european Industrial Pharmacy Issue 12 (March 2012)

ISSUE 12 • MARCH 2012www.industrialpharmacy.eu

www.eipg.eu

europeanINDUSTRIALPHARMACY

features4 THE BREAST IMPLANT SCANDAL AND EUROPEAN

MEDICAL DEVICE REGULATIONThe circumstances of the recent breast implant scandal aredescribed in detail and the actions needed to prevent it infuture are discussed.by Maria Donowa and Roger Gray

7 THE ROLE OF PHARMACISTS IN THE CLINICAL SUPPLYCHAIN FOR DRUG DEVELOPMENTThere are major benefits of including a pharmacist in the clinicalsupply chain.by Wyndi Phillips

9 PHARMACEUTICAL QUALITY BY DESIGNRationale and details of a new accredited distance learningpostgraduate course.by Walkiria Schlindwein

12 EVOLUTION OF THE JAPANESE REGULATORY SYSTEMA new approach to healthcare product regulation, thePharmaceuticals and Medical Devices Agency (PMDA), wasestablished in Japan in 2004. This article outlines the currentsituation.by David Jeffreys

16 THE FALSIFIED MEDICINES DIRECTIVE – IMPACT ONWHOLESALERSThe new Directive specifies that wholesalers need to check thesafety features on the outer packaging. However, this couldcause them major problems that would also affectmanufacturers, pharmacies and patients.by Monika Derecque-Pois

19 THE FALSIFIED MEDICINES DIRECTIVE – THE SWEDISH WAYA system of coding and identifying products throughout theentire chain is being introduced in Europe following thepublication of the Falsified Medicines Directive in 2011.A Swedish pilot study has shown the way.by Anita Finne-Grahnén

regulars3 EDITORIAL COMMENT

21 BOOK REVIEW22 REGULATORY REVIEW23 NEWS FROM THE EIPG24 EVENTS

2 european INDUSTRIAL PHARMACY March 2012 • Issue 12

europeanINDUSTRIALPHARMACY

Issue 12 March 2012ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael Anisfeld

Alexander FlorenceMichael Gamlen

Linda HakesJohn Jolley

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european INDUSTRIAL PHARMACYis the official publication of the EuropeanIndustrial Pharmacists Group (Groupement desPharmaciens de l’Industrie en Europe)www.eipg.eu

Cover picture: The Tower of Babel.Engraved by Isaac Basire and publishedin the works of Flavius Josephus, 1733.(See pages 7-8). Image: Fotolia

Belgium: Philippe Bollen

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Denmark: Marie Fog

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Shilpa Gohil

Greece: Margarita Efthymiopoulou

Hungary: Georgina Gal

Ireland: Anna O’Mahony

Italy: Piero Iamartino

Latvia: Inta Saprovska, Anita Senberga

Malta: Claude Farrugia

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european INDUSTRIAL PHARMACY March 2012 • Issue 12 3

editorialDear ColleaguesIt is that time of year where as the EIPG President I have to write an editorial relating to IndustrialPharmacy and EIPG objectives.

This year despite being early March I have tocomment on 2 areas which impact the PharmaceuticalIndustry as a whole.

The first announcement is that of AstraZenecawhich announced 7,000 job losses around the globeand which unfortunately means a number of siteclosures and job losses in Europe. When these eventsoccur they are sad occasions and we within theBureau of the EIPG provide our support and thoughtsto those who have been affected. In particular, ifthere are pharmacists who need advice and supportplease feel free to contact the Bureau, your countryrepresentative or myself or Jane Nicholson via ourwebsite. We will do our utmost to help you and tolink you to appropriate organisations who can alsohelp. Not much I know, but as a very famous UKretailer often quotes, 'every little helps'. The EIPG isthe Association for the Industrial Pharmacist whetheryou work in a large multi-national or in a SmallMedium Enterprise and its times such as these whenwe can help.

The second announcement and one which mayimpact the European Industry as a whole are thecomments of Sir Andrew Witty the CEO ofGlaxoSmithKline Pharmaceuticals. On the 7thFebruary, Sir Andrew quoted the following:

Europe has slipped in terms of its willingness to payfor innovation,” ........And so for GSK the answer toEurope’s unwillingness to pay for innovation is to “goand focus elsewhere,” Witty said. This will meannovel drugs are tailored to markets that are receptiveto innovation, with clinical trials moved out of Europe.Payers in Japan and the US, “are not pushovers” butthey are more pro-innovation. “We will still registerdrugs in Europe, but we won’t [shape] them forEurope,” Witty said. “At least for the next few years,Europe is stuck in a bad place."

Strong words indeed, which we were reinforced onthe 25th February when Sir Andrew with obviousfrustration accused the British Government ofdelaying the use of new medicines.

As an Industrial Pharmacist and now Academic,

I can understand why Sir Andrew is frustrated and infact is so alarmed with the current trend of approvaldelays and non reimbursement of new medicinesparticularly in the EU.

As a Professor of Pharmaceutical Innovation atKing's College London, I know only too well thedangers of not investing in Innovation or beingencouraged to Innovate. Having worked in theEmerging Markets and just returned from anextensive visit in the Middle East, the environment inthese countries positively encourages innovation andit is heartening to see how much a prominent rolethat Industrial Pharmacists play in these regions of theworld.

The industry has its detractors BUT a balance needsto be struck and even though I accept that the sectoris profitable, it is saving lives and helping people tolive longer – it is without a shadow of doubt that myfather is only alive and well due to intervention by thePharmaceutical Industry. The industry also invests inR&D within the EU and around the world andprovides a research base which underpins ourUniversities and Research Institutes.

Perhaps the Industry has been a victim of its ownsuccess, in that a recent UK Government survey haspredicted that 1 in 3 UK women will live to beyond a100 years, 1 in 4 UK men will live beyond 100 yearsand if MIT is to be believed that a baby has beenborn today, who will live to 150 years old!

Nevertheless, one of the founding principles of theEIPG is to promote the Industrial Pharmacist and theIndustry itself and as a consequence we shall takeevery opportunity to promote and to defend thisIndustry whenever the opportunity arises. The EIPGwill also help colleagues and advise students whowant to enter this sector of pharmacy and to providea network of mentors.

Best wishes Gino

european INDUSTRIAL PHARMACY March 2012 • Issue 124

What were the events thatled to the discovery ofsubstandard materials beingused to manufacture thebreast implants?During the last quarter of 2009, theFrench Competent Authority formedical devices, the Agence françaisede sécurité sanitaire des produits desanté (Afssaps) noted an increasingnumber of adverse event reports ofshell ruptures of silicone-filled breastimplants manufactured by the Frenchcompany, Poly Implant Prothese (PIP).

Following several unsuccessfulexchanges with PIP, in March 2010,Afssaps conducted an inspection ofthe company, which revealed thatfrom 2001 to the time of theinspection, most of the 400,000implants manufactured by PIPcontained a silicone gel differentfrom the one it declared in theimplant’s design dossier andmanufacturing files1.

Afssaps immediately suspendedthe marketing and use of PIPimplants, informed the EuropeanCommission of the events, andstrongly advised other EUCompetent Authorities to take allmeasures to verify that the implantswere no longer distributed, used orexported2. The agency then beganassessing whether or not there wereincreased risks of adverse eventsrelated to these implants. In March2010, PIP filed for bankruptcy.

In September 2010, Afssapsreported that the analysis confirmedthat the gel filling the testedimplants was not as described in thePIP design file. The tests revealedthat the gel was not of the level ofquality required for breast implants.The implants showed a higher thanaverage fragility in an elongationtest, and a significant heterogeneityof mechanical properties among theimplants was revealed.

A June 2011 report provides anoverview of Afssaps activities anddetails of the tests conducted, asummary of the vigilance dataanalysed, and follow-uprecommendations for women withPIP implants3.

Despite the release of an expertreport by French National CancerInstitute concluding there were nogrounds for emergency removalunless there was the presence ofclinical and/or radiological signssuggesting a change in the implant,the French Minister for Labor,Employment and Health,recommended explantation of thePIP silicone breast implants, evenwithout any clinical signs ofdeterioration.

How are medical devices,specifically, breast implantsregulated in Europe? Breast implants are regulated by theMedical Devices Directive

(93/42/EEC; MDD), covering thevast majority of medical devices,which became mandatory in June19984. Directives must betransposed into European nationallaws in order for their requirementsto be mandatory. Medical devicesthat comply with any nationaltransposition of the Directive can beaffixed with the CE mark and soldthroughout Europe.

The European regulatory systemfor medical devices is risk-based. Asthe risks related to the use of adevice increase, so does the level ofregulatory control. The MDDrequires that manufacturersdetermine the classification of theirdevices based on a set of rulesfound in Annex IX of the Directive.The four classes of devices underthe MDD correspond to increasinglevels of risk and therefore control:class I (lowest risk), class IIa (lowerintermediate risk), class IIb (higherintermediate risk), and class III(highest risk).

The conformity assessmentprocedures, which are necessary fordemonstrating compliance with theMDD, are carried out under the soleresponsibility of the manufacturerfor devices in class I. For devices inthe higher risk classifications, theintervention of a third partyconformity assessment body, calleda “Notified Body” is required.

These bodies are designated byMember State CompetentAuthorities to carry out conformityassessment procedures. It isimportant to note that the medicaldevice Competent Authorities havevery limited pre-marketresponsibilities, and are notresponsible for conducting CEmarking conformity assessmentprocedures. The Notified Bodyresponsible for conformityassessment activities for PIP wasTÜV Rheinland®.

From 1998 to 2003, most breastimplants were in class IIb; however,in September 2003, they werereclassified into class III. All existingdesigns of breast implant, includingthe PIP implants, had to bereassessed against the moreextensive requirements for class IIIdevices before they could continueto be marketed.

THE BREAST IMPLANTSCANDAL AND EUROPEANMEDICAL DEVICEREGULATION by Maria Donawa and Roger Gray

The recent silicone breast implant scandal in Europehas led to questions about whether or not European

medical device regulations are sufficient to protectpatients not only from unsafe breast implants, butunsafe medical devices in general.

Maria Donawa, MD is President and Roger Gray is VP Quality and Regulatory ofDonawa Lifescience Consulting, Rome, Italy. Website: www.donawa.com


The MDD offers several means ofdemonstrating that class III devicescomply with the Directive, whichrange from establishing qualitysystems to test programs. However,the vast majority of manufacturersselect the conformity assessmentprocedure requiring theimplementation of a full qualityassurance system for the design,manufacture and final inspection ofthe device. This route was alsochosen by PIP.

The full quality assurance systemroute to the CE mark for class IIIdevices also requires thedevelopment of a design dossiercontaining detailed information onthe device design, and this must besubmitted to the Notified Body forapproval and issuance of a designexamination certificate. The NotifiedBody must also conduct periodicsurveillance quality audits to ensurecontinuing compliance.

