegration of in vitro and in silicoapproaches will provide abiopharmaceutics toolkit, validatedusing clinical data, to acceleratedrug development. The mainobjectives of the OrBiTo project areas follows.

• To increase the understandingof the GI drug absorptionprocess as a prerequisite forimproved biopharmaceuticalpredictions.

• To create new or refined in vitroand in silico methodscontributing to improved in vivopredictions.

• To develop a framework for theoptimal use of predictive toolsand preclinical models.

OrBiTo is structured in fourresearch work packages (WPs)focusing on physico-chemical tools(WP1)2, in vitro tools (WP2)3 and invivo understanding and tools (WP3),with the integration of results anddata across all WPs being achievedthrough the application of in silicomodels of drug absorption in WP4(Figure 2)4.

WP1 seeks to improve theunderstanding of the physico-chemical and biopharmaceuticalproperties, which affect the in vivoperformance of poorly solubleactive pharmaceutical ingredients(APIs; BCS class II and IV drugs).The data generated by the new

models and characterisation testsdeveloped though WP1 will informthe selection of candidatemolecules during preclinical testingand guide appropriate formulationselection for first use in humanstudies. Characterisation datadescribing biopharmaceutical

properties will also be used as akey input for the integrated in silicomodels being developed as part ofWP4. WP2 will focus on in vitrodevelopment tools in thedissolution and permeability areathat provide high qualityquantitative predictions for latestage/market formulationdevelopment. WP3 will focus ongenerating in vivo understanding inareas where remaining gapshamper the development ofpredictive methods. This willinclude regional permeabilitystudies, enhanced systemcharacterisation of the GIphysiological conditions as well asstudies of model drugs to elucidatespecific biopharmaceuticalprocesses, providing a basis forimproved in vitro and in silico tools.In addition to integrating theresults from WP 1–3 within PBPKmodels of the GI absorptionprocess, WP 4 will also seek tobuild on and improve existingprediction algorithms to improvethe accuracy of simulation and

Table 1: OrBiTo project consortium

EFPIA member Universities, research organisations, SMEscompanies public bodies, non-profit groupsAstraZeneca AB, Sweden Uppsala Universitet, Uppsala, Simcyp Limited,

Sweden Sheffield, UKAbbvie GmbH & CoKG, Copenhagen University, Denmark Sirius Analytical Ltd, Germany Forest Row, UKBayer Pharma AG, Ernst Moritz Arndt University Simulations Plus, Inc., Germany Greifswald, Germany Lancaster, USABoehringer Ingelheim Johann Wolfgang Goethe-International GmbH, Universität Frankfurt am Main, Germany GermanyGlaxoSmithKline Research Johannes Gutenberg Universität and Development Ltd, UK Mainz, GermanyH. Lundbeck A/S, Katholieke Universiteit Leuven, Denmark BelgiumJanssen Pharmaceutica Medical Products Agency, Uppsala,NV, Belgium SwedenMerck Sharp & Dohme National and Kapodistrian Corporation University of Athens, GreeceNovartis Pharma AG, Netherlands Organization for Switzerland Applied Scientific Research TNOOrion Corporation, University of Manchester, UKFinlandPfizer Ltd, UK University of Strathclyde, UKSanofi-Aventis Research and Development, France

Figure 2: Overview of the OrBiTo work packages.


THE INNOVATIVE MEDICINES INITIATIVE OrBiTo PROJECT continued

prediction of in vivo performance.Much of the work described in

WP 1-4 will be underpinned by thedevelopment of a novel and uniquedatabase containing in vivo data ofwell-characterised novel APIs anddiverse oral pharmaceuticalproducts. It will mainly consist ofnovel material from the EFPIApartners and the first version of thisdatabase is expected to includedata from more than 100 clinicalstudies. EFPIA partners will alsosupply APIs or formulated drugproduct for additional experimentalcharacterisation. An importantaspect of the research concept is touse this material and databaseresource across the different WPs inthe project to generate commondata which can be integratedthroughout the programme toidentify a generally applicableframework for use of predictivetools. The database will besupplemented by literature dataand it will also be open foradditions with novel EFPIAcompounds during the project.However, it is emphasised that thevast majority of work will be doneon novel APIs with the exception ofthe prospective human clinicalstudies to be performed within

OrBiTo which will use well-characterised marketed APIs asmodel drugs.

The OrBito Project consortiumcomprises 12 EFPIA companies andan academic–SME group with 14members as shown in Table 1.

ConclusionsOver the 5-year duration of theproject, it is hoped that thecombination of industrialbiopharmaceutics expertise,specialist technology providers andacademic centres of excellence willcreate the next generation of toolsfor oral biopharmaceutics andtransform our ability to predict oralformulation performance. The IMIprinciples and framework for pre-competitive collaboration arecentral to OrBiTo’s researchstrategy. This is clearly illustrated bythe development of a cross-company physicochemical andpharmacokinetic databasecontaining extensive and diversedata-sets which will be used todevelop and validate new in vitroand in silico tools. In conclusion,the OrBiTo project provides atremendous opportunity toadvance our understanding of oralbiopharmaceutics and offers a

template for collaborative efforts inother areas of pharmaceuticalscience.

References1.Lennernäs H et al. Oral biopharmaceuticstools – time for a new initiative – anintroduction to the IMI project OrBiTo. EurJ Pharmaceut Sci 2013, in press(http://dx.doi.org/10.1016/j.ejps.2013.10.012).

2.Bergström CAS et al. Early pharmaceuticalprofiling to predict oral drug absorption:current status and unmet needs. Eur JPharmaceut Sci 2013, in press(http://dx.doi.org/10.1016/j.ejps.2013.10.015).

3.Kostewicz ES et al. In vitro models for theprediction of in vivo performance of oraldosage forms. Eur J Pharmaceut Sci 2013,in press(http://dx.doi.org/10.1016/j.ejps.2013.08.024).

4.Kostewicz ES et al. PBPK models for theprediction of in vivo performance of oraldosage forms. Eur J Pharmaceut Sci 2013,in press(http://dx.doi.org/10.1016/j.ejps.2013.09.008).

AcknowledgementsThis information is provided onbehalf of the IMI OrBiTo consortium.

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IntroductionSignificant advances in thetreatment of HIV infection haveoccurred since its identificationaround three decades ago, leadingto a reduction in its incidence andlonger life expectancy of infectedindividuals1. Although a cure stillremains an aspiration, anti-retroviraldrugs have been an important factorin managing the infection and theneed for new therapies andimproved versions of existing drugsremains important to assureeffective viral suppression, to enablepatient compliance with medicationregimens, and to deal with thedevelopment of drug resistance1,2.

