european Industrial Pharmacy Issue 2 (February 2009) by European Industrial Pharmacists Group (EIPG)

european INDUSTRIAL

PHARMACY FEATURES 4

PARTNERSHIPS CREATE VALUE FOR HEALTHCARE CUSTOMERS

Pharma companies and healthcare professionals alike need to develop new marketing strategies to meet the new healthcare needs of their customers and patients by Mats Olsson and Pär Tellner FRAMEWORK FOR A CONTINUING PROFESSIONAL DEVELOPMENT (CPD) – A UK PERSPECTIVE The requirement for pharmacists to take part in a CPD programme is detailed and discussed by Fred Ayling

DOES CHANCE FAVOUR THE PREPARED MIND?

Many of today’s drugs were discovered by chance. But as the wellknown story of Sir Alexander Fleming’s discovery of penicillin shows, the true scientist is the one who questions anomalies by Dave Sharma CHOCOLATE: A THERAPEUTIC AND NUTRACEUTICAL DELIVERY SYSTEM The ingredients of chocolate have been shown to have a number of health benefits and so one should not feel guilty about eating it. by Tim Ridgway VACUUM FOAM DRYING: A NEW TECHNOLOGY FOR PRESERVING SENSITIVE BIOMOLECULES

This technology has several advantages over freeze drying and is therefore worth further development. by Ashok Hajare, Harinath More, Sambhaji Pisal

VISIONS AND NIGHTMARES OF A MICROBIOLOGIST

The author urges the need for a re-evaluation and harmonisation of microbiological test methods and comments on the need to rely on conventional pharmacopoeial methods. by Klaus Haberer

REGULARS

3 21 22 25

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

ISSUE 2 • FEBRUARY 2009

www.industrialpharmacy.eu www.eipg.eu

Associate Editors

european INDUSTRIAL

PHARMACY

Belgium: Philippe Van der Hofstadt Bulgaria: Valentina Belcheva

Issue 2 February 2009

Czech Republic: Miloslava Rabiskova

ISSN 1759-202X

Denmark: Michiel Ringkjøbing Elema

EDITOR Joe Ridge, MRPharmS PRODUCTION Sue Feather

Finland: Tuula Lehtela France: Jean-Pierre Paccioni

SUBSCRIPTIONS Jill Monk

Germany: Armin Hoffmann

EDITORIAL BOARD Michael Anisfeld Michael Gamlen Linda Hakes Larry Hurst John Jolley Pär Tellner

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

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

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

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

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

european INDUSTRIAL

PHARMACY discussion group:

Spain: Mercé Pujol

www.pharmweb.net/gmp.html

Sweden: Pär Tellner

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

Switzerland: Renato Kaiser

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

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

Cover picture: Water treatment plant in India.

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

E D I TO R I A L C O M M E N T Another busy year

I would like to welcome 2009 with the second issue of European Industrial Pharmacy. The feedback from the launch of the first issue has been very well received and in my opinion demonstrates the need for such a communication forum to exist. This year promises to be to a very busy one for the EIPG as we will continue our consultative process with the Regulatory Agencies and other interested parties in the following areas: ♦ Preventing the spread of

counterfeit medicines ♦ Promoting the Responsible

Pharmacist principles in wholesaling ♦ Providing Guidance for Good

Regulatory Practice ♦ Providing Guidance for The

Qualified Person ♦ Providing Guidance of Biological

IMPs ♦ Supporting Continuing

Professional Development initiatives for branches of Industrial Pharmacy ♦ Maintaining the academic

standards required for Industrial Pharmacy

These subjects will be discussed at our annual General Assembly being held in Latvia and hosted by Ms Inta Saprovska who heads the Latvian Industrial Pharmacists Group. I would like to thank Inta for agreeing to host this important meeting for EIPG and the EIPG will continue its mandate to expand its membership to newer accession countries.

Pharmaceutical and Healthcare Sciences Society entitled “The Continuing Professional Development framework for the European Pharmacist”. This was an opportunity to question the technical developers of the online system and those responsible for the implementation of mandatory CPD in the UK.

In partnership with the European Association of Faculties of Pharmacy, substantial funding has been provided by the European Commission to review the competencies required to be a Pharmacist working in Industry. EIPG will dedicate resources to make sure that this PHARMINE initiative is a success. High educational standards are one the Guiding Principles in the Statutes upon which the EIPG was founded in 1966.

You can contact me using my email Luigi.G.Martini@gsk.com or contact Jane Nicholson, the Executive Director to EIPG on jane@nicholj.plus.com.

Simply put, the Pharmaceutical Industry will continue to need access to high calibre graduates who have an appreciation of how drugs are discovered, developed, manufactured and regulated. Industrial pharmacists need to audit their competencies and to identify priorities for their professional development. In November, EIPG held a joint seminar with the

This electronic Journal is your Journal and we would be very happy to hear from you or in fact receive any contributions you may like to see published.

Best Wishes for 2009

Gino Martini President, EIPG

gmp-review news free news service for gmp revıew subscribers Monthly news service will keep you up-to-date on new developments in GMP and associated regulations. gmp-review news will be sent by email only to current gmp revıew subscribers. Subscribers should contact subs@euromed.uk.com to register european INDUSTRIAL PHARMACY • Issue 2 February 2009

PARTNERSHIPS CREATE VALUE FOR HEALTH CARE CUSTOMERS by Mats Olsson and Pär Tellner

echnical advances within medicine are making doctors lose their monopoly on information. In the new information age consumers are becoming more knowledgeable and demanding, wanting to be seen as individuals with individual needs. This will place new demands on all stake holders involved in health care. Industrial pharmacists will play a key role in taking care of multiple-drug consumers and the increasing elderly population, with the possibility of cooperation with doctors to develop safer drugs. The days when scientists and clinicians pontificated on the lives and deaths of patients while hardly talking to them are gone. With the improved welfare systems in the middle of the 20th century the issue was living longer. Now, in the 21st century, that is not good enough. Today we want perfect health. In the consumption of health and health care we are going from satisfying needs to satisfying wants. Consumers refuse to be part of the mass market

The individualistic mega-trend represents consumers´ desires to be seen as who they are, and recognized as having individual needs, rather than being part of the mass market. The individual’s responsibility for his own health, and the desire for wellbeing, instead of just living longer, will emerge as powerful driving forces. The focus will be on how individuals are experiencing their health, rather than on actual medical status. This paradigm shift will severely challenge the health care sector, as well as the whole system of financing based on cure rather than on promotion of wellbeing. When talking about how to develop health care, it is important to stress that there is no universal model, not even within the EU. Each country and its population is at a different development stage. There are post-modern societies versus non-post-modern, materialistic values versus post-materialistic. There are different kinds of welfare systems. There are differences in life expectancy at birth. There are cultural and historical differences and so on. MATS OLSSON is Business Consultant at Kairos Future, working with societal analyses within health, healthcare and the pharma industry PÄR TELLNER is Compliance Officer of the Swedish Association of the Pharmaceutical Industry (LIF)

Le partenariat crée de la valeur pour les consommateurs de soins

Les avancées techniques en médecine font perdre aux médecins leur monopole en termes d’information. Dans cette ère nouvelle de l’information, les consommateurs ont de plus en plus de connaissance et sont de plus en plus exigeants, voulant être reconnus comme des individus avec des besoins individuels. Les nouvelles exigences vont donc concerner tous les acteurs impliqués dans le système de soin. Les pharmaciens industriels vont jouer un rôle clef en tenant compte des consommateurs poly médicamentés, du vieillissement de la population et de la coopération possible avec les médecins pour développer des médicaments plus sûres. L’époque où les cliniciens et scientifiques pontifiquaient sur la vie et la mort des patients en leur adressant à peine la parole est révolue. Avec l’amélioration des systèmes de protection sociale dans le milieu du 20° siècle, la problématique était d’augmenter la durée de vie et aujourd’hui au 21° siècle, ce n’est plus suffisant. Aujourd’hui nous voulons une santé parfaite. Dans la consommation de soins et de santé, nous passons de la satisfaction des besoins à la satisfaction des exigences. Mutual European problems

However, the ageing of the population, due to increased life expectancy and reduced fertility, will undoubtedly help inflate demand for health care products and services throughout the EU. These demographic dynamics will lead to difficult financial and logistical questions. Adding to the financial burden will be the fact that over time the value of services will, therefore, become greater than that of products. A growing share of revenue in society, and of many industrial firms, therefore, will come from services and maintenance. Productivity improvements are more significant in the production of goods than services, because the production of man hours grows more expensive in relation to the production of goods. This phenomenon, Baumol’s disease, or the post industrial dilemma, means that the cost of personal intensive products and services,