An important feature of theEuropean device regulatory systemis that the directives contain onlygeneral requirements, whereasdetailed technical specifications arecontained in European harmonisedstandards. For example, EN 13485 isthe harmonised standard formedical device quality managementsystems. In addition to generalstandards, those covering specifictypes of product have also beenmandated. For example, EN 14607specifies requirements for mammaryimplants.

In addition to harmonisedstandards, a series of Europeanguidance documents have beendeveloped to promote a commonapproach to compliance with theDirective. In the case of breastimplants, the European guidancedocument, Guidelines forConformity Assessment of BreastImplants According to Directive93/42/EEC Relating to MedicalDevices5, was issued in 1998. Thedocument provides importantguidance on pre-market activitiessuch as: the evaluation of hazardsapplicable to breast implants;review of clinical data by theNotified Body; requirements forpost-market surveillance; and the

need to provide information on therisks of surgery. Informative annexesinclude detailed guidance on pre-clinical tests that should beconducted, an example of a clinicalevaluation plan and criteria ofacceptability.

Once all applicable requirementsof the MDD have been met and theNotified Body has approved thedesign dossier and certified thecompany’s quality managementsystem, the manufacturer issues aDeclaration of Conformity, statingthe device regulatory requirementshave been met, and places thedevices affixed with the CE mark onthe European market. The MDDrequires that the manufacturerimplements a system of active post-market surveillance, which includesthe obligation to report seriousdevice adverse events to theCompetent Authority. Vigilanceprocedures and records areroutinely checked during NotifiedBody audits.

Did the European regulatorysystem function adequately?Afssaps recognised an increase inPIP silicone breast implant rupturerates in the last quarter of 2009,conducted an inspection of PIPfacilities in March 2010, discoveredthe use of substandard devicematerials, removed the devicesfrom the market and conductedanalytical testing to evaluate thehealth risks. In addition, from April2010 to January 2012, fourteenpublications were posted on theAfssaps website providinginformation on the events andadvice to women who had beenimplanted with PIP silicone breastimplants. On this evidence, it wouldappear that Afssaps met itsresponsibilities for post-marketsurveillance.

Although serious problems werenot found until 2010, the fraudulentactivity reportedly began in 2001,allowing hundreds of thousands ofsilicone breast implants of varyingquality to be implanted inunsuspecting patients. Why werethese problems not discovered bythe Notified Body? A TÜV

Rheinland® press release6 statesthat its auditors were shownconforming silicone samples andcorresponding documents duringPIP quality system audits. TheNotified Body stated that thesematerials must have been replacedwith the substandard materials oncethe auditors left the premises.

In any case, to better assess whythe use of unapproved materialsduring production of the PIPsilicone breast implants was notidentified during Notified Bodyaudits, it would be necessary toexamine the Notified Body auditreports and relevant PIP design andmanufacturing documentation,discuss how the Notified Bodyaudits were performed, be informedof whether or not Afssapspreannounced its inspection, andconsider any differences betweenhow the Notified Body audits andAfssaps inspection were conducted.

It was widely reported in themedia that PIP personnel hiddocumentation on the actualmaterials used. Wouldunannounced audits haveuncovered the deception? Perhaps– however, it is interesting to notethat the US FDA conductedunannounced domestic deviceinspections for many years beforechanging to the current policy ofpre-announced device inspections.Unannounced Notified Body auditsmay be introduced as a result of thePIP event, but the benefits of doingso must be seen to outweigh thedisadvantages. It may prove muchmore useful to examine audit timeconstraints and the manner anddepth to which audits areconducted.

What enforcement powers doregulators have regardingmedical device compliancewith the MDD?The MDD contains four articles thatMember States must transpose intonational law that concern MemberState enforcement powers. Readersshould refer to the MDD for thecomplete provisions of thesearticles and to the national laws andregulations of each Member State

THE BREAST IMPLANT SCANDAL AND EUROPEAN MEDICAL DEVICE REGULATION continued


to understand how they havetransposed them.

What changes are beingdiscussed regarding theEuropean regulation ofmedical devices?In 2008, the European Commissionbegan considering a revision of thelegal framework for the regulationof medical devices. Backgroundinformation and the results of apublic consultation can be found onthe European Commission website,as well as a ‘Roadmap’7on thechanges being contemplated.According to the Roadmap,proposals will be made for amedical device regulation instead ofa directive. The change fromdirective to regulation is importantbecause a regulation does not needto be transposed into national laws;regulations become law Europe-wide upon implementation. The useof directives has previously led tocertain variations in implementationof some provisions among MemberStates, which the Commission iskeen to limit in the future.

The Roadmap provides generalinformation regarding the possiblechanges; however, draft proposedtexts of the regulatory revision havebeen leaked, revealing the currentthinking on features that theEuropean regulatory system formedical devices should possess. Forexample, it is possible that NotifiedBodies will be required to payunannounced visits tomanufacturers and that morestringent conformity assessmentprocedures for high risk medicaldevices will be required. Thecurrently expected date ofpublication of the proposedregulation is June 2012, but it wouldnot be surprising if this date slippedbecause of the PIP furor.

Need for careful analysis andeffective decisionsThe medical devices Directives wereadopted to ensure that medicaldevices provide patients, users andthird parties with a high level ofprotection and attain theperformance levels attributed to

them by the manufacturer. Such aregulatory system needs to beefficient as well as effective. It alsoneeds to ensure that medicaldevices are available so we canbenefit from the technologicalinnovation that is the hallmark ofthe medical device industry.

A regulatory system to cover allmedical devices, which range fromthe simple to the most complextechnologies imaginable, is noteasy to create or maintain and forthis reason, it should be periodicallyanalysed and modified to makeneeded improvements. This is whatis occurring in the midst of theevents surrounding the PIP scandal.Of course all reasonable measuresshould be taken to prevent suchevents from occurring in future, butat the same time, any changesshould not jeopardise theavailability of the medical devicesthat we need.

What immediate actions are beingtaken? A European Commission pressrelease8 lists the immediate actionsbeing requested of Member States:

• Verify the designations ofnotified bodies to ensure thatthey are designated only forthe assessment of medicaldevices and technologies thatcorrespond to their provenexpertise and competence.

• Ensure that all notified bodiesin the context of the conformityassessment make full use oftheir powers given to themunder the current legislation,including the powers toconduct unannouncedinspections.

• Reinforce market surveillanceby national authorities, inparticular spot checks inrespect of certain types ofdevices.

• Improve the functioning of thevigilance system for medicaldevices.

• Support the development oftools ensuring the traceabilityof medical devices as well astheir long-term monitoring interms of safety andperformance.

Furthermore, it was announced thatthe European Commission isconducting a 'stress test' intendedto identify any shortcomings thathave come to light as a result of thePIP case. Thus far, it appears thatcareful analysis is underway, whichwill hopefully allow effectivedecisions to be made withoutjeopardising future innovation.

References1 Afssaps information sheet, Silicone gel

breast implants from Poly ImplantProthèse Company – Information (15 July2010);www.afssaps.fr/var/afssaps_site/storage/original/application/63285b895bc9b60c15a7743e08432dc1.pdf

2 Afssaps website, Information for womenwith PIP breast implants-Questions/answers (26/7/2010);www.afssaps.fr/Afssaps-media/Publications/Information-in-English

3 Afssaps report, Topical report on PIPsilicone gel-prefilled implants (29 June2011);http://www.afssaps.fr/var/afssaps_site/storage/original/application/39acdab927235584ccfa340e4a9d3896.pdf

4 Council Directive 93/42/EEC of 14 June1993 concerning medical devices (OJ L169, 12.7.1993, p. 1) http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1993L0042:20071011:EN:PDF

5 Guidelines for Conformity Assessment ofBreast Implants According to Directive93/42/EEC Relating to Medical Devices,MEDDEV 2.5-7 rev 1 (July 1998)

6 TÜV Rheinland® press release, Concerninglatest media articles concerning Silicone-filled breast implants (29 December 2011)www.tuv.com/en/corporate/about_us_1/press/news_2/news_5.jsp

7 Regulatory Framework Revision Roadmaphttp://ec.europa.eu/governance/impact/planned_ia/docs/2008_sanco_081_proposal_medical_devices_en.pdf

8 European Commission Press Release,Medical devices: European Commissioncalls for immediate actions - tightencontrols, increase surveillance, restoreconfidence (9 February 2012);http://europa.eu/rapid/pressReleasesAction.do?reference=IP/12/119&format=HTML&aged=0&language=EN&guiLanguage=en.

THE BREAST IMPLANT SCANDAL AND EUROPEAN MEDICAL DEVICE REGULATION continued


Though pharmacy students areoften not exposed to clinical trialresearch during school, they maydevelop an interest duringpostgraduate study or get exposurewhile working in a hospital or clinic.Pharmacists are becomingincreasingly engaged in moreopportunities involving thedevelopment of new drug products.Pharmacists can be a valuableresource in clinical trials as they helpcoordinate the research anddevelopment process and overseethe clinical supply chain.

Study designPharmacists can assist sponsors andCROs during the study design phaseby helping to ensure proper drugpreparation, comparator drugsourcing, labeling and blinding oftreatments to prevent bias. They arein a position to offer insight intostudy drug assignment andmanagement, drug accountabilityand reconciliation, and datacollection. Pharmacists are ofteninvolved in investigator meetings andon-site training sessions. Throughoutstartup and maintenance of the trial,pharmacists provide ongoingsupport to site personnel.

Pharmacists on the clinical suppliesteam communicate with InteractiveResponse Technology (IRT) teams,

globally-situated depots, and othergroups involved in study startup toensure that the drug will be availablewhen the first site is ready. Once thestudy begins, the pharmacistoversees the drug inventorythroughout the world. They offerinvaluable input into the design ofresupply timelines and manage theinventory in a cost-efficient mannerwithout excess overages ordisruption of supply to sites.

Patient focusesThe input of the pharmacist into thedesign of the study drug iscomprehensive and patient-focused.Pharmacists understand how thedrug needs to be prepared anddispensed at the study sites. Theirknowledge and interaction with theclinical community results inpackaging that works effectively in aclinical setting. When designing thelabels to be used in a study, theyconsider what will offer ease ofdispensing at the site and ease ofuse by the study participants.

The review of the protocol by thepharmacists assures that it containsreasonable instructions for thepreparation of the study drug atsites, and their added input resultsin a comprehensive clinical materialssection in the protocol.

