european Industrial Pharmacy Issue 2 (February 2009)

europeanINDUSTRIALPHARMACY

ISSUE 2 • FEBRUARY 2009www.industrialpharmacy.eu

www.eipg.eu

FEATURES4 PARTNERSHIPS CREATE VALUE FOR HEALTHCARE

CUSTOMERSPharma companies and healthcare professionals alike need todevelop new marketing strategies to meet the new healthcareneeds of their customers and patientsby Mats Olsson and Pär Tellner

7 FRAMEWORK FOR A CONTINUING PROFESSIONALDEVELOPMENT (CPD) – A UK PERSPECTIVEThe requirement for pharmacists to take part in a CPD programmeis detailed and discussedby Fred Ayling

11 DOES CHANCE FAVOUR THE PREPARED MIND?Many of today’s drugs were discovered by chance. But as the well-known story of Sir Alexander Fleming’s discovery of penicillin shows,the true scientist is the one who questions anomaliesby Dave Sharma

13 CHOCOLATE: A THERAPEUTIC ANDNUTRACEUTICAL DELIVERY SYSTEMThe ingredients of chocolate have been shown to have a numberof health benefits and so one should not feel guilty about eating it.by Tim Ridgway

16 VACUUM FOAM DRYING: A NEW TECHNOLOGYFOR PRESERVING SENSITIVE BIOMOLECULESThis technology has several advantages over freeze drying and istherefore worth further development.by Ashok Hajare, Harinath More, Sambhaji Pisal

19 VISIONS AND NIGHTMARES OF AMICROBIOLOGISTThe author urges the need for a re-evaluation and harmonisationof microbiological test methods and comments on the need to relyon conventional pharmacopoeial methods.by Klaus Haberer

REGULARS3 EDITORIAL COMMENT21 REGULATORY REVIEW22 NEWS FROM THE EIPG25 DATES FOR YOUR DIARY

2 eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 2 February 2009

europeanIINNDDUUSSTTRRIIAALLPHARMACY

Issue 2 February 2009ISSN 1759-202X

EDITORJoe Ridge, MRPharmS

PRODUCTIONSue Feather

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldMichael Gamlen

Linda HakesLarry HurstJohn JolleyPär Tellner

European Industrial Pharmacy is published three times a year by:

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Views expressed in European IndustrialPharmacy are those of the contributors andnot necessarily endorsed by the Publisher,Editor, Editorial Board, or by our corporate

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©2009 Euromed Communications Ltd

Belgium: Philippe Van der Hofstadt

Bulgaria: Valentina Belcheva

Czech Republic: Miloslava 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

Portugal: [email protected]

Spain: Mercé Pujol

Sweden: Pär Tellner

Switzerland: Renato Kaiser

europeanIINNDDUUSSTTRRIIAALLPHARMACYdiscussion group:

www.pharmweb.net/gmp.html

Associate Editors

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

Cover picture: Water treatment plant in India.

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

3eeuurrooppeeaann IINNDDUUSSTTRRIIAALL PHARMACY • Issue 2 February 2009

EEDDIITTOORRIIAALL CCOOMMMMEENNTTThese subjects will be discussed atour annual General Assembly beingheld in Latvia and hosted by Ms IntaSaprovska who heads the LatvianIndustrial Pharmacists Group. Iwould like to thank Inta foragreeing to host this importantmeeting for EIPG and the EIPG willcontinue its mandate to expand itsmembership to newer accessioncountries.

In partnership with the EuropeanAssociation of Faculties ofPharmacy, substantial funding hasbeen provided by the EuropeanCommission to review thecompetencies required to be aPharmacist working in Industry.EIPG will dedicate resources to makesure that this PHARMINE initiative isa success. High educationalstandards are one the GuidingPrinciples in the Statutes uponwhich the EIPG was founded in1966.

Simply put, the PharmaceuticalIndustry will continue to needaccess to high calibre graduates whohave an appreciation of how drugsare discovered, developed,manufactured and regulated.Industrial pharmacists need to audittheir competencies and to identifypriorities for their professionaldevelopment. In November, EIPGheld a joint seminar with the

Another busy year

I would like to welcome 2009 withthe second issue of EuropeanIndustrial Pharmacy. The feedbackfrom the launch of the first issuehas been very well received and inmy opinion demonstrates the needfor such a communication forum toexist.

This year promises to be to a verybusy one for the EIPG as we willcontinue our consultative processwith the Regulatory Agencies andother interested parties in thefollowing areas:

� Preventing the spread ofcounterfeit medicines

� Promoting the ResponsiblePharmacist principles inwholesaling

� Providing Guidance for GoodRegulatory Practice

� Providing Guidance for TheQualified Person

� Providing Guidance of BiologicalIMPs

� Supporting ContinuingProfessional Developmentinitiatives for branches ofIndustrial Pharmacy

� Maintaining the academicstandards required for IndustrialPharmacy

Pharmaceutical and HealthcareSciences Society entitled “TheContinuing ProfessionalDevelopment framework for theEuropean Pharmacist”. This was anopportunity to question thetechnical developers of the onlinesystem and those responsible for theimplementation of mandatory CPDin the UK.

This electronic Journal is yourJournal and we would be veryhappy to hear from you or in factreceive any contributions you maylike to see published.

You can contact me using my [email protected] or contactJane Nicholson, the ExecutiveDirector to EIPG [email protected].

Best Wishes for 2009

Gino MartiniPresident, EIPG

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PARTNERSHIPS CREATE VALUE FORHEALTH CARE CUSTOMERSby Mats Olsson and Pär Tellner

MATS OLSSON is Business Consultant at KairosFuture, working with societal analyses within health,healthcare and the pharma industry

PÄR TELLNER is Compliance Officer of the SwedishAssociation of the Pharmaceutical Industry (LIF)

Le partenariat crée de la valeur pourles consommateurs de soins

Les avancées techniques en médecine font perdreaux médecins leur monopole en termesd’information. Dans cette ère nouvelle del’information, les consommateurs ont de plus enplus de connaissance et sont de plus en plusexigeants, voulant être reconnus comme desindividus avec des besoins individuels.

Les nouvelles exigences vont donc concerner tousles acteurs impliqués dans le système de soin. Lespharmaciens industriels vont jouer un rôle clef entenant compte des consommateurs polymédicamentés, du vieillissement de la populationet de la coopération possible avec les médecinspour développer des médicaments plus sûres.

L’époque où les cliniciens et scientifiquespontifiquaient sur la vie et la mort des patients enleur adressant à peine la parole est révolue. Avecl’amélioration des systèmes de protection socialedans le milieu du 20° siècle, la problématique étaitd’augmenter la durée de vie et aujourd’hui au 21°siècle, ce n’est plus suffisant.

Aujourd’hui nous voulons une santé parfaite. Dansla consommation de soins et de santé, nouspassons de la satisfaction des besoins à lasatisfaction des exigences.

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Mutual European problems

However, the ageing of the population, due to increasedlife expectancy and reduced fertility, will undoubtedlyhelp inflate demand for health care products andservices throughout the EU. These demographicdynamics will lead to difficult financial and logisticalquestions. Adding to the financial burden will be thefact that over time the value of services will, therefore,become greater than that of products. A growing shareof revenue in society, and of many industrial firms,therefore, will come from services and maintenance.

Productivity improvements are more significant in theproduction of goods than services, because theproduction of man hours grows more expensive inrelation to the production of goods. This phenomenon,Baumol’s disease, or the post industrial dilemma, meansthat the cost of personal intensive products and services,

Technical advances within medicine are makingdoctors lose their monopoly on information. In

the new information age consumers are becomingmore knowledgeable and demanding, wanting tobe seen as individuals with individual needs. Thiswill place new demands on all stake holdersinvolved in health care. Industrial pharmacists willplay a key role in taking care of multiple-drugconsumers and the increasing elderly population,with the possibility of cooperation with doctors todevelop safer drugs.

The days when scientists and clinicians pontificated onthe lives and deaths of patients while hardly talking tothem are gone. With the improved welfare systems inthe middle of the 20th century the issue was livinglonger. Now, in the 21st century, that is not goodenough. Today we want perfect health. In theconsumption of health and health care we are goingfrom satisfying needs to satisfying wants.

Consumers refuse to be part of the massmarket

The individualistic mega-trend represents consumers´desires to be seen as who they are, and recognized ashaving individual needs, rather than being part of themass market. The individual’s responsibility for his ownhealth, and the desire for wellbeing, instead of justliving longer, will emerge as powerful driving forces. Thefocus will be on how individuals are experiencing theirhealth, rather than on actual medical status. Thisparadigm shift will severely challenge the health caresector, as well as the whole system of financing based oncure rather than on promotion of wellbeing.

When talking about how to develop health care, it isimportant to stress that there is no universal model, noteven within the EU. Each country and its population is ata different development stage. There are post-modernsocieties versus non-post-modern, materialistic valuesversus post-materialistic. There are different kinds ofwelfare systems. There are differences in life expectancyat birth. There are cultural and historical differences andso on.

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demographic and economic environment in which theindustry operates is undergoing huge changes and thepharma industry is at a pivotal point in its evolution.

The next few years will be tough for pharma companies.Health care will be expecting further development ofworking methods and more transparent ethicalprinciples in the sales and marketing process. There is aprevailing crisis of trust, which the drug industry musttake seriously. Also, there are ever increasingexpectations on the drug companies to justify pricingand improve transparency, when it comes to, forinstance, documentation.

The pharma change process in Sweden

A few years ago the polarization between health careand the pharma industry in Sweden became evident.The old fashioned working methods in the industryresulted in a negative attitude towards industry repsfrom governmental medical institutions. The talksbetween health care and The Swedish Association of thePharmaceutical Industry (LIF) that followed resulted inThe Ethical Code of Practice, with the first editionpublished in the summer of 2004.

Pharma companies have started to think about newways to handle sales and marketing. LIF have gone outtheir way to create conditions for member companies tostart off in another direction when meeting health care.A few companies started this change process, workingclosely with The Ethical Code of Practice 2004 and othersfollowed in 2006 and 2007.

Industry stuck in old-fashioned ways

At that time a number of interviews were published inthe book From Conflict to Cooperation in Tomorrow’sPharmaceutical Market, published by Kairos Future. Thekey point which emerged was that health care hadmoved to another level and was waiting for thepharmaceutical industry to change their old-fashionedmarketing methods. Key representatives interviewed inthe book confirmed the conflict situation and spokeabout the barriers to change and how they could beovercome.