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

PARTNERSHI PS C REATE VALUE FOR HEALTH CARE CUSTOMERS (Cont .) like health care and care production, are increasing. This leads to decreasing costs of products, but not necessarily decreasing costs of services. Over time, the value of services will, therefore, become greater. The blessings of technology

Health care must do what it can to increase productivity using new technology and new drugs. Other industries have already launched various do-it-yourself concepts (like self- service at supermarket checkouts), in order to cut costs. Within health care there are already constant efforts to involve consumers in doing as much as they possibly can, without risking safety and quality. In future, we will, no doubt, be able to see health care stakeholders outsourcing more and more functions. In some therapy areas, commercial companies, e.g. pharmaceutical companies, will be considered for many parts of the health care chain, from direct deliveries of drugs to facilitating treatment monitoring done by the consumer himself. The introduction of IT has been relatively slow in health care provision, but things are finally starting to move. Technology is changing the look, feel and nature of health care. New electronic health records will make it easier for patients to change care providers or to have more than one. It will be easier for providers to deliver more personalised service to patients. The tracking of health intervention outcomes – the systematic recording of the success rate of different approaches to treating a given condition – will change medicine. Machines will take care of more of the work in future, freeing up physicians for more difficult tasks, such as considering appropriate treatments and communicating them to the patients. Partnership between clinicians and patients

Health care professionals will need to develop new skills over the next few years, with a new focus on the patient as an individual customer. The relationship must change to a much greater partnership between clinicians and patients. Patient deference is disappearing as information increases. The Internet in particular is undermining medical professionals’ monopoly on information, and therefore authority. There will be a paradigm shift that includes a changing consumer role; from a passive receiver of information into a coproducer of messages and meaning. The above changes are some of the shifts that will affect the health care industry over the coming years and in such an environment, the workforce across the health care industry also needs to change. The social,

demographic and economic environment in which the industry operates is undergoing huge changes and the pharma 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 of working methods and more transparent ethical principles in the sales and marketing process. There is a prevailing crisis of trust, which the drug industry must take seriously. Also, there are ever increasing expectations on the drug companies to justify pricing and improve transparency, when it comes to, for instance, documentation. The pharma change process in Sweden

A few years ago the polarization between health care and the pharma industry in Sweden became evident. The old fashioned working methods in the industry resulted in a negative attitude towards industry reps from governmental medical institutions. The talks between health care and The Swedish Association of the Pharmaceutical Industry (LIF) that followed resulted in The Ethical Code of Practice, with the first edition published in the summer of 2004. Pharma companies have started to think about new ways to handle sales and marketing. LIF have gone out their way to create conditions for member companies to start off in another direction when meeting health care. A few companies started this change process, working closely with The Ethical Code of Practice 2004 and others followed in 2006 and 2007. Industry stuck in old-fashioned ways

At that time a number of interviews were published in the book From Conflict to Cooperation in Tomorrow’s Pharmaceutical Market, published by Kairos Future. The key point which emerged was that health care had moved to another level and was waiting for the pharmaceutical industry to change their old-fashioned marketing methods. Key representatives interviewed in the book confirmed the conflict situation and spoke about the barriers to change and how they could be overcome. The pharma industry has since been moving away from marketing to physicians and trying to influence those higher up in the decision making chain. In some cases politicians have been targeted and sales reps have been using almost identical tool kits to those they used in their earlier sales work, resulting in a number of negative reactions. In other cases, efforts to influence politicians have resulted in clumsy attempts to make them, in turn, influence purchasing managers within different county councils.

european INDUSTRIAL PHARMACY • Issue 2 February 2009

PARTNERSHI PS C REATE VALUE FOR HEALTH CARE CUSTOMERS (Cont .) Health care looks to the future

In Sweden we are presently at a stage where the biggest resistance to change from health care has subsided and been replaced by a certain measure of acceptance to taking part in discussions about future forms of interaction and cooperation. Meanwhile, the health care stakeholders in most other EU countries are somewhere in the earlier stages of the development process and therefore marked by denial, anger and resistance. The lack of a proactive approach from the industry in these countries results in a number of tough decisions and measures from health care and doctors. Reading about these things in Swedish medical trade magazines raises a number of questions among decision makers in Swedish health care. Surely they would feel more good-will towards the pharma companies if they could see some transparency in what these companies are doing at a global level. Challenges

Within health care there will be increasing demand for industrial pharmacists, due to the more complex drug regimes in the future. With an increasing number of multiple-drug consumers, we will need new ways of working to create safer treatments and fewer side effects for older patients. We will need doctors and pharmacists in cooperation for safer handling of drugs. Further reading

In the project “From Conflict to Co-operation on Tomorrow’s Pharmaceutical Market” Mats Olsson, Kairos Future, has published the following during the period 2007–2008: ♦ The book From Conflict to Cooperation on

Changes in technology are rapid, thus, being a professional purchaser is becoming more and more difficult. Customers cannot maintain competence in developments in all suppliers’ areas anymore. They, therefore, buy functions, i.e. they outsource the knowhow to the supplier. Instead of trying to find out what chemicals to buy and store, they buy the function of the chemicals. This makes the supplier responsible for maintaining quality products, meeting environmental and governmental demands, keeping and co-ordinating product flows, etc. More and more of the total value of a contract lies in services, and in after-market sales. Customers will increasingly buy functions and systems. The pharmaceutical industry has not yet started thinking seriously about providing service and solutions for their customers and patients; efforts in this direction will have to increase in the years to come. Pharma’s traditional strategy of placing big bets on a few molecules, promoting them heavily and turning them into blockbusters worked well for shareholders for many years. However, its productivity in the lab is now plummeting as it switches its attention from relatively common and easily treated diseases to those that are much more complex or unusual. Industrial pharmacists needed

Tomorrow’s Pharmaceutical Market consisting of ten interviews with representatives of the health care and pharmaceutical industry. Published in May 2007. ♦ An article based on an interview with Mr. Sören

Olofsson, County Council Director for Stockholm County: The Industry in Urgent Need of Professional Stake Holders. Published in Pharma Industry no 1/2007. ♦ An article based on an interview with Mr. Seppo

Silander, General Manager, Sanofi-Aventis Sweden: We Must Pull Ourselves Together, the Same Rules Must Apply for All. Published in Pharma Industry no 2/2007. ♦ An article based on an interview with Mrs. Karin

Lendenius, Pharma Manager of Region Västra Götaland and Mrs. Karin Bernadotte, Managing Director Merck Sharp & Dohme: One Year Later, the Antagonism Persists. Published in Pharma Industry no 1/2008. ♦ An article based on an interview with Dr. Bo

Ringertz, rheumatologist and vice chairman of the Pharmaceutical Drug Committees in Stockholm: The Doctors in a Vice Between the Stakeholders. Published in Pharma Industry no 3/2008. ♦ An article based on an interview with Ms. Ingrid

Both the industry and health care will in future require more industrial pharmacists with new competencies. Within research, new technology and new molecular methods today give more data in a couple of hours than that formerly obtained through years of work. The need to be able to handle extensive amounts of data is rapidly increasing. The know-how of linking preclinical and

clinical data will be crucial in order to develop new drugs faster and in a reliable way. New peptide- based pharma drugs and their kinetic qualities will require more extensive knowledge about preparation forms and bodily distribution mechanisms.

Carlberg, journalist and writer. A Clearer Identity a Must for the Industry. Published in Pharma Industry no 4/2008.

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

FRAMEWORK FOR A CONTINUING PROFESSIONAL DEVELOPMENT (CPD) – A UK PERSPECTIVE by Fred Ayling n 2010, a new regulator, the General Pharmaceutical Council (GPhC), will be established in Great Britain. This new body will take over the regulatory functions currently undertaken by the Royal Pharmaceutical Society of Great Britain. As part of these functions, the GPhC will implement mandatory CPD requirements for pharmacists and pharmacy technicians.

objectives that are specific, measurable, achievable, relevant and timed; they should also have a clearly identified performance outcome; that is, something the pharmacist will be able to do, either differently or better in some way. This approach is important because it helps the pharmacist to take ownership of their learning and it means that they focus their development on what is actually going to make a difference.

The approach taken to CPD for pharmacists in Great Britain is significantly different to elsewhere in Europe. It is based on one that the RPSGB has been developing since 1998 and has been made available to pharmacists since 2002. At the point at which CPD remained voluntary, more than 20,000, over half of the membership, had made a start at recording their CPD. This is in comparison to other professions, where voluntary uptake has been informally reported at being in only single figure percentages.

