european Industrial Pharmacy Issue 1 (October 2008) by European Industrial Pharmacists Group (EIPG)

european INDUSTRIAL

PHARMACY FEATURES 4

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QUALITY CHARTER FOR MEDICAL REPRESENTATIVE VISITS

This charter aims to strengthen the role of the medical representative visit in the rational use of drugs and in the quality of the information conveyed by Valérie Lacamoire THE PATIENT JOURNEY – THE BENEFITS OF WELL-INFORMED, TARGETED GUIDANCE AND INFORMATION Easing the patient’s journey through diagnosis, procedures and medication benefits not only the patient but also physicians, pharmacists and drug companies by Marta Garrido BIO-INSPIRATION FOR NEW PHARMACEUTICAL SPRAYS

A beetle’s protection mechanism has inspired a physics department to develop a new form of drug delivery system by Andy McIntosh LATVIAN INDUSTRIAL PHARMACISTS An active and ambitious Section by Inta Saprovska

THE ROLE OF THE QUALIFIED PERSON IN THE 21ST CENTURY

There are better ways to protect the patient than individual batch release by Joyce Ramsbotham

OPERATION STORMGRAND – A TANGLED WEB OF WORLDWIDE DECEIT

Counterfeit medicines have become a worldwide problem. This MHRA case history traces the complicated international network of a counterfeiting organisation by Joe Ridge

REGULARS

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EDITORIAL COMMENT REGULATORY REVIEW NEWS FROM THE EIPG DATES FOR YOUR DIARY

ISSUE 1 • OCTOBER 2008

www.industrialpharmacy.eu www.eipg.eu

Associate Editors

european INDUSTRIAL

PHARMACY

Belgium: Philippe Van der Hofstadt Bulgaria: Valentina Belcheva

Issue 1 October 2008

Czech Republic: Miloslavia Rabiskova

ISSN 1759-202X

Denmark: Michiel Ringkjøbing Elema

EDITOR Joe Ridge, MRPharmS PRODUCTION Sue Feather

Finland: Tuula Lehtela France: Jean-Pierre Paccioni

SUBSCRIPTIONS Jill Monk

Germany: Armin Hoffmann

EDITORIAL BOARD Michael Anisfeld Michael Gamlen Linda Hakes Larry Hurst John Jolley Valérie Lacamoire

Great Britain: Jane Nicholson Greece: Kiriasis Savvas Hungary: Sylvia Marton

European Industrial Pharmacy is published three times a year by: Euromed Communications Ltd The Old Surgery, Liphook Road Haslemere, Surrey GU27 1NL, UK

Ireland: Anna O’Mahony Italy: Piero Iamartino Latvia: Inta Saprovska

Tel: +44 (0)1428 656665 Fax: +44 (0)1428 656643 Email: info@euromed.uk.com www.industrialpharmacy.eu Annual subscription rate £58

Malta: Claude Farrugia Netherlands: Harold Smeenge Portugal: bastonaria@ordemfarmaceuticos.pt

european INDUSTRIAL

PHARMACY discussion group:

Spain: Mercé Pujol

www.pharmweb.net/gmp.html

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Views expressed in European Industrial Pharmacy are those of the contributors and not necessarily endorsed by the Publisher, Editor, Editorial Board, or by our corporate sponsors who accept no liability for the consequences of any inaccurate or misleading information

Switzerland: Renato Kaiser

A special thanks to the companies who have kindly supported the publication of this newsletter

european INDUSTRIAL PHARMACY is the official publication of the European Industrial Pharmacists Group (Groupement des Pharmaciens de l’Industrie en Europe) www.eipg.eu 2

Cover picture: Bombardier beetle – a source of inspiration for a new spray system – see page 10.

eur opean INDUSTRIAL PHARMACY • Issue 1 October 2008

E D I TO R I A L C O M M E N T Raising the profile of the Industrial Pharmacist

The old saying ‘You do not the value something until you have lost it’ springs to mind when looking at the way the role of the Industrial Pharmacist has been eroded away in recent years. I am very proud to be an Industrial Pharmacist and I have enjoyed my job in this exciting field of Pharmacy. However, these are tough times and challenges are hitting the industry on what seems to be a daily basis.

graduates with the right skills needed for Industry.

♦ To understand the impact of

Globalisation/Outsourcing upon the Industrial sector and what this means to the Industrial Pharmacist of the future ♦ The EIPG needs to engage with all

pharmacists working in industry whether it’s R&D, Regulatory, Manufacturing, Promoting the Qualified Person or on the commercial side in Sales and Marketing.

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

EIPG can raise the profile of the Industrial Pharmacist within the EC in the following ways:

It is important to note that the EIPG is a European association representing the national, professional organizations of pharmacists employed in the pharmaceutical and allied industries of the EU. Today the EIPG represents well over 10,000 Pharmacists (many of whom are Qualified Persons) working in the Pharmaceutical Industry in Europe.

♦ Contributing

I was therefore extremely proud to have been nominated and selected to be President of the EIPG. I see the following key areas for focus for the EIPG: ♦ EIPG needs to address the falling

numbers of Pharmacists entering the Industry and to ensure that the high educational standards are maintained if we are to have

to publications which are read by many constituents groups within Europe

♦ To encourage Industry to continue

to train and support Pharmacy Students and to provide work placements ♦ To

lobby Government and Academic Institutions on the importance of maintaining the high skill level and educational standards required to be an Industrial Pharmacist.

behalf of pharmacists in industry. EIPG should also encourage members to establish forums where pharmacists from different areas of the industry can come together to debate common issues. One way to promote communication is to develop a specialist publication which allows our views to be widely circulated and discussed. Therefore, it was decided to sponsor European Industrial Pharmacist, with an advisory board which reflects the various European Professional Associations who make up EIPG and so provide a truly Pan-European view of the Industry. We have also appointed Mrs Jane Nicholson as Executive Director to the EIPG Bureau. In this capacity, Jane will ensure that our links to external bodies such as EAHP, PGEU, EFPIA, EMEA, The QP Association etc will be maintained. Jane will also contribute actively to the European Industrial Pharmacist. Only by sharing knowledge, experiences and maintaining our networks can we find a way forward.

♦ To ensure that the Science behind

the Drug Discovery and Development process is still taught within the Schools of Pharmacy in Europe. It is important that EIPG continues to promote the importance of Industrial Pharmacists and lobby on

Gino Martini President, EIPG

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QUALITY CHARTER FOR MEDICAL REPRESENTATIVE VISITS by Valérie Lacamoire

s provided by the Health Insurance Reform Law of 13 August 2004, a Medical Representative Charter was signed on 22 December 2004 by LEEM, the professional association of pharmaceutical manufacturers, and CEPS, the Comité Economique des Produits de Santé (Committee for Pricing of Health Products), on behalf of the government. The pharmaceutical companies concerned are obliged to request assessment and certification of the conformity of their medical representative visit practices by accredited organisations, at the latest on the 30th of June 2008. In July 2005, an amendment added a mechanism to control the number of visits made concerning specific therapeutic drug classes. The Medical Representative Charter aims to strengthen the role of the medical representative visit in the rational use of drugs and in the quality of the information conveyed. In particular it aims to improve control of promotional practices which may reduce the quality of patient care provided. By providing information to practitioners, the medical representative visit must promote the quality of medical treatment, prevent the misuse of drugs and avoid useless expenditure. This Charter is therefore fully embedded in the efforts to preserve France's health insurance system. For the time being, the Charter only applies to those companies signing a convention with CEPS and which provide drug information and promote reimbursable proprietary prescription medicines in non-hospital environments. Very shortly, medical representative service providers will also be concerned by this Charter. A further document concerning visits to hospital practitioners is also due to be drawn up.