The pharma industry has since been moving away frommarketing to physicians and trying to influence thosehigher up in the decision making chain. In some casespoliticians have been targeted and sales reps have beenusing almost identical tool kits to those they used intheir earlier sales work, resulting in a number ofnegative reactions. In other cases, efforts to influencepoliticians have resulted in clumsy attempts to makethem, in turn, influence purchasing managers withindifferent county councils.

like health care and care production, are increasing. Thisleads to decreasing costs of products, but not necessarilydecreasing costs of services. Over time, the value ofservices will, therefore, become greater.

The blessings of technology

Health care must do what it can to increase productivityusing new technology and new drugs. Other industrieshave already launched various do-it-yourself concepts(like self- service at supermarket checkouts), in order tocut costs. Within health care there are already constantefforts to involve consumers in doing as much as theypossibly can, without risking safety and quality.

In future, we will, no doubt, be able to see health carestakeholders outsourcing more and more functions. Insome therapy areas, commercial companies, e.g.pharmaceutical companies, will be considered for manyparts of the health care chain, from direct deliveries ofdrugs to facilitating treatment monitoring done by theconsumer himself.

The introduction of IT has been relatively slow in healthcare provision, but things are finally starting to move.Technology is changing the look, feel and nature ofhealth care. New electronic health records will make iteasier for patients to change care providers or to havemore than one. It will be easier for providers to delivermore personalised service to patients. The tracking ofhealth intervention outcomes – the systematic recordingof the success rate of different approaches to treating agiven condition – will change medicine.

Machines will take care of more of the work in future,freeing up physicians for more difficult tasks, such asconsidering appropriate treatments and communicatingthem to the patients.

Partnership between clinicians andpatients

Health care professionals will need to develop new skillsover the next few years, with a new focus on the patientas an individual customer. The relationship must changeto a much greater partnership between clinicians andpatients. Patient deference is disappearing asinformation increases. The Internet in particular isundermining medical professionals’ monopoly oninformation, and therefore authority. There will be aparadigm shift that includes a changing consumer role;from a passive receiver of information into a co-producer of messages and meaning.

The above changes are some of the shifts that will affectthe health care industry over the coming years and insuch an environment, the workforce across the healthcare industry also needs to change. The social,

Health care looks to the future

In Sweden we are presently at a stage where the biggestresistance to change from health care has subsided andbeen replaced by a certain measure of acceptance totaking part in discussions about future forms ofinteraction and cooperation. Meanwhile, the health carestakeholders in most other EU countries are somewherein the earlier stages of the development process andtherefore marked by denial, anger and resistance. Thelack of a proactive approach from the industry in thesecountries results in a number of tough decisions andmeasures from health care and doctors.

Reading about these things in Swedish medical trademagazines raises a number of questions among decisionmakers in Swedish health care. Surely they would feelmore good-will towards the pharma companies if theycould see some transparency in what these companiesare doing at a global level.

Challenges

Changes in technology are rapid, thus, being aprofessional purchaser is becoming more and moredifficult. Customers cannot maintain competence indevelopments in all suppliers’ areas anymore. They,therefore, buy functions, i.e. they outsource the know-how to the supplier. Instead of trying to find out whatchemicals to buy and store, they buy the function of thechemicals. This makes the supplier responsible formaintaining quality products, meeting environmentaland governmental demands, keeping and co-ordinatingproduct flows, etc. More and more of the total value ofa contract lies in services, and in after-market sales.Customers will increasingly buy functions and systems.

The pharmaceutical industry has not yet startedthinking seriously about providing service and solutionsfor their customers and patients; efforts in this directionwill have to increase in the years to come.

Pharma’s traditional strategy of placing big bets on afew molecules, promoting them heavily and turningthem into blockbusters worked well for shareholders formany years. However, its productivity in the lab is nowplummeting as it switches its attention from relativelycommon and easily treated diseases to those that aremuch more complex or unusual.

Industrial pharmacists needed

Both the industry and health care will in future requiremore industrial pharmacists with new competencies.Within research, new technology and new molecularmethods today give more data in a couple of hours thanthat formerly obtained through years of work. The needto be able to handle extensive amounts of data is rapidlyincreasing. The know-how of linking preclinical and

clinical data will be crucial in order to develop newdrugs faster and in a reliable way. New peptide- basedpharma drugs and their kinetic qualities will requiremore extensive knowledge about preparation forms andbodily distribution mechanisms.

Within health care there will be increasing demand forindustrial pharmacists, due to the more complex drugregimes in the future. With an increasing number ofmultiple-drug consumers, we will need new ways ofworking to create safer treatments and fewer side effectsfor older patients. We will need doctors and pharmacistsin cooperation for safer handling of drugs.

Further reading

In the project “From Conflict to Co-operation onTomorrow’s Pharmaceutical Market” Mats Olsson, KairosFuture, has published the following during the period2007–2008:

� The book From Conflict to Cooperation onTomorrow’s Pharmaceutical Market consisting of teninterviews with representatives of the health careand pharmaceutical industry. Published in May2007.

� An article based on an interview with Mr. SörenOlofsson, County Council Director for StockholmCounty: The Industry in Urgent Need of ProfessionalStake Holders. Published in Pharma Industry no1/2007.

� An article based on an interview with Mr. SeppoSilander, General Manager, Sanofi-Aventis Sweden:We Must Pull Ourselves Together, the Same Rules MustApply for All. Published in Pharma Industry no2/2007.

� An article based on an interview with Mrs. KarinLendenius, Pharma Manager of Region VästraGötaland and Mrs. Karin Bernadotte, ManagingDirector Merck Sharp & Dohme: One Year Later, theAntagonism Persists. Published in Pharma Industryno 1/2008.

� An article based on an interview with Dr. BoRingertz, rheumatologist and vice chairman of thePharmaceutical Drug Committees in Stockholm: TheDoctors in a Vice Between the Stakeholders.Published in Pharma Industry no 3/2008.

� An article based on an interview with Ms. IngridCarlberg, journalist and writer. A Clearer Identity aMust for the Industry. Published in Pharma Industryno 4/2008.

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In 2010, a new regulator, the GeneralPharmaceutical Council (GPhC), will be

established in Great Britain. This new body willtake over the regulatory functions currentlyundertaken by the Royal Pharmaceutical Society ofGreat Britain. As part of these functions, the GPhCwill implement mandatory CPD requirements forpharmacists and pharmacy technicians.

The approach taken to CPD for pharmacists in GreatBritain is significantly different to elsewhere in Europe.It is based on one that the RPSGB has been developingsince 1998 and has been made available to pharmacistssince 2002. At the point at which CPD remainedvoluntary, more than 20,000, over half of themembership, had made a start at recording their CPD.This is in comparison to other professions, wherevoluntary uptake has been informally reported at beingin only single figure percentages.

For a number of years the RPSGB’s Code of Ethics hasrequired pharmacists to undertake and keep records oftheir CPD. It is anticipated that later this year the RPSGBwill start asking pharmacists to submit their CPD recordsfor review. When the GPhC is established in 2010 it willbe able to ask pharmacists for CPD records dating backto 2008 and it is anticipated it will require pharmaciststo submit a record once every five years.

What is different about CPD in GreatBritain?

Most pharmacists will be used to an approach ofaccumulating a set number of points for hours ofattendance at formal events over a period of time. Theseevents may or may not be accredited. In Great Britain,this approach is referred to as continuing educationrather than continuing professional development.

Continuing professional development is different in anumber of ways. It is perhaps best understood as anapproach adopted by pharmacists for the self-management of their development, based on a four-stage cycle. At the first stage of the cycle eachpharmacist is expected to identify personal learning

objectives that are specific, measurable, achievable,relevant and timed; they should also have a clearlyidentified performance outcome; that is, something thepharmacist will be able to do, either differently or betterin some way. This approach is important because ithelps the pharmacist to take ownership of their learningand it means that they focus their development on whatis actually going to make a difference.

Although this reflection stage of the management cycleis self-directed, it does not mean that pharmacistsnecessarily act in isolation when setting these objectives.Indeed, it would be best practice to ensure, whereappropriate, that they involve others, such as colleagues,peers and those who use their services. This method ofsetting objectives fits well with an employer’sperformance review systems, although it should bestressed that a pharmacist’s development will extendbeyond this. Each person will have their own careeraspirations and there may be aspects to theirdevelopment that an employer is not interested in. Alsothere may be issues that a pharmacist would not becomfortable discussing with the person undertakingtheir performance review, or with their employergenerally. It is also important to remember that manypharmacists in Great Britain are self-employed, or are anemployee-owner without a line manager to undertake aperformance review.

It is at this reflection stage of the management cyclewhere competences may play a part. Competency auditmay be used to identify learning objectives.Competences for industrial pharmacists have provedsomething of an issue in Great Britain. The RPSGB haspublished a set of ‘competences’ which are really just ahigh level list of the types of things that industrialpharmacists should know something about. There areonly seven items in the list and it is not really detailedor thorough enough to be of much practicable use.Fortunately, the RPSGB’s electronic recording systemsallow pharmacists to add their own competences intothe system. These additional competences may beprovided or set by an employer or by a relevantorganisation, such as those for competent persons thatare published by the European Industrial PharmacyGroup (EIPG).

At the next stage of the management cycle, thepharmacist is asked to plan how they are going toaddress the learning objective they have identified.There are two aspects to this, firstly prioritising the

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FRAMEWORK FOR A CONTINUINGPROFESSIONAL DEVELOPMENT (CPD)– A UK PERSPECTIVE by Fred Ayling

FRED AYLING is Director of CPD Services, Ltd. He wasthe Royal Pharmaceutical Society’s CPD Managerfrom 1998 to 2007.email: [email protected]

objective and secondly, identifying appropriateactivities. Clearly the pharmacist will have a number oflearning objectives at any one time and so prioritising isimportant. They will need to provide a realistic targetdate for meeting the objective and to think about thedegree of impact their learning objective will have onthem, their employer or contracting body, colleaguesand the users of their services or products.

In terms of identifying appropriate activities, the RPSGBis not prescriptive. If the appropriate activity is informal,such as having a discussion with someone, reading abook or undertaking a web search, that is fine. If it isformal, such as attending a course, it does not need to beaccredited. What is important is that the pharmacistdescribes why one activity is more appropriate thananother. This provides great flexibility for the pharmacistand reflects the way we learn. We often learn throughdiscussion, observations and other means of learning-by-doing. That’s to say, we learn through experience everybit as much as we learn through attending courses.