Although this reflection stage of the management cycle is self-directed, it does not mean that pharmacists necessarily act in isolation when setting these objectives. Indeed, it would be best practice to ensure, where appropriate, that they involve others, such as colleagues, peers and those who use their services. This method of setting objectives fits well with an employer’s performance review systems, although it should be stressed that a pharmacist’s development will extend beyond this. Each person will have their own career aspirations and there may be aspects to their development that an employer is not interested in. Also there may be issues that a pharmacist would not be comfortable discussing with the person undertaking their performance review, or with their employer generally. It is also important to remember that many pharmacists in Great Britain are self-employed, or are an employee-owner without a line manager to undertake a performance review.

For a number of years the RPSGB’s Code of Ethics has required pharmacists to undertake and keep records of their CPD. It is anticipated that later this year the RPSGB will start asking pharmacists to submit their CPD records for review. When the GPhC is established in 2010 it will be able to ask pharmacists for CPD records dating back to 2008 and it is anticipated it will require pharmacists to submit a record once every five years. What is different about CPD in Great Britain?

Most pharmacists will be used to an approach of accumulating a set number of points for hours of attendance at formal events over a period of time. These events may or may not be accredited. In Great Britain, this approach is referred to as continuing education rather than continuing professional development. Continuing professional development is different in a number of ways. It is perhaps best understood as an approach adopted by pharmacists for the selfmanagement of their development, based on a fourstage cycle. At the first stage of the cycle each pharmacist is expected to identify personal learning FRED AYLING is Director of CPD Services, Ltd. He was the Royal Pharmaceutical Society’s CPD Manager from 1998 to 2007. email: fred@cpd-services.co.uk

It is at this reflection stage of the management cycle where competences may play a part. Competency audit may be used to identify learning objectives. Competences for industrial pharmacists have proved something of an issue in Great Britain. The RPSGB has published a set of ‘competences’ which are really just a high level list of the types of things that industrial pharmacists should know something about. There are only seven items in the list and it is not really detailed or thorough enough to be of much practicable use. Fortunately, the RPSGB’s electronic recording systems allow pharmacists to add their own competences into the system. These additional competences may be provided or set by an employer or by a relevant organisation, such as those for competent persons that are published by the European Industrial Pharmacy Group (EIPG). At the next stage of the management cycle, the pharmacist is asked to plan how they are going to address the learning objective they have identified. There are two aspects to this, firstly prioritising the

european INDUSTRIAL PHARMACY • Issue 2 February 2009

FRAMEWORK FOR C ONTINUING C PD – A UK PERSPEC TI VE (C on t.) objective and secondly, identifying appropriate activities. Clearly the pharmacist will have a number of learning objectives at any one time and so prioritising is important. They will need to provide a realistic target date for meeting the objective and to think about the degree of impact their learning objective will have on them, their employer or contracting body, colleagues and the users of their services or products. In terms of identifying appropriate activities, the RPSGB is not prescriptive. If the appropriate activity is informal, such as having a discussion with someone, reading a book or undertaking a web search, that is fine. If it is formal, such as attending a course, it does not need to be accredited. What is important is that the pharmacist describes why one activity is more appropriate than another. This provides great flexibility for the pharmacist and reflects the way we learn. We often learn through discussion, observations and other means of learning-bydoing. That’s to say, we learn through experience every bit as much as we learn through attending courses. At the action stage of the cycle, the pharmacist undertakes the activities they have identified and then sums up the key learning points. This ‘summing up’ is important as it has been demonstrated that we only retain a fraction of the information that we are told when engaging in a learning event, whatever that may be. Two pharmacists engaging in the same learning event will take away different things. That is because they will come to the event with different levels of existing knowledge or skills and they will have different expectations in terms of what they want to go away with. Reflecting on their learning has a twofold benefit; it reinforces the key points they have learnt and provides a list that can be used in the future as a handy reference. In the final stage of the management cycle, the pharmacist evaluate their learning. Have they successfully addressed the learning objective they identified? If not, why not, and what are they going to do next, if anything? If the learning objective has been successfully addressed, how have they been able to apply what they have learnt in practice? What are they now doing that they didn’t do before? What feedback or indicators do they have on the effectiveness of their learning? Do they need to build on this; perhaps identify a new objective and so start the management cycle again? The CPD cycle?

The management cycle described above is referred to as the CPD cycle. But in simple terms it is a management cycle that those involved in research or project management will be familiar with: identify, plan, act and evaluate.

Reflection

Evaluation

Planning

Implementation to Action Figure 1. The learning cycle.

The RPSGB presents this cycle as in Figure 1. It refers to the identification stage as reflection. This is because the RPSGB wishes to promote a reflective approach to pharmacists’ development. This is based on the observations made by Donald A Schon in his book: The reflective practitioner: how professionals think in action. Schon observed that faced with the same event and the need to take action (make a decision, give certain advice, provide a solution and so on) professionals acted differently. This was because they brought their personal and professional experiences to bear when acting. Different professionals would provide different advice or come to different conclusions or solutions. It was not necessarily the case that one action was better or more right than another. It does follow though that if there are a range of actions in a given situation, some actions may be better than others and indeed some may be poor. The idea behind reflective practice is that it encourages the pharmacist to step back and understand that there are a range of actions and that the one they choose will be based, for good and bad, on their own experiences. By thinking this through, it is hoped that the pharmacist may be more objective and so make better decisions. So, at the identification stage, the RPSGB regards a pharmacist as reflecting on events to help them find the right or best learning objectives that arise out of them. A number of issues have arisen from this. Although pharmacists who have qualified in recent years will have been taught about reflective practice, those who have been qualified longer may be less familiar with this concept and have less understanding of the term ‘reflection’. Also, it is not always the case that much reflection really needs to go on when identifying learning objectives. It is often quite clear and selfevident what learning needs to be undertaken as a result of a certain event. If someone asks us a

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

FRAMEWORK FOR C ONTINUING C PD – A UK PERSPEC TI VE (C on t.) straightforward question, we don’t need to do much or any reflection to realise what we need to know and that we need to go away and look the answer up! On a personal note, I tend to simply refer to this stage of the CPD cycle as identification. I also regard reflective practice as happening at any stage, as at each stage I find myself making decisions that I have reflected on. For example, at planning I am reflecting on what I anticipate the impact of my learning will be and which activities are going to be appropriate based on previous experiences. A common misconception about the CPD cycle is that it is an annual exercise; the pharmacist would sit down once a year, identify their objectives and spend the next year addressing them. Although taking time out once a year to do just this is good practice, learning objectives will arise at any time throughout the year and may need to be addressed in a couple of months, weeks, days or hours. So a CPD record is a live, ongoing document and it is possible to move through the cycle in hours or years, depending on the learning objective. When the RPSGB piloted CPD and launched it nationwide in 2002, it also allowed pharmacists to start their CPD at the action stage of the cycle. This meant that pharmacists could record CPD that occurred when a learning objective had not previously been identified, for example, reading a journal or attending a routine seminar without a learning objective in mind, but simply because there was an opportunity that you may learn something. In 2007, the RPSGB allowed pharmacists to start their CPD at the planning and evaluation stages. Although a few pharmacists had requested this, the feedback I have received from most of the trainers supporting pharmacists is that this has added confusion and no real benefit. It can be quite difficult to find examples of CPD that starts at these stages and my advice is to ignore this option unless you can see any specific benefits. Why CPD instead of CE?

When we looked at the research that had been undertaken in the area of continuing education, it was clear that there was no evidence that attending courses actually made a difference. One of the leading authorities in this area is Dave Davis and his team from the Faculty of Medicine, at the University of Toronto. In their review of the literature1, they made the observation that there is a ‘diminished impact of CME along this continuum’.

Skills

Skills,

Knowledge,

Performance

Attitudes

Patient Outcomes

The thinking in the field was that it was more important to accredit the learner rather than the course. A learner who is motivated and committed may attend a course that is poor but will not leave it at that; he or she will instead find another way of learning what needs to be learnt. This is not to say that courses are not an important part of professional development and, indeed, that some form of quality assurance is required. Continuing Education should not be relegated as CPD’s poor cousin but instead regarded as part of a wider process of CPD. The suggestion is that it is important for pharmacists to take ownership of their learning and that each pharmacist will have his or her own starting point in terms of their knowledge, skills or competences and their own end point of where they need to be. It is also important that the approach to CPD encompasses all the manners in which we learn, including informal learning, as not to do so could lead to pharmacists not appreciating and engaging in all the development opportunities available to them. To bring about more effective development pharmacists were also encouraged to think about learning that would make a difference as they moved through the cycle. A professional develops over time. There are rarely big leaps, but more commonly it is the accumulation of lots of little bits of learning that can add up to something quite significant. CPD should be about continuous improvement and in developing their approach the RPSGB wanted to encourage pharmacists not just to think about what they don’t do well but what they already do well and how they could build on that. How can it be recorded?