VALÉRIE LACAMOIRE is Directeur Affaires Réglementaires/Senior Regulatory Affairs Manager Astellas Pharma SAS, 114 rue Victor Hugo 92 686 Levallois-Perret Cedex, France tel : +33 1 55 91 75 51 / fax : + 33 1 55 91 75 69

Une Charte de la Visite Médicale, prévue par la Loi sur la Réforme de l’Assurance Maladie du 13 août 2004, vise à renforcer le rôle de la visite médicale dans le bon usage du médicament et la qualité de l’information. Les entreprises concernées ont l’obligation de faire évaluer et certifier par des organismes accrédités, au plus tard le 30 juin 2008, la qualité et la conformité à la charte de leur visite médicale. MEDICAL REPRESENTATIVE CHARTER

This text contains five chapters: The medical representative’s missions: inform health professionals about proprietary medicinal products while promoting them in compliance with rules concerning rational use; Quality of information provided: rules guaranteeing the quality of information provided, of promotional documents and of medical representative training on the drug presented; Medical representative ethics: code of conduct towards different actors in the health industry: patients, practitioners, corporate competitors, drug manufacturers and health insurance organisations. Control of medical representative activity: clarification of the pivotal role of the Responsible pharmacist in relation to their mission defined by the Public Health Code. Joint monitoring, enabling tracking and update of this documentation. THE KEY POINTS OF THE CHARTER CONCERN:

1. Samples: Samples may no longer be distributed during medical representative visits. 2. Post-Marketing Authorisation studies, pharmacoeconomic studies, observational studies: These studies are no longer part of the medical representative’s missions. The representative may no longer set up these studies, but he/she may monitor them. 3. Promotional materials: All promotional documents must be dated and validated by the manufacturer’s promotional material compliance department.

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QUALI TY CHARTER FOR M EDI CAL REPRESENTATI VE VISITS (Cont .) 4. Training: Adequate initial training and in-service training must be provided to medical representatives. To ensure the quality of information conveyed, the medical representative's oral presentation must be verified by simulation prior to their visiting health professionals. This simulation is carried out in the presence of a scientific and medical manager mandated by the Responsible pharmacist. Emphasis must be put on the content of the presentation, and to a lesser extent the length of the visit, rather than the frequency of visits. 5. Professional relationships/congresses, gifts: Medical representatives are prohibited from offering gifts of any nature or value to practitioners. Invitations to professional or scientific congresses must be covered by a convention transmitted to the relevant authorities. 6. Role of the Responsible pharmacist: With a pivotal role in the implementation and respect of the Charter, the Responsible pharmacist guarantees the scientific quality of the messages conveyed by the medical representative. He/she must ensure that the representative possesses the knowledge required to exercise his/her profession and receives regular inservice training, to ensure their knowledge is up-todate and to prepare for promotional campaigns. The Responsible pharmacist is also responsible for the content of documents used. These responsibilities are completed by the control of promotional procedures such as document traceability, information feedback and monitoring of medical representative activities. 7. Certification of medical representative visits: To enable CEPS to ensure that the provisions of the Charter are correctly applied and respected by pharmaceutical companies, manufacturers are obliged to request assessment and certification of the conformity of their medical representative visit practices by accredited organisations, according to a procedure defined by the Haute Autorité de Santé (HAS – High Authority for Health). The deadline for companies to obtain certification for their visit procedures has been defined as 30 June 2008. At the start of January 2008, 30 companies out of approximately 200 were certified. CERTIFICATION CRITERIA AND IMPLICATION OF THE CENTRAL COUNCIL OF SECTION B OF THE ORDER OF PHARMACISTS

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

notably responsible for laying down certification criteria that will enable accredited organisations to assess the quality of medical representative visits and their conformity to the Charter. In light of the major role of the Responsible pharmacist, the Central Council of section B of the Order of Pharmacists (industrial professionals) actively participated alongside the HAS and other professional health organisations in drawing up the certification criteria for medical representative visits. The role of the Order of Pharmacists was to fully interpret the text and develop the criteria to ensure that missions imposed on the Responsible pharmacist under the new law are respected. In particular, the Order proposed to separate the regulatory requirements previously provided for by the Public Health Code, which were already amongst the Responsible pharmacist's responsibilities and therefore subject to inspection by the drug approval authorities, from the new requirements introduced by the Charter which would be integrated into the company's technical certification procedures. Several working groups were created within the Order in early 2005 in order to focus their attention on validating medical representative training, on the role of the Responsible pharmacist, on the certification of representative networks and the development of the certification criteria. In addition, a representative of section B has been a member of the HAS working group since 2005, alongside the other participating organisations. The objectives of the criteria are: firstly, to ensure the quality of the information conveyed by the medical representative and secondly, to ensure the quality of the manufacturer's medical representative visit practices. The fundamental points for the Order to clarify were the roles and responsibilities of each party concerned: the company, the Responsible pharmacist, the supervision of medical representatives in relation to the Charter and the company's certification, but also in relation to the specific and personal responsibility of the Responsible pharmacist as defined by the Public Health Code. The certification criteria for medical representative visits were finalised and published by HAS in July 2006 and subsequently modified in July 2007 (the document is available 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 representatives have the knowledge and skills needed to provide high-quality information; 2. the company ensures that medical representatives have the information and resources needed to carry out their missions;

european INDUSTRIAL PHARMACY • Issue 1 October 2008

QUALI TY CHARTER FOR M EDI CAL REPRESENTATI VE VISITS (Cont .) 3. the company makes available to medical representatives and their managers the resources they need to comply with ethical rules; 4. the company makes available the resources needed to ensure the quality of its medical representatives' work. In all the requirements, it is therefore the company who must ensure that it respects the various provisions laid down in the criteria. But these requirements are divided into individual criteria (eg. for requirement 1, criterion 1-1 requires that "the company holds continuing training sessions for medical representatives in accordance with the Code of Practice"), in respect of which the Responsible pharmacist may intervene in areas directly covered by his/her pharmaceutical expertise. In summary

The Quality Charter for medical representatives is a component of the health insurance reform programme which is governed by a contractual framework and which testifies to the commitment of pharmaceutical manufacturers to support a public health policy based on providing solid scientific information to health

practitioners and encouraging best use in the interest of patient care. It enables the harmonisation of existing medical representative visit practices and the definition of quality standards similar to those prevalent in other pharmaceutical industry sectors such as good manufacturing practices, good clinical practices and good pharmacovigilance practices . As part of an approach that promotes quality and continuous progress, it also enables us to: ♦ reinforce and promote of the quality of professional

ethics and of medical information conveyed; ♦ emphasise the contribution of industry professionals

to: –

developing knowledge about pathologies and their treatment,

–

correct drug use,

–

and therefore the improvement of patient care.

The coming years will allow us to make a retrospective assessment of the consequences of this Charter and the certification process on the changes that will subsequently be made to medical representative visits.

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eur opean INDUSTRIAL PHARMACY • Issue 1 October 2008

THE PATIENT JOURNEY

The benefits of well-informed, targeted guidance and information by Marta Garrido

hy is it important to consider the patient’s journey from the point of view of a service provider or medication provider? The answer: Inherent in the concept of a journey is the unknown, whether in regard to the traveler’s knowledge, experience, expectations, or perceptions. During the course of each patient’s journey, there are multiple opportunities for education and structured dialogue in order to enhance compliance and improve communication between patients, physicians and pharmaceutical brands.

allay his/her fears prior to the procedure. For example: ♦ There are many types of problems that can occur in

the colon. Directly viewing the inside of the colon by colonoscopy is usually the best exam option. ♦ Colonoscopy is used for:

• Colon cancer – a serious but highly curable malignancy • Polyps – fleshy tumors which usually are the forerunners of colon cancer • Colitis (ulcerative or Crohn's) – chronic, recurrent inflammation of the colon

The concept of a patient journey provides an opportunity for all parties involved to ease the patient through a labyrinth of procedures and medication, as well as to assist in their understanding of the disease and consequences of life-altering decisions. In a recent presentation, Paul LeVine of InfoMedics examined how the patient’s journey may be better facilitated by physicians, pharmacists and pharmaceutical companies; this article reviews the main points of that presentation and includes the author’s thoughts stemming from same.

