european industrial pharmacy issue 1 (october 2008)

europeanINDUSTRIALPHARMACY

ISSUE 1 • OCTOBER 2008www.industrialpharmacy.eu

www.eipg.eu

FEATURES4 QUALITY CHARTER FOR MEDICAL

REPRESENTATIVE VISITSThis charter aims to strengthen the role of the medicalrepresentative visit in the rational use of drugs and in the quality ofthe information conveyedby Valérie Lacamoire

7 THE PATIENT JOURNEY – THE BENEFITS OFWELL-INFORMED, TARGETED GUIDANCE ANDINFORMATIONEasing the patient’s journey through diagnosis, procedures andmedication benefits not only the patient but also physicians,pharmacists and drug companiesby Marta Garrido

10 BIO-INSPIRATION FOR NEW PHARMACEUTICALSPRAYSA beetle’s protection mechanism has inspired a physicsdepartment to develop a new form of drug delivery systemby Andy McIntosh

12 LATVIAN INDUSTRIAL PHARMACISTSAn active and ambitious Sectionby Inta Saprovska

13 THE ROLE OF THE QUALIFIED PERSON IN THE21ST CENTURYThere are better ways to protect the patient than individual batchreleaseby Joyce Ramsbotham

16 OPERATION STORMGRAND – A TANGLED WEB OFWORLDWIDE DECEITCounterfeit medicines have become a worldwide problem. ThisMHRA case history traces the complicated international network ofa counterfeiting organisationby Joe Ridge

REGULARS3 EDITORIAL COMMENT18 REGULATORY REVIEW19 NEWS FROM THE EIPG21 DATES FOR YOUR DIARY

2 eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 1 October 2008

europeanIINNDDUUSSTTRRIIAALLPHARMACYIssue 1 October 2008

ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONSue Feather

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldMichael GamlenLinda HakesLarry HurstJohn Jolley

Valérie Lacamoire

European Industrial Pharmacy is published three times a year by: Euromed Communications LtdThe Old Surgery, Liphook RoadHaslemere, Surrey GU27 1NL, UK

Tel: +44 (0)1428 656665 Fax: +44 (0)1428 656643

Email: [email protected] subscription rate £58

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

misleading information

©2008 Euromed Communications Ltd

Belgium: Philippe Van der Hofstadt

Bulgaria: Valentina Belcheva

Czech Republic: Miloslavia Rabiskova

Denmark: Michiel Ringkjøbing Elema

Finland: Tuula Lehtela

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Jane Nicholson

Greece: Kiriasis Savvas

Hungary: Sylvia Marton

Ireland: Anna O’Mahony

Italy: Piero Iamartino

Latvia: Inta Saprovska

Malta: Claude Farrugia

Netherlands: Harold Smeenge

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europeanIINNDDUUSSTTRRIIAALLPHARMACYdiscussion group:

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Associate Editors

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

Cover picture: Bombardier beetle – a sourceof inspiration for a new spray system – seepage 10.

A special thanks to the companies who havekindly supported the publication of thisnewsletter

3eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 1 October 2008

EEDDIITTOORRIIAALL CCOOMMMMEENNTTgraduates with the right skillsneeded for Industry.

� To understand the impact ofGlobalisation/Outsourcing uponthe Industrial sector and what thismeans to the IndustrialPharmacist of the future

� The EIPG needs to engage with allpharmacists working in industrywhether it ’s R&D, Regulatory,Manu facturing, Promoting theQualified Person or on thecommercial side in Sales andMarketing.

EIPG can raise the profile of theIndustrial Pharmacist within the ECin the following ways:

� Contributing to publicationswhich are read by manyconstituents groups within Europe

� To encourage Industry to continueto train and support PharmacyStudents and to provide workplacements

� To lobby Government andAcademic Institutions on theimportance of maintaining thehigh skill level and educationalstandards required to be anIndustrial Pharmacist.

� To ensure that the Science behindthe Drug Discovery andDevelopment process is stilltaught within the Schools ofPharmacy in Europe.

It is important that EIPG continuesto promote the importance ofIndustrial Pharmacists and lobby on

Raising the profile of theIndustrial Pharmacist

The old saying ‘You do not the valuesomething until you have lost it’springs to mind when looking at theway the role of the IndustrialPharmacist has been eroded awayin recent years. I am very proud tobe an Industrial Pharmacist and Ihave enjoyed my job in this excitingfield of Pharmacy. However, theseare tough times and challenges arehitting the industry on what seemsto be a daily basis.

I believe that the EuropeanIndustrial Pharmacists Group (EIPG)has a key role to play in this area.

It is important to note that the EIPGis a European associationrepresenting the national,professional organizations ofpharmacists employed in thepharma ceutical and allied industriesof the EU. Today the EIPG representswell over 10,000 Pharmacists (manyof whom are Qualified Persons)working in the PharmaceuticalIndustry in Europe.

I was therefore extremely proud tohave been nominated and selectedto be President of the EIPG. I see thefollowing key areas for focus for theEIPG:

� EIPG needs to address the fallingnumbers of Pharmacists enteringthe Industry and to ensure thatthe high educational standardsare maintained if we are to have

behalf of pharmacists in industry.EIPG should also encouragemembers to establish forums wherepharmacists from different areas ofthe industry can come together todebate common issues.

One way to promotecommunication is to develop aspecialist publication which allowsour views to be widely circulatedand discussed. Therefore, it wasdecided to sponsor EuropeanIndustrial Pharmacist, with anadvisory board which reflects thevarious European ProfessionalAssociations who make up EIPG andso provide a truly Pan-Europeanview of the Industry.

We have also appointed Mrs JaneNicholson as Executive Director tothe EIPG Bureau. In this capacity,Jane will ensure that our links toexternal bodies such as EAHP, PGEU,EFPIA, EMEA, The QP Association etcwill be maintained. Jane will alsocontribute actively to the EuropeanIndustrial Pharmacist.

Only by sharing knowledge,experiences and maintaining ournetworks can we find a way forward.

Gino MartiniPresident, EIPG

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QUALITY CHARTER FOR MEDICALREPRESENTATIVE VISITS by Valérie Lacamoire

VALÉRIE LACAMOIRE is Directeur AffairesRéglementaires/Senior Regulatory Affairs ManagerAstellas Pharma SAS, 114 rue Victor Hugo92 686 Levallois-Perret Cedex, Francetel : +33 1 55 91 75 51 / fax : + 33 1 55 91 75 69

Une Charte de la Visite Médicale, prévue par la Loisur la Réforme de l’Assurance Maladie du 13 août2004, vise à renforcer le rôle de la visite médicaledans le bon usage du médicament et la qualité del’information.

Les entreprises concernées ont l’obligation de faireévaluer et certifier par des organismes accrédités,au plus tard le 30 juin 2008, la qualité et laconformité à la charte de leur visite médicale.


MEDICAL REPRESENTATIVE CHARTER

This text contains five chapters:

The medical representative’s missions: inform healthprofessionals about proprietary medicinal productswhile promoting them in compliance with rulesconcerning rational use;

Quality of information provided: rules guaranteeing thequality of information provided, of promotionaldocuments and of medical representative training onthe drug presented;

Medical representative ethics: code of conduct towardsdifferent actors in the health industry: patients,practitioners, corporate competitors, drug manufacturersand health insurance organisations.

Control of medical representative activity: clarification ofthe pivotal role of the Responsible pharmacist inrelation to their mission defined by the Public HealthCode.

Joint monitoring, enabling tracking and update of thisdocumentation.

THE KEY POINTS OF THE CHARTERCONCERN:

1. Samples: Samples may no longer be distributedduring medical representative visits.

2. Post-Marketing Authorisation studies, pharmaco -economic studies, observational studies: These studiesare no longer part of the medical representative’smissions. The representative may no longer set up thesestudies, but he/she may monitor them.

3. Promotional materials: All promotional documentsmust be dated and validated by the manufacturer’spromotional material compliance department.

As provided by the Health Insurance Reform Lawof 13 August 2004, a Medical Representative

Charter was signed on 22 December 2004 by LEEM,the professional association of pharmaceuticalmanufacturers, and CEPS, the Comité Economiquedes Produits de Santé (Committee for Pricing ofHealth Products), on behalf of the government. Thepharmaceutical companies concerned are obligedto request assessment and certification of theconformity of their medical representative visitpractices by accredited organisations, at the lateston the 30th of June 2008.

