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europeanINDUSTRIALPHARMACY

ISSUE 7 • OCTOBER 2010www.industrialpharmacy.eu

www.eipg.eu

FEATURES4 PHARMACEUTICAL INDUSTRY ADVANCED TRAINING

(PIAT) – ACCREDITED PROFESSIONAL DEVELOPMENT FOR THEMEDICAL AND HEALTHCARE INDUSTRIES

The PIAT programme provides a distance learning opportunity toexperience Continuing Professional Development (CPD).by Brian Lockwood

7 HOT-MELT EXTRUSION TECHNOLOGY: OPTIMIZINGDRUG DELIVERYHot-melt extrusion is a new technology used to produce a varietyof solid dosage forms which offer increased dissolution propertiesand hence improved absorption and therapeutic efficacy for poorlywater-soluble compounds.by Marcia Williams, Yiwei Tian, David S Jones and Gavin P Andrews

11 MOVINGTOWARD100%RAWMATERIAL INSPECTIONWITHAHANDHELDRAMANSPECTROMETERImprovements in Raman spectroscopy and the development ofhandheld instruments makes it an attractive alternative totraditional raw material inspection methods.by Robert L Green and Christopher D Brown

15 THE QPPV – CEMENTING THE PHARMACIST’SROLE IN EUROPEWhy are there so few pharmacists in the UK who are QualifiedPersons in Pharmacovigilance (QPPV)? The author, a pharmacistQPPV himself, urges pharmacists to consider this career.by Derek Woodcock

18 DIAGNOSTICS AND THEIR ROLE INPERSONALISED MEDICINEBiomarkers and diagnostics are playing an increasing role inimproving the design and probability of success of clinical trials. Theyare also becoming more important in improving individual treatment.by Loïc Kubitza

REGULARS3 EDITORIAL COMMENT22 REGULATORY REVIEW23 NEWS FROM THE EIPG24 PHARMACEUTICAL FORUM26 JOB VACANCIES29 DATES FOR YOUR DIARY

2 eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 7 October 2010

europeanIINNDDUUSSTTRRIIAALLPHARMACYIssue 7 August 2010

ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONSue Feather

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldMichael GamlenLinda HakesJohn Jolley

European Industrial Pharmacy is published three times a year by: Euromed Communications LtdPassfield Business Centre,

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Views expressed in European IndustrialPharmacy are those of the contributors andnot necessarily endorsed by the Publisher,Editor, Editorial Board, or by our corporatesponsors who accept no liability for theconsequences of any inaccurate or

misleading information

©2010 Euromed Communications Ltd

Belgium: Philippe Van der Hofstadt

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Denmark: Michiel Ringkjøbing Elema

Finland: Tuula Lehtela

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Jane Nicholson

Greece: Kiriasis Savvas

Hungary: Sylvia Marton

Ireland: Anna O’Mahony

Italy: Piero Iamartino

Latvia: Inta Saprovska

Malta: Claude Farrugia

Netherlands: Ineke Kleefsman, Michiel Storimans

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europeanIINNDDUUSSTTRRIIAALLPHARMACYdiscussion group:

www.pharmweb.net/gmp.html

Associate Editors

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

Cover picture: Photograph of capsules andtablets from the PIAT brochure (see p4).

3eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 7 October 2010

EEDDIITTOORRIIAALL CCOOMMMMEENNTTimportance of ensuring that thePharmacy Curriculum still producespharmacists that understand howdrugs are discovered, developed,manufactured, registered andregulated. More importantly, thatpharmacists from year 1 of being apharmacist understand whatimpacts quality and efficacy of ourmedicines.

On September 14th, EIPG wasinvited by the Manufacturing andQuality Compliance group of theEMA to participate at the GMP/GDPIWG interested parties meetingchaired by David Cockburn, where anumber of updates and discussionstook place around:

� Updates to Site Master Files

� Implementation of 'anti-falsification' legislation

� Role of the QP in supply chainoversight

� Proposals to revise GMP Annex 16for minor deviations

� Presentation on the use ofdedicated facilities for APIS andIntermediates risk-based auditing

� Survey presentation on Atypicalactives

A report of these discussions andthe GMP updates will be madeavailable on the EIPG website:www.eipg.eu

At the core of all these interactionsis the belief that pharmacists

Dear Colleagues

As I write this editorial, thePharmaceutical Industry hasentered another eventful year and aperiod of reflection as it deals withthe many challenges that it is facingwith respect to productivity, patentexpiration, increased regulation andthe ever increasing importance ofthe BRIC economies.

As always, the mandate of the EIPGis to represent IndustrialPharmacists working in all areas ofpharmacy with respect toProfessional, Educational andTechnical affairs. The EIPG isapolitical and has at its core credothat 'Pharmacists continue to enterand contribute to this importantsector of pharmacy'. The EIPGwebsite (www.eipg.eu) has beenmodified to allow the posting of jobopportunities and we have had amajor multinational companyasking to use our website to posttheir openings.

This year has seen EIPG activelyengaging with the EuropeanMedicines Agency, EuropeanFederation of PharmaceuticalIndustries and Associations,European Pharmaceutical StudentsAssociation, European Association ofHospital Pharmacists,Pharmaceutical Group of theEuropean Union and the EuropeanCommission. In particular, I amproud of the role that EIPG hasplayed in Pharmine and the

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continue to play a role in thisindustry and the experiences of'grass roots' Industrial Pharmacistscan be shared with thoseorganisations who perhaps are notas close to their core membership asthey think they are.

I have taken this comment on boardand as President of EIPG willconduct a Strategy Day in Novemberin Paris with an expanded Bureau toaddress what the EIPG of the futurewill look like and how it cancontinue to deliver its credo in thesechallenging times.

Already, I can share with you theknowledge that there have been anumber of radical suggestions for arevamped EIPG organisation butclearly all suggestions will bebrought to the General Assembly fordiscussion and approval before theirimplementation.

I finish this editorial by encouragingreaders to visit our website and toread the various EIPG updates withinthe Journal which can provide moredetails of our activities. As always,you can contact me or my ExecutiveDirector, Mrs Jane Nicholson,through our website.

Dr Gino Martini FRPharmSPresident of EIPG


BRIAN LOCKWOOD is Directorof PIAT, School of Pharmacy& Pharmaceutical Sciences,University of Manchester, Manchester M13 9PT

science graduates. No prior learning isrequired for individual modules, but fourcredited modules with a pass mark of50% equate to degree equivalence.Recently we enrolled students with MBAsand law degrees!

Individual course modules have aworkload of 150 hours per module, andthe course content consists of aworkbook of 150-300 pages, writtenassignments, and a workshop (tutorial) of2-4 hours with the module tutor. There isa 2-hour written examination required formost modules. Other benefits includefulltime contact with a tutor, available viae-mail, and continual updates of moduleson an annual basis.

University awards include module credits,15 per module, a Diploma for 8x15credits, and an MSc is gained after theDiploma, plus Dissertation of 60 credits,making a total of 180 credits. The degreeawarded for this is an IndustrialPharmaceutical Sciences MSc. Distinctionsare awarded for marks of ≥70% in all themodules and the Dissertation, and 12have been awarded over the last 4 years.

Industrial Pharmacyprogramme

The original Industrial Pharmacyprogramme consists of 17 modules todate. Box 1. lists the module titles. Three

History and delivery

The original PIAT programme wasproposed in 1989 in collaboration withthe UK Pharmaceutical Industry. Moduleswere written by experts based in majorPharma from UK, Japan, Switzerland,Thailand and academia.

Originally there were eight modules, nowthere is a choice of 17 modules availablein the Industrial Pharmacy Programme.The modules have EU and US relevance,and are applicable worldwide due to theoverriding importance of FDA and EMEAregulations. The aims of the programmewere to have a flexible structure of freestanding modules. These have an openand distance learning style, allowingminimum time to be absent from theworkplace, which benefits both employerand student. Rigorous quality assurance iscarried out by the University ofManchester. All module tutors areaccredited University staff, and results aremoderated by an accredited externalexaminer. There are a range of entryoptions; a minimum of an HND is usuallyrequired for a Diploma, and a degreelevel scientific qualification is usuallyneeded for an MSc, most students are

PHARMACEUTICALINDUSTRY ADVANCEDTRAINING (PIAT) – ACCREDITED PROFESSIONALDEVELOPMENT FOR THEMEDICAL AND HEALTHCAREINDUSTRIES

by Brian Lockwood

Career development and progression for staff in theindustry and ancillary organisations is as important for

employers as employees. PIAT programmes are unique intheir distance learning format, and have contributed toindustry success for nearly 20 years.

French

Le développement du parcours professionnel et la progression des collaborateurs dans l'industrie et les organisations connexes sont aussi importants pour les employeurs que pour les salariés. Les programmes PIAT (Pharmaceutical Industry Advanced Training) offrent un format unique de formation à distance et contribuent à la réussite de l'industrie depuis près de 20 ans.

Italian

Los viluppo del percorso professionale ed il progresso del personale dell’industria ed organizzazioni collegate sono importanti tanto per i datori di lavoro quanto per i dipendenti. I programmi PIAT (Pharmaceutical Industry Advanced Training) offrono un metodo di formazione a distanza unico nel suo genere e contribuiscono al successo dell’industria da circa un ventennio.

5eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 7 October 2010

PPHHAARRMMAACCEEUUTTIICCAALL IINNDDUUSSTTRRYY AADDVVAANNCCEEDD TTRRAAIINNIINNGG ((CCoonntt..))

of different employers, including theUK NHS. The programme consists ofeight modules in a logicaldevelopment of the subject, whichare shown in Box 2.

Toxicology

The Toxicology Programme was setup as there is currently a severeshortage of toxicologists in theindustry, and this programme aimsto help this situation. The ToxicologyProgramme consists of ninemodules which are shown in Box 3.

Microbiology

The Pharmaceutical MicrobiologyAdvanced Training (PMAT) programmewas planned in collaboration withPharmig, a non-profit organisationproviding a forum for microbiologyin the pharmaceutical, healthcareand allied industries and wasestablished in 1991 to meet theneeds of PharmaceuticalMicrobiologists.

The modules were designed to meetthe needs of those responsible forand/or working in the area ofpharmaceutical microbiology in theindustry, and feedback from theindustry highlighted the need for aflexible learning and developmentprogramme.

The ten modules are shown in Box 4.

Business development

The Pharmaceutical BusinessDevelopment and Licensing

and students have started on allprogrammes.

The benefits for students nowinclude programmes tailored totheir individual needs, particularlywith the new programmes, allowingselection from all of the differentprogrammes. The title of the awardwill still bear the name of theprincipal modules selected,provided that the following numberof modules in the programme are:

� Certificate: 3 out of 4

� Diploma: 5 out of 8

� MSc: 5 out of 8

Financial benefits accrue to bothstudents and employers in terms oftime and money spent, the studentdoes not need to leave the workplaceand the employer keeps and retainsstaff during the programme. Otherbenefits include improved workperformance, and careerdevelopment. One extreme exampleis that of one student who developedto become a Module author. Thesenew modules are believed to be idealfor continual professionaldevelopment (CPD), which isincreasingly important to bothemployers and employees in thepharmaceutical industry. Wecurrently have a range of 1-3 creditunits in preparation, specificallydesigned for CPD.

Clinical trials

The Clinical Trials Programme hasattracted students from a wide range

of the modules do not requireexamination, only writtenassignments, see Box 1.