The efforts of drug discoveryscientists have generated a numberof new anti-HIV agents3 but, as isthe case for many emerging drugcandidates across all therapeutic

areas, the physicochemical andpharmacokinetic properties of anumber of the new entities haveprovided challenges to formulationscientists to assure that the finishedmedicine delivers the desiredclinical profile to realise therapeuticsuccess. This challenge may befurther emphasised if doses in thehundreds of milligrams are required,as is the case for a number of HIVtherapies. With the emergence ofthe highly active antiretroviraltherapy (HAART) approach in thelate 1990s, as newer agents thattargeted different stages of viralreplication life cycle4 appeared andmade this possible, combinationdrug therapy advanced andeventually provided for simplifiedtreatment regimens with co-formulated drugs5.

Assuring the performance of the

newer drugs with their inherentchallenges, as well as supportingsimplified dosing of multiplemedicines therefore defines animportant role for pharmaceuticalformulation. This review focuses onhow formulation science haseffectively enabled the utility ofsome newer, as well as some moreestablished, treatments for HIVinfection and illustrates examplesthat inform how to deal withformulation challenges of today’smedicines irrespective oftherapeutic class.

Formulation of HIV medicines– case historiesEfavirenz Efavirenz (Sustiva, Bristol-MyersSquibb, and a component of Atripla,Bristol-Myers Squibb/Gilead) is apoorly soluble, non-nucleosidereverse transcriptase inhibitor(NNRTI) reported as showingsensitivity of bioavailability to tabletdisintegration time. Therefore, theoriginal single entity formulations6

employed optimised disintegrantchoices and levels, along with acareful distribution of disintegrantbetween intragranular andextragranular phases of the tablet,to assure very rapid disintegration.Tablets formulated in this way werebioequivalent to earlier marketedcapsule formulations (200mgefavirenz per capsule) and as theycontained a higher dose of drug perunit dose form (600mg) in anacceptably sized tablet, offer greaterconvenience to patients where adose of 600mg is prescribed.

Other work suggested that thevisually observed tabletdisintegration alone is not the keyfactor that determines bioavailabilityfor efavirenz, but what is mostimportant is the completion ofdisintegration down to primaryparticles and dispersion of the activeingredient7. For two tabletformulations, in vitro disintegrationand the time to completedisintegration in vivo as measuredby gamma scintigraphy weredifferent, but the one that exhibitedslower disintegration both in vitroand in vivo had slower in vitrodissolution but had the highestbioavailability, with higher area

FORMULATIONTECHNOLOGY ENABLES THEDELIVERY OF HIV MEDICINESby Peter Timmins, Jonathan Brown

The most recent entrants into clinical practice for thetreatment of human immunodeficiency virus (HIV)

infection include a number of compounds with drugdelivery challenges. Innovative formulation technologieshave been developed and applied to overcome thesechallenges and provide medicines suitable for the clinicalneed. Problems of solubility, pharmacokinetics andphysical material properties are described along withtheir resolution in a series of case examples that areillustrative not only of HIV medicines but are applicablesolutions to similar problems in other therapeuticclasses.

Peter Timmins is head of Portfolio Enabling Technology, a group that is part of DrugProduct Science and Technology within the Pharmaceutical Development organisationwithin Bristol-Myers Squibb Research and Development. He has research interestsacross the oral drug delivery arena and his group is responsible for developing drugdelivery solutions for the small molecule candidates for oral administration thatrequire resolution of solubility or/and pharmacokinetic challenges to enable them forclinical evaluation. Peter’s group has staff and operations in UK and USA. Email:[email protected]

Jonathan Brown is a Principal Scientist within the Portfolio Enabling Technologygroup. He has research interests in oral modified release formulation technologiesand physiologically-based pharmacokinetic modelling.


under the plasma concentration-time curve, higher maximum plasmaconcentration and an earlier time tomaximum plasma concentration. Itwas suggested that the reason forthe delay in absorption for theapparently faster disintegratingformulation was that it wasdisintegrating to larger aggregatesin vivo relative to the betterperforming formulation but thisdifference is not discernible in visualobservation of disintegration. Fromthese larger particles, resultingperhaps from poorer effectiveness inthis specific formulation of theincluded sodium starch glycolatedisintegrant, drug release wasslower. Also it was suggested that invivo gelation of the sodium starchglycolate also acted as a furtherbarrier for drug release7.

Translating this learning to a fixedcombination dosage form,containing efavirenz withemtricitabine and tenofovirdisoproxil fumarate, led to choice ofa bilayer tablet to mitigatecompatibility problems and toassure the efavirenz layer coulddisintegrate readily and disperse thepoorly wetting efavirenz particles invivo to assure bioavailability8,9. Anon-bilayer formulation based onwet granulation led to instability,attributed to high water levelsneeded for efavirenz granulationthat allowed a eutectic formationbetween emtricitabine and tenofovirdisoproxil fumarate which dried as a

glassy or amorphous unstableform10. Additionally, interaction withthe surfactant included to help wetand disperse the efavirenz wasimplicated, but its removal led toimpaired bioavailability8. A bilayertablet that separated the efavirenzcomponent showed good stabilityand bioequivalence of itscomponents to the single entityformulations9. It combines threemedicines useful together to treatHIV infection as they come frommore than one therapeutic targetclass, that have pharmacokineticssuited to once daily dosing and allhave the same lack of restrictionregarding dosing with food. As such,formulation science has provided fora fixed combination, one tablet,once daily dosing treatment for HIVinfection, offering an opportunity toimprove the patient adherence totherapy that is critical to maintainingdisease control11.

Etravirine Etravirine (Intelence, Jannsen-Cilag),a second generation NNRTI, is avery insoluble weak base.Conventional and nanosized drugformulation approaches resulted innegligible blood levels on oraldosing. It was necessary to doseamorphous drug, where the barrierof crystal lattice breakdown as a firststep in dissolution was absent inorder to achieve an acceptabledegree of absorption12. However,preparing amorphous drug required

cryomilling of crystalline drug for 3hours at –196°C and the amorphousdrug had poor physical stability,being prone to partialrecrystallization13. Due to its lowsolubility and its low to moderatepermeability (BiopharmaceuticsClassification System Class IVcompound)12, effective drug deliveryrequires consideration of not onlyoptimising the etravirine physicalform, but also to assure very rapiddisintegration and in vivo drugrelease from the dosage form. Thisis to minimize any impact ofvariability in gastrointestinal transittime on presentation of the poorlypermeable drug to the sites wheredrug has highest absorptionpotential (the very high surface areaproximal small intestine).