In July 2005, an amendment added a mechanism tocontrol the number of visits made concerning specifictherapeutic drug classes.

The Medical Representative Charter aims to strengthenthe role of the medical representative visit in therational use of drugs and in the quality of theinformation conveyed.

In particular it aims to improve control of promotionalpractices which may reduce the quality of patient careprovided.

By providing information to practitioners, the medicalrepresentative visit must promote the quality of medicaltreatment, prevent the misuse of drugs and avoiduseless expenditure. This Charter is therefore fullyembedded in the efforts to preserve France's healthinsurance system.

For the time being, the Charter only applies to thosecompanies signing a convention with CEPS and whichprovide drug information and promote reimbursableproprietary prescription medicines in non-hospitalenvironments.

Very shortly, medical representative service providerswill also be concerned by this Charter. A furtherdocument concerning visits to hospital practitioners isalso due to be drawn up.

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notably responsible for laying down certification criteriathat will enable accredited organisations to assess thequality of medical representative visits and theirconformity to the Charter.

In light of the major role of the Responsible pharmacist,the Central Council of section B of the Order ofPharmacists (industrial professionals) activelyparticipated alongside the HAS and other professionalhealth organisations in drawing up the certificationcriteria for medical representative visits. The role of theOrder of Pharmacists was to fully interpret the text anddevelop the criteria to ensure that missions imposed onthe Responsible pharmacist under the new law arerespected. In particular, the Order proposed to separatethe regulatory requirements previously provided for bythe Public Health Code, which were already amongst theResponsible pharmacist's responsibilities and thereforesubject to inspection by the drug approval authorities,from the new requirements introduced by the Charterwhich would be integrated into the company's technicalcertification procedures.

Several working groups were created within the Order inearly 2005 in order to focus their attention on validatingmedical representative training, on the role of theResponsible pharmacist, on the certification ofrepresentative networks and the development of thecertification criteria. In addition, a representative ofsection B has been a member of the HAS working groupsince 2005, alongside the other participatingorganisations.

The objectives of the criteria are: firstly, to ensure thequality of the information conveyed by the medicalrepresentative and secondly, to ensure the quality of themanufacturer's medical representative visit practices.

The fundamental points for the Order to clarify were theroles and responsibilities of each party concerned: thecompany, the Responsible pharmacist, the supervisionof medical representatives in relation to the Charter andthe company's certification, but also in relation to thespecific and personal responsibility of the Responsiblepharmacist as defined by the Public Health Code.

The certification criteria for medical representative visitswere finalised and published by HAS in July 2006 andsubsequently modified in July 2007 (the document isavailable for consultation in English on the HAS website(http://www.has-sante.fr). It sets out four requirements:

1. the company ensures that its medical representativeshave the knowledge and skills needed to providehigh-quality information;

2. the company ensures that medical representativeshave the information and resources needed to carryout their missions;

4. Training: Adequate initial training and in-servicetraining must be provided to medical representatives.To ensure the quality of information conveyed, themedical representative's oral presentation must beverified by simulation prior to their visiting healthprofessionals. This simulation is carried out in thepresence of a scientific and medical managermandated by the Responsible pharmacist. Emphasismust be put on the content of the presentation, andto a lesser extent the length of the visit, rather thanthe frequency of visits.

5. Professional relationships/congresses, gifts: Medicalrepresentatives are prohibited from offering gifts ofany nature or value to practitioners.

Invitations to professional or scientific congressesmust be covered by a convention transmitted to therelevant authorities.

6. Role of the Responsible pharmacist: With a pivotalrole in the implementation and respect of theCharter, the Responsible pharmacist guarantees thescientific quality of the messages conveyed by themedical representative. He/she must ensure that therepresentative possesses the knowledge required toexercise his/her profession and receives regular in-service training, to ensure their knowledge is up-to-date and to prepare for promotional campaigns. TheResponsible pharmacist is also responsible for thecontent of documents used. These responsibilities arecompleted by the control of promotional proceduressuch as document traceability, information feedbackand monitoring of medical representative activities.

7. Certification of medical representative visits: Toenable CEPS to ensure that the provisions of theCharter are correctly applied and respected bypharmaceutical companies, manufacturers areobliged to request assessment and certification of theconformity of their medical representative visitpractices by accredited organisations, according to aprocedure defined by the Haute Autorité de Santé(HAS – High Authority for Health).

The deadline for companies to obtain certification fortheir visit procedures has been defined as 30 June2008.

At the start of January 2008, 30 companies out ofapproximately 200 were certified.

CERTIFICATION CRITERIA ANDIMPLICATION OF THE CENTRAL COUNCILOF SECTION B OF THE ORDER OFPHARMACISTS

In accordance with the Law of August 2004 introducingthe Medical Representative Charter, the HAS is chargedwith implementing a certification procedure. It is

3. the company makes available to medicalrepresentatives and their managers the resourcesthey need to comply with ethical rules;

4. the company makes available the resources neededto ensure the quality of its medical representatives'work.

In all the requirements, it is therefore the company whomust ensure that it respects the various provisions laiddown in the criteria. But these requirements are dividedinto individual criteria (eg. for requirement 1, criterion1-1 requires that "the company holds continuingtraining sessions for medical representatives inaccordance with the Code of Practice"), in respect ofwhich the Responsible pharmacist may intervene inareas directly covered by his/her pharmaceuticalexpertise.

In summary

The Quality Charter for medical representatives is acomponent of the health insurance reform programmewhich is governed by a contractual framework andwhich testifies to the commitment of pharmaceuticalmanufacturers to support a public health policy basedon providing solid scientific information to health

practitioners and encouraging best use in the interest ofpatient care.

It enables the harmonisation of existing medicalrepresentative visit practices and the definition ofquality standards similar to those prevalent in otherpharmaceutical industry sectors such as goodmanufacturing practices, good clinical practices andgood pharmacovigilance practices .

As part of an approach that promotes quality andcontinuous progress, it also enables us to:

� reinforce and promote of the quality of professionalethics and of medical information conveyed;

� emphasise the contribution of industry professionalsto:

– developing knowledge about pathologies andtheir treatment,

– correct drug use,

– and therefore the improvement of patient care.

The coming years will allow us to make a retrospectiveassessment of the consequences of this Charter and thecertification process on the changes that willsubsequently be made to medical representative visits.

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Why is it important to consider the patient’sjourney from the point of view of a service

provider or medication provider? The answer:Inherent in the concept of a journey is theunknown, whether in regard to the traveler’sknowledge, experience, expectations, orperceptions. During the course of each patient’sjourney, there are multiple opportunities foreducation and structured dialogue in order toenhance compliance and improve communicationbetween patients, physicians and pharmaceuticalbrands.

The concept of a patient journey provides anopportunity for all parties involved to ease the patientthrough a labyrinth of procedures and medication, aswell as to assist in their understanding of the diseaseand consequences of life-altering decisions. In a recentpresentation, Paul LeVine of InfoMedics examined howthe patient’s journey may be better facilitated byphysicians, pharmacists and pharmaceuticalcompanies; this article reviews the main points of thatpresentation and includes the author’s thoughtsstemming from same.

From the patient’s perspective, we can divide thejourney into three different stages:

1 Fear-laden diagnostic phase: In which the patientwants information about his condition, prescribeddiagnostic tests and what will happen next.

2 Early experience: During which a patient isundergoing tests and procedures and begins toquestion: Why must I have this procedure? What didthe physician find that necessitates going through it?When will it take place? And what will they do?

3 Post-procedure: At this final stage, the patientrequires information about medication, long-termmanagement and his/her future outlook.

A real example: “Colonoscopy”. The patient asks:

Why am I getting this?

At this point, there is an opportunity to provide thepatient with factual, easy-to-understand information, to

allay his/her fears prior to the procedure. For example:

� There are many types of problems that can occur inthe colon. Directly viewing the inside of the colon bycolonoscopy is usually the best exam option.