At the action stage of the cycle, the pharmacistundertakes the activities they have identified and thensums up the key learning points. This ‘summing up’ isimportant as it has been demonstrated that we onlyretain a fraction of the information that we are toldwhen engaging in a learning event, whatever that maybe. Two pharmacists engaging in the same learningevent will take away different things. That is becausethey will come to the event with different levels ofexisting knowledge or skills and they will have differentexpectations in terms of what they want to go away with.Reflecting on their learning has a twofold benefit; itreinforces the key points they have learnt and providesa list that can be used in the future as a handy reference.

In the final stage of the management cycle, thepharmacist evaluate their learning. Have theysuccessfully addressed the learning objective theyidentified? If not, why not, and what are they going todo next, if anything? If the learning objective has beensuccessfully addressed, how have they been able toapply what they have learnt in practice? What are theynow doing that they didn’t do before? What feedback orindicators do they have on the effectiveness of theirlearning? Do they need to build on this; perhaps identifya new objective and so start the management cycleagain?

The CPD cycle?

The management cycle described above is referred to asthe CPD cycle. But in simple terms it is a managementcycle that those involved in research or projectmanagement will be familiar with: identify, plan, actand evaluate.

The RPSGB presents this cycle as in Figure 1. It refers tothe identification stage as reflection. This is because theRPSGB wishes to promote a reflective approach topharmacists’ development. This is based on theobservations made by Donald A Schon in his book: Thereflective practitioner: how professionals think in action.

Schon observed that faced with the same event and theneed to take action (make a decision, give certainadvice, provide a solution and so on) professionals acteddifferently. This was because they brought their personaland professional experiences to bear when acting.

Different professionals would provide different advice orcome to different conclusions or solutions. It was notnecessarily the case that one action was better or moreright than another. It does follow though that if thereare a range of actions in a given situation, some actionsmay be better than others and indeed some may bepoor. The idea behind reflective practice is that itencourages the pharmacist to step back and understandthat there are a range of actions and that the one theychoose will be based, for good and bad, on their ownexperiences. By thinking this through, it is hoped thatthe pharmacist may be more objective and so makebetter decisions.

So, at the identification stage, the RPSGB regards apharmacist as reflecting on events to help them find theright or best learning objectives that arise out of them.

A number of issues have arisen from this. Althoughpharmacists who have qualified in recent years will havebeen taught about reflective practice, those who havebeen qualified longer may be less familiar with thisconcept and have less understanding of the term‘reflection’. Also, it is not always the case that muchreflection really needs to go on when identifyinglearning objectives. It is often quite clear and self-evident what learning needs to be undertaken as aresult of a certain event. If someone asks us a


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Reflection

PlanningEvaluation

Implementation to Action

Figure 1. The learning cycle.

straightforward question, we don’t need to do much orany reflection to realise what we need to know and thatwe need to go away and look the answer up!

On a personal note, I tend to simply refer to this stage ofthe CPD cycle as identification. I also regard reflectivepractice as happening at any stage, as at each stage I findmyself making decisions that I have reflected on. Forexample, at planning I am reflecting on what I anticipatethe impact of my learning will be and which activities aregoing to be appropriate based on previous experiences.

A common misconception about the CPD cycle is that itis an annual exercise; the pharmacist would sit downonce a year, identify their objectives and spend the nextyear addressing them. Although taking time out once ayear to do just this is good practice, learning objectiveswill arise at any time throughout the year and may needto be addressed in a couple of months, weeks, days orhours. So a CPD record is a live, ongoing document andit is possible to move through the cycle in hours or years,depending on the learning objective.

When the RPSGB piloted CPD and launched it nationwidein 2002, it also allowed pharmacists to start their CPD atthe action stage of the cycle. This meant that pharmacistscould record CPD that occurred when a learning objectivehad not previously been identified, for example, readinga journal or attending a routine seminar without alearning objective in mind, but simply because there wasan opportunity that you may learn something.

In 2007, the RPSGB allowed pharmacists to start theirCPD at the planning and evaluation stages. Although afew pharmacists had requested this, the feedback I havereceived from most of the trainers supportingpharmacists is that this has added confusion and no realbenefit. It can be quite difficult to find examples of CPDthat starts at these stages and my advice is to ignore thisoption unless you can see any specific benefits.

Why CPD instead of CE?

When we looked at the research that had beenundertaken in the area of continuing education, it wasclear that there was no evidence that attending coursesactually made a difference.

One of the leading authorities in this area is Dave Davisand his team from the Faculty of Medicine, at theUniversity of Toronto. In their review of the literature1,they made the observation that there is a ‘diminishedimpact of CME along this continuum’.

The thinking in the field was that it was more importantto accredit the learner rather than the course. A learnerwho is motivated and committed may attend a coursethat is poor but will not leave it at that; he or she willinstead find another way of learning what needs to belearnt.

This is not to say that courses are not an important partof professional development and, indeed, that someform of quality assurance is required. ContinuingEducation should not be relegated as CPD’s poor cousinbut instead regarded as part of a wider process of CPD.The suggestion is that it is important for pharmacists totake ownership of their learning and that eachpharmacist will have his or her own starting point interms of their knowledge, skills or competences andtheir own end point of where they need to be. It is alsoimportant that the approach to CPD encompasses all themanners in which we learn, including informal learning,as not to do so could lead to pharmacists notappreciating and engaging in all the developmentopportunities available to them. To bring about moreeffective development pharmacists were alsoencouraged to think about learning that would make adifference as they moved through the cycle.

A professional develops over time. There are rarely bigleaps, but more commonly it is the accumulation of lotsof little bits of learning that can add up to somethingquite significant. CPD should be about continuousimprovement and in developing their approach theRPSGB wanted to encourage pharmacists not just tothink about what they don’t do well but what theyalready do well and how they could build on that.

How can it be recorded?

Pharmacists can record their CPD in three ways. There is anonline recording system, CPD Online; PC-based software,CPD Desktop; or a paper-based system using a formatprovided by the RPSGB or a format accredited by them.

CPD Online is by far the best format in terms of itsfunctionality. More than 50% of pharmacists are recordingtheir CPD in this way, that’s over 20,000 people.

CPD Online allows pharmacists to tailor various aspects ofthe recording system, including competences and optionsfrom other menus. It also allows pharmacists to shareaspects of their CPD with others online. These may befriends and colleagues or their employer, so making it easierto integrate into employers’ HR systems. The pharmacist isin control of who sees what and when. Regular backups alsomean that the pharmacist cannot accidentally delete theirCPD record or lose it if their computer system crashes.

A personal development plan that interacts with theirCPD record is also provided to help the pharmacistidentify learning objectives.



Skills Skills,Patient

Knowledge, Performance

Attitudes AttitudesOutcomes

Recording consists of a mixture of free text andselections made by means of checkboxes and dropdownmenus. Once familiar with the system, it should takeabout 30 minutes to record one entry in a CPD record,taking in all four stages of the CPD cycle.

How will the CPD record be reviewed andwill the pharmacist receive feedback?

CPD will be reviewed according to the goodmanagement practice described by the RPSGBreviewers. They will consider whether the learningobjectives are specific, measurable, achievable, relevantand timed; whether there has been a thought-throughoption appraisal at the planning stage; and whether theCPD has actually made a difference.

The purpose of the review is primarily to look at how thepharmacist has been managing his CPD and to providehim with meaningful and formative feedback. Some of itwill be used to establish whether the pharmacist has metthe required standards, but most aspects will simply be

used to provide feedback. For example, when receivingfeedback the pharmacist will be able to see at a glancewhere his CPD has been focused in terms of competences.For good reasons, it may be quite narrow or broad andthere is no reason why any two pharmacists should havethe same focus. The intention is simply to providefeedback to help the pharmacist understand where theymay take their professional development in the future.

Although the RPSGB is taking a formative approach, theyand the GPhC will need to set a minimum requirement.I do not expect it to be terribly taxing but then theintention is to engage pharmacists in a formative wayand not to be heavy-handed.

Reference1. Davis D, O’Brien MAT, Freemantle N, et al. Impact of formal continuing

medical education – do conferences, workshops, rounds and othertraditional continuing education activities change physicianbehaviour or healthcare outcomes? JAMA 1999; 282: 867–874.



COMBATING COUNTERFEITING – CURRENTSTATUS OF THE NEW TECHNOLOGIESAND RAISING PUBLIC AWARENESS

Seminar 18 March 2009 at the RPSGB1 Lambeth High Street, London SE1 7JN

Global trade arrangements and internet sales are dramatically changing the worldwide market in medicines, favouring an increase in counterfeiting activities.

The meeting will review the anti-counterfeitingtechnologies available to the pharmaceuticalindustry, the MHRA’s current anti-counterfeitingstrategy and the efforts being made to improve public awareness of the dangers of counterfeit medicines.

The chair for the seminar will be Dr John Kerridge

Details and registration:www.rpsgb.org/worldofpharmacy/events


Leo Sternbach, a pharmacist and a chemist, is theman to whom the discovery of benzodiazepines

is attributed. Born one hundred years ago,Sternbach earned his Master of Pharmacy and thena PhD in chemistry from the University of Kraków,(Poland). In his early years he developed severalheptoxdiazine compounds in an effort to developsynthetic dyes1. However, these compounds did notlend themselves as useable dyes and Sternbachwrote: “with regret, we dropped these compoundsand turned to other things”2.

Then, in the 1950s, inspired by the success ofmeprobamate to treat anxiety, Sternbach returned to hisresearch on heptoxdiazines in the hope of findingcompounds with psychopharmacological activity. By1954, he realised that what he initially perceived asbeing heptoxdiazines were in actual factbenzoxdiazines. Although this group of compoundswere pharmacologically inert, he decided to stabiliseone of the benzoxdiazines and labelled it Ro-50690.There it sat, on a shelf in the laboratory, for three years.

Sternbach’s team was clearing the laboratory in 1957 tomake way for new projects when a co-worker, EarlReeder stumbled across the compound and brought it toSternbach’s attention. This was then sent forpharmacological evaluation. The news was good; morepotent than meprobamate and less sedative. Ro-50690was, in 1960, the first anxiolytic benzodiazepineintroduced into clinical use. It is now better known aschlordiazepoxide or under its brand name Librium. A fewyears later, Sternbach went on to develop Valium(diazepam). Is it true to say that he discoveredbenzodiazepines? Or did he in fact stumble across themby chance? This is one example of serendipity in thepharmaceutical industry. More famous instancesinclude the discovery of Viagra for erectile dysfunction,Retrovir for the use of Aids patients and Minoxidil forthose of us going bald.