An initial formulation for clinicaltrials that attempted to resolvethese drug delivery problems,referred to as a granulo-layeredformulation14, required a dose ofdrug of 800mg twice daily toachieve desired pharmacokinetics.Layering amorphous drug asdispersion inhydroxypropylmethylcellulose(HPMC) from organic solventsolution onto excipient beads15 wasused to improve etravirinedissolution rate, a technologyapproach previously applied tocommercial formulations of theantifungal itraconazole16. Thisformulation strategy is one of theoral drug delivery approaches

FORMULATION TECHNOLOGY ENABLES THE DELIVERY OF HIV MEDICINES continued

Figure 1: Process train for manufacture of etravirine tablets based on spray-dried amorphous dispersion based ondescription in innovator patent application18.


described for etravirine in a drugsynthesis patent17.

Spray drying drug from organicsolution together with a polymerwas subsequently pursued as anapproach to further improve drugdissolution and hence bioavailability,but initial dispersions of drug inHPMC yielded particles on spraydrying that were of low bulk densityand gave problems with tableting.Co-spray drying etravirine, HPMCand microcrystalline cellulose, withdrug and polymer in solution andwith microcrystalline cellulosesuspended in the spray drying feed,led to denser particles highly suitedto processing into tablets (Figure 1)18.This formulation technologyprovided for significantly improvedbioavailability of etravirine in HIV-infected subjects, as indicated byarea under the plasmaconcentration-time curve over theperiod to 12 hours post-dosing, andallowed for smaller and a reducednumber of tablets to achieve theclinically effective dose. The rangeof exposure seen with 200mg of thespray dried formulation given twice

daily was comparable to thatyielded by 800mg of the granulo-layered formulation dosed twicedaily and with reduced interpatientvariability19.

Novel HIV attachmentinhibitors Novel HIV attachment inhibitorsinterfering with the binding of theviral gp120 glycoprotein to the hostcell CD4 have been identified byBristol-Myers Squibb20. One suchcompound, BMS-626529, is apotent inhibitor of viral replicationin vitro but exhibits low oralbioavailability and a very shortapparent half-life in vivo. Toovercome the low bioavailability ofthe compound associated with itspoor water solubility, a prodrugstrategy was pursued in which thechemical structure was modified bythe addition of hydrophiliccleavable substituent groups toimprove solubility. Enzymatichydrolysis in vivo enabled effectivedelivery of the parent molecule.Based upon animal and human invivo screening experiments, BMS-

663068, a phosphonoxymethylprodrug of BMS-626529, wasselected for evaluation in theclinic21.

The highly soluble prodrug, whendelivered orally, is converted locallyvia intestinal brush border alkalinephosphatase to the poorly solubleparent, BMS-626529, immediatelyprior to/during absorption.Maintaining a threshold minimumplasma concentration (Cmin) prior toadministration of the next dose isconsidered important to efficacy,whilst the minimisation of maximumplasma concentration (Cmax) maymitigate peak-related adverseevents. Sustained absorption ofparent throughout thegastrointestinal tract via slow releaseof prodrug from a formulation isrequired to achieve this andovercome the short half-life of thecompound.

The achievement of targetpharmacokinetics was enabledthrough the design of a novelextended-release (ER) tablet22.Tablet development was based onin silico modelling and built upon


Figure 2: HME process to make amorphous dispersion formulations (e.g. lopinavir with ritonavir). The HMEapproach involves dispersing the drug within a pharmaceutically-acceptable polymer in an extruder with theapplication of heat. If it is done by raising the drug and the polymer in admixture to above the melting point of thedrug and the glass transition temperature of the polymer and then cooling without allowing the drug torecrystallize, then the resultant solid dispersion is amorphous. The physical stability of such a formulation might bedependent on the miscibility of the drug and polymer, i.e. the amount of drug dispersed in the polymer,temperature and humidity at which the solid dispersion is stored, and whether there are molecular levelinteractions between drug and polymer that impair its propensity to recrystallise. Commercial equipment is usuallya twin screw extruder which enables feeding of drug and polymer (and other excipients if needed) into theextruder where specifically-designed motor driven screws convey the materials along the heated barrel, mix them,allow them to melt and soften as appropriate, knead and densify them, shear and cut the formed mass and allow itto cool as it leaves the extruder barrel. The resultant material can be further processed into granules and, ifneeded, blended with other excipients to make it suitable for tableting.


careful evaluation of bioavailabilityin specific areas of the intestine andcolon to gain an understanding ofhow gastrointestinal physiology andlumenal fluid volume andcomposition could influenceprodrug conversion and absorptionof the parent23. The formulation wasdeveloped as a non-disintegratingmonolithic, matrix tablet utilisinghydrophilic swellable cellulose etherpolymer technology. Althoughunbound alkaline phosphatase wasshown to penetrate the hydratinggel layer of the tablet and representan in vivo risk from lumenal alkalinephosphatase, conversion of prodrugto parent within the hydrateddosage form was shown to beinhibited24. This is essential tomaintaining the required releaserate and pharmacokinetics aspremature conversion to parentwithin the dosage form would leadto reduced bioavailability. Theoptimised, in vivo stabilised ERformulation was found to besuitable for once to twice dailydosing.

Lopinavir with ritonavir Lopinavir with ritonavir (Kaletra,AbbVie) commercial formulationemploys hot melt extrusion(HME), resulting in anamorphous drug dispersion inthe finished product.Amorphous dispersions havebeen progressed as a solutionto overcome poor drug-likeproperties, solubility anddissolution rate, and mitigatepoor bioavailability relating tothose properties25. HMErepresents a commercialisableapproach to manufacturing suchdispersions26 (Figure 2). It haslong been used in otherindustries where a thermoplasticmaterial is softened undertemperature and shear force,usually admixed with othermaterials (fillers, pigments,stabilisers, etc), then extrudedto form granules/pellets, tubes,rods or sheets. HME was firstdescribed for creatingpharmaceutical dosage formsover 40 years ago27 but only

became of demonstratedpotential for creation ofcommercialisable products inthe last 15–20 years28.

The commercial lopinavir 200mgwith ritonavir 50mg combinationtablet employs copovidone andsorbitan laurate as the polymericcomponents to provide the materialfor tableting. The amount ofcopovidone in the product washigher than previously usedaccording to the US FDA InactiveIngredient Listing and required thesubmission of a package of toxicitystudies to support the higher level,including data on repeat dosetoxicity, genotoxicity andcarcinogenicity29.

As well as reducing the number ofdosage forms the patient has totake in transferring to the HMEformulation from the prior availableliquid-filled capsule formulation, theHME formulation avoids therequirement to store the medicine ina refrigerator. The tablet showslower variability in pharmacokineticparameters relative to the capsuleand has a much diminished foodeffect, allowing for the possibility ofnot restricting to dosing withfood30,31. These are valuableimprovements in terms ofsupporting patient compliance withthis medicine resulting from theapplication of modern formulationscience.