� Colonoscopy is used for:

• Colon cancer – a serious but highly curablemalignancy

• Polyps – fleshy tumors which usually are theforerunners of colon cancer

• Colitis (ulcerative or Crohn's) – chronic, recurrentinflammation of the colon

• Diverticulosis and diverticulitis – pockets alongthe intestinal wall that develop over time and canbecome infected

• Bleeding lesions – bleeding may occur fromdifferent points in the colon

• Abdominal symptoms, such as pain ordiscomfort, particularly if associated with weightloss or anemia

• Abnormal barium x-ray exam

• Chronic diarrhea, constipation, or a change inbowel habits

• Anemia

What should I expect?

� Preparation. To obtain the full benefits of the exam,the colon must be clean and free of stool. The patientreceives instructions on how to do this. It involvesdrinking a solution which flushes the colon clean ortaking laxatives and enemas. Usually the patientdrinks only clear liquids and eats no food for the daybefore the exam. The physician advises the patientregarding the use of regular medications during thattime.

� The Procedure. Colonoscopy is usually performed onan outpatient basis. The patient is mildly sedated, theendoscope is inserted through the anus and movedgently around the bends of the colon. If a polyp isencountered, a thin wire snare is used to lasso it.Electrocautery (electrical heat) is applied to painlesslyremove it. Other tests can be performed duringcolonoscopy, including biopsy to obtain a small tissuespecimen for microscopic analysis.

� Recovery. The procedure takes 15 to 30 minutes and isseldom remembered by the sedated patient. A

THE PATIENT JOURNEYThe benefits of well-informed, targeted guidance and informationby Marta Garrido

DR MARTA GARRIDO PhD, is a medical writer withMerit Publishing Internationalemail: [email protected]


recovery area is available to monitor vital signs untilthe patient is fully awake. It is normal to experiencemild cramping or abdominal pressure following theexam. This usually subsides in an hour or so.

What happens after the procedure? Whatdo the results mean? What do I need todo next?

After the exam, the physician explains the findings tothe patient and family. If the effects of the sedatives areprolonged, the physician may suggest an appointmentat a later date. If a biopsy has been performed or a polypremoved, the results of these are not available for threeto seven days.

How was it? Is there any value in lettingthe physician or the facility know aboutthe patient’s experience?

The patient understood the reason for the procedure;understood what to expect during the preparationsversus the actual procedure. Because of this, the patientwent home after the procedure feeling at ease with whathappened and what could happen next.

The previous example has given us a tangible exampleof what information would be beneficial to a patientbefore, during and after a very stressful procedure.

Now let’s translate this to a patient’searly medication experience

In this example, the patient is newly diagnosed withhypertension and is prescribed two medications for hiscondition. What should the patient know and howshould the physician approach the prescribingeducation of the hypertensive patient?

The physician should provide the patient with the nameof medication, explain exactly what the medication willdo, how long he/she will have to be on this prescriptionmedication, and be very clear about the dosage amountand frequency, as well as possible adverse effects. Also,it is important the physician speaks to the patientregarding drug interaction with other prescribedmedication and possible herbal products the patientmay be taking.

In this scenario, the impact of failure on the physician’spart to interact with the patient in a systematic andunderstandable manner – the impact of physicianslacking the time they need with patients – wasexamined in a 2006 study by Tarn et al, at UCLA1. Thestudy reported on the extent of communication by thephysician of critical medication information uponprescribing a new medication. The patients’ visits wereaudio-taped and evaluated using the following fivecriteria:

� Name of Medication

� Purpose

� Duration

� Dosage (amount/frequency)

� Adverse Events

The results were staggering. Thirty-eight percent of theessential criteria of the prescribed medication were notcommunicated. The resulting impact: Less communi -cation and fewer explanations about the medication led tolower compliance and poorer outcomes.

In addition to in-person communication, the printedmaterial available to patients with their prescriptions isoften unhelpful. Patient prescription information (PI),included with most prescriptions, contains numerouscolumns of printed details in a size that often requires amagnifying glass to read. Should a patient attempt toread it, the clinical content in many cases would be fartoo difficult to understand. Overall, PI sheets lack aphysician’s personal touch, which is vitally important forpatient compliance.

Addressing the need to revise patient informationregarding prescribed medication is vital to targetingpatient compliance. Low compliance translates not onlyinto poorer outcomes for the patient but also into anenormous amount of missed revenue opportunity forthe pharmaceutical industry.

Providing a patient education program with feedbackloops engages the client from the initial contact point ofprescribing, and encourages patients to continue takingmedication for the duration of the therapeutic period.This assertion was borne out by a case study by theHeart Alliance conducted between October 2001 –August 2003, which engaged 52,000 patients throughover 14,500 physicians, showing the following results:

� 91% of patients indicated the educational supportprogram helped them take medication at onset

� 95% of patients thought the program was helpful and92% thought it helpful in managing their flushingspecifically

� 98% of patients indicated the Heart Alliance programwould be helpful to others

� 88% of patients reported better perception ofphysician care because of program

� 93% of patients agreed to be re-contacted in thefuture about this program or others

The Program Objectives for the above study were asfollows:

� Actively resolve significant product drop-off andincrease product persistency

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� Reduce level of physician resistance towardprescribing by providing patient education andsupport

The Financial Impact in terms of drug sales showed:

� 71% improvement in product persistency

� 89% of patients report taking the medication all thetime; 8% report taking it nearly all the time

� 93% of patients indicate intent to continuemedication use

This study demonstrates the potential for pharmaceuticalcompanies and providers to enhance the outcome ofthe “patient journey” discussed in our introduction. It isimportant for prescribing physicians to maintain theflow of information and advice begun with the initialprescription. Below are some suggestions on how tomaintain dialogue with the patient in order to keephim/her engaged and so enhance the chances for bettermedication adherence:

Shift the emphasis

� Simple definitions that were used initially do notneed to be emphasized now. Definitions may expandto include more information about the relevantdisease and medications.

Provide targeted “needs-based”interactions

� It is important to move on to other moresophisticated and/or long-term needs. What does thepatient need now? He/she has been on X medicationfor six months and at this time, she/he may beasymptomatic and ready to “forget” to take themedication or even to refill the prescription.

Increase the focus on adherence andpersistency

� After the initial experience, more of the interactionsdeal with issues related to continuing use. Why dopatients stop taking medications? What can be doneto increase compliance?

Modify the frequency of interactions, asneeded

� Over time, feedback frequency may decrease as thepatient reaches equilibrium.

Summary

� There are still gaps in patients’ full understanding oftreatment and physicians or institutions’ knowledgeof treatment outcomes.

• Knowledge of condition

• Treatment expectations

• Early experience

� There are multiple ways of aiding understandingthrough the use of printed materials, interactivesurveys, interactive programs, on-line programs andothers.

� Using a feedback loop provides benefits throughoutthe patient journey – potentially helping theprocesses of care, outcomes and the understandingof the treatment experience.

� However, embedded within the challenges this maypose is the potential for providing net newinformation – configured in ways unseen to date

Reference1. Tarn DM et al. Physician communication when prescribing new

medications. Arch Intern Med 2006;166: 1855–1862.

The above article is based on a presentation by PaulLeVine, Vice President, Analytic Services, InfoMedics, Inc.given at the Patient Centered Marketing Conference onSeptember 2007 in Princeton, New Jersey.

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The beetle and its valve system

Anew spray system known as µMist® has beendeveloped, inspired by the physics of the

remarkable spray mechanism of the Bombardierbeetle. This unusual Bombardier beetle (seeFigure 1) heats up water to above boiling point in atiny combustion chamber less than 1mm in size byan exothermic chemical reaction and then sprays itfrom a moveable turret in its posterior in anydirection it wishes (even over its head…!). Thebeetle uses this mechanism for warding off attacksfrom spiders, frogs, ants and birds. The beetleforms the noxious spray1 (which is in a solutionmainly composed of water) by reacting smallamounts of hydroquinone with hydrogen peroxidein the tiny combustion chamber in the presence ofthe catalysts catalase and peroxidase. Thisexothermic reaction then produces benzoquinoneand water, and heats up the solution (mainly water)to above boiling.

The pioneering work by Professor Tom Eisner of CornellUniversity2 showed that the mixture ejection is notcontinuous but is in fact a series of explosions similar topulse combustion. The reactants fill the chamber, reactand are ejected, then more reactants enter and the cycleis repeated at a frequency so high (400-500Hz) that ittook a high speed camera operating at kHz to resolve theindividual explosions.