To date there have been over 200MSc s, and 3000 individual modulesgained in the PIAT programmes.Students have come from a widerange of employers including majorPharma, biotech companies and theNHS, and have been mainly stafffrom Production, and R & D.Worldwide take-up of theprogrammes includes S. America, N.America, the Far East, and Europe.

New initiatives started in 2007include programmes in:

� Clinical Trials

� Toxicology

� Pharmaceutical Microbiology

� Pharmaceutical Business andDevelopment

Two of these programmes werefunded by HEFCE & NWRDA, andothers by the University ofManchester, or via collaboration.

The 1st modules were available inFebruary 2007, and this allows for agreater selection of modules for anMSc. Currently we have 34 out of atotal of 35 new modules completed

Box 1.

1 Basic Principles2 Preformulation studies I3 Preformulation studies 24 Solid oral dosage forms5 Liquid and semisolid dosage forms6 Sterile dosage forms7 Controlled release dosage forms8 Operations management9 Quality assurance10 Packaging11 Regulatory affairs *12 Pharmaceutical engineering13 Quality control laboratory testing14 Safety, health and environment *15 Inhalation dosage forms16 Product development management *17 Medical writing*

*Assessed by assignments only (nowritten examination)

Box 2.

1. Introduction to clinical trials 2. Planning, setting up, and runningclinical trials

3. Phase I clinical trials 4. Phases II / III (1) 5. Phases II / III (2)6. Statistical requirements and studydesign

7. Pharmacovigilance8. Regulatory issues

Box 3.

1. Principles of Toxicology2. Assessment of Toxicity3. Biotransformation and Kinetics4. Regulatory Toxicology5. Target Organ Toxicology (1)6. Target Organ Toxicology (2)7. Mechanisms of Toxicity8. Molecular and Cellular Methods inToxicology

9. Integration and Risk Assessment

PPHHAARRMMAACCEEUUTTIICCAALL IINNDDUUSSTTRRYY AADDVVAANNCCEEDD TTRRAAIINNIINNGG ((CCoonntt..))


programme was established incollaboration with UK PLG (ThePharmaceutical Licensing Group).PLG is the professional associationfor people in business developmentand licensing and again it is a notfor profit organisation, industry

based, and has no service providers.The primary role of PLG isnetworking and continuousprofessional development.

In the UK there are over 200members covering all areas of theindustry pharma, OTC, biotech, drug

Box 5.

1. Introduction to the HealthcareIndustry*

2. Business Development Operations 3. Financial Modelling in thePharmaceutical Industries

4. Legal Issues in BusinessDevelopment Contracts

5. Negotiation and Interpersonal Skills6. Marketing and Commercialisation7. Intellectual Property Rights8. Research & Development andManufacturing

*all modules are assessed byassignment only

Box 4.

1. Introduction to PharmaceuticalMicrobiology and Technology

2. Water Systems3. Microbiological EnvironmentalMonitoring & Control (steriles &non-steriles)

4. Microbiological aspects of SterilePharmaceutical Manufacturing

5. Quality Assurance in MicrobiologyLaboratories

6. Engineering Principles forPharmaceutical Microbiologists

7. Application of Microbiology inBiopharmaceuticals

8. Antimicrobials9. Antibiotics and Vitamins10. Key Management Tools

delivery and generics, and there arenine other PLGs in Europe plusJapan and Canada with over 1,500members. PLG was founded in 1994,and organises a number of trainingcourses in business professionaldevelopment. The programmeconsists of eight modules which areshown in Box 5.

University accreditation ofindividual modules has taken placealongside their completion, andaccreditation of the completeprogramme is on track for late 2010.Student uptake to date is 35modules (by 18 students), and thereis demand for others whencompleted. Promotion of theprogramme is planned, includingvisits to major Pharma, and furtherpresentations at learnedconferences, in addition to ourexhibitions at BPC 2008 and 2009,and EUFEPS 2009.

www.pharmacy.manchester.ac.uk/postgraduate/piat/

Manufacture of Sterile Products

Available in one pocket-sized booklet

MHRA: Revised Annex 1 to EU Guide

PIC/S: Validation of Aseptic Processes

FDA: Sterile Drugs Produced by Aseptic Processing

Quantity DiscountsPacks of 10 booklets at £80.00 per pack(plus postage at cost) minimum order one pack of 10

This handy pocket guide conveniently provides all the major sterile products manufacturing regulations. Order now for yourself, your staff and your clients.To order contact Jill Monk at +44 (0)1428 656665 or email: [email protected]

NEW

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eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 7 October 2010 7

HOT-MELT EXTRUSIONTECHNOLOGY:OPTIMIZING DRUGDELIVERYby Marcia Williams, Yiwei Tian, David S Jones and Gavin P Andrews

Hot-melt extrusion (HME) technology was first utilizedpredominantly in the plastic industry and to a lesser

extent in the food industry since the 1930’s. The manyadvantages of HME over conventional solid dosage formmanufacturing have piqued the interest of thepharmaceutical industry and academia as a novel drugdelivery technology. This innovative technology has beenshown to be extremely robust and a viable method ofproducing many different drug delivery systems, includingimplantable reservoirs, pellets, films, capsules and tablets.Moreover, the possibility of forming solid dispersionsoffering improved bioavailability renders HME an excellentalternative to other conventionally employed techniques.

supports a drive system, an extrusionbarrel, a rotating screw arranged on ascrew shaft and an extrusion die fordefining product shape. Irrespective ofthe complexity of the machine, theextruder must be capable of rotating thescrew(s) at a selected speed, whilecompensating for the torque generatedfrom the material being extruded. Theextudate may be shaped into tablets,rods, pellets, or milled and mixed withother extra-granular excipients fordifferent purposes.

The single screw extruder is the mostwidely used extrusion system. It can beeither flood or starve fed, high-pressurepumped and finally the molten materialsare pumped to the die to form theextrudate4. The extrusion barrel may beconveniently divided into three distinctzones: feed zone, compression zone andmetering zone. The depth and/or pitch ofthe screw flights differ within each zonegenerating variable pressure along thescrew length (zone dependent). Due tothe large screw flight depth and pitch, thepressure within the feed zone is very lowallowing for consistent feeding from thehopper and gentle mixing of API andexcipient. The primary function of thesubsequent compression zone is to melt,homogenize and compress the extrudateso that it reaches the metering zone in asuitable form for extrusion. Consequently,products are formed through the diecontinuously (Figure 1).

The single screw extrusion, however, doesnot provide the high mixing capability ofa twin-screw machine, and therefore isnot the preferred approach for theproduction of pharmaceuticalformulations. Moreover, dispersing andmixing of drugs with other ingredientsinvolve breaking the aggregates of theminor drug particles. In order to achievethis, a critical amount of force must beapplied during the process5. This forcecannot be achieved with the single-screw,but the twin-screw extruder with its co-rotating or counter-rotating screws wouldprovide the high energy necessary.

In addition, the versatility of a twin-screwextruder (process manipulation andoptimisation) and the ability toaccommodate various pharmaceuticalformulations makes it much more

Dr Gavin P Andrews is aSenior Lecturer inPharmaceutics at the Schoolof Pharmacy, Queen’sUniversity Belfast, UK.

Professor David S Jones is thechair of biomaterial scienceat the School of Pharmacy,Queen’s University Belfast,UK.

Mr Yiwei Tian and Ms. MarciaWilliams are PhD students atthe School of Pharmacy,Queen’s University Belfast,UK.

Correspondence: DR GAVIN P ANDREWS, Lecturer in PharmaceuticsSchool of Pharmacy, Queens University Belfast,Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UKTel: +44 (0) 28 90 97 2646Fax: +44 (0) 28 90 247794Email: [email protected]

This article aims to provide an overviewof the technique, a basic guide toextrusion equipment and processtechnology, the fundamental principles ofoperation and to discuss the most recentapplications of HME within the field ofdrug delivery.

Introduction

Extrusion is a process that involves forcinga raw material or blend through a die ororifice under set conditions such astemperature, pressure, rate of mixing andfeed-rate, for the purpose of producing astable product of uniform shape anddensity1. Since the 1930’s, hot-meltextrusion has mainly been utilized in theplastic industry in the production of plasticproducts such as bags, sheets, and pipes2.The process is also utilized to a limitedextent in the food industry in for example,extrusion cooking for the manufacture ofcereals3. The technology has now foundapplication in the pharmaceutical industryin the area of drug delivery.

The Hot-Melt Extrusion Process

At the most fundamental level, anextruder consists of a platform that

French

La technologie de l'extrusion par fusion à chaud (HME - Hot-melt extrusion) a d'abord été utilisée principalement dans l'industrie des plastiques et, dans une moindre mesure, dans l'industrie alimentaire à partir des années 1930. Les nombreux avantages de l'HME par rapport à la fabrication de formes pharmaceutiques solides classiques ont suscité l'intérêt de l'industrie pharmaceutique et des chercheurs qui y voient une nouvelle méthode de distribution des médicaments. Il a été démontré que cette technologie novatrice était extrêmement robuste et constituait une méthode viable pour produire de nombreux systèmes de distribution des médicaments, notamment pour la production de réservoirs implantables, pastilles, films, capsules et comprimés. En outre, la possibilité de former des dispersions solides offrant une meilleure biodisponibilité fait de l'HME une excellente alternative aux autres techniques classiques.

Italian

La tecnologia dell'estrusione per fusione a caldo (HME - Hot-melt extrusion) è stata in un primo tempo utilizzata principalmente nell'industria della plastica ed in misura minore in quell’alimentare a partire dagli anni Trenta. I numerosi vantaggi della HME rispetto ai metodi di fabbricazione tradizionali delle forme di dosaggio solide hanno suscitato l'interesse dell'industria farmaceutica e dei ricercatori che l’hanno considerata nuova tecnologia per la somministrazione dei farmaci. Si è dimostrato che questa tecnologia innovativa è estremamente valida e costituisce un metodo percorribile per la produzione di numerosi sistemi di somministrazione dei farmaci, cquali la produzione di “serbatoi” (reservoir) impiantabili, pastiglie, pellicole, capsule e compresse. Inoltre, la possibilità di formare dispersioni solide offrenti una migliore biodisponibilità rendono la HME un’eccellente alternativa ad altre tecniche tradizionali.

favourable and is the preferredchoice for pharmaceuticals. Anothersignificant design variable iswhether the two screws areintermeshing or non-intermeshing,the former being preferred due tothe greater degree of conveyingachievable and the shorterresidence times.

Industrially, due to processpracticality and the ability tocombine separate batch operationsinto a single continuous process,twin-screw extrusion significantlyincreases manufacturing efficiency.Recent FDA guidelines (FDAPharmaceutical cGMP for the 21stCentury, 2004) for the enhancementand modernization of thepharmaceutical industry hasfacilitated the move towardscontinuous manufacturing processesand the implementation of processanalytical technologies (PAT) tomonitor, control and understandmanufacturing processes. These areachievable with HME technology.The continuous nature of HME hasmost recently been extendedthrough the use of a cylindrical dieand an inner rotating knife6. Thisdesign has helped to furtherenhance the continuity of theprocess through the generation ofmelt extruded pellets without theneed for a separate spheronizationstep.

Pharmaceuticalapplications of hot-meltextrusion:

Background

Solid dosage forms in the form oftablets and capsules are by far themost popular dosage forms in usetoday, due to the enhanced stabilityand ease of use. Althoughcomparatively more stable thanliquid dosage forms, solid dosageforms do present bioavailability,stability and manufacturingchallenges. Due to the significantlimitations in unit operationsinvolved in the production of these

dosage forms, as well as the need toremain competitive and maintainconstant growth, pharmaceuticalmanufacturers are constantlyseeking innovative processes toincrease the efficiency ofmanufacturing operations whilstimproving therapeutic efficacy. HMEtechnology is one such technologythat has captured the interest of thepharmaceutical industry particularlyin the area of solid dispersions7.Several advantages over traditionalprocessing methods have beenidentified, and some are listed inTable 17-10.