Additionally, the pharmacist may

write the dosing instructions andcreate pharmacy calculationworksheets to be a part of study-specific pharmacy manuals or pocketcards to benefit the site pharmacists,nurses or physicians. The completedcalculation worksheets and drugaccountability logs can be returnedto the unblinded study pharmacist toreview for accuracy. A pharmacist inthe clinical supplies group may serveas an unblinded source ofinformation on drug preparation,dosing questions and compatibilityissues to the site pharmacist.

A case historyThe importance of the involvementof pharmacists to the completion ofa study trial is illustrated in thefollowing example of a complexglobal trial involving two studyprograms which were divided intofour Phase III, randomised trials. Theprograms involved differenttherapeutic indications for the samestudy drug which allowed the teamto pool the drug across the fourstudies for a streamlined supplychain. The four trials included 39countries, approximately 3,000patients, different sponsor teams foreach study, multiple CROs, ninedepots, two IRT teams, and theclinical supplies team.

The responsibilities of the studypharmacist included:

• Clinical supplies management

• Site pharmacist training

• Development of drug relatedtraining material for sites andCROs

• Oversight of labeling,packaging, and distribution ofdrug supply

• Depot management

• Sourcing of comparators andconcomitant medicationsworldwide

• Arranging and organisingQualified Person (QP) releaseinto the European Union (EU)

• Retest/expiry datemanagement.

Sourcing the comparatorOne challenge of this clinical trialwas the difficulty in sourcing of thecomparator drug due to drug

THE ROLE OF PHARMACISTSIN THE CLINICAL SUPPLYCHAIN FOR DRUGDEVELOPMENTA case history

by Wyndi Phillips

Acareer in clinical research is a somewhat uncommonpath for a pharmacist, but it is becoming more

widespread in the pharmaceutical industry, ContractResearch Organisations (CROs), speciality clinicalsupplies companies and in consulting groups.

Wyndi Phillips, PharmD is Project Group Manager at Almac Clinical Services, Durham,NC, USA. Website: www.almacgroup.com


THE ROLE OF PHARMACISTS IN THE CLINICAL SUPPLY CHAIN FOR DRUG DEVELOPMENT continued

shortages at the time of the study.Labeling the comparator drugposed problems resulting from thedifferences in labeling requirementsof the countries participating in thestudy. The comparator was able tobe sourced locally in only 15 of the39 countries. The remainingcountries were supplied with drugsourced either in the United Statesor the United Kingdom. Issues withQP release added to thecomplexities encountered in thesourcing of the comparator drug.

Inventory managementAnother supply challenge was theinventory management for thestudies. Label groupingdetermination was hindered by anever-changing list of participatingcountries, a wide time interval overwhich startup times occurred, and abalance of study drug located in anumber of different depots.

The calculation of the bulk supplyof drugs actually required by eachstudy site was difficult to ascertainwith the use of weight-based dosingregimens and varying lengths oftreatment based on laboratoryvalues.

There were numerous expiry andretest dates to manage as multiplelots of study drug and comparatorswere involved. The team pharmacistmonitored all expiry and retestdates and managed the retest dateextensions throughout all of thecountries involved in the trial.

The IRT system was set up to orderstudy drug, not the comparator drug,as that need had not been identifiedat the time that the IRT specificationswere finalised. The sites reorderedcomparator drugs by fax, based onapproval from the sponsor. Theclinical supplies team monitored theglobal inventory levels.

BlindingThe study drug was provided as abulk, open-label supply. It was theresponsibility of the site pharmacistto blind the study drug againststandard therapy. The dosing ofboth the study drug and thecomparator was based on patientweight and required continualadjustments dependent uponlaboratory values which wereprovided only to the pharmacists.The laboratory results directed thelength of treatment infusions andthe selection of the comparatordrug.

The volume required for theintravenous medication, timing ofmedication administration, and thedosing interval introduced issueswith blinding, which were addressedby the site pharmacists incollaboration with the unblindedclinical supplies team pharmacist.

The site pharmacist wasresponsible for maintaining theblind with all of these issues, for theduration of the therapy, which variedfrom 2-3 weeks for each patient.Patients were allowed to completethe therapy at home with drugsupplied by a home health agency.The local home health agency wasresponsible for maintaining theblind and following the sameprocedures required of the sitepharmacists.

CommunicationsThe clinical supplies teampharmacist trained the investigatorsand site pharmacists usinginteractive teleconferences,supplemented with printedmaterials, and acted as anunblinded source of informationregarding questions on maintainingthe blind. Additionally, thepharmacist provided the sites with

detailed written information ondosing, drug preparationinstructions, and guidelines fordosing adjustments and the timingof blood draws for laboratory resultsand was available to the site on a24-hour basis to answer any drug-related questions.

Benefits of including apharmacist on thesupply teamThis example demonstrates how theuse of an unblinded pharmacist onthe clinical supplies team was ableto assist sites in managing thechallenges of individualised patienttherapy while maintaining the blind.The benefit of including thepharmacist on the clinical supplyteam was to provide anunderstanding of how and why thestudy drug and comparator needswould vary throughout the world sothat the team was in a position tobetter manage the inventory.

The responsibilities of clinicalsupply team pharmacists extendfrom the beginning of a trial,throughout start up andmaintenance, to a successfullycompleted study.

The unique perspective of apharmacist provides insight andsolutions to drug related concernsraised by the study team or clinicalsites during planning stages of thetrial. Their knowledge and skills areuseful in working with increasinglycomplex trial designs and with drugformulations that require specialstorage conditions or preparation.

A pharmacist’s expertise on theclinical supplies team helpssupport a strong relationship withthe clinical team and can be avaluable component of a successfuldrug trial.

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For example, IBM in 2005 producedsome reviews that showed howinefficient the pharmaceuticalindustry was compared to otherindustries1. Price WaterhouseCooper (PWC) started to publishtheir 2020 series2, which showed thisindustry had to start to change. TheUS Regulator, the Food and DrugIndustry (FDA) publicly said that theindustry continued to have a rathertraditional approach, despite whenfines were applied to companies.

The International Conference onHarmonisation (ICH), which includesregulators and industries from US,EU and Japan and observers fromWHO and other countries, set out in2003 to produce some new sets ofdocuments that would lay out ascience and risk-based approach topharmaceutical development andmanufacture. The need for changewas evident.

The term Quality by Design, nowcommonly referred to by itsacronym, QbD, was first defined inthe ICH document Q8 (R2) –Pharmaceutical Development as3:

“A systematic approach todevelopment that begins withpredefined objectives andemphasizes product and processunderstanding and process control,based on sound science and qualityrisk management.”

Equally important are the ICH Q9,Quality Risk Management4 and ICH

Q10, Pharmaceutical QualitySystem5 documents that set out theprinciples and tools of QbD.

New distance learningcourseDe Montfort University’s (DMU)School of Pharmacy is supportingthe industry’s new approach toquality with a new Distance Learningtraining course. The course is aunique collaboration betweenindustry-leading experts, companiesand academia and it comprises ofover 40 recorded lectures by 29industry experts from 15 companies.

These companies include: Pfizer,AstraZeneca, GlaxoSmithKline,Bristol-Myers Squibb, FMC,Lyosolutions Ltd, GEA PharmaSystems, CAMO software AS, JMPDivision of SAS, PerceptiveEngineering, PMcG Consulting,Lundsberg Consulting, AffinisLbD,Bruce Davis-Global Consulting andMedicines Healthcare productsRegulatory Agency (MHRA).

The course was validated inDecember 2010 with multiple startdates each year, in October, Januaryand May.

Why Quality by Designmatters? The Pharmaceutical industry isgoing through a period of majorchanges catalysed by:

• Growing demand for efficiency

• Pressure on drug prices(increase of Generic drugs)

• Market access • Rising regulatory requirements • Increasing risk in R&DQbD has the potential to make a

positive contribution to drugdevelopment and manufacturing inthe light of these changes.

Why is this course important? This course provides:

• A firm academic foundation toimplementing QbD

• Expert lecturers from industrywho have real experience ofQbD

• Build a common language foracademia, industry, regulatorsand suppliers.

This highly flexible course isdelivered online and can be studiedin its entirety or as separatemodules. All lecturers are based inindustry and have hands-on QbDexperience. Each module has a DeMontfort University accreditedacademic staff member leading itsdelivery. The module’s assessmentsare conducted with rigour. Marksare internally moderated beforebeing confirmed by an accreditedexternal examiner and the relevantPostgraduate examination board.

The course is applicable to thosein large and small pharmaceuticalcompanies, contract manufacturers,generics and consumer health,based in either R&D ormanufacturing, including supportfunctions such as regulatory,engineering and specialisttechnologies. It provides informationon guidance notes from theInternational Conference onHarmonisation ICH Q8, Q9, Q10 andQ11. It covers the understanding of:

• Quality Target Product Profile(QTPP),

• Critical Quality Attributes (CQA),• Critical Process Parameters

(CPP),• Design Space, • Control Strategy and• Continuous Improvement over

the product lifecycle from R&Dto manufacturing to productdiscontinuation.

PHARMACEUTICAL QUALITYBY DESIGN:Accredited distance learning postgraduatecourse

by Walkiria Schlindwein

The pressures that caused the term Quality by Designto emerge and its principles established cannot be

pinpointed to any one incident, but to a series of eventsthat influenced the changes that industry is facing inrecent years.

Walkiria Schlindwein, PhD is Programme Leader for the Leicester School ofPharmacy’s Postgraduate Course in Pharmaceutical quality by Design and PrincipalLecturer in Pharmaceutical Technologies at De Montfort University, UK.Email: [email protected]. Website: www.dmu.ac.uk/qbd


It includes subjects such as:

• Multivariate data analysis,

• Quality risk management (QRM),

• Experimental design,

• Process analytical technology(PAT),

• Real time release testing (RTRT),

• Analytical methods verification,

• Regulatory aspects from theMedicines and Healthcareproducts Regulatory Agency(MHRA).

Course structureThere are a total of 4 modules thatadd to a total of 60 credits (Figure1). One of the modules (optional)can be selected from a range ofoptions in different specialised areas.Most modules are 10 credits, each ofwhich contains 100 student learninghours. There is one module that is 30credits, the work-based project. It isrecommended that the selection ofthe elective module be dictated bythe student’s choice of project area,where possible. The decision can bemade in consultation with individualacademic tutors (including anydirection that might be provided byindustrial line managers).

Modules are combined to form acoherent pathway of study. Thesuccessful completion of 60 creditsleads to the conferment of thePostgraduate Certificate in

Pharmaceutical Quality by Designaward.

Module structureEach module is designed to bestudied over 7-9 weeks, except forthe project which will be around 15weeks. At the start of each modulethe students will be enrolled intoour website (www.dmu.ac.uk/qbd )and BlackBoard© from where theyhave access to the videos andPowerPoint presentations for eachlecture of the module. Figure 2illustrates how the learning materialis delivered. The video issynchronised with the PowerPoint

presentation. The PP presentationsare provided as PDF files for thestudents to keep. These arecompleted away from the University,giving the student the flexibility toarrange their studies to suit. Theassessment components are doneelectronically.