This inspired Professor Andy McIntosh and his researchteam (including research fellow Novid Beheshti and PhDstudent Andreas Prongidis) at Leeds University, UK, toinvestigate the physics of the combustion chamber byfirst using CFD (computational fluid dynamics)modelling supported by EPSRC (Engineering andPhysical Sciences Research Council), and then with thesupport of Swedish Biomimetics 3000®, building aworking model of the beetle combustion chamber.

The dynamics of the actual physical mechanism of thebeetle ejection system only really became understoodwhen Andy McIntosh and Tom Eisner were discussingthe nature of one of the dissections Tom had made ofthe beetle chamber (Figure 1a). It was one of thoseinspirational ‘lightbulb’ moments. The inlet valvemechanism is an ingenious mechanism as illustrated inFigure 1b. When the inlet hydroquinone and hydrogenperoxide has filled the chamber, the extremities of thechamber itself pinch the inlet tubes rather like a ’boxingglove’ (see the top left of the picture where the frayedtissue from the inlet tubes is visible). At the other end,the exit tube for each chamber is shown at the bottomright of the photograph. At first it was presumed thishad been sliced and that one was looking on the insideof the exit tubes. However the Leeds team was assuredby Tom Eisner this was not the case, and that all thechamber is shown from an external perspective. Oncethis was established, it became evident that the exittube with the membrane of cuticle hanging down, is infact a pressure relief valve. This now made the overallejection mechanism clear. With the inlet valve shut atatmospheric pressure and the exhaust valve shut, theboiling water mixture raises the pressure to a pointwhere the only way out is to push against the exhaustvalve by pushing the fluid against the membrane. This isdone till the membrane gives way, and the pressurerelief valve now becomes open, leading to flashevaporation as the fluid boils under suddendecompression. The low pressure following such anexplosion, then enables the inlet valve to open (the‘boxing glove’ releases its stranglehold on the inlettubing) and more fuel enters the chamber, and the cycleis repeated. The key finding was the nature of this valvesystem.

The physical interpretation of the CFD simulationsshowed that flash evaporation was indeed the keyprinciple involved, and that with an appropriate criticalrelease pressure, strikingly similar results in terms ofpredicted mass ejection and frequency are obtainedbetween the CFD simulations and the measurableresults from Tom Eisner’s experiments3. One can likenthe beetle’s defence mechanism to a pressure cookercontrolled by an additional system of valves: Theessential feature is a repetitive high-force steamcavitation explosion, but from a chamber less than onemillimetre long!

BIO-INSPIRATION FOR NEWPHARMACEUTICAL SPRAYS… by Andy McIntosh

ANDY MCINTOSH is Professor of Thermodynamicsand Combustion Theory, Energy and ResourcesResearch Institute, School of Process, Environmentaland Materials Engineering, University of Leeds, UKemail: [email protected] BEHESHTI was formerly a Research Fellow atthe University of Leeds and is now TechnicalPrincipal at Swedish Biomimetics 3000 UK Ltd.


Inspiration for pharmaceutical sprays

The prospect of a µMist® technology where droplet size,temperature and velocity could be closely controlled,led to the strong interest from Swedish Biomimetics3000® and the support to build an experimental rigwhich replicated the core technical features of thebeetle, ie the important combustion chamber and valvesystem of the Bombardier beetle.

So an experimental rig was designed and built to test outthe theory in practice (Figure 2). The catalytic chemistryof the beetle is not copied in the rig, but instead theheating is done electrically. Excellent results wereobtained from this experimental research rig. Forinstance the throw ratio (maximum throw distancedivided by the length of the combustion chamber) wasthe same for both the beetle and the rig. The beetle’scombustion chamber is less than 1mm long and throwsto about 20cm. So the throw ratio is 200. Theexperimental rig has a chamber length of approx 2cm sothe maximum throw distance is an impressive 4 metres.In accordance with the best global innovation practices,a characterisation and development program inconsultation with Quintiles Consulting Europe led fromthis initial research rig to the development of a pre-prototype µMist® spray system – leading to a potentialInhaled drug delivery system using the µMist®Technology.

The µMist® spray system enables spray droplet size,temperature and velocity to be closely controlled,allowing applications in a variety of areas where theproperties of the mist are critical. These applications ofthe generic technology include many areas besidemedicine (such as fuel injection, aerosols, fire

extinguishers and fire suppression), all of which facemajor challenges relating to the demands of greaterperformance and reduced environmental impact ofhigh performance mists.

A major application is to medical drug delivery systems.In application areas such as soft mist inhalers, the newtechnology offers a potentially major leap forward inperformance, since µMist® can deliver highly

BBIIOO--IINNSSPPIIRRAATTIIOONN FFOORR NNEEWW PPHHAARRMMAACCEEUUTTIICCAALL SSPPRRAAYYSS…… ((ccoonntt..))

Figure 1a. The twin combustion chambers and nozzles in the bombardier beetle (Stenaptinus insignis) from a dissection by Professor TomEisner (Cornell University) and their pressure-release exit valves. Figure 1b. On the right a schematic diagram of the cross section of theexit valve in open and closed conditions is shown. These valves are in fact in a closed condition in the photograph on the left.

Figure 2. Experimental rig inspired by the Bombardier beetlecombustion chamber – scaled up to 2cm long and able to fire 4metres. The bombardier Beetle Rig was built by the research teamled by Professor McIntosh of University of Leeds, This has thecapacity to eject very fine mist or large droplets. The maximumthrow ratio (distance thrown divided by chamber dimension) is200 – the same as the beetle itself which throws a mixture ofwater, steam and quinones a distance of 20cm from a chamberless than 1mm long.


LATVIAN INDUSTRIAL PHARMACISTSby Inta Saprovska

INTA SAPROVSKA is Head of the Industrial PharmacistsSection of the Pharmacists Society of Latvia

characterised droplets with variable sizes4 between 2µmand 100µm, including what we believe to offer thefinest-in-class performance inhalers. The technologycould function as a water-based carrier for propellingand delivering various therapeutic substances withoutthe use of conventional propellants, some of which arepotential pollutants. Nebulisers, inhalers, needle-freeinjection systems and hand and wound cleansers alldemand carefully designed spray systems with preciselycontrolled droplet properties.

A major advantage of the µMist® spray system is theability to choose and adjust the mist’s characteristics byadjusting the electronic control panel parameters of therig.

In summary, the main features are that droplet size canbe readily adjusted to provide an optimal carrierperformance through the electronic control interface.

This can achieve – with an aqueous carrier – dropletswhich have controllable sizes, size distribution,temperatures, ejection frequencies and ejectionvelocities. The ability to alter the mist output provides acapability which can be optimised for a particulartherapeutic utilisation – and this facilitates the greattherapeutic potential of this radical technology.

References1. Schildknecht H, Holoubek K. Angew. Chem., 1961; 73: 1–7.2. Aneshansley DJ, Eisner T. Spray aiming in the bombardier beetle:

photographic evidence. Proc. Natl Acad.Sci. USA, 1999 96: 9705–9709.3. See Beheshti N, McIntosh AC. The bombardier beetle and its use of a

pressure relief valve system to deliver a periodic pulsed spray.Bioinspiration and Biomimetics, 2007; 2: 57–64.

4. This droplet size is on the basis that 90% of the droplets are less thanthe quoted value. Termed DV90, this means that the DV50 (50%) leveloften quoted by manufacturers and the SMD (Sauter Mean Diameter)are smaller still.

BBIIOO--IINNSSPPIIRRAATTIIOONN FFOORR NNEEWW PPHHAARRMMAACCEEUUTTIICCAALL SSPPRRAAYYSS…… ((ccoonntt..))


Some years ago, the newly formed IndustrialPharmacists Section of the Pharmacists Society

of Latvia started a rather wide online discussionbecause many pharmacists didn’t understand whatindustrial pharmacists were. The idea of creatingsuch a section in Latvia occurred after attendingthe International Congresses of FIP.

In the industrial pharmacist circle, both Latvian andforeign drug manufacturer representatives (pharmacists,wholesalers, academic faculty and other persons)considered themselves as belonging to a society of non-pharmacy pharmacists.

In 2004, when EIPG was looking for co-operationpossibilities with newly-joining EU countries, Latvianindustrial pharmacists proved to be the most active Sectionand in 2006 the Latvian Industrial Pharmacists Sectionbecame EIPG observers. Last year at the EIPG GeneralAssembly in Prague, it was enrolled as an official associationmember, as the first and currently only Baltic State. Nextyear’s EIPG General Assembly will be held in Riga.