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Figure 1. Typical hot-meltextruder.

Table 1. Advantages of hot-melt extrusion.

Features and benefits of hot-melt extrusion

Feature Benefit

Solvents not required Environmentally friendly, economical;No residual solvent in final product.

Continuous process Fewer unit batches required; Efficientscale-up from laboratory to large-scaleproduction

Intense mixing and agitation achieved Improved content uniformity

Compressibility not required Useful for powders with lowcompressibility index

Polymers serve multiple Less number of excipientspurposes required; Cost effective.

Greater thermodynamic stability than Less tendency towardsthat produced by other hot-melt methods recrystallization

Formation of soliddispersions

Not only is HME an efficientmanufacturing process, additionally itmay enhance the quality and efficacyof manufactured products4. Ofparticular interest is the use of HME todisperse active pharmaceuticalingredients (APIs) in a matrix at themolecular level, thus forming solidsolutions (see Figure 2). HME is anapproach commonly utilised in thedelivery of poorly water-soluble, classII compounds due to the increaseddissolution achievable, and henceimproved absorption and therapeuticefficacy12. Whilst the formation ofsolid solutions may significantlyenhance drug dissolution rate of classII compounds in vivo, the presence ofa metastable state, high internalenergy and specific volume of theamorphous state leads to a tendencyduring storage (thermal and/orhumidity stress) towardsrecrystallization. Interestingly,extruded solid solutions offer greaterthermodynamic stability than thoseprepared by alternative processes suchas spray drying, solvent evaporationand other hot-melt methods11.

The polymers used in the extrusionprocess may function as thermalbinders, drug stabilisers, drugsolubilisers and/or drug releasecontrolling excipients with nocompressibility requirements.Typical examples of pharma -ceutically approved polymericmaterials include vinyl polymers(polyvinylpyrrolidone (PVP), PVP-vinyl acetate (PVP-VA)), polyethyleneoxide (PEO), Eudragit® (acrylates), PEglycol (PEG) and cellulosederivatives. While residence timewithin the extruder and high

processing temperatures (requiredto melt the polymeric carrier) wereinitially projected as significantdisadvantages of this technology,the ability to modify screwconfiguration and the high-shearforces generated within the extruderallow for processing at lowertemperatures. Additionally, the useof plasticizing agents and theintroduction of twin-screwextruders, removed such concerns.Typical plasticizing agents for HMEinclude PEGs, triacetin, citrateesters, citric acid, and the API’sthemselves in some cases12.

A recent development is the use ofsurfactants to improve the releaseprofile of solid dispersions14. Thesurface activity improves thesolubility and aids in preventingprecipitation and also protects thefine crystalline particles fromagglomeration. High levels ofsolubility improvement have beenachieved using this approach.

The ability to predict the suitabilityof a polymer for the process shouldbe viewed as another favourableadvantage. Using small quantities ofdrug and polymer, thermal,spectroscopic and rheologicalmethods may be used to determinedrug/polymer miscibility thusproviding information on theprobability of forming a suitabledispersed (down to the molecularlevel) drug polymer platform8.

Dosage forms preparedusing HME technology

This technology has proven useful inthe design of a number of drugdelivery systems such as immediateand modified release tablets, granules,

pellets, implants, matrix systems,transdermal drug delivery systems andocular inserts, and targeted deliverysuch as enteric matrix tablets andcapsules1,15,16. De Brabander et al.17

described the use of HME in thepreparation of matrix mini-tablets thatminimise the risk of dose dumping,reduce inter- and intra-subjectvariability and provide highly dispersiveformulations within the gastrointestinaltract. Miller et al.18 have demonstratedthe ability of HME to act as an efficientprocess for the wettability and henceimprove drug release properties ofengineered particles. Additionally, thecoating of hot-melt extruded tabletswith suitable polymers has been shownto significantly delay the onset ofcrystallization during dissolution andstorage19.

Future developments

The pharmaceutical industry is goingthrough a period of unparalleledchange that has been brought about bya number of factors. In particular,globalization of the industry, increasedrisk/cost associated with thedevelopment of new drug compoundsand patent expiry on numerous highrevenue drugs are the most compellingfactors. As a result of such dramaticchanges, the demand for new drugcompounds to bridge the gap in lostrevenue within shorter timeframes isincreasing significantly. Thisundoubtedly means that the industrycan no longer focus on projects that donot provide early promise.Furthermore, it is well accepted thatthe major changes being implementedwithin the pharmaceutical industry willresult in focus on areas that will offersignificantly high growth potential. Thiswill involve the development of



Figure 2. Schematic presentation of the extrusion process.


dormant pharmaceutical compoundsthat have been abandoned prior toFDA approval or approved but nevercommercialized. Due to the imple -ment ation of high throughputscreening over the last decade thesecompounds have been designed for thetreatment of conditions that have moredifficult and complex targets. Althoughthis may provide enhanced clinicaloutcomes and reduce adverse effects,these drugs commonly exhibit poorsolubility in gastrointestinal fluids andhence are often not absorbed after oralingestion.

Hot-melt extrusion (HME) is anemerging drug delivery technologythat is currently being investigated bythe industry as a suitable method forthe production of solid drugdispersions exhibiting enhancedsolubility in gastrointestinal fluids. Todate, the development of soliddispersions using HME has beenempirical and the rationale for theselection of polymers is unclear andthe prediction of the stability of theresultant drug delivery platform hasnot been addressed sufficiently.Therefore in order for the industry toreduce the time required to developand release new products on to themarket a greater understanding ofthe formulation and engineering

aspects of this process is required toensure that stable solid dispersionsmay be both predicted andprepared. This will undoubtedly bethe focus of both industrial andacademic research in the foreseeablefuture so that bio-enhancedformulations with improved efficacymay be developed.

References

1. Breitenbach J. Melt extrusion: from processto drug delivery technology, European J ofPharmaceutics and Biopharmaceutics, 2002;54: 107–117.

2. Kaufman HS, Falcetta JJ. Introduction toPolymer Science and Technology: An SPETextbook, 1977; John Wiley & Sons, New York.

3. Guy R. Extrusion Cooking – Technologies andApplications 2001; Woodhead Publishing.

4. Ghebre-Sellassie I, Martin C. PharmaceuticalExtrusion Technology 2003; Marcel Dekker,New York.

5. Douglas P, Andrews GP, Jones DS, Walker G.Chemical Engineering Journal, 2010, doi:10.1016/j.cej.2010.03.077.

6. Radl S, Tritthart T, Khinast J. Science Direct –Chemical Engineering Science 2010; 65(6):1976–1988.

7. Forster AH, Rades T, Hempenstall J.Selection of Suitable Drug and ExcipientCandidates to prepare Glass Solutions byMelt Extrusion for Immediate Release OralFormulations. Pharmaceutical Technology,Europe 2002; 14(10): 27–37.

8. Chokshi RJ, Sandhu HK, Iyer RM et al.Characterization of Physico-MechanicalProperties of Indomethacin and Polymers toAssess their Suitability for Hot-Melt ExtrusionProcess as a Means to Manufacture SolidDispersion/Solution. J Pharmaceutical Sciences2005; 94(11): 2463–2474.


9. Andrews GP, Jones DS, Abu Diak O, et al.Hot-Melt extrusion: an emerging drugdelivery technology. PharmaceuticalTechnology, Europe 2009; 21(1).

10. Forster A, Hempenstall J, Tucker I, Rades T.The potential of small-scale fusionexperiments and the Gordon-Taylorequation to predict the suitability ofdrug/polymer blends for melt extrusion.Drug Development and Industrial Pharmacy,2001; 27: 549–560.

11. Rades T, Patterson JE, James MB, et al.Preparation of glass solutions of threepoorly water soluble drugs by spray drying,melt extrusion and ball milling. Int JPharmaceutics. 2007; 336: 22–34.

12. Ford JL. The current status of soliddispersions, Pharmaceutica Acta Helvetiae1986; 61(3): 69–88.

13. McGinity JW, Zhang F, Repka M, Koleng JJ.American Pharmaceutical Review 2001; 4:25–36.

14. Bley H, Fussnegger B, Bodmeier R.International Journal of Pharmaceutics2010; 390: 165–173.

15. Mehuys E, Remon JP, Vervaet C. Productionof enteric capsules by means of hot-meltextrusion. European J PharmaceuticalSciences 2005; 24: 207–212.

16. Andrews GP, Jones DS, Abu Diak O, et al. Themanufacture and characterisation of hot-melt extruded enteric tablets, Eur JPharmaceutics and Biopharmaceutics. 2008;69(1): 264–273.

17. De Brabander C, Vervaet C, Remon JP.Development and evaluation of sustainedrelease mini-matrices prepared via hot-meltextrusion, J Controlled Release 2003; 89:235–247.

18. Miller DA, Jason TM, Yang W, et al. Hot-MeltExtrusion for Enhanced Delivery of DrugParticles, J Pharmaceutical Sciences 2007;96(2): 361–376.

19. Bruce D, Fegely KA, Rajabi-Siahboomi AR,McGinity W. Drug Development andIndustrial Pharmacy 2010; 36(2): 218–226.


MOVING TOWARD 100%RAW MATERIALINSPECTION WITH AHANDHELD RAMANSPECTROMETERby Robert L Green and Christopher D Brown

Pharmaceutical manufacturers are facing mountingpressure to reduce costs, improve quality control, and

increase productivity. Since inspection of incoming rawmaterials is a significant portion of manufacturing costs,companies are exploring opportunities in this area. Inaddition to minimizing costs, companies need to performeven more tests to accommodate increased productionvolume and regulatory requirements.

An assessment of the workflow associatedwith incoming raw material inspectionreveals numerous opportunities toimprove both the efficiency of the processand the quality of results. For the majorityof raw materials, containers are openedfor sampling. Samples are then transferredto QC for analysis. While awaiting results,incoming materials are not available forproduction. Additionally, this processcarries risks of contamination caused bysampling, mislabelling of test samples,and production delays if the QC laboratoryhas a higher than normal work load.

In recent years, the availability ofportable and handheld instruments hascreated the potential for movinganalytical testing from the laboratory tothe manufacturing floor.

Current instrumentaltechniques

The most common analytical techniquesused for identification of raw materials areHPLC (high performance liquidchromatography), NIR (near infrared) andmid-IR (mid-infrared) spectroscopies, pluswet chemical methods. Ramanspectroscopy is also effective and efficientfor raw material identification, in-processanalysis, and final product authentication1.

The Raman light scattering effect hasbeen historically difficult to detectbecause the scattering phenomenon isvery weak. The increased availability oflonger wavelength diode lasers, chargecoupled devices, and Rayleigh rejectionfilters has increased its sensitivity anddecreased nuisance signal contributionfrom fluorescence. Today, Ramanspectroscopy is a practical laboratorytechnique, and modern Ramaninstrumentation is faster, more robust,and less expensive than earlier versions.Additional advances in componentminiaturization and embedded softwarealgorithms have enabled development ofdecision-capable handheld Ramansolutions for environments beyond thelaboratory.