Pharmacists can record their CPD in three ways. There is an online recording system, CPD Online; PC-based software, CPD Desktop; or a paper-based system using a format provided by the RPSGB or a format accredited by them. CPD Online is by far the best format in terms of its functionality. More than 50% of pharmacists are recording their CPD in this way, that’s over 20,000 people. CPD Online allows pharmacists to tailor various aspects of the recording system, including competences and options from other menus. It also allows pharmacists to share aspects of their CPD with others online. These may be friends and colleagues or their employer, so making it easier to integrate into employers’ HR systems. The pharmacist is in control of who sees what and when. Regular backups also mean that the pharmacist cannot accidentally delete their CPD record or lose it if their computer system crashes. A personal development plan that interacts with their CPD record is also provided to help the pharmacist identify learning objectives.

european INDUSTRIAL PHARMACY • Issue 2 February 2009

FRAMEWORK FOR C ONTINUING C PD – A UK PERSPEC TI VE (C on t.) Recording consists of a mixture of free text and selections made by means of checkboxes and dropdown menus. Once familiar with the system, it should take about 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 and will the pharmacist receive feedback?

CPD will be reviewed according to the good management practice described by the RPSGB reviewers. They will consider whether the learning objectives are specific, measurable, achievable, relevant and timed; whether there has been a thought-through option appraisal at the planning stage; and whether the CPD has actually made a difference. The purpose of the review is primarily to look at how the pharmacist has been managing his CPD and to provide him with meaningful and formative feedback. Some of it will be used to establish whether the pharmacist has met the required standards, but most aspects will simply be

used to provide feedback. For example, when receiving feedback the pharmacist will be able to see at a glance where his CPD has been focused in terms of competences. For good reasons, it may be quite narrow or broad and there is no reason why any two pharmacists should have the same focus. The intention is simply to provide feedback to help the pharmacist understand where they may take their professional development in the future. Although the RPSGB is taking a formative approach, they and the GPhC will need to set a minimum requirement. I do not expect it to be terribly taxing but then the intention is to engage pharmacists in a formative way and not to be heavy-handed. Reference 1. Davis D, O’Brien MAT, Freemantle N, et al. Impact of formal continuing medical education – do conferences, workshops, rounds and other traditional continuing education activities change physician behaviour or healthcare outcomes? JAMA 1999; 282: 867–874.

COMBATING COUNTERFEITING – CURRENT STATUS OF THE NEW TECHNOLOGIES AND RAISING PUBLIC AWARENESS Seminar 18 March 2009 at the RPSGB 1 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-counterfeiting technologies available to the pharmaceutical industry, the MHRA’s current anti-counterfeiting strategy 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

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

DOES CHANCE FAVOUR THE PREPARED MIND? by Dave Sharma

eo Sternbach, a pharmacist and a chemist, is the man to whom the discovery of benzodiazepines is attributed. Born one hundred years ago, Sternbach earned his Master of Pharmacy and then a PhD in chemistry from the University of Kraków, (Poland). In his early years he developed several heptoxdiazine compounds in an effort to develop synthetic dyes1. However, these compounds did not lend themselves as useable dyes and Sternbach wrote: “with regret, we dropped these compounds and turned to other things”2. Then, in the 1950s, inspired by the success of meprobamate to treat anxiety, Sternbach returned to his research on heptoxdiazines in the hope of finding compounds with psychopharmacological activity. By 1954, he realised that what he initially perceived as being heptoxdiazines were in actual fact benzoxdiazines. Although this group of compounds were pharmacologically inert, he decided to stabilise one 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 to make way for new projects when a co-worker, Earl Reeder stumbled across the compound and brought it to Sternbach’s attention. This was then sent for pharmacological evaluation. The news was good; more potent than meprobamate and less sedative. Ro-50690 was, in 1960, the first anxiolytic benzodiazepine introduced into clinical use. It is now better known as chlordiazepoxide or under its brand name Librium. A few years later, Sternbach went on to develop Valium (diazepam). Is it true to say that he discovered benzodiazepines? Or did he in fact stumble across them by chance? This is one example of serendipity in the pharmaceutical industry. More famous instances include the discovery of Viagra for erectile dysfunction, Retrovir for the use of Aids patients and Minoxidil for those of us going bald. Serendipity

The role of serendipity, which is the finding of one thing while looking for something else, in drug discovery is DAVE SHARMA, MRPharmS, is the Associate Director for Genzyme Clinical Research Pharmacy Services. He is currently undertaking a PhD on the role of play in research environments at Cranfield University Email: dave.sharma@genzyme.com

Leo Sternbach

largely underplayed. One could be mistaken in thinking that our understanding of science today is leading to a rational drug design model only. This is an approach in which a priori assumptions are made about the activity of the compounds, based on pharmacological hypotheses, and/or fundamental knowledge about the nature of the disease at the molecular level. Drug discovery and development becomes the incremental process by which facts, theories and methods have been added to the ever growing stockpile of scientific knowledge. The history of science becomes the discipline that chronicles successive developments and obstacles. The danger of scientific textbooks is, as Thomas Kuhn3 points out in his masterpiece “The Structure of Scientific Revolutions”, that their aim is “persuasive and pedagogic”. He goes further and states that “science students accept theories on the authorities of teacher and text, not because of evidence. What alternatives have they, or what competence?” The result is that there is a persistent tendency to make the history of science look linear or cumulative, a tendency that even affects scientists looking back at their own research. But that is not what history shows. Was there scientific accrual or incrementalism that led to the discovery of chlordiazepoxide? No, it was luck. Yet it is tempting to rewrite history so that theory “fits the facts”. Numerous literature sources attribute the discovery of benzodiazepines to Sternbach which is somewhat reductive because it downplays the role of chance. Rational drug design

In 1988, George Hitchings, an industrial pharmacologist,

european INDUSTRIAL PHARMACY • Issue 2 February 2009

DOES C HANC E FAVOUR THE PREPARED MI ND? (Cont .) shared the Nobel Prize for Physiology or Medicine along with Gertrude Elion and the British pharmacologist, Sir James Black. This was “for their discoveries of important principles for drug treatment,” Hitchings’ specifically for his work on chemotherapy. It was an award made a posteriori, which recognised the important contribution their rational approach to drug design had made to medicine. The award stressed the researchers’ reliance on an “understanding of basic biochemical and physiological processes”. However, eight years prior to the award, Hitchings himself had argued to the contrary that basic science was more often the result, than the cause of drug discovery: “Much of basic science supported by the industry is, in a sense, retrospective. A semi-empirical discovery of a useful drug provides the stimulus for deeper probing into how and why it works, and thus to a deeper understanding of the underlying disease. This may in turn give rise to new concepts and new discoveries.”4 Reading pharmaceutical textbooks and the websites of prominent pharmaceutical organisations would prime recipients that it’s the other way round. That is, the development of new drugs follows a linear path as we get to understand the disease, identify a target and then subsequently develop a drug to interact with that target. This process is often compared to the building block model, but that is not the only way a new drug develops. Interestingly, for those of you who believe that discoveries are synonymous with having a Ph.D, take heart from the fact that Gertrude Elion did not possess one. Yet she became a world renowned scientist, at a time where females were far less visible in pharmaceutical research environments. And it was a chance meeting with Hitchings himself that led to her first appointment within the industry. When something “new” is found, it often takes years before we know how new, true or useful it really is. If we look back on how the finding was done, the possibility for forming a legend is there. The serendipity of it can easily become underestimated and even denied. This is mainly and unintentionally caused by the way we rationalise a posteriori about theoretical and experimental research and its results, when we publish5. The not strictly rational – chronological or searched components (like chance or accidents) which led to the results are therefore underestimated and sometimes not mentioned at all. The prepared mind