Until now the Pharmacists Society of Latvia hadconcentrated its attentions on the interests of communitypharmacists, thereby neglecting the activity of thosepharmacists involved in drug manufacturing and otherfields. At their first meeting, local drug producers admittedthat the main problem of this branch was pharmacisteducation, as there was a dire need for pharmacists at

drug manufacturing units. They also recognized thenecessity to increase the prestige of pharmacists working inthe industry and pharmacist prestige in general. It was alsodecided to involve quality individuals, heads of productiondepartments and pharmacists working at laboratories in theactivities of the Section. It would be also be valuable forpharmacists working in drug manufacturing to improve theirpostgraduate training; for this reason, special programmes, ofwhich Latvia currently has a shortage, would be developed.

The main aims of the Industrial Pharmacists Section are: tocreate and to maintain relations between pharmacists,whose work is connected with matters of industrialpharmacy practice, to support the industrial pharmacistsspecialization and educational programme for in-servicetraining, to favour participation of pharmacists in industrialmanufacturing and to increase their prestige in theindustrial field, to support the professional contribution ofpharmacists to the pharmaceutical industry and other largescale conventions with European industrial pharmacistaims. More ambitious aims exist in future as well, forexample, certification of quality individuals according toemerging European viewpoints.

With the intent to share their experiences, members of theSection visit drug manufacturing units and wholesalers,meet each other to discuss the activities and updates inlegislation, and regularly receive information on theSection’s activities via electronic newsletter and publicationsin the pharmaceutical magazine Materia medica. Themeeting place at the Pharmaceutical Museum creates thelink between the past and the future of pharmacies and isa treasury of historical events of Latvian Pharmacydevelopment for future pharmacists.

Times are changing

The development and manufacturing environ mentin the pharmaceutical industry is changing rapidly

and one has to wonder if the current concept of therole and responsi bilities of the Qualified Person alsoneed to change. We are moving from “Quality bytesting and inspection” to the concept of “Quality byDesign”, where quality is built into the product andprocess during the development phase. We aremoving away from traditional specifications to aconcept of monitoring quality during processing withsuitably chosen in-process controls and continuousverification, which is also going to replace traditional3-batch validation. This in turn is also going to allowreal-time or parametric release of batches instead ofend point testing.

Assuring quality and continuation of supply ofmedicines to the patient requires not only individualbatches to be within specification, but also processesthat are robust and reliable. Process understanding,quality risk management and continual improvementare becoming the cornerstones of the quality paradigm.Risk-based and science-based decisions are nowexpected instead of compliance-based decisions. Alsothe logistics of our supply chain are becoming morecomplex as we move away from local stand-aloneprocesses to complex international supply chains and aswe move away from only supplying local markets tosupplying multiple international markets from strategicmanufacturing facilities. We are also seeing an increasein the number of and the time spent on inspections, notjust from our own local inspectorates but from manyother inspectorates from the markets which we supplyaround the world, who all expect us to comply with theirown local GMPs.

In this rapidly changing environment, the traditionalrole of the Qualified Person that focuses on certificationof each individual batch seems outdated. Surely thereare better ways to protect the patient than focussing onindividual batch release. This paper will examine someof the changes mentioned above and how the role and

responsibilities of the QP need to be adapted to respondto these new concepts.

Quality by design and processunderstanding

There is no disputing the concept that the QualifiedPerson (QP) remains responsible for the quality of theproduct released to the market. But as we see morereliance placed on building the quality into the design ofthe product and the design of the process, more reliancewill be placed on process understanding, criticalparameters and in-process controls. The QP has to finda new way to assure him/her self of the quality of theproduct instead of relying on final product testing. TheQP must be assured that quality is indeed built into theprocess during development and must also have athorough understanding of the critical parameters, thedesign space parameters and the controls required. Ithas been said that in spite of these new concepts, mostprocess understanding will be gained after productlaunch. Process under standing is the key to:

� product quality,

� process robustness,

� change management decisions,

� quality risk management decisions,

� decisions on deviations, and

� decisions on process improvement,

all of which require a strong involvement of the QP.Therefore, the QP must be satisfied that the level ofprocess understanding is sufficient for him/her to certifythe product for release to the market, even on the firstday after launch and should be part of the team thatdecides how much process understanding is required tolaunch the product onto the market. The QP must alsoensure that there is a system in place to ensure thatchanges are made either within the design space andthe Marketing Authorisation or that, where necessary,changes are submitted for marketing authorisationapproval by the competent authorities.

The design space concept, as developed in ICH Q8,together with process analytical technology also allowsus to move away from traditional specifications to acontrol strategy based on in-line and at-line processcontrols. As a consequence, routine end product testingmay not be necessary and batches may be certifiedbased on process control measurements that assureproduct quality. A “Process Signature” may be used that

THE ROLE OF THE QUALIFIED PERSONIN THE 21ST CENTURYby Joyce Ramsbotham

JOYCE RAMSBOTHAM was formerly InternationalQuality Specialist at Solvay and Chairperson of theEFPIA Manufacturing-GMP Working Group, TheNetherlands


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will look very different from what we see in currentrelease specifications. Decisions then have to be made,based on risk assessment, on:

� the frequency of the controls,

� sample size, and

� the alert and alarm limits.

The QP should approve the control strategy in the sameway that he/she approves traditional specifications andshould be assured that the control strategy guaranteesthe quality of the product.

Traditional validation and continuousverification

Continuous verification has the advantage that it isalways representative of routine production under allconditions, it consistently ensures that the process isunder control and it makes real-time or parametricrelease possible. In addition, it provides more datawhich contributes to process understanding, it enablesmeasurement of process capability and it establishes aframework for continuous improvement. However,carrying out continuous verification by (almost)continuous monitoring of the process does have adrawback – it may well produce more deviations, i.e.values that are outside their limits. In other words thelarger the sample size and the more frequent thesampling the more likely, by normal distributionstatistics, a value will be found which is outside thelimits, whereas the same batch would have been wellwithin specifications if tested by traditional end pointtesting. This presents a dilemma for the QP of whetherthe batch can be released or not. In fact it adds anadditional dimension to the control strategy mentionedearlier. The control strategy on which batch release canbe based needs to include not only the criticalparameters to be tested, the sample size and frequency,the upper and lower limits but also the permitted sigmadeviations, based on a risk assessment. Furthermore theQP must ensure that systems are in place to:

� identify causes of values found at the extremes of theGaussian distribution and to take corrective action,

� monitor and review trends and take preventiveaction,

� ensure continual improvement of the process.

The process should still be considered to be operating ina state of control, when, as a result of the increasedsampling level, values are found within pre-set actionlimits and within the predicted normal distribution range.

Batch certification

Traditionally batch certification took place based on theresults of end product testing, on GMP compliance and

on compliance with the Marketing Authorisation.However, if there is no end point testing done, how doesthe QP certify the batch? In such cases, the QP has tohave assurance that the control strategy is appropriateand was followed, and that systems are in place for thereview of the batch record and the in-process controlresults. However, there is a dilemma, as a traditionalCertificate of Analysis cannot be issued giving the resultsof end point testing compared to final productspecifications. Probably QPs are going to have to runhybrid systems for those countries or customers stillinsisting on a Certificate of Analysis and somepersuasion may be needed before a Certificate ofConformance or Compliance, in which the QP certifiesthat the batch has the required quality, wasmanufactured under GMP and was manufacturedaccording to the Marketing Authorisation, is universallyaccepted.

The case for quality and reliability

The release of individual batches based on end producttesting, begs the question of what the QP should dowhen batches are failing with too high a frequency.Should the QP certify the passing batches while rejectingthe failing batches? If the sample size is small, then thechances are that some batches are being passed thatshould be failed and vice versa. The robustness of theprocess is surely a far better indicator of product qualitythan individual batch results. As Moheb Nasr from FDAhas said, “A robust process is capable of handlingchanges in process inputs without negative impact onend product quality” and “Reproducible meansconsistently and predictably delivering the same qualitymaterial”. A process with a high reject rate probably hasa high chance of unreliability of supply and the patientis surely far better served by relying on process reliabilitythan on a concept of individual batch quality.