Module 1 – PharmaceuticalQuality by Design: principles,tools and approachesThis module was designed toprovide the fundamental conceptsand tools applied to pharmaceuticalproduct design, process design,process monitoring and continuous

PHARMACEUTICAL QUALITY BY DESIGN continued

Figure 2. Screen capture showing how the learning material is presented, video in synchronism with the PowerPointpresentation (first MHRA lecture by Mustafa Zaman and Gustavo Marco).

Figure 1. Course structure showing the modules available.


verification based on up-to-dateQuality by Design principles.

Module 2 – Product &process designThe aim of this module is tounderstand the iterative nature offormulation and process design andthe link to patient requirements fordeveloping medicines based onquality by Design principles.

Module 3 – OptionsAll optional modules have beendesigned to be in two parts. The firstpart is common to all of them andconsists of 5 lectures that address:

• 3 – Manufacturing & AdvancedProcess Controls.

The second part contains lecturesspecific to a subject are (the studentselect one of the three options):

• 3a – Inhalation/Sterile Products

• 3b – Continuous Processing

• 3c – Analytical MethodDevelopment

Module 4 – Work-based project This module provide each work-based student with an opportunityto consolidate their knowledge ofQuality by Design applied topharmaceutical science by carryingout a research or developmentproject in an area directly related totheir work context.

New initiatives1 Regulatory aspects of QbDDe Montfort University is delighted towelcome a distinctive series ofrecorded lectures from the UKRegulatory body, the Medicines &Healthcare products RegulatoryAgency, MHRA. The first in the series,for the January 2012 intake, is entitled“The Regulatory Aspects of QbD:Introduction to Regulatory Affairs”,prepared by Mustafa A. Zaman andGustavo Marco. The forthcominglectures from the MHRA, planned forMay 2012, will cover the practicalaspects of a QbD submissionpresented from both an assessor andan inspector's point of view.

Diploma and MSc distancelearning optionsDe Montfort University QbD teamis working on the expansion of thePostgraduate Certificatequalification (60 credits) to give thestudents options for progressioninto a distance learning Diploma(120 credits) and MSc (180 credits)programmes. The validationprocess should be complete by thesummer 2012 ready for the October2012 intake.

Entry requirementsThe course is open to graduates andpostgraduates and to individualswith relevant pharmaceutical or

industry experience. Students shouldideally be employed within thepharmaceutical or health sectors. Ifyour first language is not English werequire a minimum IELTS score of 6.5or TOEFL 250 (computer score) 600(written paper). We have multiplestart dates: October, January andMay per year.

AcknowledgementsWe would like to thank allcontributors from industry involvedwith the development and deliveryof the course and all De MontfortUniversity academic staff from thePharmaceutical Technologies Groupinvolved with the course.

References1 IBM – The Metamorphosis of

Manufacturing – from Art to Sciencewww-935.ibm.com/services/us/imc/pdf/ge510-4034-metamorphosis-of-manufacturing.pdf

2 Pharma 2020: The vision, PriceWaterhouse Cooper,www.pwc.com/gx/en/pharma-life-sciences/pharma-2020/pharma-2020-vision-path.jhtml

3 ICH Q8 Pharmaceutical Development,www.ich.org/products/guidelines/quality/article/quality-guidelines.html

4 ICH Q9 Quality Risk Management,www.ich.org/products/guidelines/quality/article/quality-guidelines.html

5 ICH Q10 Pharmaceutical Quality Systemwww.ich.org/products/guidelines/quality/article/quality-guidelines.html

PHARMACEUTICAL QUALITY BY DESIGN continued

AAPS Graduate Student Symposium Awardin Manufacturing Science and Engineering

Sponsored by Bristol-Myers Squibb Co. (Deadline: May 9)

This program is designed to recognise excellence in graduate education in the fields of manufacturingscience and engineering. There are no citizenship requirements for this award. All interested candidates

are encouraged to apply. Your research may be submitted to only one AAPS graduate symposiumcommittee for consideration or your submission will be disqualified from all symposia. Students must be intheir final year of graduate studies leading to the doctorate degree (or will be awarded their doctorate in2012). On the basis of submitted abstracts and summaries, two students will be selected to present theirresearch in the Graduate Symposium at the 2012 AAPS Annual Meeting and Exposition. Selection will be

made on the basis of those students judged by the committee to have provided the most outstandingcontributions in the above fields through their graduate research. Each student selected will receive a

complimentary registration to the 2012 AAPS Annual Meeting and Exposition, a cash award of $250, anda commemorative plaque. In addition, travel expenses will be reimbursed (up to $1,000 domestic/$1,500

international) following the meeting.

http://www.aaps.org/uploadedFiles/Content/About_AAPS/12 AM GRAD MSE.DOC




The healthcare sector has beentargeted as a major growth centrefor the Japanese economy andincreasingly Japanese companiesare becoming global players, eitherthrough partnership arrangementsor by establishing themselves in theUS and European markets.

Japan is a major player in both theInternational Conference forHarmonisation (ICH) being one ofthe 3 regions which established theICH in 1991. As a result there hasbeen a harmonisation of theregulatory requirements in thepharmaceutical sector betweenJapan and the USA and Europe.The extent of the changes within theJapanese regulatory system hasbeen considerable over the past fewyears. In April 2004, the PMDA (thePharmaceutical and Medical DeviceAgency) was established, which hasbrought about a major change inthe approach to healthcare productregulation in Japan.

RECENT CHANGES AND THEESTABLISHMENT OF THE PMDAPrior to April 2004, Japan had asomewhat different system for theevaluation and approval ofhealthcare products than was foundin other countries.

A review of the increasingly

complex Japanese regulations forthe evaluation and approval ofhealthcare products led to theestablishment of a unified singleagency. The Pharmaceuticals andMedical Devices Agency (PMDA)was established on 1st April 2004 asan incorporated administrativeagency with non civil servant status.This agency has many similarities tothose found in Europe and otherparts of the world.

The new agency is responsible forproviding advice and conductingreviews of quality, efficacy, and thesafety of pharmaceuticals andmedical devices. It now hasresponsibility for assessing clinicaltrial applications, for discussing thedevelopment of the product andevaluating the dossier as part of theapproval review. It also has theresponsibility for collecting,analysing and providing informationon post marketing safety measures.

In 2006, the Japanese governmentintroduced a reform programmeacross the industrial sectors called“Innovation 25”. This identified thepharmaceutical and medical deviceindustries as key sectors forinnovation in the Japaneseeconomy. The report highlightedthe importance of the regulatoryprocess and noted that there was a

significant “drug lag” in Japancompared to other countries. Part ofthis related to the shortage ofresource within the regulatoryprocess, whilst part was attributed tothe relatively late conduct of phaseII and phase III trials in Japan by thepharmaceutical industry. Thegovernment and the agency put inplace an impressive programme ofchange which has paid off. Newtargets on performance have beenagreed and there has been asignificant expansion in the numberof agency staff, particularlyreviewers. The PMDA is currentlyfunding much more efficiently. Theagency has also explored a numberof links with other South East Asiancountries with a view to establishingpossible exchange of assessmentsreports. In addition the agency hasencouraged companies toincorporate Japanese subjects(where appropriate) in multi-nationalphase III clinical trials. This policy isallowing companies to includeJapan in ‘first wave’ global dossiersubmissions

THE DOSSIER REQUIREMENTSAs a founder member of both ICHand GHTF, Japan now has the sameinternational requirements for thedossier as in the USA and EuropeanUnion. For pharmaceutical products,Japan has adopted the commontechnical document (the CTD).

The Japanese Agency obtains asubstantial part of its income fromfees just as do other agencies.These fees have to be paid with theapplication. Details can be obtaineddirectly from the PMDA.(www.pmda.go.jp). The Englishlanguage section of this website hasbeen expanded and muchinformation is available in English.

THE REVIEW PROCESSWith the creation of the new agency,all the functions of the reviewprocess are located within thePMDA. Single teams are nowallocated to handle the entireprocess of an application from theclinical trial stage through toapproval. The agency has beenrecruiting and training significantnumbers of additional staff. Theinternal reviewers undertake the

EVOLUTION OF THEJAPANESE REGULATORYSYSTEMPRODUCTION

With its population of around 127 million people,Japan is the second largest market by sales value

for both pharmaceutical products and medical devices.The sales volume in Japan is approximately 15% of theglobal total, compared to 50% in the USA and 27% inthe European Economic Area. Japan is therefore a verysignificant market for healthcare products. It is also aleading player in the development and production ofboth medicines and devices.

Dr David Jeffreys, Senior Vice President, Global Regulatory, Government RelationsAnd Public Affairs Department, Eisai Europe Ltd, European Knowledge Centre,Mosquito Way, Hatfield, Herts AL10 9SN


evaluation of the dossier but haveaccess to, and are supported by,external independent experts andby advisory committees.

The PMDA review all types ofpharmaceuticals, including OTCdrugs. The PMDA also hasresponsibility for the evaluation ofall medical devices. This is thereforeanalogous to the system adoptedwithin the centre for devices andradiological health (CDRH) of theFDA and also the system found inCanada and Australia. This differsfrom the European system in thatthe evaluation is undertaken withinthe agency, whereas in Europe, theevaluation is undertaken by aNotified Body designated by theNational Competent Authority.

The review and the evaluation ofhealth care products are undertakenunder the provision of thepharmaceutical affairs law of Japan.It also takes into account therelevant international guidelines ofICH and international standards.

OFFICESThere are currently three offices ofnew drug evaluation, separate officeof biologics, an office for theevaluation of urgency and genericdrugs, an office for the evaluation ofmedical devices, and an office ofconformity audit. These reportthrough to the director for thecentre for product evaluation.Separately there are offices of safetyand of compliance of standardreporting to the Chief Safety Officer.Within the centre for productevaluation there is also a priorityreview director to handleaccelerated or expedited reviews.

A brief review of the key featuresof the current regulations and theassessment procedures is set outbelow. In an article such as this it isdifficult to cover all the details. RAPS(Regulatory Affairs ProfessionalSociety) has set up an organisationin Japan covering medicines anddevices. As a result of this it hasproduced a comprehensive guide toregulations in Japan calledJapanese Fundamentals. This canbe viewed on the RAPS website(www.raps.org).

CLINICAL TRIALAPPLICATIONSIn Japan a clinical trial application isrequired for all phases ofdevelopment including phase onetrials. On request, the PMDA willprovide face-to-face consultationand will give guidance and adviceon the clinical trial for both newpharmaceuticals and medicaldevices. It will give advice for thedevelopment of new formulationsand new indications. The advice hasnow been extended to cover OTCdrugs and generics.