Cobicistat Cobicistat (Tybost, and componentof Stribild, Gilead) is a novelcytochrome P450 (CYP) enzyme(CYP3A4) inhibitor used as a“booster” in combination with someHIV treatments e.g. proteaseinhibitors, to reduce theirmetabolism during absorption andso increase the amount ofunchanged drug reaching thesystemic circulation. Ritonavir is alsoused as such a boosting agent butcobicistat differs in that it has noanti-viral activity of its own and ispurely used to modifypharmacokinetics.

Cobicistat drug substance doesnot occur in crystalline form and isisolated as an amorphous,

hygroscopic solid foam of low glasstransition temperature which readilytransforms under ambientconditions via a moisture- andtemperature-driven phasetransformation into a rubber-likematerial that is difficult to processinto dosage forms. The removal ofthe absorbed moisture andreversion to the original solid formdoes not occur32.

Initial approaches to making soliddosage forms involved handling thedrug substance in solution in anappropriate organic solvent, such asethanol33. This solution is added tosilica and then excipients and waterin a high shear mixer to wetgranulate. Fluid bed drying achievesremoval of the organic solvent aswell as the water. The challenges ofhandling large volumes offlammable solvent in a drug productprocessing facility, whilst notinsurmountable, can be avoided ifthe drug is loaded on to a suitablecarrier material that impart superiorhandling properties to the drugsubstance prior to introduction intoa dosage form manufacturing area.

By adsorbing onto silica byevaporation from a dichloromethanesolution of drug as part of theisolation of the cobicistat33, a free-flowing powder is produced.Although still hygroscopic, moistureuptake is now reversible and thecobicistat no longer undergoesphase transformation. The drugadsorbate is highly suited to furtherprocessing into pharmaceuticaldosage forms. The finished dosageform using the adsorbate showedbioequivalence for cobicistat withdosage forms prepared by theethanol/water high sheargranulation process. For cobicistat,formulation technology has dealtwith challenging physical propertiesof an active pharmaceuticalingredient and provided anapproach to improved handling andmanufacturing of dosage forms.

NevirapineNevirapine, a well-establishedNNRTI, has recently becomeavailable as an ER formulation(Viramune Prolonged-Release,



Boehringer Ingleheim). Although itis inherently a long half-life drug, t½>45 hours34, there are advantagesin offering patients an ER nevirapineformulation. Despite the long half-life, immediate-release nevirapine istypically dosed in treatment-stabilised patients at 200mg twicedaily35. A concern with using a400mg once daily immediate-release dose is that it results in highmean peak and low mean troughplasma concentrations of drugrelative to using a dose of 200mgtwice daily, although the exposureto drug as measured by the areaunder the plasmaconcentration–time curve wasequivalent for once and twice dailydosing regimens. Higher peakconcentrations give concern as toan increased risk of liver toxicity andlower trough concentrations raiseconcern as to risk of emergence ofviral resistance35. Also, twice dailydosing is less convenient for HIVpatients taking multiplemedications where many of theirother medicines have once dailydosing. Hence, there is goodclinical relevance to creating the ERformulation. Predicting ordemonstrating that there is effectivedrug absorption from the colon isessential to determining the viabilityof developing an oral ERformulation36. Nevirapine deliveredto the ascending and descendingcolon had 82 and 58%bioavailability, respectively, relativeto an orally-administeredsuspension of nevirapine37,exceeding the value of ≥40%suggested as an indicator of likelysuccess38, and supported thedevelopment of the ER product.

The commercial formulation wasselected on the basis ofpharmacokinetic evaluation of aseries of hydrophilic matrix tabletsthat employed different amountsand grades of HPMC as a releaserate controlling polymer. Tabletscontained 20, 25, 30 or 40% w/w ofHPMC 2208 4000 cps grade oralternatively 20 or 25% w/w HPMC2910 4000 cps grade and theamount and grade of polymer usedyielded a range of in vitro release

rates that translated to a range of invivo pharmacokinetic profiles39 withthe lower amount of polymerleading to a faster release rate, andwith the 2910 polymer leading tofaster release rates than the 2208polymer. The marked change inrelease rate with polymer amount,given similar tablet sizes across therange studied, suggests a degree ofdependency on erosion as a keyrate controlling mechanism from thehydrated polymer matrix in vitro andin vivo. It was possible to build acorrelation between the in vitrorelease profile and the in vivoperformance enabling prediction ofthe pharmacokinetic behaviour ofdosage forms as in vitro release ratewas changed, which would enablefurther formulation developmentstudies to be prosecuted using invitro drug release rate for decisionmaking40. Contrary to what was seenin the single-dose human studyused to establish the in vitro–in vivocorrelation, in a steady state humanbioavailability study of the 20 and25% w/w polymer ER formulations,the (more slowly releasing) 25% w/wpolymer formulation showed higherbioavailability compared to the 20%w/w polymer formulation41. Asmetabolism of nevirapine isimpacted by induction of CYPenzymes, which include CYP3A442

(which is more extensively expressedin the upper gastrointestinal tract), amore slowly releasing formulationmight deliver more drug to theregions where the enzyme is notexpressed compared to the fasterreleasing formulation, and result inincreased exposure that is moreobvious in a steady state study. Thisobservation offers the caution thatthe performance of an enabledformulation has to be considered inlight not only of its fabricationtechnology, but the physiologicalenvironment in which it has tooperate, including gastrointestinaltransit, absorption sites,metabolising enzymes, etc.

SummaryThe development of modernmedicines for the treatment of HIVinfection has benefitted from

formulation technology toaccommodate the inherentproperties of the activepharmaceutical ingredient andassure that pharmacokinetic andphysiochemical challenges aremanaged. HIV medicineformulations offer examples ofextended release technologies,managing in vivo disintegration anddispersion, adsorption on to acarrier, spray drying and meltextrusion. All of these technologiesare in place for commercializedproducts and demonstrate howformulation technology in generalmay be deployed to deal with thechallenges inherent incontemporary potential therapeuticagents of any disease class.

References 1 Benzer JA, et al. The current state of HIVtherapy. Formulary 2013;48:213–223.

2 Arribas JR, Eron J. Advances inantiretroviral therapy. Curr Opin HIV AIDS2013;8:1– 9.

3 Kumari G, Singh RK. Anti-HIV drugdevelopment: structural features andlimitations of present day drugs andfuture challenges in the successfulHIV/AIDS treatment. Curr PharmaceutDesign 2013;19:1767–1783.