Serendipity

The role of serendipity, which is the finding of one thingwhile looking for something else, in drug discovery is

largely underplayed. One could be mistaken in thinkingthat our understanding of science today is leading to arational drug design model only. This is an approach inwhich a priori assumptions are made about the activityof the compounds, based on pharmacological hypotheses,and/or fundamental knowledge about the nature of thedisease at the molecular level. Drug discovery anddevelopment becomes the incremental process by whichfacts, theories and methods have been added to the evergrowing stockpile of scientific knowledge. The history ofscience becomes the discipline that chronicles successivedevelopments and obstacles.

The danger of scientific textbooks is, as Thomas Kuhn3

points out in his masterpiece “The Structure of ScientificRevolutions”, that their aim is “persuasive andpedagogic”. He goes further and states that “sciencestudents accept theories on the authorities of teacherand text, not because of evidence. What alternativeshave they, or what competence?” The result is that thereis a persistent tendency to make the history of sciencelook linear or cumulative, a tendency that even affectsscientists looking back at their own research. But that isnot what history shows. Was there scientific accrualor incrementalism that led to the discovery ofchlordiazepoxide? No, it was luck. Yet it is tempting torewrite history so that theory “fits the facts”. Numerousliterature sources attribute the discovery ofbenzodiazepines to Sternbach which is somewhatreductive because it downplays the role of chance.

Rational drug design

In 1988, George Hitchings, an industrial pharmacologist,

DOES CHANCE FAVOUR THEPREPARED MIND? by Dave Sharma

DAVE SHARMA, MRPharmS, is the Associate Directorfor Genzyme Clinical Research Pharmacy Services.He is currently undertaking a PhD on the role ofplay in research environments at CranfieldUniversityEmail: [email protected]

Leo Sternbach


shared the Nobel Prize for Physiology or Medicine alongwith Gertrude Elion and the British pharmacologist, SirJames Black. This was “for their discoveries of importantprinciples for drug treatment,” Hitchings’ specifically for hiswork on chemotherapy. It was an award made a posteriori,which recognised the important contribution theirrational approach to drug design had made to medicine.The award stressed the researchers’ reliance on an“understanding of basic biochemical and physiologicalprocesses”. However, eight years prior to the award,Hitchings himself had argued to the contrary that basicscience was more often the result, than the cause ofdrug discovery:

“Much of basic science supported by the industry is, in asense, retrospective. A semi-empirical discovery of auseful drug provides the stimulus for deeper probinginto how and why it works, and thus to a deeperunderstanding of the underlying disease. This may inturn give rise to new concepts and new discoveries.”4

Reading pharmaceutical textbooks and the websites ofprominent pharmaceutical organisations would primerecipients that it’s the other way round. That is, thedevelopment of new drugs follows a linear path as weget to understand the disease, identify a target and thensubsequently develop a drug to interact with that target.This process is often compared to the building blockmodel, but that is not the only way a new drug develops.Interestingly, for those of you who believe thatdiscoveries are synonymous with having a Ph.D, takeheart from the fact that Gertrude Elion did not possessone. Yet she became a world renowned scientist, at atime where females were far less visible inpharmaceutical research environments. And it was achance meeting with Hitchings himself that led to herfirst appointment within the industry.

When something “new” is found, it often takes yearsbefore we know how new, true or useful it really is. If welook back on how the finding was done, the possibilityfor forming a legend is there. The serendipity of it caneasily become underestimated and even denied. This ismainly and unintentionally caused by the way werationalise a posteriori about theoretical andexperimental research and its results, when we publish5.The not strictly rational – chronological or searchedcomponents (like chance or accidents) which led to theresults are therefore underestimated and sometimes notmentioned at all.

The prepared mind

However, as Kuhn demonstrates, an understanding ofanomaly is vital for scientific discoveries. He alsopostulates that reading and interpreting textbooks (as ameans to understanding the discovery process) caninadvertently brainwash the researcher into thinking in

one way only3. This can cause a loss of serendipity. So-called experts can quite often delay the uptake of aparticular hypothesis. During the discovery of Captopril,the first ACE inhibitor, the therapeutic hypothesis thatthe inhibition of ACE is useful in the treatment ofessential hypertension was regarded as doubtful bymost clinical experts. It even proved difficult to findmedics who would participate in the original studies.Today, it is now recognised that understanding therenin-angiotensin system and ACE inhibition hasprovided excellent therapy for hypertension. Anotherclassic example was the hypothesis put forward by thethen young scientists Dr Marshall and Dr Warren in1983. They proposed that peptic ulcers were generallycaused not by excess acid or stress, but by a bacterialinfection. This hypothesis was viewed as preposterous bythe scientific community. This is somewhatunderstandable as people with increased acid werefound to suffer with peptic ulcers. Treatments such asRanitidine or Cimetidine were found to be effective incontrolling acid production and therefore a good meansto allow ulcers to heal. Physicians therefore had both anexplanation and treatment, so why look elsewhere. It isquite often the naive gaze of young scientists that allowsthe evidence to ‘flow’ in rather than remain stuck in thetradition of a particular paradigm. In scientific research,no discovery has ever been made by pure luck alone. Allchance discoveries have one point in common: “eachwas recognised, evaluated and acted upon in the light ofthe discoverer’s total intellectual experience.”1

When developing new drugs, it is important to recognisethat serendipity does exist. In practice, it appears thatwhen serendipity does play a role, this role is normallysecondary but essential. Scientists often publish theirresults in a rational manner, underplaying or omittingthe role of chance. The scientific community, includingstudents, then read these findings and unwittingly fallinto the mindset of a logical, linear mechanism forunderstanding every experiment. This can result in aloss of serendipity. A successful researcher is someonewho has one eye open for sought findings and anothereye open for unsought findings. Or as Pasteur put it soeloquently, “Chance favours the prepared mind.”1

References1. Ban TA. The role of serendipity in drug discovery. Dialogues Clin

Neurosci. 2006; 8(3): 335–44.2. Oransky I. Leo H Sternbach The Lancet 2005; 366: 1430.3. Kuhn TS. The structure of Scientific Revolutions, 1996; 3rd Ed,

University of Chicago.4. Quirke V. Drugs by serendipity or by design? Applying science to the

pharmaceutical industry in 1950s Britain and France. Paper presentedat EBHA Conference 2001.

5. Van Andel P. Anatomy of the Unsought Finding. Serendipity: Origins,History, Domains, Traditions, Appearances, Patterns, andProgrammability. Brit J Phil Sci. 1994; 45: 631–48.

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Based on the premise that most women likeeating chocolate and the evidence that

nutraceutical isoflavones are good for women’shealth1, by putting nutraceutical isoflavones in achocolate bar you could potentially have a winningguilt-free confectionary product, the ‘Venus Bar’.

This is an example of how in the future chocolatemanufacture and nutraceutical provision may combine.As it turns out, however, chocolate itself may be a lotmore virtuous than previously thought; it may actuallypromote good health through its high content of plantpolyphenols, in particular the flavanols, catechin andepicatechin.

The bioactive ingredients of chocolate

Epidemiologic evidence has suggested that certain plantpolyphenols, in particular the flavonoids, promote goodhealth and help to prevent the onset of chronic diseases,including cardiovascular disease and cancer2. Amongstthe flavonoids the flavanols have received specificattention for their potential to prevent cardiovasculardisease and are present in wine, tea, and various fruitsand berries. Chocolate also contains large amounts offlavanols and is now thought to have a potentialcardioprotective role in the diet3.

The flavanols in chocolate consist of the monomersepicatechin and catechin plus oligomeres of epicatechinand catechin which are known as procyanidins. Bothflavanol monomers and oligomeres are thought torepresent bioactive ingredients. Flavanols are distinctfrom other types of flavanoid as they tend not to appearas glycosides, but are present as aglycones or areesterified with gallic acid3.

Bioavailability and metabolism

Following absorption from the gut, flavanols aremethylated and glucuronidated with some sulphonicationtaking place in the liver. These metabolites may thenrepresent the actual bioactive forms in the body. Inaddition colonic microflora can degrade the flavan ringstructure to form simple phenolic and ring fissionmetabolites that may be physiologically active.Nevertheless, in studies following human cocoa

ingestion, catechin and epicatechin have actually beendetected in human plasma as has the epicatechin dimerB2 (epicatechin-(4β-8)-epicatechin), showing aproportion of dietary flavanols to be bioavailable inunmodified form4.

Mechanisms of action

Flavanols in chocolate are thought to offercardioprotection by a variety of mechanisms includingantioxidant action, the result of which is that LDL (lowdensity lipoprotein) is protected from oxidation thusreducing the formation of atherosclerotic lesions. Othercellular mechanisms of action of flavanols include thereduction of inflammation, the reduction of plateletaggregation and an increase in the production of nitricoxide resulting in vasodilation3.

The structural characteristic of flavanols that confirmstheir excellent antioxidant properties is thehydroxylation of the basic flavan structure, in particularthe formation of 3?,4?-dihydroxy groups on the B-ring,ie. the formation of catechol structures5. Cocoa powderand cocoa extracts have been shown to exhibit greaterantioxidant capacity than many other flavanoid-richfoods, including green and black tea, red wine,blueberry, garlic and strawberry3.

Clinical trials

Over the past decade many clinical trials have beencarried out to investigate the potential health benefits ofchocolate; these works being recently reviewed byCooper et al.6 Most of the clinical trials appeared to showa positive outcome for chocolate as a cardioprotectiveagent, although the fact that the scale of the trials wasgenerally small should be taken into account beforedrawing any conclusions. As an example of a recentstudy, which used 39 healthy Japanese men, it wasfound that flavonoid-rich dark chocolate significantlyimproved coronary circulation as measured by non-invasive transthoracic Doppler echocardiography(TTDE)7.

Dark, milk or white?

The flavanols in chocolate come from the cocoa liquorformed as a result of processing the cocoa beans. Aswhite chocolate contains no cocoa liquor, it contains noflavanols and could thus be expected to have nocardioprotective properties; hence its use as a controlwhen investigating the prospective benefits of flavanolsin chocolate7.

CHOCOLATE: A THERAPEUTIC ANDNUTRACEUTICAL DELIVERY SYSTEMby Tim Ridgway

TIM RIDGWAY PhD is a science writer.email: [email protected]


Similarly, milk chocolate contains proportionally lesscocoa liquor than dark chocolate, but in addition it hasbeen hypothesised that milk proteins bind cocoaflavanols which prevent their absorption in thegastrointestinal tract. This hypothesis has beensupported by some studies, but disproved by others andremains controversial8.