CLINICAL TRIALNOTIFICATIONSClinical trial notifications (CTN) arerequired for all stages of clinicaldevelopment. No formal approval isgiven; rather a study can begin 31days after submission unless theapplicant receives questions or arefusal from the Agency. A trial drugor medical device can be importedinto Japan once the CTN has beensubmitted and can then besupplied to the investigator hospitalon day 31. Ethical committeeapproval has to be obtainedseparately and the Agency has tobe informed of both the approvaland the comments from the ethicalcommittee.

THE EVALUATION PROCESSUnder the new system, the dossieris submitted to the agency.Following submission, a reviewteam will be constituted. Thedossier will first be reviewed by theoffice of conformity audit whichchecks that all the documents anddata included in the applicationcomplies with the provisions of GLP,GCP and also GPMSP (Good PostMarketing Surveillance Practice).Following this compliance review,the dossier will be evaluated by ateam of reviewers to assess thesafety and quality of theapplication. During the reviewprocess, the team will seek opinionsfrom external experts. A separateoffice will consider biotechnologyapplications. The agency has nowset target review times for theassessment process and compliance

with these targets are published bythe Agency.

Once the review has beencompleted and a report generated,this is then shared at a meetingbetween the reviewers and externalexperts the main issues and thepreliminary conclusion of theassessment are discussed. Asummary of the main issues is thenpresented to the review meeting.This is attended by the applicantcompany who may be supported byspecialists and by the reviewers andexternal experts.

Following the initial review, theinternal team will consideradditional information andclarification submitted by theapplicant.

A second expert discussion willthen take place between thereviewers and the external expertsand a revised or updated report willbe generated along with thesummary of all the discussions. Thiswill be provided together with a setof recommendations to the MHLW(the Ministry of Health Labour andWelfare), which will then considerwhether the application should beapproved.

For complex and difficultapplications advice may be soughtfrom the Pharmaceutical Affairs andFood Sanitation Council. This is aformal body established under theJapanese Pharmaceutical AffairsLaw.

GMP AUDIT SERVICE ANDQUALITY MANAGEMENTREVIEWPMDA is now responsible forundertaking good manufacturingpractice audits. The agencyconducts these as both on site anddocument reviews. The agency willreview on a regular basismanufacturing facilities within Japanand will conduct audits on thosedomestic sites that requiremanufacturing licences. The agencywill also undertake accreditation ofoverseas manufacturing sites wherethis is appropriate and not coveredby reciprocal accreditationagreements.

The agency will undertake a

EVOLUTION OF THE JAPANESE REGULATORY SYSTEM continued


specific, product focused audit onthe manufacturing facility for newpharmaceuticals, new medicaldevices and vaccines and any facilitymanufacturing high risk medicaldevices. The agency undertakes asimilar product specific audit to thatundertaken by the EMEA forcentralised applications.

EVALUATION OF QUASI-DRUGS The Japanese pharmaceutical affairslaw has a definition of apharmaceutical product which isvery similar to those in thelegislation of the USA and theEuropean Union. There is inaddition a class of agents known as“quasi-drugs” which are evaluatedby the PMDA in Japan. Theseagents provided that they did notmake a medical claim, would beregarded as cosmetics in bothEurope and the United States. Theyrange from deodorants,depilatories, medicated soap,dentifrices and insect repellents.

In Japan the quasi-drugs have tobe approved by the PMDA beforethey are marketed, a dossier has tobe submitted and address therelevant efficacy safety and quality.Clearly there is aboundary betweenthese products and overthe counter medicines.This is a uniquecategory of products tothe Japanese marketand it is important foran applicant to checkwhether they would be classifiedunder this group in Japan, whereasthey would be available as generalconsumer products in other markets.

GENERIC DRUGSGeneric drugs take a much

smaller proportion of the market inJapan than in the USA and Europe.Generic substitution is slowly beingintroduced into Japan with plans fora significant increase. In mostmarkets the introduction of genericsis dependent on the exclusivityperiod provided to the innovativedrug and its period of patentprotection. In Japan there is nospecific period of exclusivity. There

is however a first renewal (or re-evaluation) of the authorisation. Thisnormally takes place after six years.

A generic application cannot beconsidered until this first evaluationhas taken place. On occasions asecond re-evaluation may berequired. If so the generic will notbe considered until after the secondevaluation. On occasions this can bean important provision becausewhilst some applications areapproved in Japan, significantlyahead of those in other countries, itis the case that many applicationswill be submitted to Japan laterthen any other markets because ofthe requirements for additionalphase three studies to beperformed on Japanese subjects.

CLINICAL DATAREQUIREMENTS FOR JAPANESEREGISTRATIONWhen considering developing adrug for use in Japan a series ofissues need to be considered. Theseinclude possible pharmacogeneticdifferences due to polymorphisms,different pharmaco-dynamicresponses and differences inreceptive sensitivity.

The effect of diet and food needto be considered along with dosetolerance.

There are well documenteddifferences in the reporting and inthe tolerance of adverse eventreactions between western andJapanese populations, which needto be carefully considered.

There may also be significantdifferences in comparator therapiesand interventions which need to bedetermined in advance ofconstructing a clinical protocol.

Differences in the prevalence andnature of a disease being studiedand the relevance of historicalcomparisons need to be explored.

Careful consideration should begiven to the ICH E5 Guideline(Ethnic factors in acceptability offoreign clinical data).

For a successful drugdevelopment programme, it isnecessary to have data in Japanesepatients. Japan usually requires a fullor appropriate phase 1development programme onJapanese subjects. If a phase I and aphase IIa study in the programmehave been undertaken in Japanesesubjects, then it is possible toproceed directly to a Japanesephase III study, although this may beinfluenced by the stage and extentof development outside Japan. If aphase IIb study has been performedin Japanese patients then it will bepossible to discuss with the Agencywhether phase III data generated inan EU/US programme can beaugmented by a bridging study.

Data obtained in non residentJapanese subjects can beconsidered by the Agency butpatients who have lived outsideJapan for more than 4 years wouldnot usually be accepted as part ofthe Japanese data. Such patientsmust be first generation Japanese

subjects. Exceptions to the more

rigorous phase IIIdevelopment can occurwith the use of anadequate bridging studyand phase IIb data, or foroncology products whereconditional approvals may

be granted by the Agency or if thereare adequately powered Japanesecentres as part of a multi-nationalmulti-centred developmentprogramme.

The health ministry in Japan andthe Agency are seeking toencourage companies to includeJapanese subjects whereappropriate in major phase IIIinternational trials. Clearly this maynot be possible for several classes ofdrugs because of differentpharmacogenetic,pharmacodynamic and dosingissues, but for several types of drugit is possible to include Japan in theglobal development programme.


❝ ...it is important to discuss with theJapanese Authorities any particular issues.Under the new system such consultation is

both possible and welcomed. ❞


The Agency is particularly willing todiscuss such programmes. This is animportant development whichneeds to be closely watched as partof a global drug approval strategy.

Increasingly companies wish topursue a single global developmentprogramme and to makesimultaneous global filings. Tofacilitate this, it is recommended,that where marketing conditions areappropriate, the phase I programmefor Japan is commenced at thesame time as, or shortly after, thephase I development programmefor the USA and Europe. This thenallows an early discussion withPMDA and the option of including asignificant number of Japanesesubjects in a worldwidedevelopment programme.

POST MARKETING SAFETYJapan has adopted the postmarketing safety requirement of ICHand GHTF. This has made matters

very much easier for companies asthey now have a single set of globalrequirements. The Agency hasdeveloped a system fordisseminating safety information tohealth care professionals withinJapan. There is an interesting andunique system for the surveillance ofnew medicines.

In October 2001, the EPPV (earlypost-marketing phase vigilances)programme was introduced inJapan. This programme has manysimilarities to the black trianglescheme operated by the Committeeon the Safety of Medicines in theUnited Kingdom. The EPPV requiresthat medical institutionsexpeditiously report on theoccurrence of serious ADRs for newproducts during the first six monthsafter their launch. Within two monthsof the end of the vigilance period afull report on the adverse eventexperience has to be submitted tothe Agency for consideration.

CONCLUDING REMARKSThe pharmaceutical regulatorysystem in Japan has undergoneextensive change in the last fewyears as a result of the ICH initiative.At the same time, Japan hasreorganised its control system so itis now very similar to those found inother major markets. This process ofharmonisation has been a greatachievement. It has accelerating thedevelopment of the global healthcare industry.

An article such as this can nevercover all the details and therefore itis important to discuss with theJapanese Authorities any particularissues. Under the new system suchconsultation is both possible andwelcomed.

A full version of this article isavailable in the form of aSupplement to the Clinical ResearchManual published by EuromedCommunicationswww.euromedcommunications.com


Email: [email protected] Phone: (0)207 017 7690

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Harmonised pan-Europeansafety featuresThe Directive on Falsified Medicinesintroduces mandatory, harmonisedpan-European safety features in theform of tamper evident packagingand a unique identifier to be appliedto all prescription medicines, subjectto possible exclusions based on arisk assessment.

The European Commission istasked with defining, in DelegatedActs, the mechanics of how thissystem will work. First consultationsare expected to be launched at thebeginning of 2012 with adoptionscheduled for 2014. The DelegatedActs will define the characteristicsand technical specifications of the“unique identifier” allowingidentification of individual packs,and the accessibility of nationalproduct databases or repositoriesthat allow verification of eachdispensed pack.

GIRP believes that the informationcontent as well as the data carrierneeds to be harmonised atEuropean level. In the light of thevery limited space on a onedimensional code and the highcosts and relatively low reliability of

RFID tags on medicinal products,GIRP opts for the adoption of a 2dimensional matrix code which as aminimum includes the nationalidentification number, the batchnumber and the expiry date inaddition to the randomised serialnumber.

In partnership with otherpharmaceutical supply chainstakeholder organisations – theEuropean Federation ofPharmaceutical Industries andAssociations (EFPIA) and thePharmaceutical Group of theEuropean Union (PGEU), GIRP isworking to jointly promote thedevelopment of an efficient,workable and cost effective productverification system that is to be runby stakeholder organisations on anon-profit basis.

The system proposed by thestakeholders is composed of aEuropean central hub connected toa series of national or regional datarepositories that serve as theverification platforms whichpharmacies and other registeredusers including an interface forwholesale distributors to check aproduct’s authenticity.