4 Pomerantz RJ, Horn DL. Twenty years oftherapy for HIV-1 infection. Nat Med2003;9:867–873.

5 Flexner C. HIV drug development: thenext 25 years. Nat Rev Drug Discov2007;6:959–966.

6 Batra U, et al. Compressed tabletformulation. US Patent US7707294; 2006.

7 Gao JZ, et al. Investigation of humanpharmacoscintigraphy behaviour of twotablets and a capsule formulation of ahigh dose, poorly water soluble/highlypermeable drug (efavirenz). J Pharm Sci2007;96:2970–2977.

8 Dahl TC, et al. Unitary pharmaceuticaldosage form. US patent applicationUS2007/0099902; 2007.

9 Hussain MA, et al. Development ofAtripla®, a fixed dose combination tabletof three drugs: efavirenz, emtricitabine,and tenofovir disoproxil fumarate.Presented at AAPS Annual Meeting, NewOrleans, LA, USA; 2010.

10Dahl TC, et al. Dry granulatedcomposition comprising emtricitabine andtenofovir disoproxil fumarate. Europeanpatent specification EP1890681; 2009.

11Airoldi M, et al. One-pill once-a-dayHAART: a simplification strategy thatimproves adherence and quality of life inHIV-infected patients. Patient PreferAdherence 2010;4:115–125.



12Weuts I, et al. Physicochemical propertiesof the amorphous drug, cast films, andspray dried powders to predictformulation probability of success for soliddispersions: etravirine. J Pharm Sci2011;100:260–274.

13Qi S, et al. An investigation into thecrystallisation behaviour of an amorphouscryomilled pharmaceutical material aboveand below the glass transitiontemperature. J Pharm Sci2010;99:196–208.

14 Kakuda TN, et al. Assessment of thesteady-state pharmacokinetic interactionbetween etravirine administered as twodifferent formulations and tenofovirdisoproxil fumarate in healthy volunteers.HIV Med 2009;10:173–181.

15Anonymous. Intelence 100 mg tablets(Tibotec) 01/18/2008 approval [HIV-1]:clinical pharmacology andbiopharmaceutics. Sourced from FOIServices, Inc., Gaithersberg, MD, USA;2008. Downloaded from foiservices.comon April 20, 2010.

16Gilis PMV, et al. Beads having a corecoated with an antifungal and a polymer.US patent 5633015; 1997.

17De Corte B, et al. HIV replicationinhibiting pyrimidines. US patent7037197; 2006.

18 Kiekens FRI, et al. Process for preparingspray dried formulation of TMC125. USpatent application 2009/0197903; 2009.

19 Kakuda TN, et al. Single and multiple-dose pharmacokinetics of etravirineadministered as two different formulationsin HIV-1-infected patients. Antiviral Ther2008;1:655–661.

20 Kadow JF, et al. Discovery anddevelopment of HIV-1entry inhibitors thattarget gp120. In: Antiviral Drugs: FromBasic Diiscovery Through to Clinical Trials(Kazmierski WM, Ed). Hoboken, NJ, USA:Wiley; 2011.

21Wang T, et al. Use of a phosphonoxymethylprodrug approach to successfully improvethe oral delivery of HIV-1 attachmentinhibitors: design, preclinical profile andhuman exposure. Presented at: AmericanChemical Society National Meeting, SanFrancisco CA, USA; 2010.

22 Brown JR, et al. Stable pharmaceuticalcomposition for optimized delivery of anHIV attachment inhibitor. European patentspecification EP 2323633; 2012.

23 Brown J, et al. Compartmental AbsorptionModeling and Site of Absorption Studiesto Determine Feasibility of an Extended-Release Formulation of an HIV-1Attachment Inhibitor Phosphate EsterProdrug. J Pharm Sci 2013;102:1742–1751.

24Hanley S, et al. Investigation into thepotential for prodrug hydrolysis within ahydrated HPMC matrix. Presented at APSPharmSci Conference, Edinburgh, UK;2013.

25 Van den Mooter G. The use of amorphoussolid dispersions: a formulation strategyto overcome poor solubility anddissolution rate. Drug Discov Today:Technologies 2012;9:e79–e85.

26 Shah S, et al. Melt extrusion with poorlysoluble drugs. Int J Pharm2013;453:233–252.

27 El-Agakey MA, et al. Hot extrudeddosage forms. Part 1: technology anddissolution of polymeric matrices. PharmActa Helv 1971;46:31–52.

28 Breitenbach J, et al. Solid dispersions byan integrated melt extrusion system. ProcIntl Symp Control Rel Bioactive Mater1998;25:804–805.

29 EMA. Kaletra, Scientific Discussion 27 April2006. Downloaded on 9 October 2013 fromwww.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000368/human_med_000867.jsp&mid=WC0b01ac058001d124

30Breitenbach J. Melt extrusion can bringnew benefits to HIV therapy: the exampleof Kaletra tablets. Am J Drug Deliv2006;4:61–64.

31 Klein CE, et al. The tablet formulation oflopinavir/ritonavir provides similarbioavailability to the soft-gelatin capsuleformulation with less pharmacokineticvariability and diminished food effect. JAcquir Immune Defic Syndr2007;44:401–410.

32 EMA. Committee for Medicines forHuman Use, Assessment Report: Stribild,21 March 2013. Downloaded on 18October 2013 from

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33Kozlara JM, et al. Use of solid carrierparticles to improve the processability ofa pharmaceutical agent. US patentapplication US 2009/0324729; 2009.

34 Lamson MJ, et al. Single dosepharmacokinetics and bioavailability ofnevirapine in healthy volunteers.Biopharm Drug Dispos 1999;20:285–291.

35Cooper CL, van Heeswijk RP. Once-dailynevirapine dosing: a pharmacokinetics,efficacy and safety review. HIV Med2007;8:1–7.

36 Brown J, et al. Predicting feasibility andcharacterizing performance of extended-release formulations using physiologicallybased pharmacokinetic modelling.Therapeut Deliv 2012;3:1047–1059.

37Macha S, et al. Assessment of nevirapinebioavailability from targeted sites in thehuman gastrointestinal tract. J ClinPharmacol 2009;49:1417–1425.

38Connor A, et al. Evaluation of humanregional bioavailability to assess whethermodified release development is feasible.Presented at AAPS Annual Meeting, SanDiego CA, USA; 2007.

39Cappola ML, et al. Extended releaseformulation of nevirapine. US patent US8460704; 2013.

40Macha S, et al. In vitro-in vivo correlationfor nevirapine extended release tablets.Biopharm Drug Dispos 2009;30:542–550.

41 Battegay M, et al. Bioavailability ofextended-release nevirapine 400 and 30mg in HIV-1: a multicenter, open-labelstudy. Clin Ther 2011;33:1308–1320.