However, as Kuhn demonstrates, an understanding of anomaly is vital for scientific discoveries. He also postulates that reading and interpreting textbooks (as a means to understanding the discovery process) can inadvertently brainwash the researcher into thinking in

one way only3. This can cause a loss of serendipity. Socalled experts can quite often delay the uptake of a particular hypothesis. During the discovery of Captopril, the first ACE inhibitor, the therapeutic hypothesis that the inhibition of ACE is useful in the treatment of essential hypertension was regarded as doubtful by most clinical experts. It even proved difficult to find medics who would participate in the original studies. Today, it is now recognised that understanding the renin-angiotensin system and ACE inhibition has provided excellent therapy for hypertension. Another classic example was the hypothesis put forward by the then young scientists Dr Marshall and Dr Warren in 1983. They proposed that peptic ulcers were generally caused not by excess acid or stress, but by a bacterial infection. This hypothesis was viewed as preposterous by the scientific community. This is somewhat understandable as people with increased acid were found to suffer with peptic ulcers. Treatments such as Ranitidine or Cimetidine were found to be effective in controlling acid production and therefore a good means to allow ulcers to heal. Physicians therefore had both an explanation and treatment, so why look elsewhere. It is quite often the naive gaze of young scientists that allows the evidence to ‘flow’ in rather than remain stuck in the tradition of a particular paradigm. In scientific research, no discovery has ever been made by pure luck alone. All chance discoveries have one point in common: “each was recognised, evaluated and acted upon in the light of the discoverer’s total intellectual experience.”1 When developing new drugs, it is important to recognise that serendipity does exist. In practice, it appears that when serendipity does play a role, this role is normally secondary but essential. Scientists often publish their results in a rational manner, underplaying or omitting the role of chance. The scientific community, including students, then read these findings and unwittingly fall into the mindset of a logical, linear mechanism for understanding every experiment. This can result in a loss of serendipity. A successful researcher is someone who has one eye open for sought findings and another eye open for unsought findings. Or as Pasteur put it so eloquently, “Chance favours the prepared mind.”1 References 1. 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 presented at EBHA Conference 2001. 5. Van Andel P. Anatomy of the Unsought Finding. Serendipity: Origins, History, Domains, Traditions, Appearances, Patterns, and Programmability. Brit J Phil Sci. 1994; 45: 631–48.

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

CHOCOLATE: A THERAPEUTIC AND NUTRACEUTICAL DELIVERY SYSTEM by Tim Ridgway

ased on the premise that most women like eating chocolate and the evidence that nutraceutical isoflavones are good for women’s health1, by putting nutraceutical isoflavones in a chocolate bar you could potentially have a winning guilt-free confectionary product, the ‘Venus Bar’. This is an example of how in the future chocolate manufacture and nutraceutical provision may combine. As it turns out, however, chocolate itself may be a lot more virtuous than previously thought; it may actually promote good health through its high content of plant polyphenols, in particular the flavanols, catechin and epicatechin. The bioactive ingredients of chocolate

Epidemiologic evidence has suggested that certain plant polyphenols, in particular the flavonoids, promote good health and help to prevent the onset of chronic diseases, including cardiovascular disease and cancer2. Amongst the flavonoids the flavanols have received specific attention for their potential to prevent cardiovascular disease and are present in wine, tea, and various fruits and berries. Chocolate also contains large amounts of flavanols and is now thought to have a potential cardioprotective role in the diet3. The flavanols in chocolate consist of the monomers epicatechin and catechin plus oligomeres of epicatechin and catechin which are known as procyanidins. Both flavanol monomers and oligomeres are thought to represent bioactive ingredients. Flavanols are distinct from other types of flavanoid as they tend not to appear as glycosides, but are present as aglycones or are esterified with gallic acid3. Bioavailability and metabolism

Following absorption from the gut, flavanols are methylated and glucuronidated with some sulphonication taking place in the liver. These metabolites may then represent the actual bioactive forms in the body. In addition colonic microflora can degrade the flavan ring structure to form simple phenolic and ring fission metabolites that may be physiologically active. Nevertheless, in studies following human cocoa

TIM RIDGWAY PhD is a science writer. email: tim.tridgway@wanadoo.co.uk

ingestion, catechin and epicatechin have actually been detected in human plasma as has the epicatechin dimer B2 (epicatechin-(4β-8)-epicatechin), showing a proportion of dietary flavanols to be bioavailable in unmodified form4. Mechanisms of action

Flavanols in chocolate are thought to offer cardioprotection by a variety of mechanisms including antioxidant action, the result of which is that LDL (low density lipoprotein) is protected from oxidation thus reducing the formation of atherosclerotic lesions. Other cellular mechanisms of action of flavanols include the reduction of inflammation, the reduction of platelet aggregation and an increase in the production of nitric oxide resulting in vasodilation3. The structural characteristic of flavanols that confirms their excellent antioxidant properties is the hydroxylation of the basic flavan structure, in particular the formation of 3?,4?-dihydroxy groups on the B-ring, ie. the formation of catechol structures5. Cocoa powder and cocoa extracts have been shown to exhibit greater antioxidant capacity than many other flavanoid-rich foods, including green and black tea, red wine, blueberry, garlic and strawberry3. Clinical trials

Over the past decade many clinical trials have been carried out to investigate the potential health benefits of chocolate; these works being recently reviewed by Cooper et al.6 Most of the clinical trials appeared to show a positive outcome for chocolate as a cardioprotective agent, although the fact that the scale of the trials was generally small should be taken into account before drawing any conclusions. As an example of a recent study, which used 39 healthy Japanese men, it was found that flavonoid-rich dark chocolate significantly improved coronary circulation as measured by noninvasive transthoracic Doppler echocardiography (TTDE)7. Dark, milk or white?

The flavanols in chocolate come from the cocoa liquor formed as a result of processing the cocoa beans. As white chocolate contains no cocoa liquor, it contains no flavanols and could thus be expected to have no cardioprotective properties; hence its use as a control when investigating the prospective benefits of flavanols in chocolate7.

european INDUSTRIAL PHARMACY • Issue 2 February 2009

C HOCOL ATE: A THERAPEUTIC AND NUTRACEUTICAL DELIVERY SY STEM (Cont.) Similarly, milk chocolate contains proportionally less cocoa liquor than dark chocolate, but in addition it has been hypothesised that milk proteins bind cocoa flavanols which prevent their absorption in the gastrointestinal tract. This hypothesis has been supported by some studies, but disproved by others and remains controversial8.

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

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

Isoflavone-containing chocolate has in fact recently become commercially available, although it has not been marketed on the basis of its potential health benefits, presumably as the strict criteria surrounding health claims for food products have not been met. However, clinical trials of a high flavonoid and soya supplemented chocolate are about to start in Norwich UK, investigating its potential cardioprotective effects on postmenopausal women with type 2 diabetes.

Development of high monomer flavanoid types

The production of procyanidin oligomers (and longer chain polymers) from catechin and epicatechin is dependent on a production process termed fermentation, but which is actually the oxidation of catechin and epicatechin by plant polyphenoloxidases; the same enzymic oxidation which is responsible for the production of black tea. As the flavanol monomers are regarded as having greater therapeutic potential than the procyanidins and any oxidization products, an unfermented (and nonroasted and blanch-treated) cocoa product has been developed9. The resulting cocoa powder contains four times as much procyanidins than a conventional powder and will hopefully lead to the development of commercial chocolates with greater therapeutic potential. Development of nutraceutical containing types

As exemplified by the ‘Venus Bar’ proposal, there is in addition to chocolate’s endogenous bioactive compounds, great potential to supplement them with additional plant-derived nutraceuticals, for example; flavonoids/isoflavonoids, stilbenes and phytosterols, as described below: Isoflavonoids

As previously described, the ‘Venus Bar’ would be the result of the addition of the soya-derived isoflavonoids, genistein and diadzein. This could potentially not only help to prevent cardiovascular disease, but could help prevent hormonal dependent diseases such as breast cancer and osteoporosis. The therapeutic effects are due to blocking estrogen (antagonist) at estrogen receptor sites in the case of breast cancer prevention, and mimicking estrogen (agonist) at estrogen receptor sites in the case of osteoporosis treatment1. Isoflavones are

Stilbenes

Another clear candidate for addition to chocolate is the stilbene, resveratrol. This plant polyphenol is found most famously in red wine and has been postulated as being responsible for the ‘French Paradox’ whereby the French population shows a low rate of cardiovascular disease, despite a diet containing significant amounts of saturated fat10. There is also great interest in resveratrol as regards its potential prevention of cancer11. Recently it has been postulated that much of the therapeutic potential of resveratrol is due to its great ability to activate the human sirtuin 1 (SIRT1) gene. SIRT1 is thought to regulate such processes as insulin production and fat metabolism. This has led to speculation that sirtuins might mediate the effects of calorific restriction and prove particularly useful in the prevention of diabetes12. As with the isoflavonoids, there is actually a chocolate product on the market containing resveratrol (in the form of a grape extract), although again it is not marketed for its health promoting effects, relying instead on consumer knowledge. ‘Superantioxidants’

The flavanols endogenous in chocolate have excellent antioxidant properties, but these could be enhanced further by the addition of a new generation of ‘superantioxidants’; hydroxylated derivatives of common and cheap to produce polyphenols, such as piceatannol derived from resveratrol13 and 3–Hydroxyphloridzin derived from the flavonoid (dihydrochalcone) phloridzin14. Phytosterols

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

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

C HOCOL ATE: A THERAPEUTIC AND NUTRACEUTICAL DELIVERY SY STEM (Cont.) included in the diet they lower the absorption of cholesterol thereby promoting good health. They have for a number of years been successfully included in a range of products, in particular margarine, yoghurt and milk15. Small scale clinical trials have been carried out with phytosterol-enhanced chocolate, the development of which will perhaps eventually extend to commercial products16. Improving cognitive function

Chocolate has been reported as improving mood and aiding sexual desire in women, although there is controversy surrounding such work17. Nutraceutical additions to chocolate could, however, potentially aid cognitive function as phytochemicals, in particular the isoflavones genistein and diadzein, have been shown to improve cognitive function in humans in a number of studies1. Similarly the flavonoid phloridzin, found principally in apples, is well known to improve cognitive function in rats. Marketing phytochemical-enhanced chocolate to improve cognitive function is therefore a possibility, 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 of promoting good health. As these are ideally suited for inclusion in the food matrix of a chocolate bar, complementing the endogenous flavanols, chocolate could be developed as the ideal nutraceutical-polypill delivery system, enhancing health in the form of a tasty treat. A few squares of chocolate are a lot more enticing than supplements/pills and therefore sales and compliance for any prospective ‘Venus Bar’ would be likely to be assured if the required evidence for therapeutic benefit was forthcoming.