Impact for wholesaledistributor The new Directive insists, “wholesaledistributors must verify that theproducts they have received are notfalsified by checking the safetyfeatures on the outer packaging”.Whereas the detailed procedure onhow this requirement should befulfilled in practice will only becovered in the “Delegated Acts” itcauses a lot of concern as it canpotentially have major negativeimplications, not only for wholesaledistributors but also formanufacturers, pharmacies andpatients. If significant individual packscanning is involved it presentsmajor practical and costlychallenges to the smooth operationof the distribution chain and willseverely impact the speed ofdelivery of vital medicinal productsto pharmacies and ultimately topatients. Today, the averageEuropean delivery time is 2-4 hoursand we do not think it is necessaryto let patients wait longer throughunnecessary procedures.

For this reason GIRP urges theEuropean Commission whendrafting the Delegated Acts to takeaccount of the need forproportionate, pragmatic andworkable solutions for allstakeholders concerned. Inparticular, rather than a systematicprocess of checking all medicinalproducts received by wholesaledistributors, GIRP proposes the‘selective, risk based’ verification ofthe authenticity of medicines inforwards logistics. This would be thecase for medicinal productsobtained by wholesale distributorsfrom sources other than themarketing authorisation holder or aperson who is authorised by themarketing authorisation holder tosupply these products. Concerningbackwards logistics wholesaledistributors should verify theauthenticity of all returnedmedicines before putting them backto saleable stock.

GIRP strongly believes that a pointof dispense verification system witha wholesalers interface to verify theauthenticity of medicines in case ofdoubt is the most efficient and costeffective way to protect patients

THE FALSIFIED MEDICINESDIRECTIVEImpact on wholesalers

by Monika Derecque-Pois

With the adoption of the European FalsifiedMedicines Directive, the pharmaceutical sector is at

a critical point in the development of coding andserialisation systems in Europe. While the main force ofthe Directive is very much welcomed by GIRP, theumbrella organisation of pharmaceutical full-linewholesalers in Europe, some aspects of the brand newlegislation need to be defined further as they presentsignificant concerns to the sector and could have anadverse impact on the current speed of delivery ofmedicines to Europe’s pharmacies.

Monika Dereque-Pois is Director-General of the European Association ofPharmaceutical Full-line Wholesalers (GIRP), Brussels, Belgium.Email: [email protected] Web: www.girp.eu


from receiving falsified medicinalproducts. It is also the mostproportionate solution for meetingthe requirements of the Directive asit does not compromise the deliveryprocess of medicinal products andmost importantly it ensures thatpatients can trust that they receiveonly genuine products through thelegal supply chain.

Ongoing and next stepsA stakeholder-developed proposalfor complying with the terms of theDirective by a result orientatedprocess should be welcomed by theEuropean Commission. GIRPtogether with its stakeholderpartners will propose to theEuropean Commission a system thatensures verification of productauthenticity by professionals at thepoint of dispense and provide amodern technology solution that willensure patient safety.

To this effect 10 key principleshave been developed between thestakeholder associations and we arecurrently working on getting allinvolved stakeholders on board aswell as on conceptualising theframework for the stakeholder ledorganisation for governing theproposed system.

Ten core principles to protectpatients from falsifiedmedicines.EFPIA/PGEU/GIRP Joint PositionPaper, March 2011.

1. Combining tamper-evidentpackaging with a unique serialnumber:

• EFPIA, PGEU and GIRP supportthe requirement in the falsifiedmedicines directive that thesafety features should consist of aunique serial number placed oneach pack together withpackaging that would reveal if apack has been opened ortampered with.

• Checking a unique, randomised,serial number placed on eachpack against a central databaseat the point of dispensing iscurrently one of the most secureways to verify product

authenticity. However, a productverification system can onlysecure the content of the pack ifit remains sealed at all times.Using tamper evident packagingmakes it clear whether the packhas been opened or tamperedwith and is therefore an essentialcomplement to a productverification system.

• EFPIA and PGEU consider thatsafety features should be appliedto all prescription medicines toensure the same level of security.Therefore if a risk-basedapproach for prescriptionmedicines is pursued,exemptions should be based ontherapeutic categories, narrowlydefined (e.g. ATC 4 level), ratherthan individual products tominimise the risk to patientsafety.

2. Guaranteeing continuity ofprotection throughout theentire supply chain:

• As regards the obligations on therepackager to replace mandatorysafety features, the original packserial number should becancelled in the database by therepackager and a new numberprovided. The original and newnumbers must be linked in thedatabase to enable the productto be tracked in case of recalls orother safety issues.

3. Ensuring a single coding andidentification system on eachpack across the EU:

• Given the movement ofmedicines across nationalborders, any effective coding andidentification system must beable to exchange informationbetween Member States. Thereshould therefore be a harmonisedstandard coding system acrossthe EU.

• In order to ensure that thecoding system facilitates otherfunctionalities such asreimbursement, the EUharmonised standards shouldallow for the incorporation of

relevant national codes.

• EFPIA and GIRP propose using atwo-dimensional code(i,ii)

containing a unique serialnumber to encode all selectedproducts. This code can beverified against a database. Thismeans that pharmacists canrapidly verify the status of eachpack before dispensing it to thepatient. As well as the serialnumber, the code would storethe expiry date along withproduct identification (includingnational code) and batchnumbers, providing additionalpatient safety enhancements.

4. Ensuring product verificationdatabase systems can worktogether across the EU:

• In addition to using a commonstandard for pack identification inEurope, all national databasesystems must also be able towork together and exchangeinformation in order to allow anypharmacist, and wholesaler wheredeemed necessary, in anyMember State to check whetherthe pack has been dispensedbefore, irrespective of its countryof origin.

• There should be sufficientflexibility to implement nationalor regional solutions within anoverall EU technical framework.

• National database systemsshould meet equivalent qualityassurance requirements.

• Without this interoperability,counterfeiters would be able toexploit gaps between nationalsystems to insert falsifiedmedicines into the legitimatesupply chain.

5. Verifying every serialisedpack at pharmacy level:

• It is everyone’s responsibility inthe supply chain to ensure thatmedicines delivered to patientsare safe and genuine.

• Pharmacy level verification at thepoint of dispensing with aninterface for wholesalers is a

THE FALSIFIED MEDICINES DIRECTIVE continued


robust and cost-effective way toimprove patient protection.

• However, unless every individualserialised pack is verified at thepoint of dispensing, patients willnot benefit fully from the safetyfeatures. The unique serialnumber can only provideprotection against counterfeits ifit is routinely checked against acentral database and the statuschanged on the database to‘dispensed’ when the product ishanded to the patient.

• Systems should be configured sothat pharmacists can undertakechecks when medicines enterpharmacy stock, as well as atpoint of dispensing. Since thetechnical challenges of point ofdispensing verification vary acrossthe EU, pharmacists may initiallyadopt a system of verificationwhen medicines enter thepharmacy, until such time as anytechnical issues with regard topoint of dispensing verificationhave been resolved.

• The process of verification in thepharmacy should be virtuallyinstantaneous in order to ensureefficient pharmacy workflow andthe avoidance of delays. In orderto ensure that products areverified in one scanning action,verification software should beintegrated with existingpharmacy software. The processof verification at the wholesalelevel should allow products to bechecked during forward logisticsas well as for returningmedicines and without changingthe status on the database.

• Stakeholders shall worktogether to define standardprocedures for exceptionalevents such as verificationfailure, system failure etc.

6. Maximising all the potentialbenefits of mass serialisation:

• Using mass serialisation providesbenefits over and above improvedcounterfeiting prevention.Maximising these should help toencourage widespread use of

identification systems and assist allstakeholders.

• The coding system enables thepharmacist to automatically readthe batch number, serial numberand expiry date, significantlyenhancing patient safety andimproving product recallprocedures.

• The system may also facilitate theprovision of additional services topatients by pharmacists.

7. Focusing on securing patientsafety and protecting patientprivacy:

• Verification systems are forpreventing counterfeits, not foraccessing individual pharmacydata.

• Manufacturers do not seek, andwill not have access to, individualpatient/prescribing profileinformation.

• Transactional data belongs to thepharmacist, or in relation towholesaler verification, to thewholesaler. However, relevantstakeholders will need to seecertain data to help investigatewhen there is a verificationfailure, a product recall or a levelof unusual activity related to aspecific serial number, inaccordance with nationalcircumstances.

• Any additional use oftransactional data would need tobe agreed between thestakeholders in accordance withnational circumstances.

8. Using safety features that aresimple, robust and cost-effective:

• The product verification solutionproposed should meet thecriteria of being practical,affordable and accessible.Unnecessarily complex andcostly solutions should beavoided.

9. Working Together in theInterests of Patient Safety:

• As key stakeholders in the

verification process, we arecommitted to working togetherto establish an efficient, viableand effective system to protectpatients against the threat ofcounterfeit medicines.

• The establishment andmanagement of productverification systems should beundertaken by relevantstakeholders. For the governanceof product verification systems,EFPIA, PGEU and GIRP favour thesetting up of independent non-profit organisations to be jointlymanaged by relevantstakeholders, building on thecurrent coding environment inthe various countries andmeeting the needs of patientsand all players in the supplychain.

• Each stakeholder will be severallyresponsible for the system.

10. Involving other stakeholders

• EFPIA, PGEU and GIRP welcomethe involvement of other relevantstakeholder organisations whichplay an active role in thepharmaceutical supply chain inthe further elaboration of theproduct verification system atpoint of dispensing. Together wecan ensure a strong andcomprehensive system to takeforward the fight againstcounterfeiters.

Notes:(i) Data matrix ECC 200(ii) PGEU does not endorse a particular

technology at this stage

THE FALSIFIED MEDICINES DIRECTIVE continued


What is new?The Pharmaceutical Directive2001/83/EC is changed so thatprescription-only medicines mustbear safety features that allowverification of authenticity andidentification through the entiredistribution chain of every singlepack. Non-prescription medicineswill normally not bear safetyfeatures. The Commission will aftera risk assessment publish a list ofprescription-only medicines thatdue to a low frequency of falsifiedproduct reporting will be exemptedfrom safety features (White list).They will also publish acorresponding list of the non-prescription medicines that willneed safety features due to risk offalsification (Black list). The productsmust also bear a device allowingverification of whether the outerpackaging has been tampered with.

Repackaging (e.g. for parallelimport) will still be possible, but ifsafety features on the originalpackage are removed or covered,either fully or partially, they will haveto be replaced by equivalent safetyfeatures.

There has to be a repository setup by the manufacturingauthorisation holders. Thisrepository shall include informationon the safety features, enabling theverification of the authenticity andidentification of medicinal products.

The costs of the repository systemshall be borne by the manufacturingauthorisation holders of medicinalproducts bearing the safety features.

The illegal sale of medicinalproducts to the public via theInternet is an important threat topublic health as falsified medicinalproducts may reach the public inthis way. In order to meet this threatthe Commission shall decide on alogo to be put on legal websites forthe public to be able to identifywebsites that are legally offeringmedicines. Websites offeringmedicines for sale at a distance tothe public should be linked to thewebsite of the competent authorityconcerned. In addition, theCommission should, in cooperationwith the Agency and MemberStates, run awareness campaigns towarn of the risks of purchasingmedicinal products from illegalsources via the Internet. Memberstates will still be free to banInternet sales of medicines.