42 Lamson M, et al. Nevirapine induces bothCYP3A4 and CYP2B6 metabolic pathways.Clin Pharm Ther 1999;65:137.


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Falsified Medicines Directive:fighting a growing problem Counterfeiting is a crime with veryreal consequences: it presents amajor threat to patient safety and wehave seen the devastating evidenceof this. Just this past October,customs agents seized 1 million fakeXanax pills at Zurich airport1. In Mayof this year, French customs officersseized 1.2 million doses ofcounterfeit aspirin – an over-the-counter medicine that could havereached patients even more easilythan the fake anti-anxiety pills seizedin Switzerland2. Germany,meanwhile, experienced one of itsmost significant counterfeiting scaresin March, when it was discovered

that a common heartburn counterfeitor sub-standard medication hadmade it onto the market3. In 2011alone, approximately 30 million fakemedicines were seized at EUborders4. What makes thesestatistics even more troubling is thefact that it is impossible to knowwhat the real numbers are – but wecan be sure they are much higherthan what is reported. The peoplebehind counterfeiting are criminals –they aren’t reporting earnings andsales, they aren’t releasing quarterlyreports. It is impossible to gauge justhow big the problem is. And that iscause for serious concern. All we canknow is that we need to act – andquickly.

In an attempt to fight back againstcounterfeiters and the dangerousgoods they bring into the markets,the European Union (EU) put forththe Falsified Medicines Directive(FMD; 2011/62/EU) first published inthe EU Official Journal on 1 July2011. The FMD sets out steps tosecure the supply chain of medicinesin Europe. It asserts that allprescription-only medicines will haveto bear safety features (i.e. a uniqueserial number placed on each pack,together with tamper-evidentpackaging)*. The FMD also requiresthe establishment and managementof a repositories system that willstore the unique identifiers of theserial packs, and contain informationon the safety features. The EuropeanCommission will determine thespecifications of the serial number tobe placed on packs when it sets outthe rules for implementation in the“Delegated Acts”. Once theDelegated Acts are published –anticipated in the second half of2014 – EU Member States andpharmaceutical companies supplyingthe EU market will have 3 years totake the necessary steps and ensurethey are in compliance.

A solution in the EuropeanStakeholder ModelIn Europe, the FMD is an importantstep in better protecting patientsfrom counterfeit medicines. TheEuropean Federation ofPharmaceutical Industries andAssociations (EFPIA) sees the need tomove as quickly as possible to ensurethe legitimate supply chain is as safeas possible. One of the FMD’s keyelements is the onus it places onpharmacists to be able to verify thatthe medicine they dispense topatients is genuine. Towards this end,EFPIA has joined together with thePharmaceutical Group of theEuropean Union (PGEU), theGroupement International de laRepartition Pharmaceutique (GIRP)and the European Association of theEuro-Pharmaceutical Companies(EAEPC) to develop the EuropeanStakeholder Model (ESM) MedicinesVerification System. Theseorganisations – representing

TAKING STEPS TO IMPLEMENTTHE FALSIFIED MEDICINESDIRECTIVE AND COMBATCOUNTERFEITING IN EUROPE– THE EUROPEANSTAKEHOLDER MODELby Richard Bergström

Falsified medicines present a public health threat atglobal level, with counterfeit goods threatening the

health of patients in countries around the world. Withthe increased prevalence of unlicensed online“pharmacies” and points-of-sale, the problem isattracting growing attention – inspiring governments,security officials and the pharmaceutical industry to takeaction. The pharmaceutical industry has a vested interestin fighting counterfeiting: developing new medicines isonly one part of providing healthcare treatments forpatients – we also have to ensure that people benefitfrom those medicines. Part of that involves making surethat any medicine we produce reaches the patient in thesame condition as when it leaves the manufacturing site.

Richard Bergström was appointed as Director General of the EFPIA in April 2011.Over the past 20 years he has worked for Roche, Novartis and with the Swedishpharmaceutical industry association (LIF). Since 2006, he has been an Advisor to theWHO on good governance in medicine.

* Certain products or product categories of prescription-only medicines might be exempted according to a risk assessment. Over-the-counter medicines, for instance, are excluded – unless there is a risk of falsification.


pharmacists, wholesalers, and paralleltraders, respectively – came togetherwith the aim of developing a systemthat will provide a high level ofsecurity for patients while being cost-effective, pan-European andinteroperable, and capable of beingeffectively integrated into existingstructures and practices in thedistribution chain. The result is theEuropean Medicines VerificationSystem (EMVS; Figure 1), a systemdesigned to ensure the medicinesare making it safely from the point ofmanufacture to the point of sale – tothe patient.

The EMVS proposed by EFPIA,EAEPC, PGEU and GIRP iscomprised of the European Hub andthe National Blueprint Systems(nBPS). The European central hub isconnected to a series of single-country or multi-country datarepositories that serve as verificationplatforms; pharmacies and otherregistered parties can use these tocheck a product’s authenticity. Thesystem will be interoperablebetween EU countries and will allowfor the reconciliation of productstraded between EU member states(known as parallel traded products)through the European central hub. Itwill also offer those countries that donot want to set up their own nationalsystem the opportunity to join anexisting product verificationinfrastructure. These componentsare to be managed by the EuropeanMedicines Verification Organisation

(EMVO), which is to be founded inthe course of 2014 and foreseesparticipation of authorities and otherrelevant stakeholders in the overallgovernance.

The EMVS was successfully testedin a pilot project in Sweden from2009–2010. Stakeholders inDenmark, Finland, Norway andSweden have already expressedtheir commitment to the BlueprintSystem. Meanwhile, developmentand implementation of theEuropean Hub is well under way. Bythe first quarter of 2014, results areexpected from user-acceptedtesting in Germany, in which theHub was connected to the GermansecurPharm system†, demonstratingthe first scenario covering the fullinformation chain at European level– from manufacturer to pharmacy.

Fighting counterfeiting in acollaborative andcomprehensive wayThe measures set forth by the FMD,and the systems being developed tohelp implement its provisions are amajor step forward in the EU againstcounterfeiting. But fightingcounterfeiting requires acollaborative, multi-faceted effort.Part of this simply involveseducation: when it comes to thedangers of counterfeit medicinessold on the Internet, for instance,patients need to be aware that thevast majority of medicines theycome across on the Internet are

either counterfeit or unsafe. The pharmaceutical industry

invests huge amounts of time andmoney into developing medicines totreat a huge variety of illnesses – butthis work is irrelevant if we can’tensure that patients are safelyreceiving these medicines. Anymedicine that reaches the patientshould be in the same condition aswhen it leaves the manufacturingsite. That is the goal of initiativeslike the ESM and the FMD. Thesooner we can implement suchmeasures, the sooner we will bemaking patients that much safer.