• Diverticulosis and diverticulitis – pockets along the intestinal wall that develop over time and can become infected • Bleeding lesions – bleeding may occur from different points in the colon • Abdominal symptoms, such as pain or discomfort, particularly if associated with weight loss or anemia • Abnormal barium x-ray exam • Chronic diarrhea, constipation, or a change in bowel habits

From the patient’s perspective, we can divide the journey into three different stages: 1 Fear-laden diagnostic phase: In which the patient wants information about his condition, prescribed diagnostic tests and what will happen next. 2 Early experience: During which a patient is undergoing tests and procedures and begins to question: Why must I have this procedure? What did the physician find that necessitates going through it? When will it take place? And what will they do?

• Anemia What should I expect? ♦ Preparation. To obtain the full benefits of the exam,

the colon must be clean and free of stool. The patient receives instructions on how to do this. It involves drinking a solution which flushes the colon clean or taking laxatives and enemas. Usually the patient drinks only clear liquids and eats no food for the day before the exam. The physician advises the patient regarding the use of regular medications during that time.

3 Post-procedure: At this final stage, the patient requires information about medication, long-term management and his/her future outlook. A real example: “Colonoscopy”. The patient asks:

♦ The Procedure. Colonoscopy is usually performed on

an outpatient basis. The patient is mildly sedated, the endoscope is inserted through the anus and moved gently around the bends of the colon. If a polyp is encountered, a thin wire snare is used to lasso it. Electrocautery (electrical heat) is applied to painlessly remove it. Other tests can be performed during colonoscopy, including biopsy to obtain a small tissue specimen for microscopic analysis.

Why am I getting this?

At this point, there is an opportunity to provide the patient with factual, easy-to-understand information, to DR MARTA GARRIDO PhD, is a medical writer with Merit Publishing International email: merituk@aol.com

♦ Recovery. The procedure takes 15 to 30 minutes and is

seldom remembered by the sedated patient. A

european INDUSTRIAL PHARMACY • Issue 1 October 2008

THE PATIENT JOURNEY (Cont .) recovery area is available to monitor vital signs until the patient is fully awake. It is normal to experience mild cramping or abdominal pressure following the exam. This usually subsides in an hour or so. What happens after the procedure? What do the results mean? What do I need to do next?

After the exam, the physician explains the findings to the patient and family. If the effects of the sedatives are prolonged, the physician may suggest an appointment at a later date. If a biopsy has been performed or a polyp removed, the results of these are not available for three to seven days. How was it? Is there any value in letting the physician or the facility know about the patient’s experience?

The patient understood the reason for the procedure; understood what to expect during the preparations versus the actual procedure. Because of this, the patient went home after the procedure feeling at ease with what happened and what could happen next. The previous example has given us a tangible example of what information would be beneficial to a patient before, during and after a very stressful procedure. Now let’s translate this to a patient’s early medication experience

In this example, the patient is newly diagnosed with hypertension and is prescribed two medications for his condition. What should the patient know and how should the physician approach the prescribing education of the hypertensive patient? The physician should provide the patient with the name of medication, explain exactly what the medication will do, how long he/she will have to be on this prescription medication, and be very clear about the dosage amount and frequency, as well as possible adverse effects. Also, it is important the physician speaks to the patient regarding drug interaction with other prescribed medication and possible herbal products the patient may be taking. In this scenario, the impact of failure on the physician’s part to interact with the patient in a systematic and understandable manner – the impact of physicians lacking the time they need with patients – was examined in a 2006 study by Tarn et al, at UCLA1. The study reported on the extent of communication by the physician of critical medication information upon prescribing a new medication. The patients’ visits were audio-taped and evaluated using the following five criteria:

♦ Name of Medication ♦ Purpose ♦ Duration ♦ Dosage (amount/frequency) ♦ Adverse Events

The results were staggering. Thirty-eight percent of the essential criteria of the prescribed medication were not communicated. The resulting impact: Less communication and fewer explanations about the medication led to lower compliance and poorer outcomes. In addition to in-person communication, the printed material available to patients with their prescriptions is often unhelpful. Patient prescription information (PI), included with most prescriptions, contains numerous columns of printed details in a size that often requires a magnifying glass to read. Should a patient attempt to read it, the clinical content in many cases would be far too difficult to understand. Overall, PI sheets lack a physician’s personal touch, which is vitally important for patient compliance. Addressing the need to revise patient information regarding prescribed medication is vital to targeting patient compliance. Low compliance translates not only into poorer outcomes for the patient but also into an enormous amount of missed revenue opportunity for the pharmaceutical industry. Providing a patient education program with feedback loops engages the client from the initial contact point of prescribing, and encourages patients to continue taking medication for the duration of the therapeutic period. This assertion was borne out by a case study by the Heart Alliance conducted between October 2001 – August 2003, which engaged 52,000 patients through over 14,500 physicians, showing the following results: ♦ 91% of patients indicated the educational support

program helped them take medication at onset ♦ 95% of patients thought the program was helpful and

92% thought it helpful in managing their flushing specifically ♦ 98% of patients indicated the Heart Alliance program

would be helpful to others ♦ 88% of patients reported better perception of

physician care because of program ♦ 93% of patients agreed to be re-contacted in the

future about this program or others The Program Objectives for the above study were as follows: ♦ Actively resolve significant product drop-off and

increase product persistency

eur opean INDUSTRIAL PHARMACY • Issue 1 October 2008

THE PATIENT JOURNEY (Cont .) ♦ Reduce level of physician resistance toward

prescribing by providing patient education and support

Modify the frequency of interactions, as needed ♦ Over time, feedback frequency may decrease as the

patient reaches equilibrium.

The Financial Impact in terms of drug sales showed: ♦ 71% improvement in product persistency ♦ 89% of patients report taking the medication all the

time; 8% report taking it nearly all the time

Summary ♦ There are still gaps in patients’ full understanding of

treatment and physicians or institutions’ knowledge of treatment outcomes.

♦ 93% of patients indicate intent to continue

medication use This study demonstrates the potential for pharmaceutical companies and providers to enhance the outcome of the “patient journey” discussed in our introduction. It is important for prescribing physicians to maintain the flow of information and advice begun with the initial prescription. Below are some suggestions on how to maintain dialogue with the patient in order to keep him/her engaged and so enhance the chances for better medication adherence:

• Knowledge of condition • Treatment expectations • Early experience ♦ There are multiple ways of aiding understanding

through the use of printed materials, interactive surveys, interactive programs, on-line programs and others. ♦ Using a feedback loop provides benefits throughout

the patient journey – potentially helping the processes of care, outcomes and the understanding of the treatment experience.

Shift the emphasis ♦ Simple definitions that were used initially do not

need to be emphasized now. Definitions may expand to include more information about the relevant disease and medications. Provide targeted “needs-based” interactions

♦ However, embedded within the challenges this may

pose is the potential for providing net new information – configured in ways unseen to date Reference 1. Tarn DM et al. Physician communication when prescribing new medications. Arch Intern Med 2006;166: 1855–1862.