Operational attributes ofinfrared and Ramanspectrometers

A significant advantage of handheldspectrometers is their ability to quicklyverify material identity at the point ofneed. The ability to acquire Ramanspectra through transparent packaging,such as plastic bags1, 2, eliminates the riskof contamination created by traditionalsampling. While both Raman and NIRspectra can be acquired throughtransparent packaging, NIRmeasurements can produce markedlydifferent spectra as a result of subtlevariations from one container to another.In comparison to solids sampling withRaman and NIR, mid-IR techniquesrequire direct contact with the materialbeing tested. Raman is unique amongstthe three techniques in its ability tomeasure liquids through a container in abackscattering geometry. This negates theneed for additional transmission optics orimmersed sensors wetted by the sample,as in NIR or mid-IR.

Analytical characteristics ofinfrared and Ramanspectrometers

Every chemical compound with covalentbonds produces a characteristic pattern ofRaman shifts and Raman spectra offer ahigh degree of selectivity, making themparticularly effective for identity testing.For example, the Raman spectra of acetylsalicylic acid and acetaminophen

ROBERT GREEN is ananalytical chemist withexpertise in an array ofspectroscopic/opticalmethods and chemometrics.He is currently a ResearchScientist at Thermo FisherScientific.

CHRISTOPHER BROWN, PhD iscurrently the Director ofSystem Analytics &Applications at ThermoFisherwhere he leads thedevelopment of theembedded analytics andchemometrics software forthe company’s analyticaldevices. Correspondence to: AlyssaKnightleyemail:[email protected]

French

Les fabricants de produits pharmaceutiques sont confrontés à une pression croissante pour réduire les coûts, améliorer le contrôle de qualité et accroître la productivité. Dans la mesure où l'inspection des matières premières entrantes représente une portion importante des coûts de fabrication, les entreprises explorent de nouvelles opportunités dans ce domaine. Outre le besoin de minimiser les coûts, les sociétés doivent également effectuer un plus grand nombre de tests pour accommoder des volumes de production croissants et des exigences réglementaires toujours plus contraignantes.

Italian

Le case farmaceutiche devono far fronte a pressioni crescenti per la riduzione dei costi, il potenziamento del controllo di qualità e la crescita della produttività. Nella misura in cui l’ispezione delle materie prime di produzione rappresenta une quota considerevole dei costi d produzione, le imprese stanno esplorando nuove opportunità in questo campo. Oltre a dover far fronte all’esigenza di minimizzare i costi, le società del settore, dati i volumi di produzione crescenti e i sempre più stringenti requisiti regolamentari, devono pure effettuare un numero maggiore di test.

comprise distinct peaks that can beused to chemically fingerprint eachcompound.

Compared to Raman spectra, NIRspectra are less distinct, withbroader peaks resulting in poorerselectivity. Computationallyintensive methods may be necessaryto detect differences. Additionally,when using NIR, physical attributesof the sample can affect thespectrum and interfere with theidentification. Variability in theoptics and other components of NIRinstruments can result in spectraldifferences of the same order ofmagnitude as the compounds beingtested. Transferring an NIR methodfrom one instrument to anothermay require a multitude ofreference spectra and/or tuning ofmethod parameters.

Methods of quantifyingspectral differences

The most common approach tospectral comparison is to calculatethe wavelength correlation. Theresulting correlation coefficientequals –1 when the spectra are inperfect correspondence and 0 whenthey are orthogonal. The correlationcoefficient provides some indicationof the similarity between twospectra but is not particularlysensitive to discrepancies betweenspectra, and values other than 0 or1 have no direct interpretation.Despite these deficiencies,regulatory guidance states, “Unlessotherwise justified, a [correlation]threshold below 0.95 is notacceptable …”3.

An example of how using acorrelation threshold to comparespectra can yield erroneous results isshown in Figure 1. A Ramanreference spectrum of pure glycerinis compared to the spectrum of an“unknown” substance composed ofglycerin contaminated with 20%diethylene glycol (DEG). In spite ofclear differences in the highlightedareas of the spectra, the correlation


MMOOVVIINNGG TTOOWWAARRDD 110000%% RRAAWW MMAATTEERRIIAALL IINNSSPPEECCTTIIOONN ((CCoonntt..))

Table 1. Common pharmaceutical raw materials used for reference spectra andtheir average measurement times using handheld Raman spectrometers.

Material Average MeasurementTime(seconds)*

1 Titanium (IV) oxide, anatase 12 a-Lactose monohydrate 153 Polyvinylpyrrolidone 694 Dextrose anhydrous 115 Dextrose monohydrate 186 Sodium bicarbonate 97 Potassium bicarbonate 118 Calcium carbonate 69 Cellulose 3610 Ethyl cellulose 28411 Hydroxypropyl cellulose 39012 Dextrin from corn 4913 Calcium stearate 7914 Magnesium stearate 5415 Stearic acid 4216 Citric acid 2217 Potassium citrate tribasic

monohydrate 2118 Sodium citrate 2119 (+)-Sodium L-ascorbate 820 Sulfanilamide 121 Acetaminophen 522 Sodium phosphate monobasic 1523 Sodium phosphate dibasic 2924 Calcium phosphate dibasic 3525 Trimagnesium phosphate 12426 Zinc sulfate 427 Calcium sulfate 1428 Calcium sulfate dihydrate 7

* rounded to nearest second

Figure 1. Raman reference spectum of pure vs contaminated glycerin.

400 600 800 1,000 1,200 1,400 1,600 1,800 2,000Raman Shift (∆cm–1)

–––––––––– Glycerin

–––––––––– Glycerin Contaminated with DEG

r = 0.96p-value = 3.2 x 10–3


coefficient at 0.96, would identifythe unknown as glycerin if athreshold of 0.95 were used.

The Raman units used in this studyemploy an alternative approach towavelength correlation, evaluatingwhether the measured spectrum lieswithin the specified multivariatedomain of the reference spectrum(or spectra). The multivariatedomain is defined by theuncertainty characteristics of eachmeasurement, including exposuresettings, instrument andenvironmental properties (eg.temperature, dark current, ambientlight) and the optical properties ofthe sample itself. Rather thancomparing the bulk spectra, thisapproach looks for spectral featuresthat contradict the referencespectrum given the uncertainties ofthe measurement.

Like most statistical tests, theanalysis is distilled into a p-value,which in this case is the probabilitythat the observed differencesbetween the sample and referencespectra arose simply by chance.High p-values signify a highprobability that spectral differencesarise only from the uncertainty ofmeasurement, meaning that themeasured spectrum is consistentwith the reference. In such cases theinstrument returns a “PASS” result.Low p-values (0.05 is the PASS/FAILthreshold for the device) indicate alow probability that discrepanciesbetween spectra arise solely frommeasurement uncertainty, meaningthat the test sample is spectrallyand chemically different from thereference. In Figure 1, the p-value is3.2 x10–3, which results in theinstrument returning a “FAIL” result.

Experimental design

Six handheld Raman spectrometerswere used in this work. Threereference devices were used toacquire spectra from 32 commonpharmaceutical raw materials toevaluate the applicability of thetechnology. For each of the 32 rawmaterials, a single referencespectrum was acquired by one ofthe reference devices. The spectrawere then consolidated upon asingle master unit for methoddevelopment. Using a web-basedsoftware utility, a method for eachmaterial was generated. A method isa statistical comparison of a knownreference spectrum versus a samplespectrum to verify the identity ofthe incoming material. The finalmethod library was then cloned tothe two remaining referencedevices.


Figure 2. p-values for each sample-method measured across all three test devices.

1

§§

123451678910111213141516171819202122232425262728

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

p<10–15 10–15≤p<10–4 10–4≤p<0.01 0.01≤p<0.1 p>0.1

§ Material 10 (fail, pass, fail); Material 11 (fail, pass, pass); all other categorisation (pass/fail) sameacross all three units


Samples of approximately 2g ofeach test material were sealed in2ml thick polyethylene bags in aneffort to emulate expected-usescenarios. Three measurements ofeach sample were made, one witheach of the test devices. Tothoroughly evaluate the specificityof the Raman spectrometers, eachsample spectrum from each of thethree test devices was evaluatedagainst the entire method library of32 raw materials. For example, thecellulose sample was evaluatedagainst the cellulose method andagainst the methods for all otherraw materials. Using the probabilityapproach described previously, eachof the three test devices calculated aunique p-value for all of the 32sample-method pairs.

Results and discussion

During the collection of referencespectra, it was determined thatcolloidal silica, talc, sodiumcarboxymethyl cellulose, andhydroxypropyl methyl cellulose didnot produce an adequate signal toacquire spectra in a practical periodof time for handheld deployment.The remaining 28 materials andtheir average measurement timesare listed in Table 1. The variationsin measurement time are functionsof characteristics of the material(Raman cross section, etc.) andrange from 1 second to more than 6min, with the average being lessthan 1 min.

As indicated above, a p-value foreach sample-method pair wasgenerated for measurements acrossall three test devices. The p-valueswere averaged for presentationpurposes. Figure 2 shows the p-values for each averaged pair,ranging from p<10–15 to p>0.1. Thedefault threshold for “PASS ” isp≥0.05. The values along thediagonal represent cases where thesample was tested against its owncorresponding method, whichshould produce a “PASS ” result. Allother values arise from the sample

being tested against one of theother raw material methods, whichshould produce a “FAIL" result.

With the exception of ethyl celluloseand hydroxypropyl cellulose (items10 and 11 in Table 1), the p-valuesalong the diagonal are all greaterthan 0.1, indicating these materialsare consistent with the methodreference spectrum. For ethylcellulose and hydroxypropylcellulose, p-values were between0.01 and 0.1, which are very close tothe default threshold of 0.05. As aresult, the three test devicesreturned different PASS-FAIL resultsfor these materials. Furtherinspection of the spectral datarevealed subtle features in theunknown samples that were notfound in the reference materials.Examination of a polyethylene bagfound bands corresponding to theextra peaks in the unknown spectra.This suggests the weak Ramansignals and long measurementtimes for these cellulose materialscreated subtle interference from thepolyethylene bags.

Examination of the off-diagonalelements confirms the excellentselectivity of the technology asevidenced by p<10–15 for theoverwhelming majority ofunknown-methods pairs. The onlymaterials lacking acceptableselectivity are the alkali metalstearates. Both calcium andmagnesium stearate are readilydifferentiated from stearic acid(p<0.01), but they cannot bedifferentiated from each other.While smaller molecules differingonly in their cation can be easilydifferentiated with the handheldRaman system (eg. bicarbonate andsulfate), the large stearate moleculeproduces the majority of the Ramansignal, which minimizes spectraldifferences caused by the cations. Inthis case, Raman spectroscopywould verify that the incomingmaterial was stearate, andsecondary testing would determinethe cation.

Conclusion

Handheld Raman spectroscopy is anexcellent alternative to traditionalincoming raw material verificationmethods. The excellent specificity ofRaman spectroscopy, coupled withintelligent on-board algorithms,reduces the time and effort todevelop and validate methods.Furthermore, methods loaded ontodifferent Raman systems produceconsistent data and materialverification without loadingadditional spectra or performingother customization.

In addition to their analyticalcharacteristics, today’s Ramansolutions are environmentallyrobust and can be used by non-technical personnel. This is incontrast to Raman instruments ofthe past, which were bulky, slow,expensive, and delicate. Based onthis study of commonpharmaceutical materials, thehandheld Raman spectrometeroffers an attractive option forachieving 100% inspection of mostraw materials used bypharmaceutical manufacturingfacilities.

References

1. Compton DAC, Compton SV. “Examination ofpackaged consumer goods by using F-TRaman spectrometry”, Applied Spec., 1991;45(10): 1587–1589.