References1 BBC. Fake Xanax anxiety pills from Chinaseized in Zurich; 18 October 2013.www.bbc.co.uk/news/world-europe-24585099

2 EUbusiness. Million doses of fake aspirinfrom China seized in France; 25 May2013. www.eubusiness.com/news-eu/france-china.or9/

3 Die Welt. Razzia wegen eines gefälschtenMedikaments; 7 March 2013.www.welt.de/newsticker/news3/article114240342/Razzia-wegen-eines-gefaelschten-Medikaments.html

4 European Commission. Report on EUcustoms enforcement of intellectualproperty rights. Results at the EU border –2011; July 2012.http://ec.europa.eu/taxation_customs/resources/documents/customs/customs_controls/counterfeit_piracy/statistics/2012_ipr_statistics_en.pdf

Editor’s comment:EIPG, a stakeholder organisationrepresenting the industrialpharmacists responsible forensuring, under Art. 51 of theDirective, that the safety featureshave been affixed to the packagingof medicinal products, commentedon the EMVS during a symposium atthe University of Lisbon in 2012. Inparticular, EIPG expressed itsconcern that the model proposedvoluntary verification at thewholesaler dealer level, given thatArt. 80(ca) of the Directive stipulatesthat "Wholesale distributors mustverify that the medicinal productsreceived are not falsified by checkingthe safety features on the outerpackaging”.

TAKING STEPS TO IMPLEMENT THE FALSIFIED MEDICINES DIRECTIVE continued

Figure 1: The European Medicines Verification System (EMVS)†.

† securPharm is a national anti-counterfeiting initiative. Launched by German pharmaceutical manufacturing, pharmacist and wholesalerassociations, it is designed to test whether medicinal products are genuine or not and is intended to comply with the EU FMD.

regulatory reviewThe current review period hasseen a number of changes inthe regulation of medicinesand regulatory guidance inthe EU, USA and, Internationalmarkets.

USAProposed regulation –administrative detentionauthority during inspection ofdrugs intended for human oranimal useUnder this proposed regulation, theFood and Drug Administration(FDA) will be able to administrativelydetain drugs encountered during aninspection that an officer oremployee conducting the inspectionhas reason to believe areadulterated or misbranded untilFDA has had time to consider whataction it should take concerning thedrugs, and to initiate legal action, ifappropriate.

Draft Guidance for Industry –Specification of the UniqueFacility Identifier (UFI) Systemfor Drug EstablishmentRegistrationFDA’s preferred UFI for a drugestablishment is the Data UniversalNumbering System (DUNS) number.The DUNS number is available freeof charge to all drug establishments.Alternative identifiers may only beused after consultation with FDA.

Unique Device Identification(UDI)FDA has released a final rulerequiring that most medical devicesand certain combination productsthat contain devices that aredistributed in the USA carry a UDI.

Secure Supply Chain PilotProgram (SSCPP)Qualified firms will be enabled toexpedite the importation of activepharmaceutical ingredients andfinished drug products into the USA.Participating firms in this voluntaryprogramme must meet certaincriteria. The pilot program will runfrom February 2014 throughFebruary 2016.

Draft Guidance for Industry –Refuse-to- Receive Standards This guidance is intended to assistsponsors preparing to submitabbreviated new drug applications(ANDAs) and prior approvalsupplements to ANDAs for whichthe applicant is seeking approval ofa new strength of the drugproduct. The guidance describeswhat should be included andhighlights serious deficiencies thatmay cause refusal to receive anANDA.

EuropeQ&A – Practicalimplementation guidelines onvariations Procedural elements in relation tothe implementation of the revisedguidelines are clarified.

Improving the safety ofmedical devicesFollowing the Poly Implant Prothèsebreast implants and other scandalsthe European Commission hasadopted two measures forimmediate implementation. Thenew rules are:• a Commission Implementation

Regulation clarifying the criteria tobe met by notified bodies;

• a Recommendation clarifying thetasks these bodies have toundertake when they performaudits and assessments.

Reflection paper – coatednanomedicines general issuesfor consideration The reflection paper describesgeneral issues to consider duringthe development of nanomedicinesthat have a coating

MHRACan a single system simplifyreporting of incidents to theMHRA?The MHRA currently runs fivereporting systems to collect reportsof different types of incidentsinvolving medicines, medicaldevices and blood. MHRA isconsidering whether bringing all

five systems together under theYellow Card Scheme brand(currently used for reporting sideeffects to medicines) could helpincrease incident reporting andreduce confusion of reporters.

Proposed introduction of Tell-and-Do variations for aspecific subset of parallelimport licensesParallel Importers (PIs) must notifyMHRA if they observe certainchanges to the imported products(e.g. changed appearance ofdosage forms). While MHRA isinvestigating the changes, there is a‘stop-processing’ requirement onthe importing companies whichprohibits them from processing,repackaging or releasing theproduct onto the market until givenapproval. This can be anunexpected disruption of severalmonths and affect the importer’sbusiness negatively.

The new proposal abolishes the‘stop-processing’ requirement ifimported products are part ofEuropean Mutual Recognition orDe-Centralised procedures. PIs willnotify the Agency of the changesand release the products onto theUK market. This notificationprinciple is known as ‘Tell-and-Do’.

Falsifed Medicines Directive(FMD)The UK MHRA has published on itswebsite an overview of themedicines regulation and guidancein relation to the FMD as it appliesto the UK.

Nicotine-containing products The European parliament did notsupport The Commission’s proposalto regulate electronic cigarettes asmedicines. MHRA, however, willcontinue to encourage companiesvoluntarily to seek a licence for theirproducts.

Q&A for Specialsmanufacturers Q&As have been used in thisguidance to promote easy updates

20 european INDUSTRIAL PHARMACY December 2013 • Issue 19

Continued on page 21

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]

US PharmacopoeialConventionEIPG has received a formal invitationto be an observer organisation atthe US Pharmacopoeial Convention.The organisation is looking forEuropean candidates for the USPCouncil of Experts and ExpertCommittees to serve for the periodof 2015– 2020. Anyone wanting toimpact public health, shareexpertise and collaborate withcolleagues worldwide and add totheir career experiences can applyonline during the coming year(www.usp.org/) Please let us know ifyou are a member of your NationalAssociation within EIPG and areapplying to become an expert forthe USP.

Future training opportunitiesDiscussions are underway betweenEIPG and representatives of atraining company which coversQualified Persons (QP)/quality,Quality by Design andbiopharmaceuticals aimed, inparticular, at professionals who areworking in companies operating inniche areas. The aim is to offer on-demand training for the members ofEIPG Associations and those whovisit our EIPG website.

October EIPG BureauMeetingThe President and Treasurer’s visit toBulgaria was reported and practicalaspects of the General Assembly2014 were considered. A series ofpoints on medicines shortages weredrafted including the working ofArticle 126A. The European

Medicines Agency’s (EMA’s)dedicated facilities workshopattended by Piero Iamartino (VP,Italy) was discussed.