References 1. Wiseman H. Isoflavonoids and human health in: Flavonoids Chemistry, Biochemistry and Applications (eds Andersen OM and Markham KR). 2006; pp371–396. 2. Rimm EB. Fruit and vegetables: building a solid foundation. Am J Clin Nutr. 2002; 76: 1–2. 3. Keen CL, Holt RR, Oteiza PI et al. Cocoa antioxidants and cardiovascular 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 the consumption 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 and antioxidant activity: fast reaction kinetics. Biochem Biophys Res Commun. 2001; 282: 1161–1168. 6. Cooper KA, Donovan JL, Waterhouse AL et al. Cocoa and health: a decade of research. Br J Nutr. 2008; 99: 1–11. 7. Shiina Y, Funabashi N, Lee K et al. Acute effect of oral flavonoid-rich dark chocolate intake on coronary circulation, as compared with nonflavonoid white chocolate, by transthoracic Doppler echocardiography in 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 the bioavailability of cocoa powder flavonoid in healthy humans. Ann Nutr Metab. 2007; (E pub ahead of print). 9. Tomas-Barberan FA, Cienfuegos-Jovellanos E, Marin A, et al. A new process to develop a cocoa powder with higher flavonoid monomer content and enhanced bioavailability in healthy humans. J Agric Food Chem. 2007; 55: 3926–3935. 10. Siemann EH, Creasy LL. Concentration of the phytoalexin resveratrol in wine. 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 vivo evidence. 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 neurodegenerative maladies or just a fad? Mut Res. 2007; (E pub ahead of print). 14. Ridgway TJ, Tucker GA, Wiseman H. Novel bioconversions for the production of designer antioxidant and colourant flavonoids using polyphenoloxidases. Biotechnology and Genetic Engineering Reviews. 1997; 14: 165–190. 15. Ridgway TJ, Wiseman A. Phytosterols and phytostanols: cholesterollowering functional food ingredients. Industrial Pharmacy. 2006; 9: 23–25. 16. Polagruto JA, Wang-Polagruto JF, Braun MM et al. Cocoa flavanolenriched snack bars containing phytosterols effectively lower total and low-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 sexual health: An intriguing correlation. J Sex Med. 2006; 3: 476–482.

european INDUSTRIAL PHARMACY • Issue 2 February 2009

VACUUM FOAM DRYING: A NEW TECHNOLOGY FOR PRESERVING SENSITIVE BIOMOLECULES by Ashok Hajare, Harinath More, Sambhaji Pisal

promising and effective therapeutic biomolecule will not be of benefit if it is unstable during the processing, distribution and storage stages and at administration. Various stresses reduce clinical efficacy and increase the risk of adverse side effects if formulated as an aqueous solution. Although physical stability is maintained, most biomolecules are degraded by chemical reactions initiated by water. Lyophilisation is an alternative to aqueous solutions of sensitive biomolecules, but it has been found that the stress of acute freezing and dehydration can damage them and reduce storage stability in the dried state. Vacuum foam drying, a new technology invented by Bronshtein, is a practical solution to this type of stability dilemma.

ambient temperature for a sufficiently long time.4 Biomolecules in a liquid state are stable only for a short period due to molecular movement that may result in degradation. Pharmaceutical products must have adequate stability over storage periods of many months, typically several years and many biomolecules do not possess this long-term stability in the aqueous state at ambient temperature.5 To attain extended stability at ambient temperature, molecular movement needs to be arrested by some method that stops degradation by transforming liquid into a highly immobile, noncrystalline, amorphous solid state during storage, called vitrification. The system below its glass transition temperature (Tg) is stable due to immobilisation of the reactive entity in a solid glass-like system.6

Vacuum foam drying produces mechanically stable dry foam by boiling biological solutions or suspensions under vacuum at ambient temperature above freezing point. Stability drying is carried out at an elevated temperature to increase glass transition temperature (Tg). A yield of active samples preserved by this method after rehydration is achieved by proper selection of protectants as well as vacuum and temperature protocols.

Spray drying, freeze drying or lyophilisation, freeze thawing, precipitations with organic solvents, air drying and rotory evaporation are commonly used methods for preservation of sensitive biomolecules. These methods suffer from the following major limitations:7-12

Problems with stability

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

damage to thermolabile biomolecules, reducing their clinical efficacy and increasing the risk of adverse effects. ♦ Process is lengthy and time-consuming.

Chemical complexity and marginal stability of higherorder structures of therapeutic biomolecules present critical problems in the stability of their formulations.1 Scientists are working hard to develop a technology that can formulate and deliver life-saving and cheaper biological drugs like vaccines, proteins, enzymes and hormones without refrigeration.2 About 2 million children die every year from diseases that could be treated with biomolecule products. About 50% of these life-saving biopharmaceuticals are damaged due to improper storage as well as unavailability of facilities for storing them properly, specifically for temperature effects.3

SAMBHAJI PISAL works in the Department of Biotechnology, BVDU Poona College of Pharmacy and Research Centre, Pune, India email: asdigu@rediffmail.com

♦ Freezing and moderate low temperatures cause

♦ If formulated successfully, storage facility such as cold

chain storage transport is a must to maintain stability. ♦ Not suitable for bulk aseptic production. Evaporative versus freeze drying

Annear, Bronshtein, Roser, Kadam and co-workers separately and independently, were able to preserve biologicals, proteins, enzymes and micro-organisms by evaporative drying for long periods at ambient temperature without significant loss of activity.12-15 They clearly indicated and confirmed that the stability of sensitive biomolecules and micro-organisms dried by evaporative drying is better than that of freeze-dried samples. However, dehydrated solutions with protectants obtained by evaporative drying are very viscous and too much time is required for their evaporation as it is a diffusion-limited process; hence the process is non-scalable and unsuitable for industrial applications.16

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

VAC UUM FOAM DRYING: A NEW TECHNOLOGY FOR PRESERVATION OF B IOM OLEC ULES (Cont .) Preservation by foam formation

For the last 50 years, freeze drying has been considered the best method for stabilisation of sensitive biomolecules due to the belief that low temperatures cause minimum damage. Preservation by foam formation (PFF) is a new technology proposed by Bronshtein in 1996. According to Bronshtein, this belief in low-temperature drying with minimum damage is not correct.17 Before Bronshtein’s invention of foam formation, no scalable technology had been proposed to preserve thermolabile biomolecules at ambient temperature. Annear, while preserving bacteria in a dried state, demonstrated that viscous solutions and biological liquids can be dried by forming foam by applying a vacuum. He used this foam formation process only for a small volume of sample but not scaled up for industrial applications. Until recently, foam formation was not used for preservation because it was considered to be a process that damages biologicals. Bronshtein was the first to report that biologicals could be effectively stabilised by foam drying and he demonstrated that PFF has been used successfully to dry various volumes of biological liquids from 1100,000ml.18 The only limitation of this technology is that the volume of liquid to be dried must not be more than 20-25% of the container volume, because the sample expands during foam formation. The time required for this process is much shorter than other processes due to intensive boiling. Foam formation process

In this process, the biological solutions or suspensions are first transformed into mechanically stable dry foams by boiling them under vacuum at ambient temperature above freezing point (primary drying). Samples are then subjected to stability drying at an elevated temperature to increase the Tg Activity yield after the rehydration of the foam-dried sample is achieved by proper selection 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 less surface area exposure and less exposure time. Does not require freezing of sample before drying; it is therefore 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.