What is clear, however, is that the effect of the foodmatrix is increasingly regarded as being of importanceas exemplified by EU legislation (Directive 2000/13/EC)stating that food labelling for a high content of abeneficial compound must be backed by evidence thatthe compound is bioavailable6.

Development of high monomer flavanoidtypes

The production of procyanidin oligomers (and longerchain polymers) from catechin and epicatechin isdependent on a production process termedfermentation, but which is actually the oxidation ofcatechin and epicatechin by plant polyphenoloxidases;the same enzymic oxidation which is responsible for theproduction of black tea.

As the flavanol monomers are regarded as havinggreater therapeutic potential than the procyanidins andany oxidization products, an unfermented (and non-roasted and blanch-treated) cocoa product has beendeveloped9. The resulting cocoa powder contains fourtimes as much procyanidins than a conventionalpowder and will hopefully lead to the development ofcommercial chocolates with greater therapeuticpotential.

Development of nutraceutical containingtypes

As exemplified by the ‘Venus Bar’ proposal, there is inaddition to chocolate’s endogenous bioactivecompounds, great potential to supplement them withadditional plant-derived nutraceuticals, for example;flavonoids/isoflavonoids, stilbenes and phytosterols, asdescribed below:

Isoflavonoids

As previously described, the ‘Venus Bar’ would be theresult of the addition of the soya-derived isoflavonoids,genistein and diadzein. This could potentially not onlyhelp to prevent cardiovascular disease, but could helpprevent hormonal dependent diseases such as breastcancer and osteoporosis. The therapeutic effects are dueto blocking estrogen (antagonist) at estrogen receptorsites in the case of breast cancer prevention, andmimicking estrogen (agonist) at estrogen receptor sitesin the case of osteoporosis treatment1. Isoflavones are

thus said to be selective estrogen receptor modulators(SERM). Estrogen mimicking effects are also thought tobe of value in the prevention of cardiovascular diseaseby the maintenance of good HDL (high densitylipoprotein) to LDL (low density lipoprotein) ratios1,potentially further enhancing the cardioprotectiveeffects of isoflavone-containing chocolate.

Isoflavone-containing chocolate has in fact recentlybecome commercially available, although it has notbeen marketed on the basis of its potential healthbenefits, presumably as the strict criteria surroundinghealth claims for food products have not been met.However, clinical trials of a high flavonoid and soyasupplemented chocolate are about to start in NorwichUK, investigating its potential cardioprotective effects onpostmenopausal women with type 2 diabetes.

Stilbenes

Another clear candidate for addition to chocolate is thestilbene, resveratrol. This plant polyphenol is foundmost famously in red wine and has been postulated asbeing responsible for the ‘French Paradox’ whereby theFrench population shows a low rate of cardiovasculardisease, despite a diet containing significant amounts ofsaturated fat10. There is also great interest in resveratrolas regards its potential prevention of cancer11. Recentlyit has been postulated that much of the therapeuticpotential of resveratrol is due to its great ability toactivate the human sirtuin 1 (SIRT1) gene. SIRT1 isthought to regulate such processes as insulin productionand fat metabolism. This has led to speculation thatsirtuins might mediate the effects of calorific restrictionand prove particularly useful in the prevention ofdiabetes12.

As with the isoflavonoids, there is actually a chocolateproduct on the market containing resveratrol (in theform of a grape extract), although again it is notmarketed for its health promoting effects, relyinginstead on consumer knowledge.

‘Superantioxidants’

The flavanols endogenous in chocolate have excellentantioxidant properties, but these could be enhancedfurther by the addition of a new generation of‘superantioxidants’; hydroxylated derivatives ofcommon and cheap to produce polyphenols, such aspiceatannol derived from resveratrol13 and3–Hydroxyphloridzin derived from the flavonoid(dihydrochalcone) phloridzin14.

Phytosterols

Phytosterols are a group of plant secondary metabolitesthat closely resemble cholesterol in structure. When

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included in the diet they lower the absorption ofcholesterol thereby promoting good health. They havefor a number of years been successfully included in arange of products, in particular margarine, yoghurt andmilk15. Small scale clinical trials have been carried outwith phytosterol-enhanced chocolate, the developmentof which will perhaps eventually extend to commercialproducts16.

Improving cognitive function

Chocolate has been reported as improving mood andaiding sexual desire in women, although there iscontroversy surrounding such work17. Nutraceuticaladditions to chocolate could, however, potentially aidcognitive function as phytochemicals, in particular theisoflavones genistein and diadzein, have been shown toimprove cognitive function in humans in a number ofstudies1. Similarly the flavonoid phloridzin, foundprincipally in apples, is well known to improve cognitivefunction in rats. Marketing phytochemical-enhancedchocolate to improve cognitive function is therefore apossibility, although the prospective name ‘Student Bar’is perhaps best avoided?

Conclusion

A range of plant secondary metabolites, in particular,polyphenols, are increasingly being seen as capable ofpromoting good health. As these are ideally suited forinclusion in the food matrix of a chocolate bar,complementing the endogenous flavanols, chocolatecould be developed as the ideal nutraceutical-polypilldelivery system, enhancing health in the form of a tastytreat. A few squares of chocolate are a lot more enticingthan supplements/pills and therefore sales andcompliance for any prospective ‘Venus Bar’ would belikely to be assured if the required evidence fortherapeutic benefit was forthcoming.

References1. Wiseman H. Isoflavonoids and human health in: FlavonoidsChemistry, Biochemistry and Applications (eds Andersen OM andMarkham KR). 2006; pp371–396.

2. Rimm EB. Fruit and vegetables: building a solid foundation. Am J ClinNutr. 2002; 76: 1–2.

3. Keen CL, Holt RR, Oteiza PI et al. Cocoa antioxidants andcardiovascular health. Am J Clin Nutr. 2005; 81(suppl): 298S–303S.

4. Holt RR, Lazarus SA, Sullards MC et al. Procyanidin dimer B2[epicatechin-(4beta-8)-epicatechin] in human plasma after theconsumption of a flavanol-rich cocoa. Am J Clin Nutr. 2002; 76:798–804.

5. Pannala AS, Chan TS, O’Brian PJ et al. Flavonoid B-ring chemistry andantioxidant activity: fast reaction kinetics. Biochem Biophys ResCommun. 2001; 282: 1161–1168.

6. Cooper KA, Donovan JL, Waterhouse AL et al. Cocoa and health: adecade of research. Br J Nutr. 2008; 99: 1–11.

7. Shiina Y, Funabashi N, Lee K et al. Acute effect of oral flavonoid-richdark chocolate intake on coronary circulation, as compared with non-flavonoid white chocolate, by transthoracic Doppler echocardiographyin healthy adults. Int J Cardiol. 2007; (E pub ahead of print).

8. Roura E, Andres-Lacueva C, Estruch R et al. Milk does not affect thebioavailability of cocoa powder flavonoid in healthy humans. AnnNutr Metab. 2007; (E pub ahead of print).

9. Tomas-Barberan FA, Cienfuegos-Jovellanos E, Marin A, et al. A newprocess to develop a cocoa powder with higher flavonoid monomercontent and enhanced bioavailability in healthy humans. J Agric FoodChem. 2007; 55: 3926–3935.

10. Siemann EH, Creasy LL. Concentration of the phytoalexin resveratrol inwine. Am J Eno Victic. 1992; 43: 49–52.

11. Signorelli P, Ghidoni R. Resveratrol as an anticancer nutrient:molecular basis, open questions and promises. J Nutr Biochem. 2005;16: 449–466.

12. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivoevidence. Nature reviews – Drug discovery. 2006; 5: 493–506.

13. Saiko P, Szakmary A, Jaegar W et al. Resveratrol and its analogs:Defense against cancer, coronary disease and neurodegenerativemaladies or just a fad? Mut Res. 2007; (E pub ahead of print).

14. Ridgway TJ, Tucker GA, Wiseman H. Novel bioconversions for theproduction of designer antioxidant and colourant flavonoids usingpolyphenoloxidases. Biotechnology and Genetic Engineering Reviews.1997; 14: 165–190.

15. Ridgway TJ, Wiseman A. Phytosterols and phytostanols: cholesterol-lowering functional food ingredients. Industrial Pharmacy. 2006; 9:23–25.

16. Polagruto JA, Wang-Polagruto JF, Braun MM et al. Cocoa flavanol-enriched snack bars containing phytosterols effectively lower total andlow-density lipoprotein cholesterol levels. J Am Diet Assoc. 2006; 106:1804–1813.

17. Salonia A, Fabbri F, Zanni G et al. Chocolate and women’s sexualhealth: An intriguing correlation. J Sex Med. 2006; 3: 476–482.

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Apromising and effective therapeutic biomoleculewill not be of benefit if it is unstable during the

processing, distribution and storage stages and atadministration. Various stresses reduce clinicalefficacy and increase the risk of adverse side effectsif formulated as an aqueous solution. Althoughphysical stability is maintained, most biomoleculesare degraded by chemical reactions initiated bywater. Lyophilisation is an alternative to aqueoussolutions of sensitive biomolecules, but it has beenfound that the stress of acute freezing anddehydration can damage them and reduce storagestability in the dried state. Vacuum foam drying, anew technology invented by Bronshtein, is apractical solution to this type of stability dilemma.

Vacuum foam drying produces mechanically stable dryfoam by boiling biological solutions or suspensions undervacuum at ambient temperature above freezing point.Stability drying is carried out at an elevated temperatureto increase glass transition temperature (Tg). A yield ofactive samples preserved by this method afterrehydration is achieved by proper selection of protectantsas well as vacuum and temperature protocols.

Problems with stability

Chemical complexity and marginal stability of higher-order structures of therapeutic biomolecules presentcritical problems in the stability of their formulations.1

Scientists are working hard to develop a technology thatcan formulate and deliver life-saving and cheaperbiological drugs like vaccines, proteins, enzymes andhormones without refrigeration.2 About 2 million childrendie every year from diseases that could be treated withbiomolecule products. About 50% of these life-savingbiopharmaceuticals are damaged due to improper storageas well as unavailability of facilities for storing themproperly, specifically for temperature effects.3

To be effective, biomolecules require some mechanismthat can maintain their potency and effectiveness at

ambient temperature for a sufficiently long time.4

Biomolecules in a liquid state are stable only for a shortperiod due to molecular movement that may result indegradation. Pharmaceutical products must haveadequate stability over storage periods of many months,typically several years and many biomolecules do notpossess this long-term stability in the aqueous state atambient temperature.5 To attain extended stability atambient temperature, molecular movement needs to bearrested by some method that stops degradation bytransforming liquid into a highly immobile,noncrystalline, amorphous solid state during storage,called vitrification. The system below its glass transitiontemperature (Tg) is stable due to immobilisation of thereactive entity in a solid glass-like system.6

Spray drying, freeze drying or lyophilisation, freezethawing, precipitations with organic solvents, air dryingand rotory evaporation are commonly used methods forpreservation of sensitive biomolecules. These methodssuffer from the following major limitations:7-12

� Freezing and moderate low temperatures causedamage to thermolabile biomolecules, reducing theirclinical efficacy and increasing the risk of adverseeffects.