♦ It is important to move on to other more

sophisticated and/or long-term needs. What does the patient need now? He/she has been on X medication for six months and at this time, she/he may be asymptomatic and ready to “forget” to take the medication or even to refill the prescription.

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

Increase the focus on adherence and persistency ♦ After the initial experience, more of the interactions

deal with issues related to continuing use. Why do patients stop taking medications? What can be done to increase compliance?

european INDUSTRIAL PHARMACY • Issue 1 October 2008

BIO-INSPIRATION FOR NEW PHARMACEUTICAL SPRAYS… by Andy McIntosh

The beetle and its valve system

new spray system known as µMist® has been developed, inspired by the physics of the remarkable spray mechanism of the Bombardier beetle. This unusual Bombardier beetle (see Figure 1) heats up water to above boiling point in a tiny combustion chamber less than 1mm in size by an exothermic chemical reaction and then sprays it from a moveable turret in its posterior in any direction it wishes (even over its head…!). The beetle uses this mechanism for warding off attacks from spiders, frogs, ants and birds. The beetle forms the noxious spray1 (which is in a solution mainly composed of water) by reacting small amounts of hydroquinone with hydrogen peroxide in the tiny combustion chamber in the presence of the catalysts catalase and peroxidase. This exothermic reaction then produces benzoquinone and water, and heats up the solution (mainly water) to above boiling. The pioneering work by Professor Tom Eisner of Cornell University2 showed that the mixture ejection is not continuous but is in fact a series of explosions similar to pulse combustion. The reactants fill the chamber, react and are ejected, then more reactants enter and the cycle is repeated at a frequency so high (400-500Hz) that it took a high speed camera operating at kHz to resolve the individual explosions. This inspired Professor Andy McIntosh and his research team (including research fellow Novid Beheshti and PhD student Andreas Prongidis) at Leeds University, UK, to investigate the physics of the combustion chamber by first using CFD (computational fluid dynamics) modelling supported by EPSRC (Engineering and Physical Sciences Research Council), and then with the support of Swedish Biomimetics 3000®, building a working model of the beetle combustion chamber.

ANDY MCINTOSH is Professor of Thermodynamics and Combustion Theory, Energy and Resources Research Institute, School of Process, Environmental and Materials Engineering, University of Leeds, UK email: a.c.mcintosh@leeds.ac.uk NOVID BEHESHTI was formerly a Research Fellow at the University of Leeds and is now Technical Principal at Swedish Biomimetics 3000 UK Ltd.

The dynamics of the actual physical mechanism of the beetle ejection system only really became understood when Andy McIntosh and Tom Eisner were discussing the nature of one of the dissections Tom had made of the beetle chamber (Figure 1a). It was one of those inspirational ‘lightbulb’ moments. The inlet valve mechanism is an ingenious mechanism as illustrated in Figure 1b. When the inlet hydroquinone and hydrogen peroxide has filled the chamber, the extremities of the chamber itself pinch the inlet tubes rather like a ’boxing glove’ (see the top left of the picture where the frayed tissue from the inlet tubes is visible). At the other end, the exit tube for each chamber is shown at the bottom right of the photograph. At first it was presumed this had been sliced and that one was looking on the inside of the exit tubes. However the Leeds team was assured by Tom Eisner this was not the case, and that all the chamber is shown from an external perspective. Once this was established, it became evident that the exit tube with the membrane of cuticle hanging down, is in fact a pressure relief valve. This now made the overall ejection mechanism clear. With the inlet valve shut at atmospheric pressure and the exhaust valve shut, the boiling water mixture raises the pressure to a point where the only way out is to push against the exhaust valve by pushing the fluid against the membrane. This is done till the membrane gives way, and the pressure relief valve now becomes open, leading to flash evaporation as the fluid boils under sudden decompression. The low pressure following such an explosion, then enables the inlet valve to open (the ‘boxing glove’ releases its stranglehold on the inlet tubing) and more fuel enters the chamber, and the cycle is repeated. The key finding was the nature of this valve system. The physical interpretation of the CFD simulations showed that flash evaporation was indeed the key principle involved, and that with an appropriate critical release pressure, strikingly similar results in terms of predicted mass ejection and frequency are obtained between the CFD simulations and the measurable results from Tom Eisner’s experiments3. One can liken the beetle’s defence mechanism to a pressure cooker controlled by an additional system of valves: The essential feature is a repetitive high-force steam cavitation explosion, but from a chamber less than one millimetre long!

eur opean INDUSTRIAL PHARMACY • Issue 1 October 2008

BI O-INSPI RATION FOR NEW PHARMACEUTICAL SPRAYS… (cont.)

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

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 Biomimetics 3000® and the support to build an experimental rig which replicated the core technical features of the beetle, ie the important combustion chamber and valve system of the Bombardier beetle. So an experimental rig was designed and built to test out the theory in practice (Figure 2). The catalytic chemistry of the beetle is not copied in the rig, but instead the heating is done electrically. Excellent results were obtained from this experimental research rig. For instance the throw ratio (maximum throw distance divided by the length of the combustion chamber) was the same for both the beetle and the rig. The beetle’s combustion chamber is less than 1mm long and throws to about 20cm. So the throw ratio is 200. The experimental rig has a chamber length of approx 2cm so the maximum throw distance is an impressive 4 metres. In accordance with the best global innovation practices, a characterisation and development program in consultation with Quintiles Consulting Europe led from this initial research rig to the development of a preprototype µMist® spray system – leading to a potential Inhaled 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 the properties of the mist are critical. These applications of the generic technology include many areas beside medicine (such as fuel injection, aerosols, fire

extinguishers and fire suppression), all of which face major challenges relating to the demands of greater performance and reduced environmental impact of high performance mists. A major application is to medical drug delivery systems. In application areas such as soft mist inhalers, the new technology offers a potentially major leap forward in performance, since µMist® can deliver highly

Figure 2. Experimental rig inspired by the Bombardier beetle combustion chamber – scaled up to 2cm long and able to fire 4 metres. The bombardier Beetle Rig was built by the research team led by Professor McIntosh of University of Leeds, This has the capacity to eject very fine mist or large droplets. The maximum throw ratio (distance thrown divided by chamber dimension) is 200 – the same as the beetle itself which throws a mixture of water, steam and quinones a distance of 20cm from a chamber less than 1mm long.

european INDUSTRIAL PHARMACY • Issue 1 October 2008

BI O-INSPI RATION FOR NEW PHARMACEUTICAL SPRAYS… (cont.) characterised droplets with variable sizes4 between 2µm and 100µm, including what we believe to offer the finest-in-class performance inhalers. The technology could function as a water-based carrier for propelling and delivering various therapeutic substances without the use of conventional propellants, some of which are potential pollutants. Nebulisers, inhalers, needle-free injection systems and hand and wound cleansers all demand carefully designed spray systems with precisely controlled droplet properties. A major advantage of the µMist® spray system is the ability to choose and adjust the mist’s characteristics by adjusting the electronic control panel parameters of the rig. In summary, the main features are that droplet size can be readily adjusted to provide an optimal carrier performance through the electronic control interface.

This can achieve – with an aqueous carrier – droplets which have controllable sizes, size distribution, temperatures, ejection frequencies and ejection velocities. The ability to alter the mist output provides a capability which can be optimised for a particular therapeutic utilisation – and this facilitates the great therapeutic potential of this radical technology. References 1. 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 than the quoted value. Termed DV90, this means that the DV50 (50%) level often quoted by manufacturers and the SMD (Sauter Mean Diameter) are smaller still.