TimelinesThe Directive has to be transposedinto national law by 1 January 2013.Many requirements are to bedecided in Delegated Acts.(i)For safety features the following areto be decided:1. Characteristics and technical

specifications of the uniqueidentifier with due consideration

to the cost-effectiveness of thesafety features.

2. Lists of products or productcategories that shall/shall notbear the safety features,established on the basis of a risk-based evaluation.

3. Procedures for the notification tothe Commission, and subsequentevaluation, concerning productsto be included in the lists in 2.

4. Modalities for the verification ofthe safety features by themanufacturers, wholesalers,pharmacists and the authorities.

5. Provisions on the establishment,management and accessibility ofthe repositories system.

There are no timelines for thepublication of Delegated acts, butthe EC has made it probable thatthis will occur in 2014. In theDirective, it is stated that the above-mentioned points shall enter intoforce 3 years after the publication ofthe Delegated acts (6 years afterpublication for some countries thatalready have product verification).The logo for Internet pharmaciesshall enter into force 12 months afterpublication of the Delegated Acts.

Pilot in SwedenIn 2009 EFPIA(ii) made a pilot studyin Sweden together with ApoteketAB, the only pharmacy chain inSweden at that time2. The aim wasto approach the issue of productverification in line with the EC’ssuggestions on a new directive andto test a practical and effectivesolution for relevant stakeholders(manufacturers, pharmacists,wholesalers). The solution should beable to fully integrate with theirexisting operations and be based oncommon standards and maturetechnology.

Twenty-five pharmacies in thegreater Stockholm area participatedin the pilot. Fourteen manufacturersprovided a total of 25 differentproducts (110,000 packs). Specialroutines for ordering and delivery tothe pilot pharmacies weredeveloped. Changes in thepharmacy software to allow only onescanning were done. Thepharmacies involved informed and

FALSIFIED MEDICINESDIRECTIVEImplementation in Sweden

by Anita Finne-Grahnén

In July 2011 the European Commission (EC) published adirective from the European Parliament and the

Council of Ministers (Directive 2011/62/EU1) with theaim to prevent falsified medicines entering the legalsupply chain and reaching patients. It introducesharmonised safety and strengthened control measuresacross Europe by applying new measures.

Anita Finne-Grahnén is Director of LIF, the Swedish Association of the PharmaceuticalIndustry. Email: [email protected] Web: www.lif.se and www.fass.se


educated their staff before the pilot,that had an operational phase of 4months, could be started. The pilotshowed that the model works inpractice. The system availability andthe performance allowed work to bedone without any significantadditional effort. The system waseasy to use when fully integrated.The main lessons learnt were that asystem must provide correct answersand that the system should becustomised to the existing pharmacyworkflow, the work processes, thelocal conditions and the regulatoryrequirement. The presence of morethan one code on the pack causesconfusion at pharmacy level. Thepilot also showed that the necessarydata segregation and security couldbe technically ensured.

European levelThe EFPIA solution on productverification at the point ofdispensing is an end-to-end system.It allows pharmacists to check aunique identification code on eachindividual pack when it is dispensedto the patient3. These codes aregenerated and applied bymanufacturers using a 2D datamatrix barcode, which contains aunique serial number. The uniquerandomised code is presented incombination with additionalinformation in machine-readableform (product code, batch numberand expiry date).

On a European level there havebeen discussions betweenstakeholders. During 2011 EFPIA,together with its partners (GIRP(iii) &PGEU(iv), the Wholesalers andPharmacists at EU Level), haveagreed a Memorandum ofUnderstanding (MoU) which outlinesthe proposed solution and steps forimplementation including:

– Unique Identifier for medicinalproducts

– Modalities for verifying thesafety features

– Provisions on the establishment,management and accessibilityof the repository system

– Lists of products to be coveredby the safety features

Based on this MoU, EFPIA, PGEUand GIRP have created a commondocument named ”Ten CorePrinciples to protect patients fromfalsified medicines”4. The latestpartner is EAEPC(v), whichrepresents parallel importers at EUlevel.

Implementation in SwedenProduct verification should becoordinated throughout Europe oron a regional level. It is important toavoid a lot of different systems,which are not compatible with eachother. Costs for product verificationwill arise at different stages. Themanufacturers will have to financethe development and managementof the repositories, the registrationof the products and also thelabelling of the safety features onevery package.

Systems at pharmacy level willhave to be adapted and thatincludes costs for introduction,validation, quality assurance andpurchase of equipment (scanners).These costs will be borne by thepharmacies.

Sweden has a highly developedinfrastructure and it will probably beeasier to implement the systemsthan in a lot of other Europeancountries. This will impose thatSweden ought to be able to takeadvantage of the systems otherthan just to prevent falsifiedmedicines. The costs fordevelopment could be easier to

bear if the parties see many otheradvantages. Patient safety has to beincreased and by such a systemmachine-readable expiry dates andbatch numbers can be obtained.This will enhance traceability andlead to simplified recalls andsimplified warehousing.

We are presently discussing if thecosts for our companies is lowerwith a national system or a regionalsystem (such as the Nordic one). Therespective Nordic pharmacy systemsand article registers are differentand a joint solution has to beproperly evaluated before decisionsand deeper involvement of thenational stakeholders. Pros and consmust be taken into account and wecan then decide which way to move.

References1 Directive 2011/62/EU of the European

Parliament and of the Councilhttp://ec.europa.eu/health/files/eudralex/vol-1/dir_2011_62/dir_2011_62_en.pdf

2 EFPIA Product Verification Project(www.efpia.eu/content/default.asp?PageID=559&DocID=8770)

3 EFPIA: Coding & Identification ofProducts: towards safer medicines supply(www.efpia.eu/content/default.asp?PageID=566)

4 EFPIA-GIRP-PGEU: Ten Core Principles toprotect patients from falsified medicines(www.efpia.eu/content/default.asp?PageID=559&DocID=12357)

Notes(i) Delegated acts – The law-makers can give

the EU Commission the option tosupplement or amend (which meansdecide) certain non-essential elements ofthe EU law or framework law bydelegating authority. The Lisbon Treatyintroduces delegated acts as a specialcategory of law in addition to EUdirectives and regulations. Delegated actshave also supremacy over national lawsand national constitutions although theyare to be approved in an organ where allmember states are not represented(http://en.euabc.com/word/271)

(ii) EFPIA – European Federation ofPharmaceutical Industries andAssociationswww.efpia.org/Content/Default.asp?

(iii)GIRP – The European Association ofPharmaceutical Full-line Wholesalershttp://girp.eu/cms/

(iv)PGEU – The Pharmaceutical Group of theEuropean Unionwww.pgeu.eu/

(v) EAEPC – European Association of Euro-Pharmaceutical Companies www.eaepc.org/welcome/index.php

FALSIFIED MEDICINE DIRECTIVES continued

EIPG Survey: TheUnique Identifier forMedical ProductsDirective 2011/62/EU introducesobligatory 'safety features' to allowverification of the authenticity ofmedicinal products for human use('unique identifier'). The EuropeanCommission has published aconsultation document on theDelegated Act on the Detailed Rulesfor the Unique Identifier. EIPG wouldlike to know your opinion on theproposals in this document (availableathttp://ec.europa.eu/health/files/counterf_par_trade/safety_2011-11.pdfTake the EIPG Survey atwww.surveymonkey.com/s/VG3MFL8

http://ec.europa.eu/health/files/counterf_par_trade/safety_2011-11.pdf



Computer Validation: A Common Sense Guideby Teri Stokes, Ph.D.

Reviewed by Ellis Daw

With the title “Computer Validation, ACommon Sense Guide” my firstthought was this book had to be achallenge to write, especially if thecontent lived up to the promise. Whilethe requirement for ComputerValidation has existed for the industrymore than 25 years, in practice it is stilloften seen as a subjective andchallenging activity – the intent of thebook is to provide a practical approachfor the process.

The main topics of this book of over340 pages include a history of theregulations, explanations of the numerous roles andtheir responsibilities and required activities forsuccessful outcomes, a large number of exampledocuments, and principles and guidance from anauthor who has more than 20 years experience.

It begins by providing a clear and insightful summaryof the regulations and guidance that have shaped CVpractices. Every major influence on current practice iscovered, from FDA’s Blue Book guidance in 1983 to thevery recent reissue of EU GMP Guide Annex 11 in 2011.The aims and expectations of regulatory authorities arewell summarised into common themes and the firstchapter ends with a useful summary of principles thatbring sharp clarity to the common intent of regulatorsworldwide.

Several chapters are devoted to explaining the rolesrequired for successful computer validation. The firstrole is that of managers and expectations forsponsorship and active engagement with the projectsare described. The book gets across the key messagethat validation is a process that must be stronglysupported by management, from the identification of aneed for a system through to its archival when thesystem is replaced or redundant. The guidance tomanagement rightly conveys that computer validationcannot be achieved by a single person as a one-timeactivity; it is a lifecycle activity that must be supportedby the organisation throughout the life of the system.

The book describes the typical validation activitiesfrom identifying the team, development ofrequirements for the system, dealing with suppliersincluding auditing of practices, testing, managing theinfrastructure requirements and completing thevalidation package. Useful guidance is given onbuilding reusable packages that can be repeated for

installations of similar systems. As the activities aredescribed, detailed roles and responsibilities areidentified for the activities. Some of these are toofragmented, e.g. seven roles are identified for formal

testing and this granularity couldconfuse less experienced readers –who appeared to be the key targetaudience. Another example is thetesting role of “Witness” whoseresponsibility is focused on ensuringtest materials are prepared andcollected properly rather than actuallywitnessing any activity – this and thefollow-on impact of so many roleacronyms in the example documentsis a bit confusing. To its credit thebook mentions that people canperform multiple roles and these canbe combined or split to fit the sizeand scope of the system.

There is a logical flow and value tothe real life examples providedthroughout the book and readers of

all skill levels should find useful bits to apply to theirown projects. There are some odd suggestions such asprinting different parts of the document set on differentcolour paper and keeping documentation in envelopes.It took several encounters with the term “TestEnvelope” for me to realise the author was describingthe retention of documents in an envelope rather thanintroducing some testing standard or concept.

A disappointment is that the book provides very littlein the way of risk management guidance to focusvalidation activities. Every practitioner struggles with theareas of focus, level of detail in which the effort shouldbe conducted and how to vary the intensity ofspecifications, testing and other controls. Given therevision of Annex 11 in 2011, with its expectation for theextent of validation and data integrity controls to bebased on a risk assessment, I had expected guidanceon varying the approach to match the level of risk.However, the coverage of risk analysis is limited toexample forms with yes/no questions to determine ifvalidation is required. Simple advice on where and howto focus computer validation on the functionality mostcritical to patient safety would have been a valuableaddition.