� Process is lengthy and time-consuming.

� If formulated successfully, storage facility such as coldchain storage transport is a must to maintainstability.

� Not suitable for bulk aseptic production.

Evaporative versus freeze drying

Annear, Bronshtein, Roser, Kadam and co-workersseparately and independently, were able to preservebiologicals, proteins, enzymes and micro-organisms byevaporative drying for long periods at ambienttemperature without significant loss of activity.12-15 Theyclearly indicated and confirmed that the stability ofsensitive biomolecules and micro-organisms dried byevaporative drying is better than that of freeze-driedsamples. However, dehydrated solutions withprotectants obtained by evaporative drying are veryviscous and too much time is required for theirevaporation as it is a diffusion-limited process; hencethe process is non-scalable and unsuitable for industrialapplications.16

VACUUM FOAM DRYING: A NEWTECHNOLOGY FOR PRESERVINGSENSITIVE BIOMOLECULESby Ashok Hajare, Harinath More, Sambhaji Pisal

SAMBHAJI PISAL works in the Department ofBiotechnology, BVDU Poona College of Pharmacyand Research Centre, Pune, Indiaemail: [email protected]


Preservation by foam formation

For the last 50 years, freeze drying has been consideredthe best method for stabilisation of sensitivebiomolecules due to the belief that low temperaturescause minimum damage. Preservation by foam formation(PFF) is a new technology proposed by Bronshtein in 1996.According to Bronshtein, this belief in low-temperaturedrying with minimum damage is not correct.17 BeforeBronshtein’s invention of foam formation, no scalabletechnology had been proposed to preserve thermolabilebiomolecules at ambient temperature.

Annear, while preserving bacteria in a dried state,demonstrated that viscous solutions and biologicalliquids can be dried by forming foam by applying avacuum. He used this foam formation process only for asmall volume of sample but not scaled up for industrialapplications. Until recently, foam formation was notused for preservation because it was considered to be aprocess that damages biologicals.

Bronshtein was the first to report that biologicals couldbe effectively stabilised by foam drying and hedemonstrated that PFF has been used successfully to dryvarious volumes of biological liquids from 1-100,000ml.18 The only limitation of this technology isthat the volume of liquid to be dried must not be morethan 20-25% of the container volume, because thesample expands during foam formation. The timerequired for this process is much shorter than otherprocesses due to intensive boiling.

Foam formation process

In this process, the biological solutions or suspensionsare first transformed into mechanically stable dry foamsby boiling them under vacuum at ambient temperatureabove freezing point (primary drying). Samples are thensubjected to stability drying at an elevated temperatureto increase the Tg Activity yield after the rehydration ofthe foam-dried sample is achieved by proper selection

of protectants (sugars like sucrose and trehalose), whichare dissolved in the suspension before processing.Proper selection and use of vacuum, as well astemperature protocols during drying, help to produceelegant and therapeutically active products that remainstable at an ambient storage temperature.

Applications of PFF

PFF has been used successfully for stabilisation ofthermolabile enzymes and pharmaceuticals such asamphotericin, urokinase, luciferase, ß-galactosidase,lactate dehydrogenase, isocitric dehydrogenase and ice-nucleating proteins at ambient or higher temperature. Liveviruses like Newcastle disease virus (La Sota strain),herpesviridae, paramyxoviridae, flaviviridae, parvoviridaeand retroviruses can also be stabilised by using this vacuumfoam drying technique. Gram-negative bacteria such as E.coli and B. bronchiseptica and gram-positive bacteria suchas Lactobacillus acidophilus and Lactococcus lactis subsp.cremoris can be stored for longer at 37°C temperaturewith up to 40% less viability during both log andstationary phases.

Foam formation equipment

At the present time no industrial equipment has beendesigned and is available for the bulk production ofpowders or market-ready vials by the vacuum foamdrying technique. Researchers have claimed that with afew modifications to the controls and process cycleprogramming software, commercially available freezedryers could be modified for PFF in glass vials. The mainrequirement is simultaneous control of vacuum andtemperature during foam drying.

Thus, the pharmaceutical and other industries aresuffering from an absence of effective drying equipmentthat produces bulk products stable at ambienttemperature.

Conclusion

Although foam formation is an old invention,preservation by foam formation under vacuum andcontrolled temperature is a new technology in theembryonic stage, being used for only a fewpharmaceutical applications and needs someimprovement. Elimination of uncontrolled eruptionsand spitting out of material from vials or containersduring boiling are the improvements required in thistechnology. More parameters must be studied for itscomparison with freeze drying and other known andnewly developed drying processes. Preservation by foamformation may be a substitute to freeze drying orlyophilisation and will stimulate development of newprocesses and equipment for preservation ofthermolabile biologicals in a dry state.

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Advantages of PFF

� Scalable and turbulent process.� Lends itself as an aseptic process due to higher vapour

pressure above the sample during PFF, leading to lesssurface area exposure and less exposure time.

� Does not require freezing of sample before drying; it istherefore more efficient, gentle and less damaging.

� Less time consuming and more energy efficient.� More scalable process compared to freeze drying, which

has limitation of cake height in container.� Allows high ambient temperature stabilisation with

minimum loss of activity during drying and storage.� Offers the potential to deliver biomolecules outside the

cold chain storage.


VVAACCUUUUMM FFOOAAMM DDRRYYIINNGG:: AA NNEEWW TTEECCHHNNOOLLOOGGYY FFOORR PPRREESSEERRVVAATTIIOONN OOFF BBIIOOMMOOLLEECCUULLEESS ((CCoonntt..))

Industrial Pharmaceutical MicrobiologyStandards & Controls

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References1. Cleland JL, Powell MF, Shire JS. The development of stable proteinformulations: a close look at protein aggregation, deamidation andoxidation. Crit Rev Ther Drug Carrier Syst 1993; 10: 207–377.

2. Kathy S, Rouan E. Biotechnology-based pharmaceuticals. In: Banker GS,Rhodes CT eds. Modern Pharmaceutics, New York, Marcel Dekker, Inc.1990. 843–874.

3. Wang W. Lyophilization and development of solid proteinpharmaceuticals. Int J Pharma 2000; 203: 1.

4. Rodriguez W, Koval R, Chogprasert S. Optimizing storage stability oflyophilized recombinant human interleukin-11 withdisaccharide/Hydroxyethyl starch mixtures. J Pharm Sci. 2004; 93:684–696.

5. Manning M, Patel K. Stability of protein pharmaceuticals. Pharm Res.1989; 6: 903–918.

6. Franks F. Freeze drying: from empiricism to predictability, Cryo. Letter1990; 11: 93–100.

7. van de Beek MJ, Gerisma SY. Preservation of enzymatic activity of raninduring storage and the effect of sugars and certain other additives.Neth Milk Dairy J. 1969; 23: 46–54.

8. Corrasquillo KG, Sanchez C, Griebenowl K. Relation betweenconformational structural changes of chymotrypsin. Biotechnol ApplBiochem. 2000; 31: 41–53.

9. Maa Y, Zhao L, Payne L. Stabilization of alum adjuvanted vaccine drypowder formulation: Mechanism and application. J Pharm Sci. 2003;92: 319–332.

10. Kramer M, Sennhenn B, Lee G. Freeze-drying using vacuum-inducedsurface freezing. J Pharm Sci 2002; 91: 433–443.

11. Miller D, Anderson R, Pablo J. Stabilization of lactate dehydrogenasefollowing freeze thawing and vacuum drying in the presence oftrehalose and borate. Pharm Res 1998; 15: 1215–1221.

12. Annear DI. Observations on drying bacteria from the frozen and fromthe liquid state. Austral J Expt Biol. 1958; 36: 2111–2222.

13. Bronshtein V. Preservation by foam formulation. Pharm Tech. 2004; 4:86–92.

14. Roser BJ, Gribbon EM. Methods for stably incorporating substanceswith dry, foamed glass matrices and compositions obtained thereby.US Patent – W09640077.

15. Kadam SS, Pisal SS, Mane JJ, Shah MH. Effect of excipients on productcharacteristics and structure of lyophilized lasota vaccine. IJ Biotech2005; 4(1): 106–114.

16. Adams J, Ramsay R. Optimizing the lyophilization cycle and the consequenceof collapse on the pharmaceutical acceptability of EL Asparaginase.J Pharm Sci 1996; 85: 1301–1305.

17. Bronshtein V. Preservation by foam formation. 1998 US Patent5766520, 1–6.

18. Bronshtein V. Scalable long-term shelf preservation of sensitivebiological solutions of suspensions. 2003; US Patent – 6509146, 1–14.


What should our aims be – protecting the patient,the company or our own backside – or all three?

To protect the patient, we have to balance healthrisk with health cost. To protect the company, wehave to consider the risk of unnecessary qualitycost, the financial risk of product recall or possiblelitigation and the risk of loss of reputation with theresultant loss of stock value.

As for protecting our own backside, we may find thatcases of recall or litigation could affect our future career.Then there is the need for scientific correctness, whichwe obviously need to maintain.

Let me outline my vision for an ideal world and thencompare it with the nightmare of the real world.

In the ideal world, we can assure quality of easilycontrollable, safe, robust manufacturing processes usinglow cost, state of the art technology equipment whichwould be readily available. All process risks would beunderstood and controlled; quality control tests wouldhave clear-cut results that immediately show anydeviations. Personnel would be dedicated and welltrained. The marketing product would have a stablehigh price.

Now let’s look at the nightmares of the real world. Weproduce high volumes of complicated products underconstant time pressure in a crowded facility.Manufacturing is carried out on old equipment as a newline is too expensive to be an option. The process itselfrequires many steps including interventions that areimpossible to validate comprehensively. Personnel aremore interested in football than manufacturing SOPs,and errors occur frequently. QC tests give results that aredifficult to interpret and failure investigations end in themist of uncertainty about the root cause.