of protectants (sugars like sucrose and trehalose), which are dissolved in the suspension before processing. Proper selection and use of vacuum, as well as temperature protocols during drying, help to produce elegant and therapeutically active products that remain stable at an ambient storage temperature. Applications of PFF

PFF has been used successfully for stabilisation of thermolabile enzymes and pharmaceuticals such as amphotericin, urokinase, luciferase, ß-galactosidase, lactate dehydrogenase, isocitric dehydrogenase and icenucleating proteins at ambient or higher temperature. Live viruses like Newcastle disease virus (La Sota strain), herpesviridae, paramyxoviridae, flaviviridae, parvoviridae and retroviruses can also be stabilised by using this vacuum foam drying technique. Gram-negative bacteria such as E. coli and B. bronchiseptica and gram-positive bacteria such as Lactobacillus acidophilus and Lactococcus lactis subsp. cremoris can be stored for longer at 37°C temperature with up to 40% less viability during both log and stationary phases. Foam formation equipment

At the present time no industrial equipment has been designed and is available for the bulk production of powders or market-ready vials by the vacuum foam drying technique. Researchers have claimed that with a few modifications to the controls and process cycle programming software, commercially available freeze dryers could be modified for PFF in glass vials. The main requirement is simultaneous control of vacuum and temperature during foam drying. Thus, the pharmaceutical and other industries are suffering from an absence of effective drying equipment that produces bulk products stable at ambient temperature. Conclusion

Although foam formation is an old invention, preservation by foam formation under vacuum and controlled temperature is a new technology in the embryonic stage, being used for only a few pharmaceutical applications and needs some improvement. Elimination of uncontrolled eruptions and spitting out of material from vials or containers during boiling are the improvements required in this technology. More parameters must be studied for its comparison with freeze drying and other known and newly developed drying processes. Preservation by foam formation may be a substitute to freeze drying or lyophilisation and will stimulate development of new processes and equipment for preservation of thermolabile biologicals in a dry state.

european INDUSTRIAL PHARMACY • Issue 2 February 2009

VAC UUM FOAM DRYING: A NEW TECHNOLOGY FOR PRESERVATION OF B IOM OLEC ULES (Cont .) References 1. Cleland JL, Powell MF, Shire JS. The development of stable protein formulations: a close look at protein aggregation, deamidation and oxidation. 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 protein pharmaceuticals. Int J Pharma 2000; 203: 1. 4. Rodriguez W, Koval R, Chogprasert S. Optimizing storage stability of lyophilized recombinant human interleukin-11 with disaccharide/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. Letter 1990; 11: 93–100. 7. van de Beek MJ, Gerisma SY. Preservation of enzymatic activity of ranin during 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 between conformational structural changes of chymotrypsin. Biotechnol Appl Biochem. 2000; 31: 41–53. 9. Maa Y, Zhao L, Payne L. Stabilization of alum adjuvanted vaccine dry powder formulation: Mechanism and application. J Pharm Sci. 2003; 92: 319–332.

10. Kramer M, Sennhenn B, Lee G. Freeze-drying using vacuum-induced surface freezing. J Pharm Sci 2002; 91: 433–443. 11. Miller D, Anderson R, Pablo J. Stabilization of lactate dehydrogenase following freeze thawing and vacuum drying in the presence of trehalose and borate. Pharm Res 1998; 15: 1215–1221. 12. Annear DI. Observations on drying bacteria from the frozen and from the 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 substances with dry, foamed glass matrices and compositions obtained thereby. US Patent – W09640077. 15. Kadam SS, Pisal SS, Mane JJ, Shah MH. Effect of excipients on product characteristics and structure of lyophilized lasota vaccine. IJ Biotech 2005; 4(1): 106–114. 16. Adams J, Ramsay R. Optimizing the lyophilization cycle and the consequence of collapse on the pharmaceutical acceptability of EL Asparaginase. J Pharm Sci 1996; 85: 1301–1305. 17. Bronshtein V. Preservation by foam formation. 1998 US Patent 5766520, 1–6. 18. Bronshtein V. Scalable long-term shelf preservation of sensitive biological solutions of suspensions. 2003; US Patent – 6509146, 1–14.

Industrial Pharmaceutical Microbiology Standards & Controls

Editors: Norman Hodges and Geoff Hanlon

“An exceptional and unique publication in this field”

Microbiologist – September 2007

21 Chapters 450+ pages £325.00

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

Looseleaf format Special supplements Regularly updated

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

VISIONS AND NIGHTMARES OF A MICROBIOLOGIST by Klaus Haberer

hat should our aims be – protecting the patient, the company or our own backside – or all three? To protect the patient, we have to balance health risk with health cost. To protect the company, we have to consider the risk of unnecessary quality cost, the financial risk of product recall or possible litigation and the risk of loss of reputation with the resultant loss of stock value. As for protecting our own backside, we may find that cases of recall or litigation could affect our future career. Then there is the need for scientific correctness, which we obviously need to maintain. Let me outline my vision for an ideal world and then compare it with the nightmare of the real world. In the ideal world, we can assure quality of easily controllable, safe, robust manufacturing processes using low cost, state of the art technology equipment which would be readily available. All process risks would be understood and controlled; quality control tests would have clear-cut results that immediately show any deviations. Personnel would be dedicated and well trained. The marketing product would have a stable high price. Now let’s look at the nightmares of the real world. We produce high volumes of complicated products under constant time pressure in a crowded facility. Manufacturing is carried out on old equipment as a new line is too expensive to be an option. The process itself requires many steps including interventions that are impossible to validate comprehensively. Personnel are more interested in football than manufacturing SOPs, and errors occur frequently. QC tests give results that are difficult to interpret and failure investigations end in the mist of uncertainty about the root cause. So where do we go in microbiological quality assurance? Historical development

Formulation of official microbiological test methods for non-sterile pharmaceuticals started in Europe as a reaction to tragic cases in Scandinavia in the 1960s when some patients lost their eyesight after being infected

KLAUS HABERER PhD is head of Compliance Advice and Services in Microbiology, GmbH, Frankfurt, Germany email: k.haberer@compliance-asim.de

from ophthalmic products Pseudomonas aeruginosa.

contaminated

with

The experience of some of the most prominent European experts was condensed into guidance documents by a working group of the International Pharmaceutical Federation (FIP), composed of members of the pharmaceutical industry and official pharmaceutical testing laboratories from European countries (many were also delegates at the microbiological expert group of PhEur). The methods and criteria recommended reflected the experience with microbiologically contaminated pharmaceutical products around 1970, and what was done in other related areas of applied microbiology. Casein-Soy Peptone was a general medium widely used, also Sabouraud Dextrose Agar for testing of yeast and moulds; Pseudomonas aeruginosa was excluded, because it had recently caused problems; Enterobacteria and Salmonella spp. were excluded in analogy to food microbiology; Escherichia coli was excluded as a well known water contaminant, as was Staphylococcus aureus as a pathogenic Gram-positive organism. Microbiological methods and requirements of PhEur thus originated in the FIP guidance documents. However, when published as official pharmacopoeial methods, the microbiological methods have been virtually frozen. The spirit of using state of the art methods from other areas to achieve better quality control procedures has been lost. There have been modifications in details, but the basic methods applied are unchanged since 1975. It therefore appears prudent to regulators and manufacturers alike to rely on the official method and not to use alternative methods which would need to be validated, and whose equivalence to the reference methods might be difficult to prove. Need for harmonisation

There clearly needs to be a re-evaluation and harmonisation of microbiological test methods in general. The methods and media used were developed in the late 19th to mid 20th century. Since then there have been a number of fundamental developments. Microbiological examination of non-sterile products was officially introduced in the late 1960s; there has been a big increase in multinational drug companies and globalisation of the market; repeat testing is generally

european INDUSTRIAL PHARMACY • Issue 2 February 2009

V I S I O N S A N D N I G H T M A R E S O F A M I C R O B I O L O G I S T ( C on t . ) avoided; and there has been an introduction of “rapid methods” although they are not yet widely used. The pharmacopoeial methods are the reference ones used by official laboratories to verify product compliance with phamacopoeial requirements in cases of investigation, and in market surveillance. They are also used by manufacturers to verify product compliance with pharmacopoeial requirements. However, there is no requirement to use the methods for process control. Why are they used by most manufacturers?