European CommissionRepresentatives of EIPG and thecommunity and hospital pharmacists(PGEU and EAHP) attended ameeting with Dr Patrizia Tosetti, DGSANCO, to discuss medicinesshortages. Various EIPG concernswere raised and some suggestionswere made to her.

EMAa. Comments on the Revision of theGMP guidelinesEIPG submitted comments on theRevision of the GMP guidelines(Annex 16) on certification by a QPand batch release.b. Interested Parties MeetingClaude Farrugia (VP, Malta) attendedon behalf of EIPG. The EMAWorkplan was discussed and DavidCockburn, chair of the meeting,confirmed that cooperation andcollaboration with industry is one oftheir fixed topics for consideration.

Presentations were made byrepresentatives from Rx-360 andEXCiPACT on their auditingprogrammes, supply chain securityand certification scheme for activepharmaceutical ingredients (APIs)and excipients.

APIC, the APIs Committeepresented on their development ofa “how to do” document to helpindustry to comply with GoodDistribution Practice for APIs. Arepresentative from EFPIArequested clarity on the

interpretation of severalrequirements for Good DistributionPractice. Further information will bepublished on the discussions heldduring this meeting.c. Dedicated Facilities WorkshopA report from Piero Iamartino (VP,Italy) who participated on behalf ofEIPG is as follows.

The revised versions of EU GMPChapters 3 and 5, together with theEMA-proposed guidance about atoxicological tool in evaluatingdedicated manufacturing facilities,were discussed between EMA, itsregulatory partners and therepresentatives of industrycoordinated by EFPIA. The need toset health-based limits and to adoptQuality Risk Management principleswere agreed among all participants.However, industrial representativesrequested a more flexible approach,though always being adequatelyjustified. Amendments of the textwere requested for IMPs (lowtoxicological data available), APIs(specific guidance to be added),genotoxic materials (threshold limitto be in line with ICH M7).

According to industry, a suitableimplementation period is necessaryfor existing products, while theapplication to “new products”(definition still to be clarified) couldstart with usual timeframes after theguidance has been finalised. Authorities will provide a revision ofthe three documents and a secondpublic consultation is expected tobe held in 2014.

Jane Nicholson, Executive DirectorEIPG, [email protected]

news from the EIPG

21european INDUSTRIAL PHARMACY December 2013 • Issue 19

when further clarification onspecific good manufacturingpractice topics is required relatingto the manufacture of unlicensedmedicines. It does not replace anyof the requirements alreadycontained in Guidance Note 14.

InternationalWHOGood trade and distributionpractices for pharmaceuticalstarting materials (revision) A number of recent incidents havecreated awareness of the need forfurther improvement of the presentguidelines. A new draft has been issuedto a restricted audience for comment.

Regulatory ReviewContinued from page 20


eventsJANUARY21-23 January 2014 – Frankfurt,GermanyClinical Supply Chainwww.pharma-iq.com

22-24 January 2014 – London, UKUnderstanding and Preparingthe Quality and PharmaceuticalModulewww.pti-global.co.uk

28-29 January 2014 – Berlin,GermanyProtective Packaging Solutionsfor Pharmaceutical ProductStabilitywww.gmp-compliance.org

28-29 January 2014 – London, UKJoint Regulators/Industry QbDWorkshopwww.pda.org

28-29 January 2014 – Washington,Dc USA11th Annual PharmaceuticalCompliance Congresswww.cbinet.com

FEBRUARY4-5 February 2014 – London, UKEU Biosimilar Registration andMarketing Requirementswww.pti-global.co.uk

6 February 2014 – London, UKDevelopments in Analysis ofOrally Inhaled and Nasal DrugProductswww.jpag.org

11 February 2014 – Manchester,UKGood Clinical PracticeSymposiumwww.mhra.gov.uk

18–19 February 2014 – Brussels,Belgium6th Annual Disposable Solutionsfor Biomanufacturingwww.pharma-iq.com

18-19 February 2014 – Berlin,GermanyPharmaceutical Microbiologywww.pda.org

18-20 February 2014 – Munich,Germany6th Disposable Solutions forBiomanufacturing Summitwww.disposablebiomanufacturing.com

24-25 February 2014 – WashingtonDc, USA2014 Aseptic Annual Conferencewww.ispe.org

24–27 February 2014 – Montreal,Quebec, Canada12th Annual Cold Chain GDP &Temperature ManagementLogistics Summitwww.coldchainpharm.com

25-26 February 2014 – BarnardCastle, UKCleaning Validationwww.honeyman.co.uk

27-28 February 2014 – London, UKProcess Validation forPharmaceutical ProductsRegulated by EMA & FDA –Balancing Science and Riskduring the Product Lifecycle www.management-forum.co.uk

MARCH4-5 March 2014 – London, UKClinical Outsourcing &Partnership World 2014www.healthnetworkcommunications.com

11-12 March – Brussels, BelgiumParenteral Packagingwww.pda.org

13 March 2014 – London, UKThe Pharma Summit 2014 –Reinventing Business Modelsand Marketswww.economistconferences.co.uk

17-18 March 2014 – London, UKDistribution of Medicines – TheNew EU Good DistributionPractice Guide...Are You Prepared?www.management-forum.co.uk

14 March 2014 – London, UKGood Clinical PracticeSymposium 2014www.mhra.gov.uk

24-26 March 2014 – Heidelberg,GermanyICH Q7 Compliance for APIsManufactured by ChemicalSynthesiswww.gmp-compliance.org

25-26 March 2014 – Lyon, FranceModern BiopharmaceuticalManufacturingwww.pda.org

26-27 March 2014 – Frankfurt,Germany 4th Annual Pharma Packaging &Labeling Forum www.flemingeurope.com

26-28 March 2014 – Barcelona,Spain19th Congress of the EAHP: TheInnovative Hospital Pharmacist –Imagination, Skills andOrganisationwww.eahp.eu

31 March-3 April 2014 – Lisbon,Portugal9th Pharmaceuticals,Biopharmaceutics andPharmaceutical TechnologyWorld Meetingwww.apv-mainz.de

APRIL1-4 April 2014 – Barcelona, SpainWorld Generic MedicinesCongress Europe 2014www.healthnetworkcommunications.com

1-4 April 2014 – Barcelona, SpainBiosimilar Drug DevelopmentWorld Europewww.healthnetworkcommunications.com

2-3 April 2014 – Prague, CzechRepublic10th Annual BioProcessInternational European Summitwww.informa-ls.com

2-3 April 2014 – Barcelona, SpainWorld Generic MedicinesCongress Europe 2014 www.terrapinn.com

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