2. Skoulika SG, Geurgio CA. “Rapid non-invasive quantitative determination ofAcyclovir in pharmaceutical solid dosageforms through their poly(vinyl chloride)blister packages by solid-state fouriertransform Raman spectroscopy”, AppliedSpec., 2003; 57(4): 407–412.

3. European Medicines Agency (EMEA), Notefor guidance on the use of near infraredspectroscopy by the pharmaceuticalindustry and the data requirements for newsubmissions and variations (London, UK,2003).



DEREK WOODCOCK is aPharmaceutical Consultant aswell as a Qualified Person inPharmacovigilanceemail:[email protected]

type of problem. Increasingly, goodpharmacovigilance practice is being seenas the conduit for crucial data on aproduct’s use in medical practice.Companies are seeing that improvingcompliance and promoting more effectiveuse of medicines can widen accessibility(good for marketing) and also reduce riskof costly liability litigation.

This means that pharmacovigilanceprofessionals are now also helping guidefuture drug development and provide keycontributions to new marketingauthorisation applications – and so, ifharnessed properly, good PV should beseen as being an asset rather than solelyfrom the perspective of RegulatoryCompliance.

What are the responsibilities ofQPPV?

Every Marketing Authorisation Holder(MAH) must have an effectivepharmacovigilance system in place andhave appointed a suitably qualifiedperson to oversee this – the QPPV. He orshe is responsible for:

� Establishing, maintaining andoverseeing the MAH’s entire PV system.

� Preparation and submission ofsuspected serious adverse drugreaction reports (ADRs) and periodicsafety update reports (PSURs).

� Acting as a single contact point for theCompetent Authorities on a 24-hourbasis.

� Having an overview of the safetyprofiles and any emerging safetyconcerns in relation to all of theproducts of the MAH.

Depending on the number of MarketingAuthorisations, the product portfolio andthe size and nature of the organisation,the execution of these responsibilities canvary greatly between companies. TheQPPV can delegate specific tasks to others– but only under supervision. Every QPPVmust have access to a medic (if not them-selves medically qualified). It is almost acertainty that the MHRA’s PV inspectorswill pay you a visit – inspections areplanned according to a formal riskassessment which takes into account thefactors mentioned above as well as resultsfrom previous inspections and evidence of

Pharmacovigilance has grownsignificantly over recent years, both interms of number of professionalsemployed and also in its importance tothe success of an organisation. A numberof factors have been driving this; growingnumbers of adverse drug reactionreports, some high profile safety issueswith widely used drugs and greaterregulation and enforcement. Whilst theprimary goal of post-marketingsurveillance is to identify serious andunexpected risks (not detected during theclinical trial phase), and evaluate thesesignals against the reference safetyinformation (e.g. SPC), more recentdevelopments have raised thecontributions a drug safety team canmake.

A recent survey in US found that 54% ofpatients say they do not consistently taketheir prescription medicines as instructedeven though 87% believe it is importantto do so. Of patients not following theirinstructions, 37% gave concern aboutside-effects as their main reason1.Pharmaceutical companies areincreasingly developing proactive riskminimisation strategies, with moresophisticated tools, to help overcome this

THE QPPV – CEMENTINGTHE PHARMACIST’SROLE IN EUROPEby Derek Woodcock

In the June 2010 issue of European Industrial Pharmacy,Jane Nicholson stated in the editorial comment “…The

mantra of EIPG is always focussed on ensuring thatpharmacists continue to play a pivotal role in the EuropeanPharmaceutical Industry and as such we are keenchampions of education, professional competencies and inparticular the role of the Qualified Person”. Of course, thisis a reference to The Qualified Person who is responsible forcertifying the suitability for release of every batch. Perhapsnow is the time to add the role and responsibilities of theQualified Person in Pharmacovigilance (QPPV) to thismantra?

French

La pharmacovigilance a considérablement progressé ces dernières années, tant en termes du nombre de professionnels mobilisés, que d'importance pour le succès des organisations. Plusieurs facteurs influencent cette évolution : un nombre croissant de rapports de réactions indésirables aux médicaments, certaines questions de sécurité à haute visibilité concernant des médicaments largement utilisés, et une réglementation plus exigeante et plus surveillée par les autorités. Alors que l'objectif principal de la surveillance post-marketing est d'identifier les risques graves et inattendus (qui n'ont pas été détectés pendant la phase d'essai clinique) et de les évaluer par rapport aux informations de sécurité de référence, des développements plus récents ont permis d'accroître les contributions des équipes responsables de la sécurité des médicaments.

Italian

Negli ultimi anni, la farmacovigilanza ha fatto registrare una considerevole crescita, tanto in termini del personale occupato quanto sotto il profilo della sua importanza per il successo dell’organizzazione. I fattori sottesi a questa evoluzione sono molteplici: il numero crescente di rapporti concernenti le reazioni avverse ai farmaci, questioni di sicurezza di elevato profilo relative a farmaci d’ampio uso e la regolamentazione e vigilanza sempre più rigorose promosse dalle autorità. Mentre l’obiettivo primario della sorveglianza post-marketing è di identificare i rischi gravi ed inattesi (non identificati nella fase dei test clinici) e di valutarli in relazione alle informazioni di sicurezza di riferimento, sviluppi più recenti hanno portato al potenziamento dei contributi apportabili dai team preposti alla sicurezza dei farmaci.


non-compliance (eg. late reportsbeing submitted to them).

Putting a company’spharmacovigilance system intopractice requires a systematic,practical, logical and pragmaticapproach:

� How are ADRs captured by thecompany?

� How is safety informationexchanged between departments,affiliates, co-marketing partnersand distributors?

� How are ADRs evaluated, data-based and aggregate data reportsproduced?

� How is the published literaturesearched for safety information?

� How is use data collected (eg.paediatric use, off-label use,abuse/misuse, overdose,population exposure, etc.)?

� How effective is the RiskManagement strategy?

� How is compliance monitored(eg. in relation to the quality,completeness and timeliness forsubmission of reports)?

� How is the system quality-assured(eg. through audits and training)?

� Is there adequate back-up anddisaster-recovery in place?

The QPPV ensures the system willdetect, evaluate and report anypossible safety signals and must bein a position of sufficient authorityto instigate a change in the labellingthat will promote its safer use (orpossibly other urgent safety actionsor regulatory activity – including apossible product withdrawal). Suchresponsibility can produceconsiderable pressure – especiallywhen one considers today’stransparency with the CompetentAuthorities. The QPPV is open topersonal prosecution in respect ofthe numerous EU and UKPharmacovigilance Offences, so thismay not be regarded as a positionfor the faint-hearted.

Proposal for a QPPVregister

It is widely recognised and wellaccepted that to become a QP forbatch release, specialised trainingand experience is necessary. There isno equivalent formal system orrecognition for a QPPV and yet thescale of responsibilities iscomparable. The expectation is thatthe QPPV should have an in-depthknowledge of applicable PVlegislation gained through severalyears’ experience and have arelevant biological sciences,pharmacy or medical degree.

Some Member States have produced“clarifying” guidelines, for examplein Belgium, the QPPV must submit acopy of his/her diploma “…either ofpharmacist or of master ofpharmaceutical sciences, either ofphysician or of master ofmedicine…or the persons who arelegally exempted from this” [sic], aspart of a formal recognition.

Additionally, there are still Nationalregulations that overlap with theresponsibilities of the QPPV, such asthe Stufenplanbeauftragter inGermany (who must possess adegree in medicine, human biology,veterinary medicine or pharmacy)and the Pharmacien Responsible(who must be a pharmacist) inFrance. In such cases, a “doubling-up” of local and EU responsibilitiesfor one person may be the most

effective arrangement for acompany.

In the absence of a formalqualification and register, it is theresponsibility of the MarketingAuthorisation Holder to satisfy itselfthat the person named as QPPV issuitable, and then hope that therelevant inspectors of theCompetent Authorities will besimilarly satisfied when they carryout their inspection. The onlyabsolute requirement is that theperson must be an EU resident.

Pharmacists have all the skills whichare pre-requisites for an effectiveQPPV, and should play a leadingrole in championing levels ofeducation, professionalcompetencies and formalrecognition of the role and itsresponsibilities.

Qualifications of QPPVs

A search for QPPVs (and deputies)and their qualifications wasconducted through web-basedprofessional forums (see Table). Theresults showed that about half ofthe QPPVs are medics. Just over aquarter are pharmacists, with thehighest proportions in Poland (63%)and France (43%). Numerically,pharmacists were least wellrepresented in Germany; of 13QPPVs found only one is apharmacist.

Table. Qualifications of QPPVs.

First qualification Number (%)

All UK Country with Country with highest lowest

Medical degree 55 (50) 18 (42) Germany Italy10 (77) 2 (25)

Pharmacy degree 28 (25) 6 (14) Poland Germany5 (63) 1 (8)

Chemistry or biological 24 (22) 17 (40) UK France, Poland, science 17 (40) Denmark 0 (0)

Nursing/vet 3(3) 2 (5) sample too small

TTHHEE QQPPPPVV –– CCEEMMEENNTTIINNGG TTHHEE PPHHAARRMMAACCIISSTT’’SS RROOLLEE IINN EEUURROOPPEE ((CCoonntt..))

Although this is a limited surveyand there may be other regionalfactors (e.g. distribution pattern ofcompanies by size, participation inprofessional web forums), clearlythere is an opportunity to enhancethe position of pharmacists engagedin drug safety throughout Europe.

Most member states, including theUK, take a pragmatic approach –“any person who is capable ofcompetently performing thespecified duties would meet therequirement”, but there are others,as previously mentioned, where a

more formal approval is required.The consequence is that differentmember states may have differentviews on the suitability of anindividual put forward as a QPPV.

The opportunity exists for a moreformalised programme, as appliesto the QP for manufacturing andquality issues, which would ensurehigh and consistent application ofstandards. Bodies representing theprofessional bodies ofpharmacovigilance professionals,including EIPG, may have a role toplay in this.

References

1. National telephone poll was conductedOctober 22-25, 2009 by Opinion ResearchCorp. on behalf of Prescription Solutionsand NCPIE.http://news.moneycentral.msn.com/ticker/article.aspx?Feed=BW&Date=20091112&ID=10694915&Symbol=UNH

Further reading

Good Pharmacovigilance Practice Guide:Compiled by the Medicines and HealthcareProducts Regulatory Agency (MHRA).Published by The Pharmaceutical Press.

VOLUME 9A: The Rules Governing MedicinalProducts in the European Union –Guidelines on Pharmacovigilance forMedicinal Products for Human Use.Published by the European Commission;Enterprise and Industry.


TTHHEE QQPPPPVV –– CCEEMMEENNTTIINNGG TTHHEE PPHHAARRMMAACCIISSTT’’SS RROOLLEE IINN EEUURROOPPEE ((CCoonntt..))

Clean Air andContainment

ReviewThis new quarterly journal under the editorship of John Neiger, is aimed atusers, specifiers, designers, manufacturers, installers and testers ofcontamination control facilities and of clean air and containmentequipment. It contains articles of topical, technical and historical interest,updates on standards and regulations, news, views and information onrelevant events, especially training.

Visit our website to subscribe now – Issue 4 due out in October 2010

www.cleanairandcontainment.com

The future of pharma isinextricably linked with smartdiagnostics

The molecular level ofpersonalised medicine

Personalised medicine – or the use ofinformation about a person’s genes,proteins and environment to prevent,diagnose and treat disease – has beenmuch talked about in recent years. Andsome observers are wondering what theexcitement is all about. In the words ofRoche’s CEO, Severin Schwann:“Personalised healthcare is nothing new.Doctors have always tried to fit thetherapy to the patient if possible. Butwhat’s happened more recently is thatwe’ve begun to go a level deeper. We’renow exploring the biology of disease andtreatment at the molecular level.”