International multi-site supply chains

The world is becoming smaller and more complex.Today it is not unusual for APIs to be manufactured inChina or India, excipients to be bought from severalcountries around the world, for part of the processing tobe done in one country and other steps in anothercountry, with final packaging and release taking place inseveral different countries. Under current requirementsthe QP is expected to review all non-compliances withGMP at the various manufacturing sites, review allcritical deviations and investigations in the supply chain,review and approve all changes, ensure work is carriedout within the terms of the contract, certify suppliers ofAPIs, qualify suppliers of excipients and take personalresponsibility for all manufacturing stages. The job hasbecome impossible and certainly requires a super-human individual to perform it. Surely the role and


responsibility of the QP should be to ensure that thereare systems in place which:

� evaluate and approve the quality systems used by allplayers in the supply chain, and

� ensure that

– GMP is appropriate at each manufacturing site,

– deviations are reviewed and investigated correctly,

– changes are reviewed and approved correctly,

– supplies of APIs are appropriately certified,

– suppliers of excipients are qualified.

Some tasks may also be delegated to other QPs or toother suitably qualified competent experts.

Looking at the distribution network we again see supplyto multiple international markets. The QP has to certifythat the batch has been manufactured and checked inaccordance with each of the relevant marketingauthorisations, with EU GMP requirements and with thelocal GMP requirements and any other legalrequirements of the country in which the product is tobe marketed. Again, this is a very difficult task whichcould be better fulfilled by making the QP responsiblefor ensuring there is a system in place which:

� monitors global marketing authorisationsapplications, approvals and changes,

� monitors local GMP and legal requirements,

� ensures that each batch is manufactured inaccordance with its marketing authorisations andlocal legal requirements.

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Conclusion – the role of the Qualified Person should beto ensure that the Quality System is fit for purpose andoperating effectively

Probably anybody who has been a QP or has seen QPs atwork, has seen the burden of administrative paperworkfocussing on individual batch release. Yet there is abetter way to protect the patient than by individualbatch release. The role of the QP should be to ensurethat Quality Systems are in place and that these QualitySystems are fit for purpose and operating effectively, soas to:

� provide assurance that the system can be relied uponto support batch certification, and

� ensure that issues are raised, if necessary, at anappropriate level prior to batch certification.

The Qualified Person should also be able to delegateand rely on the decisions of other competentprofessionals within a proven quality system.

Finally if this view of the role and responsibility of theQualified Person is accepted, then one of theconsequences is that Management also has to take itsresponsibility for ensuring that a robust Quality Systemis in place, appropriately resourced and enforced. Onlywhen this concept is fully recognised will a company beable to claim that Quality Systems are fit for purpose.


Industrial Pharmaceutical MicrobiologyStandards & Controls

Editors: Norman Hodges and Geoff Hanlon

“An exceptional and uniquepublication in this field”

Microbiologist – September 2007

21 Chapters 450+ pages £325.00For details and to order

visit the Euromed website:www.euromed.uk.com

Looseleaf format

Special supplements

Regularly updated

In March and May 2003, UK Revenue & Customsseized some shipments of vitamins C + E. The

shipments were in fact counterfeit Viagra.

Acting on intelligence received from Revenue &Customs, MHRA officers conducted raids on twoaddresses where 150,000 counterfeit Viagra tablets wereseized along with information leaflets, a pot-sealingmachine and paperwork. Counterfeit Propecia, labelsand cartons were also discovered.

A large number of the pots of Viagra were labelled aseither Fish Protein and Mineral Supplements for Dogs orVitamin tablets (Figure 1).

The main individual, Gary Haywood, then fled the UKand went to Costa Rica; he claimed that the Triads wereafter him.

The Stormgrand network

From paperwork found at both addresses it wasestablished that invoices connected Haywood to acompany in the UK, Stormgrand. This was an unlicensedpharmaceutical wholesaler operated by Ashish Halaiwhose wife, Nena, ran a pharmacy called Nashipharmacy in London.

Hayward was also connected to companies in Sweden,three companies in the Bahamas and wholesalingcompanies in the UK.

The paperwork also indicated a storage site not knownto the investigators. This was searched and from dustpatterns on the floor it was established that two largepallets had been recently moved. At this point the caseexploded and become enormously complicated.

Further wholesalers were discovered and a company inNorway.

The Norwegian company was contacted by investigatorsworking for Pfizer and resulted in an under covermeeting to buy 21,000 Viagra tables. The MHRA seizedthe tablets at the same scene.

Haywood used a number of his own companies toimport these included:

� Gary J Haywood Pharmaceuticals Supplies

� Gary J Haywood Medical Supplies Pty

� Haywood and Co Ltd

� Lancaster House Ltd

In addition Stormgrand’s Ashish Halai was involved in acompany called Farmacia del Mundo and was also one

of the main suppliers of Viagra to three companies inthe Bahamas. Global Metz, JTR Associates (McCoyBorthers) and Betco Ltd (Robert Moffat).

It was then found that Halai also supplied MetroPharmacy, owned by Rajendra Shah, and LPCPharmaceuticals. He also supplied three companies inSweden, Planet Pharma, EcoWest and Crosstrading.

The US connection

The Robert Moffat of Betco operated a bonded warehousein the Bahamas. He has since been arrested, indicted andimprisoned by the US authorities. Moffat informed theauthorities in 2004 that a Nick Malis had put out a contracton the life of Halai. Nick Malis was subsequently arrested.

OPERATION STORMGRAND – A TANGLEDWEB OF WORLDWIDE DECEITby Joe Ridge


What are counterfeit medicines?

A counterfeit medicine is one which is deliberatelyand fraudulently mislabeled with respect to identityand/or source. Counterfeiting can apply to bothbranded and generic products and counterfeitproducts may include products with correctingredients, wrong ingredients, without activeingredients, with insufficient quantity of activeingredient or with fake packaging.

World Health Organisation

Counterfeit medicines – the facts

� The WHO estimate that up to 1% of medicine iscounterfeit in the developed world.

� Counterfeit medicine is more commonlyavailable through the unregulated supply chain,usually the Internet.

� Less frequently, but more worryingly, it issometimes available through the regulatedsupply chain via wholesalers, distributors andpharmacies to patients Figure 2.

� Counterfeit medicines available in the developedworld include ‘lifestyle’ and ‘lifesaving’ medicinesfrom conditions such as erectile dysfunction andweight loss to cancer and heart medicines.

� Visual examination alone often fails to identifythe counterfeits.

� There have been thousands of known fatalitiesaround the world.

� Counterfeits are dangerous and underminepublic confidence in medicines.

“Operation Ocean Crossing” resulted in raids in 5locations in Tianjin City and Henan province. Hugeamounts of equipment were seized, in addition to600,000 counterfeit Viagra, 440,000 counterfeit Cialisand 260kg of bulk raw material. Eleven Chinesenationals were arrested.

Cowley was charged with Misbranding and Counterfeiting,sentenced to two years imprisonment and a substantialfine.

Results of Operation Stormgrand

As a result of Operation Stormgrand in the UK, a total ofnine defendants were charged with conspiracy, atKingston Crown Court in Surrey. Ashish Halai, pleadedguilty at start of trial and was sentenced to 41⁄2 years inprison; Nena Halai, pleaded guilty and received 80hours community service; Gary Haywood was sentencedto 6 years after an 8-month trial; Ashwin Patel wassentenced to 18 months imprisonment; Zahid Mirza fledthe UK after being found guilty – he was sentenced to 21⁄2years in his absence.

Thus, one chance detection by Customs in 2003 and thefollowing investigation by the MHRA, led to intelligencebeing passed to overseas counterparts that eventuallyreached 39 countries worldwide. Industry estimatesplace the total number of individuals arrested as a resultin the region of 1,000.

Based on information provided by the Operations,Enforcement and Intelligence Group of the MHRA

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He was operating a company called One Source inDallas, Texas.

As a result of information passed to the US a total of 11individuals were arrested and prosecuted. Over 20websites have been closed down and assets involvingseveral millions of dollars have been restrained andsome already confiscated.

Further developments

In the summer of 2004, counterfeit Cialis and Reductiltablets were discovered in the UK supply chain. This wasinitially investigated as a case on its own. However, byfollowing the audit trail it quickly became apparent thatit was intricately linked to Stormgrand. Many of thesame names were cropping up time and time again. Theinvestigation was therefore merged with Stormgrandwhich became even more complex.