So where do we go in microbiological quality assurance?

Historical development

Formulation of official microbiological test methods fornon-sterile pharmaceuticals started in Europe as areaction to tragic cases in Scandinavia in the 1960s whensome patients lost their eyesight after being infected

from ophthalmic products contaminated withPseudomonas aeruginosa.

The experience of some of the most prominentEuropean experts was condensed into guidancedocuments by a working group of the InternationalPharmaceutical Federation (FIP), composed of membersof the pharmaceutical industry and officialpharmaceutical testing laboratories from Europeancountries (many were also delegates at themicrobiological expert group of PhEur).

The methods and criteria recommended reflected theexperience with microbiologically contaminatedpharmaceutical products around 1970, and what wasdone in other related areas of applied microbiology.

Casein-Soy Peptone was a general medium widely used,also Sabouraud Dextrose Agar for testing of yeast andmoulds; Pseudomonas aeruginosa was excluded,because it had recently caused problems; Enterobacteriaand Salmonella spp. were excluded in analogy to foodmicrobiology; Escherichia coli was excluded as a wellknown water contaminant, as was Staphylococcus aureusas a pathogenic Gram-positive organism.

Microbiological methods and requirements of PhEurthus originated in the FIP guidance documents.However, when published as official pharmacopoeialmethods, the microbiological methods have beenvirtually frozen. The spirit of using state of the artmethods from other areas to achieve better qualitycontrol procedures has been lost. There have beenmodifications in details, but the basic methods appliedare unchanged since 1975.

It therefore appears prudent to regulators andmanufacturers alike to rely on the official method andnot to use alternative methods which would need to bevalidated, and whose equivalence to the referencemethods might be difficult to prove.

Need for harmonisation

There clearly needs to be a re-evaluation andharmonisation of microbiological test methods ingeneral. The methods and media used were developedin the late 19th to mid 20th century. Since then therehave been a number of fundamental developments.

Microbiological examination of non-sterile products wasofficially introduced in the late 1960s; there has been abig increase in multinational drug companies andglobalisation of the market; repeat testing is generally

VISIONS AND NIGHTMARES OFA MICROBIOLOGISTby Klaus Haberer

KLAUS HABERER PhD is head of Compliance Adviceand Services in Microbiology, GmbH, Frankfurt,Germanyemail: [email protected]


avoided; and there has been an introduction of “rapidmethods” although they are not yet widely used.

The pharmacopoeial methods are the reference onesused by official laboratories to verify productcompliance with phamacopoeial requirements in casesof investigation, and in market surveillance.

They are also used by manufacturers to verify productcompliance with pharmacopoeial requirements.However, there is no requirement to use the methods forprocess control.

Why are they used by most manufacturers?

Authorities expect manufacturers to use thepharmacopoeial methods for product release as it is easierto judge a dossier if the official reference method is used.

Companies prefer to use pharmacopoeial methods as thecost to perform validation and to justify other methods islikely to be higher than using the reference methods(mostly major companies work with alternative methods).In addition, companies are afraid to lose litigation lawsuits: lack of adherence to standard procedures may beseen as not following standard technology procedures.

Microbiologists too, prefer to use pharmacopoeialmethods. For them it is the easy way as it is notnecessary to justify the use of alternative methods!

The downside

However, there are a number of problems withconventional pharmacopoeial methods. They areuniversally feasible with basic laboratory equipment butwill not detect each and every micro-organism (media arenot rich enough for some organisms, too rich for others).

They are generally applicable but not optimised for a givenprocess. They are slow and time consuming (not optimised fora rapid answer), not necessarily state of the art technologyand not necessarily the best method for process control.

The worst aspects of pharmacopoeial methods are thatthe tests are applied to the letter, leading to a recipebook approach, with SOPs copied from the book.

The lack of critical appreciation of the significance ofwhat is being done (eg. sterility tests, specified micro-organism testing) means that there is no testing relatingto the specific problems of the product, yet there is nomicrobiologist on site who dares to take responsibility.

Furthermore, there is no investigation into alternativemethods, thus neglecting the advantage of rapidmethods and results, blocking innovation and failing toinvestigate more relevant alternative information.

A vision for the future

The ideal situation and perhaps a vision for the futurewould be for pharmacopoeia tests to be applied forreference purposes only. Methods to be applied forroutine testing should be justified in each case. Whilemaking sure that compendial requirements are metwhen tested, compendial methods should not be thefirst choice. Alternative methods may have a number ofpractical advantages: shorter time to the result; teststailored to obtain better answers to specific questions;wider range of questions and answers (eg. absence ofgroups of micro-organisms).

The interpretation of the data would then be based onan understanding of the test and the significance ofresults. This would require competent microbiologists totake responsible decisions.

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European Union

Proposals from the European Commission on theFuture of the Pharmaceutical Sector

The European Commission has published acomprehensive package of measures aimed at:

� Strengthening the “pharmaceutical sector” in theEU and

� Improving access to modern, innovative, safe andeffective medicines.

This takes the form of draft legislation and a “politicalcommunication” to EU Member States covering:

� The problem of counterfeit medicines.

� Provision of better information to patients onmedicines.

� Improved pharmacovigilance arrangements.

� Increased “transparency” of pricing/reimbursement decisions.

� The encouragement of pharmaceutical researchand

� Increased international co-operation.

Proposals specific to pharmaceutical manufactureand distribution include:

� Mandatory “safety features” (e.g. pack seals) onmedicines.

� Unique identification (“mass serialisation”) ofindividual packs of high value products.

� Improved controls at external borders / entrypoints for medicines from third countries.

� Increased surveillance / control of the supplychain for Active Pharmaceutical Ingredients bymanufacturers and regulatory authorities.

The package of proposals has now to go through aprocess of consultation and discussion within theCommunity before it leads to legislation and otheractions. This is likely to take at least 2 to 3 years.

Further details appear in the “Latest News” section ofthe European Commission’s Pharmacos website.

Revision of Annex 7 to the EU GMPGuide

The European Commission has published a revisedversion of the Annex to the EU GMP Guide dealing withthe Manufacture of Herbal Medicinal Products (HMP).

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

by Steve Fairchild

The changes introduced by this revision include:

� The application of GMP to active substances usedin HMP.

� Reference to Good Agricultural Practice for theculture of medicinal plants and

� Modifications resulting from the Traditional HMPDirective.

The revised document can be found in EudralexVolume IV on the European Commission’s website. Itis due to come into effect on September 1st 2009.

New and Revised Quality Guidelines

The European Medicines Agency (EMEA) has publishedrevised versions of the Guidelines on qualityinformation in EU registration dossiers for:

� Radiopharmaceuticals and

� Allergen Products of Biological Origin.

These documents can be found on the EMEA’swebsite. Both have an effective date of May 2009.

The UK Good PharmacovigilancePractice Guide

The UK Medicines and Healthcare Regulatory Agencyhas published the UK Good PharmacovigilancePractice Guide, which provides practical guidance onimplementing a “compliant” pharmacovigilancesystem as required by EU/UK legislation.

This new guide can be purchased from thePharmaceutical Press.

International

Extension of the Scope of the EU – Switzerland MutualRecognition Agreement

The EU and Swiss Authorities have decided toimplement the provisions of this Agreement coveringActive Pharmaceutical Ingredients. This means thatthe EU and the Swiss Authorities will now recognisethe equivalence of each other’s controls of APImanufacturers including GMP inspections.

Further details can be found on the EMEA andSwissmedic websites.

Steve Fairchild is a Pharmaceutical Consultant and anExecutive Director of IAGT Ltd. Email: [email protected]


Counterfeit medicines for human use

In December 2008, the Commission published severalpieces of legislation including 104 pages of a workingdocument entitled an “Impact assessment on anti-counterfeiting measures”. The social and economicimpact of counterfeit medicines is tackled. Severalsections of the summary of responses covered thecomments made by EIPG. The Commission document isavailable on the following website: http//ec.europa.eu/enterprise/pharmaceuticals/index_en.htm

Note that the Industrial Pharmacists Group of the RoyalPharmaceutical Society of Great Britain is holding aseminar on Combating Counterfeiting in London on 18March 2009 (www.rpsgb.org/worldofpharmacy/events).

EMEA reflection paper on QualifiedPersons’ discretion

Following submission of our position on the EMEAreflection paper, EIPG has been advised that the QualityWorking Group of the CHMP and the GMP InspectorsWorking Group have reviewed and updated thereflection paper with their responses to the variousquestions raised. It is felt that there should now be aconsistent understanding amongst regulators and staffworking in the industry.

The paper was discussed at an “Interested PartiesMeeting” held in the EMEA offices during November2008 at which EIPG was represented by Vice-PresidentPhilippe Van der Hofstadt (Belgium) and John Jolley(Great Britain).

Consultation on Annex 13 update

A consolidated response from seven EIPG memberdelegations was made to the proposed update. This canbe found on the EIPG website and included commentson personnel, reference samples, IMPs, premises,equipment, labelling and packaging.

CPD for the European pharmacist

A joint seminar was held in London in November by theEIPG and PHSS (Pharmaceutical & Healthcare SciencesSociety) on a “Continuing Professional Development(CPD) for the European pharmacist”. Whilst it provided aUK perspective, the regulatory bodies in some otherEuropean countries already require and others aremoving towards requiring, participation in CPD.

In this issue of European Industrial Pharmacy, FredAyling writes about CPD as it will be applied on amandatory basis to UK community pharmacists.However, the general principles apply equally to

NEWS FROM THE EIPGindustrial pharmacists, who have particularrequirements to develop the own personal CPD plan inorder to benefit their own careers as well as enhancetheir contribution to their company.

Concept paper on a guideline on chemicaland pharmaceutical qualitydocumentation concerning biologicalinvestigational medicinal products inclinical trials

Follow submission of comments on this concept paper(see EIPG website), EIPG has been advised that adirective is being drafted and will be made available forpublic consultation.

Contact with students

A meeting was held in Denmark between EIPG Vice-President Jakob Bjerg Larsen and the EPSA Vice-President for Education to discuss ways to stimulateactive collaboration. EPSA requested industrialpharmacists’ input to their professional skills mappingexercise and welcomed the proposal for a CareersSection on the EIPG website. Suggestions for topics andspeakers were requested for their future meetingsprogramme.

General Assembly of the EIPG

The next General Assembly will be held in Riga, Latviafrom 17-19 April, 2009.