Molecular medicine does not per sedefine personalised medicine butmolecular tools are important as theyshould enable greater relevance in theinformation provided by diagnostic tests.

Personalised medicine as aspectrum

As personalised medicine means different

things to different people, additionalcomplementary ways of characterisingdiagnostics may further help distinguishdifferent shades of grey in thepersonalised medicine spectrum.

In the strictest sense, personalisedmedicine diagnostics may consistexclusively of companion diagnostics,which are by definition geared towardssupporting a therapy decision for aparticular drug, patient by patient. At themore permissive end of the spectrum,personalised medicine tests may includealso early diagnostics, prognostics andpossibly all other types of diagnostics.You may indeed argue that if a diagnosticwere not designed to inform treatmentdecisions for individual patients – oneway of defining a personalised medicinediagnostic – it would not have muchsense.

Companion diagnostics and thefuture of pharma

The concept of companion diagnostic(CD), and its role in the future ofhealthcare, was also mentioned inPharma 2020: Marketing the future, areport published byPricewaterhouseCoopers (PwC) inFebruary 2009. This report discusses thekey forces reshaping the pharmaceuticalmarketplace and the changes required tocreate a sales and marketing model thatis better adapted to the stakeholderpriorities expected for 2020. Of particularrelevance to the diagnostics industry isthe move from mass market therapies to

LOIC KUBITZA is a lifesciences expert atPricewaterhouseCoopers,Luxembourg and can becontacted at:[email protected]


DIAGNOSTICS ANDTHEIR ROLE INPERSONALISEDMEDICINEby Loïc Kubitza

Collaborations between diagnostic and pharmaceuticalindustries are expected to grow, driven by the

development of personalised medicine. This trend isevidenced by Pfizer’s August 2009 collaboration withAbbott’s diagnostics division to develop a test to screennon-small cell lung cancer tumours for generearrangements. Pfizer has developed a novelinvestigational agent, PF-02341066, that selectively targetscancer-causing genes implicated in the progress of manycancers. The test will be used for patient selection forfuture clinical trials of the agent.

� Early diagnostics: diagnostic productspermitting the detection of a diseaseat very early stages of itsdevelopment thus giving moretreatment options (eg. early lungcancer detection allowing surgery).

� Prognostics: diagnostics that providea prediction or estimate the risk ofdeveloping a particular conditionbased on

– phenotypic (e.g. transcriptomic,proteomic or metabolomic)parameters; or

– genomic (e.g. hereditary or genebased) characteristics.

French

Les collaborations entre les industries pharmaceutique et du diagnostic sont amenées à s'intensifier, sous l'impulsion du développement de la médecine personnalisée. Cette tendance est illustrée par la collaboration de Pfizer en août 2009 avec la division diagnostics d'Abbott en vue de développer un test de dépistage des tumeurs pulmonaires non à petites cellules pour le réarrangement des gènes. Pfizer a mis au point un nouveau médicament expérimental qui cible de façon sélective les gènes cancérigènes impliqués dans la progression de nombreux cancers. Le test sera utilisé dans la sélection des patients pour de futurs essais cliniques du médicament.

Italian

La collaborazione tra l’industria farmaceutica e quella della diagnostica appare destinata ad intensificarsi, sotto la spinta della medicina personalizzata. La tendenza è illustrata dalla collaborazione nell’agosto del 2009 della Pfizer con la divisione diagnostica dell'Abbott nello sviluppo di un test per lo screening dei tumori polmonari a cellule non piccole per il riarrangiamento genico. Pfizer ha messo a punto un nuovo farmaco sperimentale che mira selettivamente i geni carcinogenici implicati nel progresso di numerosi tumori. Il test verrà impiegato nella selezione dei pazienti per futuri test clinici del farmaco.


specialist therapies, which ishighlighted in the report.

Many specialist therapies are verycostly (eg. almost $300,000 annuallyfor Fabry’s or Gaucher’s disease) andare used to treat smaller targetpatient populations with specificdisease subtypes. In this context,there is thus a growing imperative,both clinical and budgetary, toaccompany therapies withdiagnostic tools of increasingsensitivity and specificity to betterenable the identification of thosepatients in the relevant diseasesubtype and most likely to benefitfrom the therapy. The marketingmodel foreseen for most specialisttherapies in 2020 will include acompanion diagnostic as a keycomponent.

Highlighting a movement towardspersonalised medicine is notstraightforward as a concept as it isso widely open to interpretation. Itis however important that we try asthe response rates on drugs are stillunsatisfactory, varying widely from20% to 75%.

Companion diagnosticspartnerships with thepharma industry

If diagnostics are so important toimproving the value of therapeuticsto patients, we should expect the

pharmaceutical industry to beentering significant CD partnershipswith the IVD industry. However, thisis not yet the case and diagnosticscollaborations with pharma have yetto become an established practice

Only seven partnerships wereannounced in 2008 betweenpharmaceutical and diagnosticcompanies to develop a companiondiagnostic. This represents asignificant drop from the 14collaborations announced in 2007but there is no clear up ordownward trend over the period2004-2008, with annual dealnumbers varying between 6 and 14throughout. Companion diagnosticspartnerships with pharma have yetto become an established industrypractice (Figure 1).

Most 2008 deals focusedon cancer and involved abig pharma partner

Three key themes were reflected inthe partnerships announced in2008:

� Cancer attracted strong interestas the disease area of choice forthe development of companiondiagnostics. In 2008, all dealsfocused on diagnostics for cancer.

� Big pharma was dominant aspharmaceutical partner forcollaborations with the

diagnostics industry. In 2008, allpharmaceutical partners weretop 20 companies by sales ofprescription pharmaceuticals(2008 ranking from IMS Health).OSI Pharmaceuticals was the onlyexception but big pharmacompany Roche was a co-partnerin OSI’s collaboration withAbbott’s diagnostics division todevelop a pharmacogenomic testto identify patients most likely torespond to cancer drug Tarceva(erlotinib) for non-small cell lungcancer. In this study, we countedany deals involving Genentech asa big pharma deal due to Roche’smajority ownership in Genentechat the time of the deal and whichbecame a full ownership during2009.

� Niche specialists dominated as invitro diagnostics partner forcollaborations with thepharmaceutical industry. In 2008,Abbott was the only IVD majorinvolved in collaborations withthird-party pharmaceuticalcompanies for companiondiagnostics. None of the otherdiagnostics partners announcingdeals in 2008 – Aureon, Celera,Dako and DxS – were rankedamong the ten largest in vitrodiagnostics companies.

Similar themes emerge when weanalyse the pharmaceutical anddiagnostics partners involved incompanion diagnostics licensingdeals over 2004-2008 in more detail.

The pharma partners

Roche, Pfizer and Merck were themost active pharma partners over2004-2008. Roche’s pharmaceuticaldivision, including Genentech,stands out as the most active third-party pharmaceutical licensingpartner for the diagnostics sectorover 2004-2008 with ten announceddeals – an average of two deals perannum. Pfizer, Merck andAstraZeneca followed Roche with 6,

DDIIAAGGNNOOSSTTIICCSS AANNDD TTHHEEIIRR RROOLLEE IINN PPEERRSSOONNAALLIISSEEDD MMEEDDIICCIINNEE ((CCoonntt..))

Figure 1. Companion diagnostics partnerships with pharma in 2004-2008.

Source: PricewaterhouseCoopers analysis using Windhover data

15

12

9

6

3

0

Num

ber of deals

2004 2005 2006 2007 2008

12

6 6

14

7

5 and 3 diagnostics partnershipsrespectively over the same period(Figure 2).

The position of Roche as the leadingpharmaceutical partner forcollaborations with diagnosticscompanies is remarkable if weconsider that none of the otherpharmaceutical companies with amajor IVD affiliate – Abbott, Bayerand J&J – announced more thanone partnership with a third partydiagnostics company over 2004-2008. However, the full pictureabout these diagnostics majors isnot available as there is littlevisibility about any intra-groupdiagnostics collaborations with theirrespective pharmaceutical divisions.

The diagnostics partners

The most active diagnostics partnersfor deals with pharma were allniche players. Serial deal making forcompanion diagnostics was limitedamongst diagnostics companies.Only four diagnostics companiesannounced at least two partnershipswith pharmaceutical companiesover 2004-2008 and they were all

niche diagnostic specialists: Celera,Dako, Epigenomics and Perlegen.Dako is the largest among thesediagnostic companies with $322million of net sales reported in2008.

Three observations follow from thisanalysis and our discussions withselected industry players:

1. The pharmaceutical industry isnot currently a priority marketfor large diagnostics companies.The development risk and timeto market associated with drugcandidates make thedevelopment of a companiondiagnostic significantly lessattractive to major diagnosticsmanufacturers than the revenuescurrently available from its moretraditional target market ofclinical laboratories.

2. The limited deal flow bycompany suggests that even forniche diagnostic companies, theprospective economics ofdeveloping a companiondiagnostic may not always beattractive. Key factors that impactthe net present value expected

from companion diagnosticsprojects include the strength ofthe intellectual property, thepricing and reimbursementcoverage and the extent oftesting required by regulators toobtain key marketingauthorisations. Achieving apositive net present value from acompanion diagnosticsdevelopment project will be achallenge unless some of thesefactors become more favourable.

For those diagnostic companies thatdo target the pharmaceuticalindustry, some are developingcompanion diagnostics withoutentering a partnership with apharmaceutical company. Whendiagnostics companies have therequired funding and access tosufficient, high-quality biologicalsamples to conduct suchdevelopment work withoutpartnering with pharma, thisapproach can help keep more of thevalue in-house. In due course,however, it can be helpful to havesome form of public support fromthe targeted drug’s marketer tounderline the validity of the test as



Figure 2. Companion diagnostics partnerships by pharma partner in 2004-2008.

Source: PricewaterhouseCoopers analysis using Windhover data

10

8

6

4

2

0

Num

ber of deals

Roche

Pfizer

Merck

AstraZeneca

Amgen

Biogen Id

ec

BMS

Ipsen

Lilly

Schering-Plough

Single Deal d

oers

10

6

5

3

3 3 3 3 3 3

9

a companion diagnostic for thedrug.

Biomarker testingrequirements

Drug approval agencies, includingthe FDA and EMA, are encouraginggreater use of biomarkers anddiagnostics in drug developmentand prescribing decisions, thuspromoting the concept ofcompanion diagnostics for drugs.

The FDA recently started reporting alist of genomic biomarkers that itconsiders valid to guide theappropriate clinical use of approveddrugs. The list is being updated on aquarterly basis and counted 32 validgenomic biomarkers in midSeptember 2009.

Most drug labels in the list providepharmacogenomic information withno immediate recommendation forgenetic testing. However, testing is“recommended” or “required” in afew cases. At 20 March 2009, onlyfour biomarkers were “required” tobe tested for – three for cancer.

Thus we are still at the start of the

process if we consider that only fourbiomarkers are “required” to betested for. However, the FDA wasprompted to publish its listfollowing a marked increase overthe last decade of approved drugslabels containing pharmacogenomicinformation. The FDA estimates that10% of approved drug labels nowcontain pharmacogenomicinformation and this is expected tocontinue increasing.