LATVIAN INDUSTRIAL PHARMACISTS by Inta Saprovska

ome years ago, the newly formed Industrial Pharmacists Section of the Pharmacists Society of Latvia started a rather wide online discussion because many pharmacists didn’t understand what industrial pharmacists were. The idea of creating such a section in Latvia occurred after attending the International Congresses of FIP. In the industrial pharmacist circle, both Latvian and foreign drug manufacturer representatives (pharmacists, wholesalers, academic faculty and other persons) considered themselves as belonging to a society of nonpharmacy pharmacists. In 2004, when EIPG was looking for co-operation possibilities with newly-joining EU countries, Latvian industrial pharmacists proved to be the most active Section and in 2006 the Latvian Industrial Pharmacists Section became EIPG observers. Last year at the EIPG General Assembly in Prague, it was enrolled as an official association member, as the first and currently only Baltic State. Next year’s EIPG General Assembly will be held in Riga. Until now the Pharmacists Society of Latvia had concentrated its attentions on the interests of community pharmacists, thereby neglecting the activity of those pharmacists involved in drug manufacturing and other fields. At their first meeting, local drug producers admitted that the main problem of this branch was pharmacist education, as there was a dire need for pharmacists at INTA SAPROVSKA is Head of the Industrial Pharmacists Section of the Pharmacists Society of Latvia

drug manufacturing units. They also recognized the necessity to increase the prestige of pharmacists working in the industry and pharmacist prestige in general. It was also decided to involve quality individuals, heads of production departments and pharmacists working at laboratories in the activities of the Section. It would be also be valuable for pharmacists working in drug manufacturing to improve their postgraduate training; for this reason, special programmes, of which Latvia currently has a shortage, would be developed. The main aims of the Industrial Pharmacists Section are: to create and to maintain relations between pharmacists, whose work is connected with matters of industrial pharmacy practice, to support the industrial pharmacists specialization and educational programme for in-service training, to favour participation of pharmacists in industrial manufacturing and to increase their prestige in the industrial field, to support the professional contribution of pharmacists to the pharmaceutical industry and other large scale conventions with European industrial pharmacist aims. More ambitious aims exist in future as well, for example, certification of quality individuals according to emerging European viewpoints. With the intent to share their experiences, members of the Section visit drug manufacturing units and wholesalers, meet each other to discuss the activities and updates in legislation, and regularly receive information on the Section’s activities via electronic newsletter and publications in the pharmaceutical magazine Materia medica. The meeting place at the Pharmaceutical Museum creates the link between the past and the future of pharmacies and is a treasury of historical events of Latvian Pharmacy development for future pharmacists.

eur opean INDUSTRIAL PHARMACY • Issue 1 October 2008

THE ROLE OF THE QUALIFIED PERSON IN THE 21ST CENTURY by Joyce Ramsbotham

Times are changing

he development and manufacturing environment in the pharmaceutical industry is changing rapidly and one has to wonder if the current concept of the role and responsibilities of the Qualified Person also need to change. We are moving from “Quality by testing and inspection” to the concept of “Quality by Design”, where quality is built into the product and process during the development phase. We are moving away from traditional specifications to a concept of monitoring quality during processing with suitably chosen in-process controls and continuous verification, which is also going to replace traditional 3-batch validation. This in turn is also going to allow real-time or parametric release of batches instead of end point testing. Assuring quality and continuation of supply of medicines to the patient requires not only individual batches to be within specification, but also processes that are robust and reliable. Process understanding, quality risk management and continual improvement are becoming the cornerstones of the quality paradigm. Risk-based and science-based decisions are now expected instead of compliance-based decisions. Also the logistics of our supply chain are becoming more complex as we move away from local stand-alone processes to complex international supply chains and as we move away from only supplying local markets to supplying multiple international markets from strategic manufacturing facilities. We are also seeing an increase in the number of and the time spent on inspections, not just from our own local inspectorates but from many other inspectorates from the markets which we supply around the world, who all expect us to comply with their own local GMPs. In this rapidly changing environment, the traditional role of the Qualified Person that focuses on certification of each individual batch seems outdated. Surely there are better ways to protect the patient than focussing on individual batch release. This paper will examine some of the changes mentioned above and how the role and

JOYCE RAMSBOTHAM was formerly International Quality Specialist at Solvay and Chairperson of the EFPIA Manufacturing-GMP Working Group, The Netherlands

responsibilities of the QP need to be adapted to respond to these new concepts. Quality by design and process understanding

There is no disputing the concept that the Qualified Person (QP) remains responsible for the quality of the product released to the market. But as we see more reliance placed on building the quality into the design of the product and the design of the process, more reliance will be placed on process understanding, critical parameters and in-process controls. The QP has to find a new way to assure him/her self of the quality of the product instead of relying on final product testing. The QP must be assured that quality is indeed built into the process during development and must also have a thorough understanding of the critical parameters, the design space parameters and the controls required. It has been said that in spite of these new concepts, most process understanding will be gained after product launch. Process understanding 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 of process understanding is sufficient for him/her to certify the product for release to the market, even on the first day after launch and should be part of the team that decides how much process understanding is required to launch the product onto the market. The QP must also ensure that there is a system in place to ensure that changes are made either within the design space and the Marketing Authorisation or that, where necessary, changes are submitted for marketing authorisation approval by the competent authorities. The design space concept, as developed in ICH Q8, together with process analytical technology also allows us to move away from traditional specifications to a control strategy based on in-line and at-line process controls. As a consequence, routine end product testing may not be necessary and batches may be certified based on process control measurements that assure product quality. A “Process Signature” may be used that

european INDUSTRIAL PHARMACY • Issue 1 October 2008

THE ROL E OF THE QUAL IFIED PERSON IN THE 2 1ST C ENTURY (C ont.) will look very different from what we see in current release 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 same way that he/she approves traditional specifications and should be assured that the control strategy guarantees the quality of the product. Traditional validation and continuous verification

Continuous verification has the advantage that it is always representative of routine production under all conditions, it consistently ensures that the process is under control and it makes real-time or parametric release possible. In addition, it provides more data which contributes to process understanding, it enables measurement of process capability and it establishes a framework for continuous improvement. However, carrying out continuous verification by (almost) continuous monitoring of the process does have a drawback – it may well produce more deviations, i.e. values that are outside their limits. In other words the larger the sample size and the more frequent the sampling the more likely, by normal distribution statistics, a value will be found which is outside the limits, whereas the same batch would have been well within specifications if tested by traditional end point testing. This presents a dilemma for the QP of whether the batch can be released or not. In fact it adds an additional dimension to the control strategy mentioned earlier. The control strategy on which batch release can be based needs to include not only the critical parameters to be tested, the sample size and frequency, the upper and lower limits but also the permitted sigma deviations, based on a risk assessment. Furthermore the QP must ensure that systems are in place to: ♦ identify causes of values found at the extremes of the

Gaussian distribution and to take corrective action, ♦ monitor and review trends and take preventive

action, ♦ ensure continual improvement of the process.