GMP guidelines for clinical trials

Considering the absence of GMP guidelines specific toClinical Research in the European Union and/or Belgiumand the different interpretation of the Member States,the VAPI-UPIP (Association of Industrial Pharmacists inBelgium) has formed a working group composed ofrepresentatives of Hospital Pharmacists, IndustrialPharmacists (Qualified Persons), Phase I Units andPharmaceutical Companies.

This guidance document (“Guidance on the GMPRequirements Phase I and Exploratory Clinical Trials inBelgium”) has been prepared in order to specify theoperational requirements applicable to definedpharmaceutical activities to be performed withInvestigational Medicinal Products in a Phase I orExploratory Trial environment. Its ultimate aim is tosupport the Belgium (FAMHP) to define which activitiescan be authorized in a non-manufacturing environmentand the operational requirements to be adhered to bythe Sponsors, QPs and Responsible Pharmacists forpharmaceutical activities in a Phase I or Exploratory


Clinical Trial environment, taking into consideration:

� the views of Hospital Pharmacists, QPs,Pharmaceutical Companies and Phase I units

� the current hospital practices.

This proposal aims to ensure that the InvestigationalMedicinal Products are handled in optimal conditions toguarantee the quality, safety and efficacy of IMPs toenhance protection of trial subjects.

FAMHP has recognized its importance and has formed aworking group with the VAPI-UPIP and pharma.be toimplement this in the Belgian legislation.

This Belgian initiative is now extended at a Europeanlevel through the EIPG. Representatives of Belgium,Denmark, Italy, United Kingdom and the Netherlandsare now consulted. The EAHP has agreed to support andprovide input into this initiative.

For further information contact [email protected].

Report on EMEA GMP/GDP Inspectorsworking group meeting held on 26November 2008

Interested parties from the pharmaceutical industry,including representatives from EIPG met with theGMP/GCP Inspectors at the EMEA offices in London.

The following presentations were made:

1.An update of GMP Guidelines wasprovided by David CockburnInspections Sector of the EMEA

� Guidelines Chapters 3&5 (Dedicated facilities):Work is ongoing to prepare a supplier risk mapidentifying high risk physico-chemical, processand pharmacological/toxicological characteristics.

� Qualification of suppliers and testing of startingmaterials for manufacture is held pendingassessment of the impact of Commissionlegislation on combating counterfeits.

� Annex 2 (Biological): Finalisation of new textexpected February 2009. Release for furtherconsultation anticipated and possible meetingwith industry.

� Annex 6 (Medicinal Gases): Agreed by group fortransmission to Commission and adoption.Release in Spring 2009.

� Annex 11 (Computerised Systems): Publicconsultation just ended. Release expected Q32009 together with consequential changes toChapter 4 (Documentation).

� Annex 13 (IMPs): Public consultation extended toFebruary 2009 in view of addition of definition of“Reconstitution”.

� Annex 14 (Blood products): Draft ready for publicconsultation early 2009.

GMP related issues

� Introduction of QRM principles into Part II of theGMP Guide: Public consultation just ended.Release expected early-mid 2009.

� Reflection paper on compliance with therequirements of the marketing authorisation:Update ready for publication. Clarifications only,no new “QP Discretion”.

� Format for Batch Certificate for IMPs (Directive2001/20/EC art. 13): Awaiting publication byCommission (possibly in Eudralex volume 10).

� QP declarations for “Atypical actives”: Q&Apublished October 2008.

� Site Master File: To be formally integrated into EUsystem once PIC/S revision is complete.

ICH issues

� Initial EU implementation strategy for ICH Q9 isalmost complete.

� Impact on GMP Guide and Compilation ofCommunity procedures.

� An initial implementation strategy for ICH Q10 isunder consideration.

� An integrated implementation strategy for ICHQ8, Q9 and Q10 will be facilitated by Q&Asprepared by the ICH-Q IWG.

Mutual Recognition agreements

� A joint statement on inclusion of the inspectionof active substances within the operational scopeof the GMP Annex of the MRA with Switzerlandwill be published shortly. Work is in progress onsimilar changes to other MRAs

2. Status report on the implementation ofthe EudraGMP database was given byFrancisco Peñaranda of the EMEAInspections Sector.

The EudraGMP database will for the first time provide anoverview of authorised manufacturing sites andinspected sites subject to this common Europeanlegislation. References to EudraGMP will be provided innew applications instead of paper copies providingpossibilities to aid planning, avoid duplication ofresources, and assist in international co-operation. Thisnew data base will also facilitate the issuing of GMPcertificates to a manufacturer and provide access to thegeneral public by Q1 2009, thus facilitating transparency.

When complete, this database will provide Inspectorsand Assessors with the latest update on the status oflicenced manufacturing resources. It will also help

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resolve the planning difficulties and duplication ofinspections, particularly for 3rd countries and theresulting non- GMP compliant and faulty manufactureinformation difficult to find and difficult to co-ordinateany follow up.

This new database will be accessible by the public to theextent that no information will be included that can beconsidered as confidential within the meaning of theAnnex to EMEA’s rules for the implementation of CouncilRegulation (EC) no 1647/2003.

Information will not be disclosed where it wouldundermine:

� Protection of the public interest as regards publicsecurity (eg. MIA/GMPc with information oncontrolled substances: Cannabis growing)

� Protection of the privacy and the integrity of theindividuals (eg. name of QPs or inspectors)

� Protection of commercially confidential nature(eg. name of products under evaluation)

� Protection of commercial interests of a natural orlegal person (eg. non-compliance)

� The effective management or operations of theNCAs (eg. API GMPc) (ie. to avoid an unnecessaryhuge volume of requests for inspections wherecompetitors have an API GMPc available)

� EU National Competent Authorities (NCAs) havefull read/write access to the EudraGMP database.

– Inspectors have currently full read/writeaccess.

– Assessors/EMEA staff have full read access.

� Read/write access to MRA partners agreed.

� Restricted access to general public has beenagreed.

� General public will have access in Q1 2009

� Non-restricted read access has been agreed withsome non-EU competent authorities (FDA, WHOand EDQM).

3.A status report on the EuropeanPharma Excipient Certification (EPEC)Project was given by Tim Boelke, BASFCare Chemicals & EFCG and IainMoore, Croda & IPEC Europe

An ambitious European pharma excipients certificationproject has been defined and launched, with the globalintent of issuing Certificates of suitability for all activepharmaceutical ingredients and major excipients thathave been assessed by third part auditors (IPEC).

4.Details of a project on supply chainsecurity were given by John Berridge,Pfizer and Bruce Davis, AstraZeneca.

Supply chain security is to be major focus of theleadership forum, which will hold education sessionsand workshops at future ISPE meetings for highlightingsecurity issues concerning medicines. The group isactively examining other opportunities to enhancesupply chain security through global standards, scienceand technology and are holding interactive sessionswith regulators to identify additional opportunities tocombat counterfeit medicines.

EMEA are to publish amendments to directive 2001/83to require full traceability of pedigree for all medicinalproducts, and similar regulations are to be implementedby FDA Globalisation regulations. EMEA are also liaisingon control of Counterfeit with WHO working group.

5. EFPIA gave a paper on the variability inGMP inspections.

They stated that this is a complex situation with manyplayers involved and requested an opportunity for:

� Increasing transparency of GMP inspectionscarried out by National authorities.

� The industry to ensure appropriate interpretationof inspection findings while reducing theregulatory burden yet ensuring patient safety.

� Regulators to apply greater consistency in thestandards of GMP required and an increased inthe harmonisation between member states.

� Rapid Alert notification to includesuspected/confirmed alerts on IMP &API and acontact list of partners to be prepared andreleased by the appropriate National authority.

6.Other items

EMEA Inspectorate informed the meeting of a pilotproject to rationalise international GMP inspectionactivities.

Notification was given that cooperation will be arrangedbetween TGA, FDA and EMEA inspectors so that evidenceof local inspections can be used to verify GMPcompliance.

PDA representatives provided an update on thetechnical reports published by PDA

Report prepared by John DR Jolley


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20-21 April 2009 – Manchester, UKAchieving operational excellence:how to simplify and improve yourbatch record review processwww.DBA-global.com

22-24 April 2009 – Nice, FranceBiotechnology for the non-biotechnologist email: [email protected]

23 April 2009 – London, UKImpact of ICH Q8, Q9 and Q10:Quality by design: fact or fiction? email: [email protected]

27-29 April 2009 – Barcelona, SpainOut-of-specification results with post-course workshop on failureinvestigationemail: [email protected]

28-29 April 2009 – Prague, CzechRepublicProduct quality review – compliant,reasonable, efficientemail: [email protected]

MMAAYY7-8 May 2009 – London, UKPre-filled syringes email: [email protected]

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

9-11 May 2009 – Athens, Greece14th Panhellenic PharmaceuticalCongress: Pharmaceutics in the 21stCenturywww.pepharm.gr

17-21 May 2009 – Cambridge, UKThe Eleventh Advanced LevelWorkshop on pharmacokinetic-pharmacodynamic data analysis: ahands-on residential course usingWinNonlin email: [email protected]/events

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8-12 June 2009 – Nice, France2nd PharmSciFairemail:[email protected]

11 June 2009 – London, UKBiosimilars and analytical challengesemail: [email protected]

15-18 June 2009 – Manchester, UKKey topics in sterile productsmanufacturewww.DBA-global.com

SSEEPPTTEEMMBBEERR

3-8 September 2009 – Istanbul, TurkeyFIP 2009 – Responsibility for patientoutcomes – are you ready?email: [email protected]/istanbul2009

DATES FOR YOUR DIARYMMAARRCCHH

18 March 2009 – London, UKCombating counterfeiting – currentstatus of the new technologies andraising public awarenessemail: [email protected]/worldofpharmacy/events

18-19 March 2009 – Frankfurt,Germany1st European Annual Conference onclinical trial suppliesemail: [email protected]

23-25 March 2009 – Berlin, GermanyEuroMeeting Berlin 2009email:[email protected]

23-25 March 2009 – Nottingham, UKAPS Inhalation 2009www.apsgb.org

23-26 March 2009 – Dublin, IrelandPharmaceutical GMPwww.DBA-global.com

23-26 March 2009 – Manchester, UKPractical aspects of pharmaceuticalvalidationwww.DBA-global.com

AAPPRRIILL

1-2 April 2009 – London, UKNasal drug delivery – AnnualInternational Conference email: [email protected]

european Industrial Pharmacy Issue 2 (February 2009)

Documents

Transcript of european Industrial Pharmacy Issue 2 (February 2009)