The EMA’s communication on therequirement for biomarker testing isless transparent than the FDA’s butits initiatives should not beoverlooked. For example, theEuropean agency played a key rolein requiring biomarker testing forAmgen’s Vectibix, following theFDA’s accelerated approval withoutspecific testing requirements. TheEMA also has a larger number ofdrugs for which biomarker testing isrequired – in mid 2009, we countedat least 11 drugs with therequirement.

We expect greater harmonisationbetween different regulatoryagencies to develop over time

through greater consultation butalso following pressure fromclinician communities asstakeholders in one country push toimplement practices alreadyincluded in drug labels in othercountries.

Moving towardspersonalised medicineIncreasingly, pharmaceuticalcompanies will not move a drugcandidate to the clinicaldevelopment stage without a clearbiomarker development program.These companies understand thecontribution of biomarkers anddiagnostics in improving the designand probability of success of clinicaltrials. In addition, pressure fromhealthcare payers is putting moreemphasis on the availability of acompanion biomarker test whendeciding on a drug’sreimbursement. These factors willcombine to accelerate thedevelopment of new diagnostics forpersonalised medicine. Weanticipate that alliances andcollaboration will be inevitable asthe market need expands.



Industrial Pharmaceutical MicrobiologyStandards & Controls

Editors: Norman Hodges and Geoff Hanlon

“An exceptional and uniquepublication in this field”

Microbiologist – September 2007

21 Chapters 450+ pages £325.00

For details and to ordervisit the Euromed website:

www.euromedcommunications.com

Looseleaf formatSpecial supplements

Regularly updated


Introduction

The current review period has seen anumber of changes in the regulation ofmedicines and regulatory guidance inboth the USA and in the EU. The mostsignificant of these are noted below.

United States of America

The Drug Safety and Accountability Actof 2010 (S.3690) was introduced by Sen.Michael Bennet. The Act seeks tostrengthen industry standards to ensurethe quality and safety of drugs madefor the US market, and to improve theUS Food and Drug Administration’s(FDA) oversight abilities, such as thepower to order a drug recall.

New and updated regulatoryguidance

The FDA has issued new and updatedguidance covering the following topics:

• The latest in a series of FDAguidances addressing the risk of CJDand vCJD transmission by bloodand blood products. The Guidanceamends the 2002 guidance.

• Post-approval manufacturingchanges reportable in annualreports. This is part of the FDA’sinitiative to ensure that its CMCregulatory review should be basedon an understanding of product riskand how best to manage such risks.

• Guidance for Industry – labelcomprehension studies for non-prescription drug products.

• Questions and Answers (Q&A) oncGMP Good Guidance Practices,Level 2 Guidance Holding andDistribution – Human Drug Recalls.

• Draft recommendation for therevision of the permitted dailyexposure for cumene according tothe maintenance procedures for ICHQ3C impurities: residual solvents.

FDA has announced

• That it will be conducting a series of

REGULATORY REVIEW Review of major developments in GMP in the EU and USA,

June to August 2010

by Malcolm Holmesinspections in an effort to evaluateindustry’s compliance and under -standing of Part 11. FDA also intendsto take appropriate action to enforcePart 11 requirements for issuesraised during the inspections that donot fall under the enforce mentdiscretion discussed in the Guidance.

Europe

The European Commission has

• Issued a further publicconsultation targeted on specificissues related to in vitro diagnosticmedical devices. This is in the formof a questionnaire aimed atrevision of Directive 98/79/EC.

MHRA

The MHRA has

• Created a specific area on its web-site dealing specifically with disputesover regulation of medicines andthe Regulation of Medicines ReviewPanel which deals with such issues.

• Provided a set of frequently askedquestions (FAQ) relating to the EUGMP Guide Part I, Chapter 1 andAnnex 20, in which the GMPexpectations and requirements forintegration and use of Quality RiskManagement in pharmaceuticalquality systems are defined. Thepurpose of the Q&A is to helpindustry understand how theexpectations of EU GMP will beinterpreted by MHRA inspectors.

• Published a new enforcementstrategy (Inspection, Enforcementand Standards Division). Thestrategy aligns UK Governmentbetter regulation initiatives, theHampton review and theRegulators Compliance Code

• Issued guidance for Marketing andManufacturing Authorisation holdersrequiring that all named sites arefully maintained as approvedsuppliers and thus available for use.Redundant sites / suppliers should

be removed from the MA bysubmission of a Type 1A Variation.

• Following 6 months experiencewith the new variations legislation,published details of experience todate and an audit of submissionsmade in June 2010. They have alsoupdated the FAQs.

International

EMA/US FDA

• Continue to seek potentialcandidate companies for a jointGMP pre-approval or re-inspectionpilot programme for manufacturersof medicinal products. Theobjective is to see whether greaterinternational collaboration can helpto distribute inspection capacityallowing more manufacturing sitesto be monitored and reducingunnecessary duplication.

PIC/S

• International collaboration on thequality of APIs (European commissionconcept paper / PIC/S role).

WHO

• World Health Organization (WHO)has issued as part of TechnicalReport Series, No. 957 significantlyrevised documents – Annex 3 goodmanufacturing practices forpharmaceutical products containinghazardous substances and Annex 5Good Distribution Practices (GDP)for pharmaceutical products.

ISPE

• Has announced the release of theBaseline Guide® Risk-basedManufacture of PharmaceuticalProducts (Risk-MaPP).

For further information on these andother topics we suggest you refer to currentand past editions of “gmp-review News”published by Euromed Communications.(www.euromedcommunications.com)


Strategy Meeting

As envisaged during the GeneralAssembly in Milan, a Strategy Meetingwill be held on 5th November inParis which will map our aims andactivities for the next 5 years. Whatdoes it mean when we say “we arethe EIPG”? The simple answer is themembership! As a member, pleasetell us what you want from EIPG.Anyone wishing to propose subjectsfor debate, please e-mail yourAssociation’s delegate or one of ourBureau members via the website.

Professional QualificationsDirective

EIPG and the European Associationsof community and hospitalpharmacists are waiting to commenton the results of a questionnairefrom the EC. This questionnaire,evaluating the ProfessionalQualifications Directive, has beensent to all Competent Authorities inpharmacy and the responses arebeing coordinated by the Ordre desPharmaciens in Paris.

Pharmaceutical EducationPHARMINE Project

Outcomes for the education andtraining of pharmacists have beendivided into “Foundation level” (Day1 of registration as a pharmacist)and “Specialisation and advancedlevel practice”.

For the “Foundation level” testingfor validity is the next step inestablishing recommendations for acore scientific set of competenciesto equip a newly qualifiedpharmacist for his/her early careeryears. The working groupresponsible for the review of theundergraduate course will test thesecompetencies via the pharmacystudents of EPSA and the youngpharmacist members of the threeprofessional groups.

For the advanced level framework,the “expert professional practice”will be sector specific. However, theworking group has reasoned that“building working relationships,evaluation and innovation,management, leadership andcontinuing education, training anddevelopment” are common to allsectors of pharmacy practice.

However, competencies for thevarious disciplines in whichindustrial pharmacists work oncethey specialize in an area ofindustry are under review.

Supply Chain Security

The European Commission’sprogress report on the prevention ofcounterfeits into the legal supplychain which was discussed duringour EIPG General Assembly wasofficially released in May.

However, the date for discussion inthe European parliament has beendelayed and is currently notexpected until this December.

European MedicinesAgency

Gino Martini and John Jolleyrepresented EIPG at theManufacturing and QualityCompliance meeting with interestedparties on 14th September at theEMA in London. The topics discussedare the subject of the Editorial in thisissue of the Journal and progressreports will be provided to MemberAssociation contacts.

EuroPharm Forum

The chairman of Pharmadanmark,Antje Marquardsen, will representEIPG at the General Assembly of theEuroPharm Forum on 2nd October.Their General Assembly inCopenhagen is organised to comeafter the Joint WHO and EuroPharmForum Conference on the role ofpharmacists in individual patient care.

Annual Symposium of thePharmaceutical Group ofEuropean Union (PGEU-GPUE), Bruges 14/06/2010

Roland Schots from our Belgianmember association representedEIPG at a Symposium in Bruges. Hissummary report is shown below:

The key question arising from thiscommunity pharmacists’Symposium was whethercommunity pharmacists will still beneeded within the next 20 years? Ifyes, what will be their role and tasksin the healthcare system?

The traditional role of thecommunity pharmacist to dispensemedicinal products is declining dueto the cost limiting policies of all EUcountries. However, the role of thecommunity pharmacist is changingfrom a dispensing function to thatof a public health adviser. Thehistorical role of "responsibility forthe quality of the dispensedmedicine" is no longer realistic andtoday this role has been taken-overby the Qualified Persons ofpharmaceutical companies. In allcountries, community pharmacistsare acting as healthcare advisers(pharmaceutical care) for patientsand, particularly, for patients with“at risk” pathologies such asdiabetes, hypertension and bloodlipid deviations.

In the future, all countries will needto devise multidisciplinaryprotocols, supported by appropriatefinancial incentives.

The meeting concluded that despitemajor changes in pharmaceuticalpractice, the pharmacist will remainan essential actor in the healthcaresystem.

Jane Nicholson, Executive Director EIPG

NEWS FROM THE EIPG


Retest period and stability testing

QI have two cycles of stability studies for acertain active substance. The second cycle

was launched when the PhEur monographwas changed and this change was major asthe limit for impurity X and the method ofexamination have been changed. The retestperiod was established as 3 years for the firstcycle of studies (before the monograph hadbeen changed) but the new cycle does notcover such time and the retest period isshorter. The problem is that our client wantsus to keep the 3-year retest period – howshould I manage this problem?

Response 1 – I suggest you consider registering thismaterial as two different active substances according tothe registration specifications: one that conforms to theold specification and the other that conforms to thenew specification. Selecting according to a specificationis common practice for particle size distributions, forexample. Your marketing team may like this because ofthe potential pricing flexibility, even though yourregulatory team may not like the extra work.

Response 2 – Not entering into thetechnical/scientific details, I would say that a retestperiod of three years is quite a long period. How longis the material kept in a facility warehouse before it isused? Will a company pay for keeping an active twoyears in stock?

Response 3 – If the old stability data shows theimpurity X below the new EP monograph limit and themethod of analysis is a validated and accepted one, aretest date of three years may be claimed with theearlier data supporting it and a commitment toprovide the ongoing data every year.

I assume the impurity X was being monitored in theearlier cycle and maybe the earlier method alsoquantifies it.

Response 4 – A combination of accelerated nadreal time studies can be used – see the ICH stabilityguideline and the relevant CHMP guidelines. Combinedwith the original data – and assuming that any newly

observed impurities can be shown to have beenpresent all the time – then the combination of newdata and old data can be used to support a reasonableretest interval. This might or might not be three yearsof course…

Response 5 – Monographs are specific to theprocesses used, both for the drug substance and thedrug product. For the drug substance, the USPmonograph will explain how to compare it to the USPReference Standard, called USP RS. You have to decidefor yourself if that is appropriate. Similarly, the USPDrug product monograph may describe a 20mg tablet,but you may want to register a cream. That’s anextreme example, but the same considerations applyeven if you want to register a 15mg tablet.

Laboratory log books and notebooks

QI have always been under the impressionthat all notebooks need to be hard-backed,

bound and page-numbered. Is this still a correctassumption and if it is, is there a specificregulatory requirement or is it simply anaccepted solution?

Response 1 – I share your opinion that a logbookshould ideally be solid as a book. However, I have noknowledge of a guidance that describes such a modelof log.

What I know (but I deplore it) is that a number ofcompanies use “flying sheets” that, when filled in, arecollected in a binder (sometimes even bound). Thesecompanies call these sytems “logbooks” too.