The process should still be considered to be operating in a state of control, when, as a result of the increased sampling level, values are found within pre-set action limits and within the predicted normal distribution range. Batch certification

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

on compliance with the Marketing Authorisation. However, if there is no end point testing done, how does the QP certify the batch? In such cases, the QP has to have assurance that the control strategy is appropriate and was followed, and that systems are in place for the review of the batch record and the in-process control results. However, there is a dilemma, as a traditional Certificate of Analysis cannot be issued giving the results of end point testing compared to final product specifications. Probably QPs are going to have to run hybrid systems for those countries or customers still insisting on a Certificate of Analysis and some persuasion may be needed before a Certificate of Conformance or Compliance, in which the QP certifies that the batch has the required quality, was manufactured under GMP and was manufactured according to the Marketing Authorisation, is universally accepted. The case for quality and reliability

The release of individual batches based on end product testing, begs the question of what the QP should do when batches are failing with too high a frequency. Should the QP certify the passing batches while rejecting the failing batches? If the sample size is small, then the chances are that some batches are being passed that should be failed and vice versa. The robustness of the process is surely a far better indicator of product quality than individual batch results. As Moheb Nasr from FDA has said, “A robust process is capable of handling changes in process inputs without negative impact on end product quality” and “Reproducible means consistently and predictably delivering the same quality material”. A process with a high reject rate probably has a high chance of unreliability of supply and the patient is surely far better served by relying on process reliability than 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 in China or India, excipients to be bought from several countries around the world, for part of the processing to be done in one country and other steps in another country, with final packaging and release taking place in several different countries. Under current requirements the QP is expected to review all non-compliances with GMP at the various manufacturing sites, review all critical deviations and investigations in the supply chain, review and approve all changes, ensure work is carried out within the terms of the contract, certify suppliers of APIs, qualify suppliers of excipients and take personal responsibility for all manufacturing stages. The job has become impossible and certainly requires a superhuman individual to perform it. Surely the role and

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THE ROL E OF THE QUAL IFIED PERSON IN THE 2 1ST C ENTURY (C ont.) responsibility of the QP should be to ensure that there are systems in place which: ♦ evaluate and approve the quality systems used by all

players 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 to other suitably qualified competent experts. Looking at the distribution network we again see supply to multiple international markets. The QP has to certify that the batch has been manufactured and checked in accordance with each of the relevant marketing authorisations, with EU GMP requirements and with the local GMP requirements and any other legal requirements of the country in which the product is to be marketed. Again, this is a very difficult task which could be better fulfilled by making the QP responsible for ensuring there is a system in place which: ♦ monitors

global marketing authorisations applications, approvals and changes,

Conclusion – the role of the Qualified Person should be to ensure that the Quality System is fit for purpose and operating effectively Probably anybody who has been a QP or has seen QPs at work, has seen the burden of administrative paperwork focussing on individual batch release. Yet there is a better way to protect the patient than by individual batch release. The role of the QP should be to ensure that Quality Systems are in place and that these Quality Systems are fit for purpose and operating effectively, so as to: ♦ provide assurance that the system can be relied upon

to support batch certification, and ♦ ensure that issues are raised, if necessary, at an

appropriate level prior to batch certification. The Qualified Person should also be able to delegate and rely on the decisions of other competent professionals within a proven quality system. Finally if this view of the role and responsibility of the Qualified Person is accepted, then one of the consequences is that Management also has to take its responsibility for ensuring that a robust Quality System is in place, appropriately resourced and enforced. Only when this concept is fully recognised will a company be able to claim that Quality Systems are fit for purpose.

♦ monitors local GMP and legal requirements, ♦ ensures that each batch is manufactured in

accordance with its marketing authorisations and local legal requirements.

Industrial Pharmaceutical Microbiology Standards & Controls

Editors: Norman Hodges and Geoff Hanlon

“An exceptional and unique publication in this field”

Microbiologist – September 2007

21 Chapters 450+ pages £325.00

For details and to order visit the Euromed website: www.euromed.uk.com

european INDUSTRIAL PHARMACY • Issue 1 October 2008

Looseleaf format Special supplements Regularly updated

OPERATION STORMGRAND – A TANGLED WEB OF WORLDWIDE DECEIT by Joe Ridge

n March and May 2003, UK Revenue & Customs seized 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 two addresses where 150,000 counterfeit Viagra tablets were seized along with information leaflets, a pot-sealing machine and paperwork. Counterfeit Propecia, labels and cartons were also discovered. A large number of the pots of Viagra were labelled as either Fish Protein and Mineral Supplements for Dogs or Vitamin tablets (Figure 1). The main individual, Gary Haywood, then fled the UK and went to Costa Rica; he claimed that the Triads were after him. The Stormgrand network

From paperwork found at both addresses it was established that invoices connected Haywood to a company in the UK, Stormgrand. This was an unlicensed pharmaceutical wholesaler operated by Ashish Halai whose wife, Nena, ran a pharmacy called Nashi pharmacy in London. Hayward was also connected to companies in Sweden, three companies in the Bahamas and wholesaling companies in the UK. The paperwork also indicated a storage site not known to the investigators. This was searched and from dust patterns on the floor it was established that two large pallets had been recently moved. At this point the case exploded and become enormously complicated. Further wholesalers were discovered and a company in Norway. The Norwegian company was contacted by investigators working for Pfizer and resulted in an under cover meeting to buy 21,000 Viagra tables. The MHRA seized the tablets at the same scene. Haywood used a number of his own companies to import these included: ♦ Gary J Haywood Pharmaceuticals Supplies

A counterfeit medicine is one which is deliberately and fraudulently mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with correct ingredients, wrong ingredients, without active ingredients, with insufficient quantity of active ingredient or with fake packaging. World Health Organisation Counterfeit medicines – the facts

♦ The WHO estimate that up to 1% of medicine is counterfeit in the developed world. ♦ Counterfeit medicine is more commonly available through the unregulated supply chain, usually the Internet. ♦ Less frequently, but more worryingly, it is sometimes available through the regulated supply chain via wholesalers, distributors and pharmacies to patients Figure 2. ♦ Counterfeit medicines available in the developed world include ‘lifestyle’ and ‘lifesaving’ medicines from conditions such as erectile dysfunction and weight loss to cancer and heart medicines. ♦ Visual examination alone often fails to identify the counterfeits. ♦ There have been thousands of known fatalities around the world. ♦ Counterfeits are dangerous and undermine public confidence in medicines. of the main suppliers of Viagra to three companies in the Bahamas. Global Metz, JTR Associates (McCoy Borthers) and Betco Ltd (Robert Moffat). It was then found that Halai also supplied Metro Pharmacy, owned by Rajendra Shah, and LPC Pharmaceuticals. He also supplied three companies in Sweden, Planet Pharma, EcoWest and Crosstrading. The US connection

♦ Gary J Haywood Medical Supplies Pty ♦ Haywood and Co Ltd ♦ Lancaster House Ltd In addition Stormgrand’s Ashish Halai was involved in a company called Farmacia del Mundo and was also one

What are counterfeit medicines?

The Robert Moffat of Betco operated a bonded warehouse in the Bahamas. He has since been arrested, indicted and imprisoned by the US authorities. Moffat informed the authorities in 2004 that a Nick Malis had put out a contract on the life of Halai. Nick Malis was subsequently arrested.

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OPERATI ON STORM GRAND (Cont .)

Manufacturer (May be licensed, typically in Far East)

Regulated chain

Trader/broker Advertised in newsgroups

Wholesaler (May be licensed)

Website operator (Unlicensed)

Grey market (Parallels? Unlicensed?)

Lifestyle products

Pharmacy Figure 1. Pot containing counterfeit Viagra.

He was operating a company called One Source in Dallas, Texas. As a result of information passed to the US a total of 11 individuals were arrested and prosecuted. Over 20 websites have been closed down and assets involving several millions of dollars have been restrained and some already confiscated. Further developments

In the summer of 2004, counterfeit Cialis and Reductil tablets were discovered in the UK supply chain. This was initially investigated as a case on its own. However, by following the audit trail it quickly became apparent that it was intricately linked to Stormgrand. Many of the same names were cropping up time and time again. The investigation was therefore merged with Stormgrand which became even more complex. Following the arrests in the US some of the arrested individuals decided to co-operate with Immigration Customs Enforcement (ICE), which let to the main defendant in the US, Richard Cowley, being charged with the counterfeiting of Viagra, Cialis and Lipitor. Whilst this was ongoing the UK suffered its 3rd counterfeit case within the space of 12 months, this time it was Lipitor. The Chinese connection

Cowley’s home PC was seized and analysis revealed details of contacts in China. As a result, ICE field office agents assisted officials of the ministry of Public Security (MPS) and the Public Security Bureau in China to determine the source of counterfeits.