Following the arrests in the US some of the arrestedindividuals decided to co-operate with ImmigrationCustoms Enforcement (ICE), which let to the maindefendant in the US, Richard Cowley, being charged withthe counterfeiting of Viagra, Cialis and Lipitor.

Whilst this was ongoing the UK suffered its 3rdcounterfeit case within the space of 12 months, this timeit was Lipitor.

The Chinese connection

Cowley’s home PC was seized and analysis revealeddetails of contacts in China. As a result, ICE field officeagents assisted officials of the ministry of Public Security(MPS) and the Public Security Bureau in China todetermine the source of counterfeits.

Figure 2. How counterfeit medicines are distributed.

Manufacturer(May be licensed, typically

in Far East)

Trader/brokerAdvertised in newsgroups

Grey market(Parallels? Unlicensed?)

Lifestyle products

Pharmacy Internet site

Patient

Regulatedchain

Unregulatedchain

Wholesaler(May be licensed)

Website operator(Unlicensed)

Figure 1. Pot containing counterfeit Viagra.


The period since the last update on developmentsin EU regulatory controls and guidance for

pharmaceuticals has seen:

� A continuation of the process of developing andupdating GMP Guidance.

� Further work on guidance for clinical trials.

� Harmonisation of pharmacopoeial methods.

� An expedited revision of the European Pharmacopeiamonographs on Heparins resulting from quality andpatient safety problems in late 2007 and in 2008.

� A new website for the British Pharmacopoeia and anew edition of the “BP”.

We hope that you find some if not all of the following tobe useful in your work and/or professional development.

Changes in EU healthcare productslegislation and good practices

Revision of EU GMP Guide

A (major) revised version of the EU GMP Annex 3 dealingwith the manufacture of radio-pharmaceuticals has beenpublished. This is due to come into effect in March 2009.

Proposed changes to the EU GMP Guide

The European Medicines Agency has published a shortpaper explaining the development of GMP for advancedtherapy medicines (ATMPs). This is likely to be achievedby modifying Annex 2 to the EU GMP Guide (theManufacture of Biological Medicinal Products).

Regulation of clinical trials in the EU

New and revised guidance has been published forclinical trials performed in the EU covering:

� The documentation required in connection withclinical trials on human subjects.

� Information to be made available in the publicdomain from the EU clinical trials database.

Consultation is in progress on:

� Good Clinical Practice for ATMPs.

� Information to be made available in the publicdomain on paediatric clinical trials.

Review of UK Medicines Legislation

For the most part European legislation is implemented inthe Member States through national laws. In the UK this

REGULATORY REVIEW:Review of major developments in GMP and the regulationof medicines in the EU and on the International Scene,June to August 2008

by Steve Fairchild

process has been taking place for some 40 years and has ledto a somewhat complex set of legal instruments and laws.The UK regulatory authority (the MHRA) has proposed arevision of the UK medicines law that will take place overthe next 2 or so years. It is hoped that this will deliversimpler and more accessible medicines regulations.

Pharmacopoeial developments

Harmonisation of General Monographswithin ICH

For a number of years the Pharmacopoeias of the three ICHRegions have been working on the harmonisation ofpharmacopoeial monographs. This process has recentlytaken a step forward with the finalisation of two general testmethods for parenteral products. These are for extractablevolume and sub-visible particulate contamination.

Draft texts have also been published for:

� Microbiological tests on non-sterile products.

� Disintegration testing solid dosage forms.

Revised Ph. Eur. Monographs for Heparins

The European Pharmacopoeia has published expeditedrevisions of the monographs for Heparin active ingredient.This was in response to serious quality and safety problemsover the last year with certain sources of Heparin. Therevisions are intended to ensure the detection of thecontaminant that was apparently the cause of the problems.

New Website for the BritishPharmacopoeia (BP)

The MHRA has launched a new website for the BP thatprovides a number of new features including asubscriber service providing accesses to documentsrelated to but not appearing in the BP, corrections anddocumentation for requesting new and modifiedmonographs.

British Pharmacopoeia 2009 Edition

The latest edition of the BP went on sale at the end oflast August and is now available from the StationeryOffice in hard copy and in 2 different electronic formats.This new edition comes into force on January 1st 2009.

For further information on these and other topics pleaserefer to current and past editions of “GMP Review News”published by Euromed Communications. To subscribe tothis monthly news service contact [email protected]

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 1 October 2008 19

2008 General Assembly of the EuropeanIndustrial Pharmacists Group

The 2008 General Assembly of the European IndustrialPharmacists Group was held in Malta on the 19th and20th April. This year, the General Assembly was precededon the 18th April by a public seminar organised jointlybetween the Malta Qualified Persons Association, EIPGand the University of Malta. The seminar was entitled"The Successes and Challenges of Today's PharmaceuticalIndustry" and featured talks by Luigi Martini (DevelopmentChallenges facing Big Pharma and the IndustrialPharmacist), Piero Iamartino (The Qualified Person andMinor Deviations), Françoise Robinet (The newRepresentatives Charter and the Quality of PromotionalMessages) and Kiriasis Savvas (Pricing of MedicinalProducts and Reimbursement Systems in Europe).

The update of the year's activities showed EIPG to havehad an active year since the last General Assembly inPrague, particularly in establishing the EIPG as an activepartner in consultations with the European MedicinesAgency, thanks to the efforts of Piero Iamartino andJohn Jolley. EIPG had also been active in mattersconcerning education. An invitation to the Conference ofthe European Association of Faculties of Pharmacy hadresulted in a joint submission between EIPG, EAHP, PGEUand EAFP for European Commission funding for twoprojects: PHARMINE – a review of undergraduatepharmacy courses – and PHARMIND – a survey of thecompetencies needed for a career as an industrialpharmacist. The new Executive Director, Jane Nicholson,also attended a meeting of the EAHP, at which an updateof the European Medicines Research Academy wasreviewed, and held discussions with the Executive Boardof the Hospital Group on matters of mutual interest.

A number of key presentations were made in the course ofthe General Assembly, foremost among them an updateon the EIPG Guide to Good Regulatory Practice, by ValérieLacamoire (France), who was assisted by regulatory affairspharmacists from Germany and Great Britain. In the lightof these recommendations, regulatory affairs pharmacistsfrom Italy, Belgium and Denmark subsequent expressedinterest in setting up a working group on ContinuingProfessional Development for pharmacists in regulatoryaffairs. John Jolley (Great Britain) delivered a talk entitled"Industry Implications of Pharmaceutical Quality ICHGuidelines", outlining the implications of ICH Q8, Q9 andQ10 guidelines in pharmaceutical product life cycles,whilst the deliberations of the Assembly on the educationof industrial pharmacists were supported by apresentation from the invited speaker Prof. Alfred Vella,Pro-Rector of the University of Malta, on "The Bolognaprocess and university reform".

National initiatives in the Member States were alsocommunicated to the Assembly. Jean-Pierre Pacconi(France) delivered two presentations, the firstrepresenting an update on the competency scheme forthe education of industrial pharmacists in France, andthe second an initiative in the form of a new workinggroup in France for recommendations in achieving areliable network for cool transport. The latter elicitedconsiderable interest amongst the delegates and willconstitute one of the topics of discussion at the nextGeneral Assembly. There was also a presentation byPhilippe Van der Hofstadt (Belgium) on a Belgianinitiative for cGMP in clinical trials, well received by Italy,Netherlands and Great Britain.

The Working Group on undergraduate and postgraduateeducation, attended by delegates from Great Britain,Czech Republic, Netherlands, Finland, Sweden, France,Hungary and Spain discussed the competencies andskills required to become an Industrial Pharmacist indifferent EU countries, with the two main strategiesbeing a specialised cycle for industrial pharmacists asseen in France and Finland, or a general degree withorientation in later years, as seen in Netherlands, Spainand Czech Republic. France and Netherlands arecurrently working on competencies for industrialpharmacists, and the next assembly will discuss theirfeedback in considering initiatives in CPD for industrialpharmacists. The second Working Group, discussingfuture employment prospects of industrial pharmacists,was attended by delegates from Germany, Belgium,France, Portugal, Hungary, Latvia and Great Britain. Thegroup conducted a SWOT analysis of future employmentprospects for industrial pharmacists in Europe in thelight of increasing globalisation trends and downsizingof companies, coupled with decreasing numbers ofNCE's and increased generic new drug approvals. A thirdWorking Group, attended by Malta, Italy, France,Netherlands and Greece, discussed an EIPG positionpaper on counterfeit medicinal products in response tothe public consultation paper issued by the EuropeanCommission. This position paper was concludedfollowing the General Assembly and submitted both tothe European Commission and the MHRA.