And I know from my experience that a number ofinspectors and a number of auditors do accept thissolution worldwide.

In my personal practice as an auditor, I only DEMANDbound logbooks for the record of the sterility testingresults. I ACCEPT “flying sheets” for most othersituations althouguh I am not really supporting them.

Response 2 – We recently had an audit and theauditor recommended we used controlled loose-leafsheets in place of our current bound notebooks,perhaps not for everything, but to improve efficiencyand reduce potential non-compliance for tests that areperformed many times, by removing the need tocontinuously write down headers and raw data in thelab books. this is something we have used in the pastand we moved to notebooks as that seemed to be theindustry standard then, but now it seems thatcontrolled loose-leafs are much more acceptable.

Response 3 – In my experience, auditors accept flyinglogs provided the control is through QA. Some QC labs also

PHARMACEUTICAL FORUMThe following questions and responses are aselection of those published on an open onlinediscussion group www.pharmweb.net/gmp.html. TheForum serves as a means of exchanging views oninternational regulations affecting thepharmaceutical industry. Readers are invited tocontribute to the Forum.


have flying sheets to record the analysis and analyticalresults and it is accepted by regulatory auditors. Mypersonal view is that bounded books should be used.

Response 4 – I have just done a search throughvarious appropriate guidances and it does seem thatboth are now acceptable – summarised maybe by thisAPIC statement: “The QC laboratory should uselaboratory notebooks (bound notebooks pre-numbered) or an equivalent system (one option is theuse of loose sheets pre-numbered, the printing has tobe controlled and also the storage as control records) torecord the raw data at the time they are produced”.

In the Eudralex and PIC/S the statement is: “Testingprocedures and records (including analyticalworksheets and/or laboratory notebooks).”

So, yes it seems that I am old-fashioned, although I feelthat issuing dedicated notebooks is an easiercompliance and control than pre-pnumberedcontrolled loose sheets including storage and retrieval.

I would add that there is a PIC/S Inspection AideMemoire which states: “Recorded/attached directly intorelevant laboratory notebooks data (no scrap or loosepaper) which is a bit the other way. Also I checkedthrough the various 483s from the FDA and certainly itwould appear that in those reports the notebook is stillcommonly found (and not infrequently mentioned).

Diisopropyl ether

QWhat limit should we define for Di-isopropylether in one of the API we intend to

manufacture, as the same solvent has insufficienttoxicity data and no standard ppm levels ismentioned in ICH guidelines?

Response 1 – As per the ICH Q3C(R4) page 1 thesubstance can be considered as an impurity:“Supporting safety data in a marketing application for anew drug product containing a new solvent may bebased on concepts in this guideline or the concept ofqualification of impurities as expressed in the guidelinefor drug substance (Q3A, Impurities in New DrugSubstances) or drug product (Q3B, Impurities in NewDrug Products), or all three guidelines.”

I found the following toxicology data to be helpful ifyou want to calculate the PDE (Permissible DailyExposure) and the allowed specification:www.epa.gov/IRIS/pdfs/Litsearch_Diisopropyl-ether.pdf.

The published information is based on Pharmaeuropa, Vol9, No 1, Supplement, April 1997 so you have to calculatethe limit based on the current toxicology data available.

Response 2 – We’ve had the same problem. Forthese kinds of solvents it is recommended to perform

PPHHAARRMMAACCEEUUTTIICCAALL FFOORRUUMM ((CCoonntt..))

the assessment of safety and toxicity on the basis ofavailable knowledge or appropriate tests. We’ve gatheredsome information from the literature and used amethod for establishing the exposure limits described inPhEur (chapter 5.4). Some widely used methods forestablishing exposure limits are also mentioned in thischapter if you assess the factors and NOEL or LOEL youwill also calculate the PDE value. You can always tightenthe limit. In my example the calculated PDE was about300ppm but we performed tests on several batches ofAPI and the limit was tightened to 170ppm.

Change in granulation process

QIf we need to change the approved wetgranulation process, what kind of submission

do we need to do to satisfy the US FDA? We wishto granulate our API with some excipients andgranulate some other excipients separately. Thenmix the granules and compress the tablets. Weare not changing any excipient nor their quantity– we are just changing the order and style ofgranulation to avoid the formation of certiandegradants.

SUPAC and Guidance for changes in theapproved NDA/ANDA do not address thischange.

Response 1 – Considering there are no guidelines,you will have to go by following worst case scenario.

1. Firstly is the end product quality the same as theealier approved product.

2 Assuming you have validated the new process the newproduct formed has to match the earlier product.

3. Since some degradation was taking place in the earlier(this must have been noted in the dossier), by the newprocess there is a better quality and technically thestability of this would entail detailed studies again.

Looks like you will have to work again and prove that thenew process and product is safe.

Response 2 – It seems that your change in process,that is, the sequence of granulation, should beregarded as a Level 3 change in manufacturing.Though there is no change in the excipient, the changein style of granulation may have an effect on theproduct quality and safety. This kind of change shouldbe pre-approved by US FDA.

Readers are invited to send their Q&As towww.pharmweb.net/gmp.html

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JJOOBB VVAACCAANNCCIIEESS ((CCoonntt..))

Senior and Junior positions in QAGlobal activities and QA BelgianoperationsGlaxoSmithKline Biologicals is one of the world's leading vaccine producerand the fastest growing business within the GSK group today.Headquartered in Rixensart & Wavre, Belgium, GSK Biologicals employsapproximately 9,000 people worldwide, including over 6,000 in Belgium.GSK Biologicals’ global production network is in the midst of becoming thelargest in the entire vaccines industry. 13 sites on three continentsmanufacture, formulate, fill, pack, check and deliver over a billion doses ofabout 30 different vaccines.

The Global Quality Department of GlaxoSmithKlineBiologicals is looking tofill several junior and senior positions in QA Global activities and QA Belgianoperations.

Candidates should have:1. Experience in the pharmaceutical area (preferably in biotechnology)2. Experience in one of the following areas

• product/raw materials release – global staff & local operationalpositions;

• deviation handling; • QA systems; • internal auditing; inspectors • QA co-ordinators/supervisors• validation managers

Profile• pharmacist or scientific university degree• 3 to 15 years experience according to the position• experience in manufacturing and/or quality is a must• GMP background• quality mindset• experienced with Health Authorities inspections• team leader skills• investigation skills• capacity to take decisions• Lean Thinking• capacity to work in a changing environment

At GSK we provide a supportive working environment, and a range ofdevelopment challenges and opportunities. We also offer competitive benefitsand compensation packages designed to attract and retain the very best.

Feel free to apply for a role by visiting our website at

www.gsk-bio.comor by sending an email to [email protected]


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Contract Clinical DataManager A global pharma is seeking ClinicalData Management professionals towork within their expanding team.Location: Belgium Salary: Negotiable rate, dependant onexperience Contact: CK Clinical – Priya Mukherjee:+44 (0) 1438 870028 /[email protected]

Associate Director BiostatisticsA leading Pharma has an opportunityfor a Statistics professional to take ona role as Associate Director.Location: NetherlandsSalary: A highly competitive base salary+ bonus + relocation packageContact: CK Clinical – Priya Mukherjee:+44 (0) 1438 870028 /[email protected]

Project BiostatisticianA leading Pharma has an opportunityfor a Statistics professional looking towork for this reputable organisation.Location: Netherlands Salary: A highly competitive base salary+ relocation packageContact: CK Clinical – Priya Mukherjee:+44 (0) 1438 870028 /[email protected]

Clinical QA ComplianceManagerThis role will be based at TheNetherlands offices of a leadingglobal pharmaceutical company. Youwill audit investigator sites and thirdparties around the world to ensureGCP compliance. Fluent English andthe ability to travel extensively on aninternational basis is essential.Location: The NetherlandsSalary: Up to €66KContact: CK Clinical – Jim Gleeson: +44 (0)1438 [email protected]

Contract SAS Programmer A leading Pharma has variousopportunities for a SAS Programmingprofessionals.Location: SwitzerlandSalary: €NegotiableContact: CK Clinical – Priya Mukherjee:+44 (0) 1438 870028 /[email protected]

Clinical QA AuditorWorking for a global CRO you willaudit study sites in Germany to ensurecomplete compliance with ICH-GCPrequirements.Location: West GermanySalary: €60-70KContact: CK Clinical – Jim Gleeson: +44 (0)1438 [email protected]

Senior CRAA home-based role with a large,international CRO. You will oversee anumber of study sites in theStockholm region. The company isexpanding it's Swedish operation, sothere will be very good careerdevelopment opportunities.Location: SwedenSalary: SK42K per monthContact: CK Clinical – Jim Gleeson: +44 (0)1438 [email protected]

Clinical Data Manager A leading CRO is seeking a DataManagement professional for one oftheir European based offices.Location: Belgium/Germany Salary: Up to €50,000 per annumContact: CK Clinical – Priya Mukherjee:+44 (0) 1438 870028 /[email protected]


DDEECCEEMMBBEERR

1-2 December 2010 – London, UKCold chain challenges, riskmanagement and lessons learned:case studieswww.smi-online.co.uk

1-3 December 2010 – Nice, France11th Conference on Europeanelectronic document managementwww.diahome.org

2 December 2010 – London, UKCharacterisation of active productingredientswww.jpag.org

6-7 December 2010 – London, UKEMA Review of the year and outlookfor 2011www.topra.org

6-8 December 2010 – London, UKDeveloping IP strategies forcrystalline formswww.pharma-iq.com/events

8-10 December 2010 – Edinburgh,ScotlandDrug delivery to the lungswww.aerosol-soc.org.uk

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24-25 January 2011 – London, UKAmorphous pharmaceutical materialswww.visiongain.com

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DATES FOR YOUR DIARYNNOOVVEEMMBBEERR

8-10 November 2010 – Köln, GermanyInnovative pharma distribution 2011www.pharma-iq.com/events

9 November 2010 – Zurich, SwitzerlandDrug & device combination products– finding the right regulatory strategywww.diaeurope.org

15-17 November 2010 – Berlin,GermanyPharma track & tracewww.pharma-iq.com/events

17-19 November 2010 – London, UKSerialisation & traceability 2010www.pharma-iq.com/events

22-24 November 2010 – Cambridge, UKTabletting technology for thepharmaceutical industrywww.rpsgb.org/events

25-26 November 2010 – London, UKQualified Person forum 2010www.qp-association.eu

29 November-1 December 2010 –Geneva, SwitzerlandWorld Orphan Drug Congress 2010www.terrapinn.com

30 November-1 December 2010 –Manchester, UKPractical application of quality bydesignwww.DBA-global.com

24-26 January 2011 – Rotterdam, TheNetherlandsCool Chain Europe 2011www.pharma-iq.com/events

26-27 January 2011 – London, UKSocial media in the pharmaceuticalindustrywww.smi-online.co.uk

26-28 January 2011 – Rotterdam, TheNetherlandsClinical trial supply Europewww.pharma-iq.com/events

30 January-2 February 2011 – Brussels,Belgium3rd Annual disposable solutions forbiomanufacturingwww.pharma-iq.com/events

FFEEBBRRUUAARRYY 220011113 February 2011 – London, UKMeasurement challenges in theanalysis of topical productswww.jpag.org

15-17 February 2011 – Copenhagen,DenmarkNordic pharmaceutical distributionwww.pharma-iq.com/events

23-24 February 2011 – Barcelona, SpainRevision of bioavailabilityrequirement for modified releaseproductswww.eufeps.org

european industrial pharmacy - eipg.eu · ♦ survey presentation on atypical actives a report of...

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