Unregulated chain

Internet site Patient

Figure 2. How counterfeit medicines are distributed.

“Operation Ocean Crossing” resulted in raids in 5 locations in Tianjin City and Henan province. Huge amounts of equipment were seized, in addition to 600,000 counterfeit Viagra, 440,000 counterfeit Cialis and 260kg of bulk raw material. Eleven Chinese nationals were arrested. Cowley was charged with Misbranding and Counterfeiting, sentenced to two years imprisonment and a substantial fine. Results of Operation Stormgrand

As a result of Operation Stormgrand in the UK, a total of nine defendants were charged with conspiracy, at Kingston Crown Court in Surrey. Ashish Halai, pleaded guilty at start of trial and was sentenced to 41⁄2 years in prison; Nena Halai, pleaded guilty and received 80 hours community service; Gary Haywood was sentenced to 6 years after an 8-month trial; Ashwin Patel was sentenced to 18 months imprisonment; Zahid Mirza fled the UK after being found guilty – he was sentenced to 21⁄2 years in his absence. Thus, one chance detection by Customs in 2003 and the following investigation by the MHRA, led to intelligence being passed to overseas counterparts that eventually reached 39 countries worldwide. Industry estimates place the total number of individuals arrested as a result in the region of 1,000. Based on information provided by the Operations, Enforcement and Intelligence Group of the MHRA

european INDUSTRIAL PHARMACY • Issue 1 October 2008

REGULATORY REVIEW:

Review of major developments in GMP and the regulation of medicines in the EU and on the International Scene, June to August 2008

by Steve Fairchild

he period since the last update on developments in EU regulatory controls and guidance for pharmaceuticals has seen: ♦ A continuation of the process of developing and

updating GMP Guidance. ♦ Further work on guidance for clinical trials.

process has been taking place for some 40 years and has led to a somewhat complex set of legal instruments and laws. The UK regulatory authority (the MHRA) has proposed a revision of the UK medicines law that will take place over the next 2 or so years. It is hoped that this will deliver simpler and more accessible medicines regulations. Pharmacopoeial developments

♦ Harmonisation of pharmacopoeial methods. ♦ An expedited revision of the European Pharmacopeia

monographs on Heparins resulting from quality and patient safety problems in late 2007 and in 2008. ♦ A new website for the British Pharmacopoeia and a

new edition of the “BP”. We hope that you find some if not all of the following to be useful in your work and/or professional development. Changes in EU healthcare products legislation and good practices

Harmonisation of General Monographs within ICH

For a number of years the Pharmacopoeias of the three ICH Regions have been working on the harmonisation of pharmacopoeial monographs. This process has recently taken a step forward with the finalisation of two general test methods for parenteral products. These are for extractable volume and sub-visible particulate contamination. Draft texts have also been published for:

Revision of EU GMP Guide

♦ Microbiological tests on non-sterile products.

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

♦ Disintegration testing solid dosage forms.

Proposed changes to the EU GMP Guide

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

The European Medicines Agency has published a short paper explaining the development of GMP for advanced therapy medicines (ATMPs). This is likely to be achieved by modifying Annex 2 to the EU GMP Guide (the Manufacture of Biological Medicinal Products). Regulation of clinical trials in the EU

New and revised guidance has been published for clinical trials performed in the EU covering: ♦ The documentation required in connection with

clinical trials on human subjects. ♦ Information to be made available in the public

domain from the EU clinical trials database.

New Website for the British Pharmacopoeia (BP)

The MHRA has launched a new website for the BP that provides a number of new features including a subscriber service providing accesses to documents related to but not appearing in the BP, corrections and documentation for requesting new and modified monographs. British Pharmacopoeia 2009 Edition

Consultation is in progress on: ♦ Good Clinical Practice for ATMPs. ♦ Information to be made available in the public

domain on paediatric clinical trials. Review of UK Medicines Legislation

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

Revised Ph. Eur. Monographs for Heparins

The latest edition of the BP went on sale at the end of last August and is now available from the Stationery Office 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 please refer to current and past editions of “GMP Review News” published by Euromed Communications. To subscribe to this monthly news service contact subs@euromed.uk.com

eur opean INDUSTRIAL PHARMACY • Issue 1 October 2008

NEWS FROM THE EIPG 2008 General Assembly of the European Industrial Pharmacists Group

The 2008 General Assembly of the European Industrial Pharmacists Group was held in Malta on the 19th and 20th April. This year, the General Assembly was preceded on the 18th April by a public seminar organised jointly between the Malta Qualified Persons Association, EIPG and the University of Malta. The seminar was entitled "The Successes and Challenges of Today's Pharmaceutical Industry" and featured talks by Luigi Martini (Development Challenges facing Big Pharma and the Industrial Pharmacist), Piero Iamartino (The Qualified Person and Minor Deviations), Françoise Robinet (The new Representatives Charter and the Quality of Promotional Messages) and Kiriasis Savvas (Pricing of Medicinal Products and Reimbursement Systems in Europe). The update of the year's activities showed EIPG to have had an active year since the last General Assembly in Prague, particularly in establishing the EIPG as an active partner in consultations with the European Medicines Agency, thanks to the efforts of Piero Iamartino and John Jolley. EIPG had also been active in matters concerning education. An invitation to the Conference of the European Association of Faculties of Pharmacy had resulted in a joint submission between EIPG, EAHP, PGEU and EAFP for European Commission funding for two projects: PHARMINE – a review of undergraduate pharmacy courses – and PHARMIND – a survey of the competencies needed for a career as an industrial pharmacist. The new Executive Director, Jane Nicholson, also attended a meeting of the EAHP, at which an update of the European Medicines Research Academy was reviewed, and held discussions with the Executive Board of the Hospital Group on matters of mutual interest. A number of key presentations were made in the course of the General Assembly, foremost among them an update on the EIPG Guide to Good Regulatory Practice, by Valérie Lacamoire (France), who was assisted by regulatory affairs pharmacists from Germany and Great Britain. In the light of these recommendations, regulatory affairs pharmacists from Italy, Belgium and Denmark subsequent expressed interest in setting up a working group on Continuing Professional Development for pharmacists in regulatory affairs. John Jolley (Great Britain) delivered a talk entitled "Industry Implications of Pharmaceutical Quality ICH Guidelines", outlining the implications of ICH Q8, Q9 and Q10 guidelines in pharmaceutical product life cycles, whilst the deliberations of the Assembly on the education of industrial pharmacists were supported by a presentation from the invited speaker Prof. Alfred Vella, Pro-Rector of the University of Malta, on "The Bologna process and university reform".