In conclusion, this is a worthwhile book that conveysa lot of practical experience and guidance for anyoneinvolved in computer validation. Overall, the bookdelivers on its title as a common sense guide.

Ellis Daw, is Director of Quality Applications Shared Service atGlaxoSmithKine, Research Triangle Park, North Carolina, U.S.A.

Published by Biopharm-Guides (www.biopharm-guides.com). ISBN: 933722-54-1. 36 pages. Price $22.

book review


United States ofAmericaFDA rule requiringmanufacturers to reportinterruptions in production ofcritical drugsFDA has issued an interim final rulethat will help prevent prescriptiondrug shortages. The rule requiresmanufacturers that are the onlyproducer of certain critical drugs toreport to FDA all interruptions inmanufacturing of products.

USP New General Chapter<1083> "Good DistributionPractices – Supply ChainIntegrity"This new chapter will be publishedin the Pharmacopeial Forum –March-April edition for comment. It will focus on packagingtechnologies (tamper proofevidence) and on identification andserialisation technologies (2DBarcode or RFID). It also covers theregulations that should bedeveloped for re-packaging and themeasures to be taken against illegalInternet pharmacies.

EuropeRevised guidance on geno-toxicity testing of medicinesDamage to the DNA, or genotoxicity,is an important consideration fordevelopers of medicines andmedicines regulators, because it hasthe potential to cause irreversiblechanges to genes and even cancer.

EMA has published a revisedguideline on how pharmaceuticalcompanies should test theirmedicines for damaging effects onthe DNA.

The guideline, effective June2012, follows the core ICH guideline.It is expected to improve theassessment of the risks of humanmedicines, to reduce the number ofanimals used in the testing and toimprove the efficiency of themedicine development process.

EMA work programme 2012EMA will focus on implementing

new pharmacovigilance legislationand also on supply shortages ofmedicines caused by insufficientGMP compliance.

Guideline on the use of NearInfrared Spectroscopy (NIRS)by the pharmaceuticalindustryThis guideline describes theregulatory requirements for MAAand variation applicationssubmitted for medicinal productsfor human or veterinary use, whichinclude the use of NIRS.

Enhancing GMP inspectioncooperation between theEMA and FDAAs the latest step in increasedcollaboration between EMA and theFDA, an initiative is in place to sharework on inspections of manufacturingsites in each other's territories.

From January 2012, they may relyon each other's inspectionoutcomes rather than carrying outseparate inspections in duplicate,enabling:

• Better use of inspectionresources

• Reduce the burden ofinspections for medicinesmanufacturers

• Shift inspection capacity toother regions

The most likely impact will be inthe area of routine post-authorisation/surveillanceinspections.

Delegated Act/detailed rules for aunique identifier for medicinalproducts and its verification.

The Commission is under anobligation to adopt delegated actssetting out the details relating to theunique identifier including:

• Characteristics and technicalspecifications

• The modalities for verification

• Establishment, managementand accessibility of therepositories system in whichinformation on the safetyfeatures is to be contained

• Lists containing the medicinalproducts or product categorieswhich, shall, or shall not bearthe safety features

• The procedures for thenotification of medicinalproducts by the nationalauthorities to the Commission,as regards medicinal products(not) at risk of falsification.

An impact assessment will bemade of the characteristics of theunique identifier, the detailedprocedures for verification, and therepositories system.

Delegated Act principles andguidelines of GMP for activesubstancesMember States must takeappropriate measures to ensure thatmanufacturers of active substanceson their territory comply with GMP.A Concept Paper has been releasedwith a view to preparing thedelegated act.

InternationalPIC/S recommended modelfor risk-based inspectionplanning in the GMPenvironmentThis PIC/S Recommendation setsout a simple and flexible QualityRisk Management tool that may beused by Inspectorates whenplanning the frequency and scopeof GMP inspections.

EMA & EC extendconfidentiality arrangementwith JapanThe EMA and the EuropeanCommission have extended theirconfidentiality arrangement with theJapanese medicines regulatoryauthorities for a year.

For further information on these andother topics please refer to thewebsites of relevant regulatorybodies and to “GMP Review News”published by EuromedCommunications. To subscribe tothis monthly news service [email protected]

by Malcolm Holmesregulatory review

Bureau MeetingThe format and agenda for the 2012General Assembly to be held on 5-6th May in Lisbon were drafted.Education and financial matterswere discussed, as was the revisionto the Statutes.

Professional QualificationsDirectiveOn 19 December 2011, theEuropean Commission adopted alegislative proposal for modernisingDirective 2005/36/EC on therecognition of professionalqualifications. Its proposals foraccelerating the update of theminimum training requirementsthrough “delegated acts”,introducing professional cards,amendments to languageknowledge and the proposals onpartial access have been discussedwith representatives of the Europeancommunity and hospital groups andthe European faculties of pharmacy.

Innovative MedicinesInitiativeEIPG responded to comments onthe summary documents onContinuing ProfessionalDevelopment produced from themeeting in Manchester. EMTRAINlaunched the on-course®: www.on-course.eu on 14 February 2012.Everyone is kindly invited to startusing on-course® and register ascourse seeker. Also, please register

if you are a course provider andenter your programmes.

Currently, EMTRAIN contains >1500 European Master courses andaround more than 700 CPD courses.PhD programmes and courses are tobe added in the near future.

EIPG Comments on TechnicalDocuments In December, EIPG submittedcomments on the EMA “RevisedGuidelines on Good DistributionPractices”. In January, EIPGsubmitted comments on the“Concept paper on Revising Annex16 of the Guide to GoodManufacturing Practice: Certificationby a Qualified Person and BatchRelease”. Both documents are onthe EIPG website under “PositionPapers”

Draft Technical DocumentsPending CommentThe European Commission haspublished a concept paper for aUnique Identifier for medicinalproducts for human use and itsverification (available athttp://ec.europa.eu/health/files/counterf_par_trade/safety_2011-11.pdfDeadline for comments to EIPG is31st March 2012.

EIPG would like to know youropinion on the proposals in thisdocument. A survey is beingconducted by Claude Farrugia andis available at:www.surveymonkey.com/s/VG3MFL8.

The European Commission hasissued a concept paper for publicconsultation on the principles andguidelines of good manufacturingpractice for active substances inmedicinal products for human use.See EIPG website under “News”.Deadline for comments to EIPG is1st April 2012.

The European Medicines Agencyhas published a draft of a Scientificguideline: Reflection paper on theuse of starting materials andintermediates collected fromdifferent sources in themanufacturing of biologicalmedicinal products. See EIPGwebsite under “News”Deadline for comments to EIPG by1st August 2012.

Any comments can be made [email protected] and I will passthem to the person drafting theresponse.

Jane Nicholson, Executive Director EIPG


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MARCH19-21 March 2012 – Amsterdam,The NetherlandsBio-Europe Spring 2012www.ebgroup.com/bes 28-29

28-29 March 2012 – London, UKAdvanced in nanomedicine fororal and non-oral drug deliverywww.controlledrelease.co.uk

APRIL16-17 April 2012 – London, UKAsthma & COPDwww.asthma-copd.co.uk

17-19 April 2012 – Reading, UKGood Manufacturing Practicewww.rssl.com

18-19 April 2012 – London, UKPharmaceutical Portfolio &Product Lifecycle Managementwww.pharma-portfolio.com

18-19 April 2012 – Prague, CzechRepublicBioProcess InternationalEuropean Conference &Exhibitionwww.bpi-eu.com

23-27 April 2012 – Glasgow, UKQualified Person & ProfessionalDevelopment Trainingwww.nsf-dba.com

24-25 April 2012 – Cambridge, UKSystems auditwww.barqa.com

26-27 April 2012 – Cambridge, UKRisks, requirements, tests andtraceability: A model forcomputerised system validationwww.barqa.com

26-27 April 2012 – Amsterdam,The NetherlandsOpen Innovation inPharmaceutical R&Dwww.flemingeurope.com

MAY13-17 May 2012 – Cambridge, UKAdvanced Level Workshop onPharmacokinetic –Pharmacodynamic Data Analysiswww.rpharms.com/events

15-17 May 2012 – Manchester, UKBest Practice for the AnalyticalLaboratorywww.nsf-dba.com

17 May 2012 – London, UKAdvances in RamanSpectroscopy in PharmaceuticalAnalysiswww.jpag.org

21-22 May 2012 – Berlin, GermanyPharma Outsourcing &Procurement Summit 2012www.outsourcingevent.com

21-25 May 2012 – Manchester, UKEffective Pharmaceutical Auditsand Self-Inspectionswww.nsf-dba.com

22-23 May 2012 – Cambridge, UKThe practical application ofQRM tools and techniqueswww.barqa.com

22-24 May 2012 – Islington, UKBiomarkers Worldwww.terrapinnmedia.com

JUNE3-5 June 2012 – Lisbon, Portugal53rd Annual General MeetingGIRP

18-22 June 2012 – Frankfurt amMain, GermanyAchema 2012www.achema.de

20 June 2012 – Cambridge, UKDissolution testing for thepharmaceutical industrywww.rpharms.com

25-28 June 2012 – Barcelona,SpainIWPCPS-14 –InternationalWorkshop on PhysicalCharacterization ofPharmaceutical Solidswww.assainternational.com/contact.cfm

SEPTEMBER24-26 September 2012 –Dusseldorf, Germany11th Annual BiologicalProduction forum 2012www.girp.eu

events

24 european INDUSTRIAL PHARMACY March 2012 • Issue 12

FIP’S WORLD CONGRESS OF PHARMACY AND PHARMACEU TICAL SCIENCES

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3-8 OCT 2012 AMSTERDAM, THE NETHERLANDSMM TSMSTERDAM, THE NETHERLANDSSSTERDAM, THE NETHERLANDSHE NETHERLANDSTHTHT,DAM, THE NETHERLANDSDAM, THE NETHERLANDSAM, THE NETHERLANDSRDAM, THE NETHERLANDSSTERDAM, THE NETHERLANDSSTERDAM, THE NETHERLANDSSTERDAM, THE NETHERLANDSSTERDAM, THE NETHERLANDSMM, THE NETHERLANDSAMSTERDAM, THE NETHERLANDSAAMSTERDAM, THE NETHERLANDSMSTERDAM, THE NETHERLANDSS DNDSDDSTTTHTH DSDSDSDANDSLAANDSRLANDSTHERLANDSTHERLANDSTHTH NDSDNETHERLANDSE NNETHERLANDSETHERLANDST

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