The General Assembly concluded on the 20th April withthe election of Jakob Bjerg Larsen (Denmark) and ClaudeFarrugia (Malta) to the Vice-Presidencies of EIPG. In theprocess of the President's concluding speech, theAssembly concurred that EIPG should, throughout thecoming year, focus its efforts on technical directives andguidelines, communications, and maintenance ofprofessional standards. The Assembly also approvedLatvia as the venue for the General Assembly of 2009.

NEWS FROM THE EIPG

recommend that companies communicate with theauthorities as soon as possible about impendingshortages that are likely to have an impact on patientcare. This early exchange of information will enable theauthorities and the industry to work together to explorethe options for managing the shortage and will allow timeto make contingency arrangements where necessary.

Compliance with the requirements of theMarketing Authorisation

A batch of medicinal product that does not comply withthe requirements of the marketing authorisation cannotlawfully be released for sale. From time to time aQualified Person (QP) can be faced with a batch ofproduct that does not fully comply with all the detailsdescribed in the authorised marketing authorisationdossier. The competent authorities have beenconsidering whether or not a QP is able to certify suchbatches, as required in Art. 55(3)/51(3) of Directive2001/82(3)/EC, thereby allowing them to be released forsale. A reflection paper is hereby published, which isintended to clarify, in the circumstances described,whether a batch complies with the requirements of themarketing authorisation or not. The paper describescertain conditions that must be met. It is hoped that thispaper will be helpful in dealing with a large proportionof cases where there has been some uncertainty in thepast. Cases of non-compliance outside the scope of thispaper must continue to be dealt with by following therelevant national procedures.

The European Commission has signalled its possiblefuture support for a corresponding amendment toAnnex 16 of the GMP Guide (Certification by a QualifiedPerson and Batch Release). This will partly depend onfeedback from the industry on the practicalimplementation of the details in this reflection paper.EMEA is presently considering, together with theCommission, how this feedback should be collected andfurther information on this will be provided in thecoming months.

Presentation of information in MA dossiers

The EMEA PAT team has published a reflection paperproviding preliminary recommendations on how PATrelated information should be presented in applicationsor variations to Marketing Authorisations. Work on thistopic is under continuing development and as a flexibleregulatory approach is important to avoid unnecessarybarriers to improved product quality, it is notappropriate to publish formal guidance at this time.Nevertheless, the paper is intended to assist companiesplanning to file PAT-based submissions in the short tomedium term. Feedback from the industry on thecontents of the paper should be sent [email protected]

eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 1 October 200820

EIPG Communication on ResponsiblePharmacists in Pharmaceutical Wholesaling

Following the recommendations of the GeneralAssembly, on the 19th June 2007 the EIPG has written tothe European Commission and EMEA, expressing itsconcerns over the recent outbreaks of counterfeitmedicines. The EIPG has commented on the potentialdiversity of the transposition in Member States' nationallegislation of Article 79 of Directive 2001/83/EC,specifically the term "qualified person designated asresponsible" (also known as the Responsible Person) inrespect of wholesale distribution of medicinal products.The EIPG has expressed its belief that the termResponsible Person should be replaced by ResponsiblePharmacist in all Member States, since the training ofpharmacists is most suited towards the establishmentand implementation of the necessary Good DistributionPractices necessary to substantially reduce the impact ofcounterfeit medicines.

EIPG Guidance on Continuing ProfessionalDevelopment for Qualified Persons

During the 2007 General Assembly in Prague, theWorking Group on Qualified Person matters presentedthe final version of a document regarding Guidance onContinuing Professional Development for QualifiedPersons. The document was approved by the GeneralAssembly, and will be proposed by EIPG as a guide for allQualified Persons, Technical Directors and otherResponsible Persons. Comments on the document arewelcome and should be submitted to [email protected].

Career Options: How does one become aqualified person?

Seen or heard the term “QP” or “qualified person” andwondered what it meant? Interested in the careeropportunities provided by the pharmaceutical industry?Malcolm E. Brown outlines what QPs do and how tobecome one, and Sadia Khan follows with a moredetailed look at the QP registration process. (Tomorrow'sPharmacist: January 2007).

Best Practice Guidelines on Notificationand Management of Medicines Shortages

The United Kingdom Department of Health, inassociation with the pharmaceutical industry, hasrecently published best practice guidelines on thenotification and management of medicines shortages.Two separate guidelines have been published, one incollaboration with the Association of the BritishPharmaceutical Industry (click here), and the other incollaboration with the British Generic ManufacturersAssociation (click here). The guidelines are designed tohelp minimise the impact of any medicine shortage. They

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eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 1 October 2008 21

19-21 November 2008 – Brussels,BelgiumProduction of highly-potent sterilepharmaceuticalswww.apv-mainz.de

24-26 November 2008 – Cambridge, UKTabletting technology for thepharmaceutical industrywww.rpsgb.org/world ofpharmacy/events

25-26 November 2008 – Copenhagen,DenmarkStability testing for drug substancesand drug productswww.gmp-compliance.org

26-27 November 2008 – Brighton, UKBioProcess International 2008www.bioprocessuk.com

26-27 November 2008 – London, UKCPD framework for the Europeanpharmacist – a joint EIPG/PHSSconferencewww.phss.co.uk

DDEECCEEMMBBEERR1-2 December 2008 – Munich,Germany1st IPEC European conference onGMP for pharmaceutical excipientswww.ipec-conference.org

Hard hitting web-based GMP training in thecomfort and convenience of your office or home(save on expensive and inconvenient travel:

These seminars are offered as web-based learning:

• Passing an FDA Inspection – Guaranteed

• Managing the QC Lab in a GMP Manner

• Fundamentals and Essentials of Validation

• Effective Investigations and Corrective Actions

• Effective Quality Assurance Auditing

For full details and registration check our website at:www.globepharm.org/seminars.html/course

GMP and Quality System Consulting:

• With over 200 clients in 27 countries, we prideourselves that every single one of our clients haspassed an FDA inspection the very first timethrough (when they have listened to us)

• We have wide expertise in evaluating GMP andQuality Systems at your facilities and inperforming third-party supplier and contractmanufacturer audits

Let us assist you. Speedily and cost effectively. Contact us at: [email protected]

World Leader in GMP gap analyses,seminars and individual GMP training

2 December 2008 – London, UKThe current state of dissolutiontestingwww.jpag.org

3-4 December 2008 – London, UKCold chain distributionwww.smi-online.co.uk/08coldchain.asp

9 December 2008 – Berlin, GermanyICH Q10 and its potential impact onthe pharmaceutical industrywww.pda-training.org

9-10 December 2008 – Amsterdam, TheNetherlandsSolubility and drug absorptionemail: [email protected]/solubility

15-18 December 2008 – Amsterdam, The NetherlandsPharmaceutical GMPwww.dba-global.com

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15-16 January 2009 – London, UKFDA approval process for medicaldeviceswww.management-forum.co.uk

DATES FOR YOUR DIARYNNOOVVEEMMBBEERR

4-5 November 2008 – Basle, SwitzerlandPoorly water soluble drugs: successfulformulation approacheswww.apv-mainz.de

4-6 November 2008 – Manchester, UKHow to simplify and improve yourchange management systemwww.DBA-global.com

10-11 November 2008 – Berlin,GermanyAnalytical data – interpretation andtreatmentwww.gmp-compliance.org

11-12 November 2008 – Liverpool, UKBest practice guidance for QualifiedPersons (QPs) and ResponsiblePersons (RPs)www.mhra.gov.uk

12-13 November 2008 – Mainz,GermanyIVIVC of special dosage formswww.apv-mainz.de

18-19 November 2008 – Berlin,GermanyReference standardswww.gmp-compliance.org

european industrial pharmacy issue 1 (october 2008)

Documents

patient journey

eufeatures4 quality

inta saprovskamalta

sourceof inspiration

official publication

new spray system seepage

european industrialpharmacy

benefits ofwellinformed