National initiatives in the Member States were also communicated to the Assembly. Jean-Pierre Pacconi (France) delivered two presentations, the first representing an update on the competency scheme for the education of industrial pharmacists in France, and the second an initiative in the form of a new working group in France for recommendations in achieving a reliable network for cool transport. The latter elicited considerable interest amongst the delegates and will constitute one of the topics of discussion at the next General Assembly. There was also a presentation by Philippe Van der Hofstadt (Belgium) on a Belgian initiative for cGMP in clinical trials, well received by Italy, Netherlands and Great Britain. The Working Group on undergraduate and postgraduate education, attended by delegates from Great Britain, Czech Republic, Netherlands, Finland, Sweden, France, Hungary and Spain discussed the competencies and skills required to become an Industrial Pharmacist in different EU countries, with the two main strategies being a specialised cycle for industrial pharmacists as seen in France and Finland, or a general degree with orientation in later years, as seen in Netherlands, Spain and Czech Republic. France and Netherlands are currently working on competencies for industrial pharmacists, and the next assembly will discuss their feedback in considering initiatives in CPD for industrial pharmacists. The second Working Group, discussing future employment prospects of industrial pharmacists, was attended by delegates from Germany, Belgium, France, Portugal, Hungary, Latvia and Great Britain. The group conducted a SWOT analysis of future employment prospects for industrial pharmacists in Europe in the light of increasing globalisation trends and downsizing of companies, coupled with decreasing numbers of NCE's and increased generic new drug approvals. A third Working Group, attended by Malta, Italy, France, Netherlands and Greece, discussed an EIPG position paper on counterfeit medicinal products in response to the public consultation paper issued by the European Commission. This position paper was concluded following the General Assembly and submitted both to the European Commission and the MHRA. The General Assembly concluded on the 20th April with the election of Jakob Bjerg Larsen (Denmark) and Claude Farrugia (Malta) to the Vice-Presidencies of EIPG. In the process of the President's concluding speech, the Assembly concurred that EIPG should, throughout the coming year, focus its efforts on technical directives and guidelines, communications, and maintenance of professional standards. The Assembly also approved Latvia as the venue for the General Assembly of 2009.

european INDUSTRIAL PHARMACY • Issue 1 October 2008

N E W S F R O M E I PG ( C o n t . ) EIPG Communication on Responsible Pharmacists in Pharmaceutical Wholesaling

Following the recommendations of the General Assembly, on the 19th June 2007 the EIPG has written to the European Commission and EMEA, expressing its concerns over the recent outbreaks of counterfeit medicines. The EIPG has commented on the potential diversity of the transposition in Member States' national legislation of Article 79 of Directive 2001/83/EC, specifically the term "qualified person designated as responsible" (also known as the Responsible Person) in respect of wholesale distribution of medicinal products. The EIPG has expressed its belief that the term Responsible Person should be replaced by Responsible Pharmacist in all Member States, since the training of pharmacists is most suited towards the establishment and implementation of the necessary Good Distribution Practices necessary to substantially reduce the impact of counterfeit medicines. EIPG Guidance on Continuing Professional Development for Qualified Persons

During the 2007 General Assembly in Prague, the Working Group on Qualified Person matters presented the final version of a document regarding Guidance on Continuing Professional Development for Qualified Persons. The document was approved by the General Assembly, and will be proposed by EIPG as a guide for all Qualified Persons, Technical Directors and other Responsible Persons. Comments on the document are welcome and should be submitted to info@eipg.eu. Career Options: How does one become a qualified person?

Seen or heard the term “QP” or “qualified person” and wondered what it meant? Interested in the career opportunities provided by the pharmaceutical industry? Malcolm E. Brown outlines what QPs do and how to become one, and Sadia Khan follows with a more detailed look at the QP registration process. (Tomorrow's Pharmacist: January 2007). Best Practice Guidelines on Notification and Management of Medicines Shortages

The United Kingdom Department of Health, in association with the pharmaceutical industry, has recently published best practice guidelines on the notification and management of medicines shortages. Two separate guidelines have been published, one in collaboration with the Association of the British Pharmaceutical Industry (click here), and the other in collaboration with the British Generic Manufacturers Association (click here). The guidelines are designed to help minimise the impact of any medicine shortage. They

recommend that companies communicate with the authorities as soon as possible about impending shortages that are likely to have an impact on patient care. This early exchange of information will enable the authorities and the industry to work together to explore the options for managing the shortage and will allow time to make contingency arrangements where necessary. Compliance with the requirements of the Marketing Authorisation

A batch of medicinal product that does not comply with the requirements of the marketing authorisation cannot lawfully be released for sale. From time to time a Qualified Person (QP) can be faced with a batch of product that does not fully comply with all the details described in the authorised marketing authorisation dossier. The competent authorities have been considering whether or not a QP is able to certify such batches, as required in Art. 55(3)/51(3) of Directive 2001/82(3)/EC, thereby allowing them to be released for sale. A reflection paper is hereby published, which is intended to clarify, in the circumstances described, whether a batch complies with the requirements of the marketing authorisation or not. The paper describes certain conditions that must be met. It is hoped that this paper will be helpful in dealing with a large proportion of cases where there has been some uncertainty in the past. Cases of non-compliance outside the scope of this paper must continue to be dealt with by following the relevant national procedures. The European Commission has signalled its possible future support for a corresponding amendment to Annex 16 of the GMP Guide (Certification by a Qualified Person and Batch Release). This will partly depend on feedback from the industry on the practical implementation of the details in this reflection paper. EMEA is presently considering, together with the Commission, how this feedback should be collected and further information on this will be provided in the coming months. Presentation of information in MA dossiers

The EMEA PAT team has published a reflection paper providing preliminary recommendations on how PAT related information should be presented in applications or variations to Marketing Authorisations. Work on this topic is under continuing development and as a flexible regulatory approach is important to avoid unnecessary barriers to improved product quality, it is not appropriate to publish formal guidance at this time. Nevertheless, the paper is intended to assist companies planning to file PAT-based submissions in the short to medium term. Feedback from the industry on the contents of the paper should be sent to David.Cockburn@emea.eu.int

eur opean INDUSTRIAL PHARMACY • Issue 1 October 2008

DATES FOR YOUR DIARY

N OV E M B E R

4-5 November 2008 – Basle, Switzerland Poorly water soluble drugs: successful formulation approaches www.apv-mainz.de 4-6 November 2008 – Manchester, UK How to simplify and improve your change management system www.DBA-global.com 10-11 November 2008 – Berlin, Germany Analytical data – interpretation and treatment www.gmp-compliance.org

19-21 November 2008 – Brussels, Belgium Production of highly-potent sterile pharmaceuticals www.apv-mainz.de

2 December 2008 – London, UK The current state of dissolution testing www.jpag.org

24-26 November 2008 – Cambridge, UK Tabletting technology for the pharmaceutical industry www.rpsgb.org/world of pharmacy/events

3-4 December 2008 – London, UK Cold chain distribution www.smionline.co.uk/08coldchain.asp

25-26 November 2008 – Copenhagen, Denmark Stability testing for drug substances and drug products www.gmp-compliance.org

9 December 2008 – Berlin, Germany ICH Q10 and its potential impact on the pharmaceutical industry www.pda-training.org

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

9-10 December 2008 – Amsterdam, The Netherlands Solubility and drug absorption email: registrations@informa-ls.com www.informa-ls.com/solubility

12-13 November 2008 – Mainz, Germany IVIVC of special dosage forms www.apv-mainz.de

26-27 November 2008 – London, UK CPD framework for the European pharmacist – a joint EIPG/PHSS conference www.phss.co.uk

15-18 December 2008 – Amsterdam, The Netherlands Pharmaceutical GMP www.dba-global.com

D E C EM B E R

JANUARY 2009

18-19 November 2008 – Berlin, Germany Reference standards www.gmp-compliance.org

1-2 December 2008 – Munich, Germany 1st IPEC European conference on GMP for pharmaceutical excipients www.ipec-conference.org

15-16 January 2009 – London, UK FDA approval process for medical devices www.management-forum.co.uk

11-12 November 2008 – Liverpool, UK Best practice guidance for Qualified Persons (QPs) and Responsible Persons (RPs) www.mhra.gov.uk

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european INDUSTRIAL PHARMACY • Issue 1 October 2008