Authorities expect manufacturers to use the pharmacopoeial methods for product release as it is easier to judge a dossier if the official reference method is used. Companies prefer to use pharmacopoeial methods as the cost to perform validation and to justify other methods is likely to be higher than using the reference methods (mostly major companies work with alternative methods). In addition, companies are afraid to lose litigation law suits: lack of adherence to standard procedures may be seen as not following standard technology procedures. Microbiologists too, prefer to use pharmacopoeial methods. For them it is the easy way as it is not necessary to justify the use of alternative methods! The downside

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

They are generally applicable but not optimised for a given process. They are slow and time consuming (not optimised for a rapid answer), not necessarily state of the art technology and not necessarily the best method for process control. The worst aspects of pharmacopoeial methods are that the tests are applied to the letter, leading to a recipe book approach, with SOPs copied from the book. The lack of critical appreciation of the significance of what is being done (eg. sterility tests, specified microorganism testing) means that there is no testing relating to the specific problems of the product, yet there is no microbiologist on site who dares to take responsibility. Furthermore, there is no investigation into alternative methods, thus neglecting the advantage of rapid methods and results, blocking innovation and failing to investigate more relevant alternative information. A vision for the future

The ideal situation and perhaps a vision for the future would be for pharmacopoeia tests to be applied for reference purposes only. Methods to be applied for routine testing should be justified in each case. While making sure that compendial requirements are met when tested, compendial methods should not be the first choice. Alternative methods may have a number of practical advantages: shorter time to the result; tests tailored to obtain better answers to specific questions; wider range of questions and answers (eg. absence of groups of micro-organisms). The interpretation of the data would then be based on an understanding of the test and the significance of results. This would require competent microbiologists to take responsible decisions.

BIOTECH INFORMA

The Biotech industry database & news portal

TARGET – THE BIOTECH INDUSTRY

The Biotech sector of the pharma industry is growing at an amazing rate. Whether you are a Biotech company needing information and resources or a supplier of these resources, you need to regularly browse and be part of the Biotech Informa experience.

♦ Our news service brings you up-to-the-minute information on developments in the Biotech industry ♦ You can showcase your products and services to your target audience by banner advertising, enhanced listing, hyperlinks to your home page and a variety of custom packages.

On offer from Biotech Informa ♦ An extensive worldwide listing of Biotech companies and their suppliers

Contact: www.biotechinforma.com sales@biotechinforma.com 0870 919 4990

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

REGULATORY REVIEW:

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

by Steve Fairchild

European Union Proposals from the European Commission on the Future of the Pharmaceutical Sector The European Commission has published a comprehensive package of measures aimed at: ♦ Strengthening the “pharmaceutical sector” in the EU and ♦ Improving access to modern, innovative, safe and effective medicines. This takes the form of draft legislation and a “political communication” to EU Member States covering: ♦ The problem of counterfeit medicines. ♦ Provision of better information to patients on medicines. ♦ Improved pharmacovigilance arrangements. ♦ Increased “transparency” of pricing/ reimbursement decisions. ♦ The encouragement of pharmaceutical research and ♦ Increased international co-operation. Proposals specific to pharmaceutical manufacture and distribution include: ♦ Mandatory “safety features” (e.g. pack seals) on medicines. ♦ Unique identification (“mass serialisation”) of individual packs of high value products. ♦ Improved controls at external borders / entry points for medicines from third countries. ♦ Increased surveillance / control of the supply chain for Active Pharmaceutical Ingredients by manufacturers and regulatory authorities. The package of proposals has now to go through a process of consultation and discussion within the Community before it leads to legislation and other actions. This is likely to take at least 2 to 3 years. Further details appear in the “Latest News” section of the European Commission’s Pharmacos website. Revision of Annex 7 to the EU GMP Guide The European Commission has published a revised version of the Annex to the EU GMP Guide dealing with the Manufacture of Herbal Medicinal Products (HMP).

The changes introduced by this revision include: ♦ The application of GMP to active substances used in HMP. ♦ Reference to Good Agricultural Practice for the culture of medicinal plants and ♦ Modifications resulting from the Traditional HMP Directive. The revised document can be found in Eudralex Volume IV on the European Commission’s website. It is due to come into effect on September 1st 2009. New and Revised Quality Guidelines The European Medicines Agency (EMEA) has published revised versions of the Guidelines on quality information in EU registration dossiers for: ♦ Radiopharmaceuticals and ♦ Allergen Products of Biological Origin. These documents can be found on the EMEA’s website. Both have an effective date of May 2009. The UK Good Pharmacovigilance Practice Guide The UK Medicines and Healthcare Regulatory Agency has published the UK Good Pharmacovigilance Practice Guide, which provides practical guidance on implementing a “compliant” pharmacovigilance system as required by EU/UK legislation. This new guide can be purchased from the Pharmaceutical Press. International Extension of the Scope of the EU – Switzerland Mutual Recognition Agreement The EU and Swiss Authorities have decided to implement the provisions of this Agreement covering Active Pharmaceutical Ingredients. This means that the EU and the Swiss Authorities will now recognise the equivalence of each other’s controls of API manufacturers including GMP inspections. Further details can be found on the EMEA and Swissmedic websites. Steve Fairchild is a Pharmaceutical Consultant and an Executive Director of IAGT Ltd. Email: sbfairchild@aol.com

european INDUSTRIAL PHARMACY • Issue 2 February 2009

NEWS FROM THE EIPG Counterfeit medicines for human use

In December 2008, the Commission published several pieces of legislation including 104 pages of a working document entitled an “Impact assessment on anticounterfeiting measures”. The social and economic impact of counterfeit medicines is tackled. Several sections of the summary of responses covered the comments made by EIPG. The Commission document is available on the following website: http//ec.europa.eu/ enterprise/pharmaceuticals/index_en.htm Note that the Industrial Pharmacists Group of the Royal Pharmaceutical Society of Great Britain is holding a seminar on Combating Counterfeiting in London on 18 March 2009 (www.rpsgb.org/worldofpharmacy/events). EMEA reflection paper on Qualified Persons’ discretion

Following submission of our position on the EMEA reflection paper, EIPG has been advised that the Quality Working Group of the CHMP and the GMP Inspectors Working Group have reviewed and updated the reflection paper with their responses to the various questions raised. It is felt that there should now be a consistent understanding amongst regulators and staff working in the industry. The paper was discussed at an “Interested Parties Meeting” held in the EMEA offices during November 2008 at which EIPG was represented by Vice-President Philippe Van der Hofstadt (Belgium) and John Jolley (Great Britain). Consultation on Annex 13 update

A consolidated response from seven EIPG member delegations was made to the proposed update. This can be found on the EIPG website and included comments on personnel, reference samples, IMPs, premises, equipment, labelling and packaging. CPD for the European pharmacist

A joint seminar was held in London in November by the EIPG and PHSS (Pharmaceutical & Healthcare Sciences Society) on a “Continuing Professional Development (CPD) for the European pharmacist”. Whilst it provided a UK perspective, the regulatory bodies in some other European countries already require and others are moving towards requiring, participation in CPD. In this issue of European Industrial Pharmacy, Fred Ayling writes about CPD as it will be applied on a mandatory basis to UK community pharmacists. However, the general principles apply equally to

industrial pharmacists, who have particular requirements to develop the own personal CPD plan in order to benefit their own careers as well as enhance their contribution to their company. Concept paper on a guideline on chemical and pharmaceutical quality documentation concerning biological investigational medicinal products in clinical trials

Follow submission of comments on this concept paper (see EIPG website), EIPG has been advised that a directive is being drafted and will be made available for public consultation. Contact with students

A meeting was held in Denmark between EIPG VicePresident Jakob Bjerg Larsen and the EPSA VicePresident for Education to discuss ways to stimulate active collaboration. EPSA requested industrial pharmacists’ input to their professional skills mapping exercise and welcomed the proposal for a Careers Section on the EIPG website. Suggestions for topics and speakers were requested for their future meetings programme. General Assembly of the EIPG

The next General Assembly will be held in Riga, Latvia from 17-19 April, 2009. GMP guidelines for clinical trials

Considering the absence of GMP guidelines specific to Clinical Research in the European Union and/or Belgium and the different interpretation of the Member States, the VAPI-UPIP (Association of Industrial Pharmacists in Belgium) has formed a working group composed of representatives of Hospital Pharmacists, Industrial Pharmacists (Qualified Persons), Phase I Units and Pharmaceutical Companies. This guidance document (“Guidance on the GMP Requirements Phase I and Exploratory Clinical Trials in Belgium”) has been prepared in order to specify the operational requirements applicable to defined pharmaceutical activities to be performed with Investigational Medicinal Products in a Phase I or Exploratory Trial environment. Its ultimate aim is to support the Belgium (FAMHP) to define which activities can be authorized in a non-manufacturing environment and the operational requirements to be adhered to by the Sponsors, QPs and Responsible Pharmacists for pharmaceutical activities in a Phase I or Exploratory

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

N E W S F RO M T H E E I P G (C o n t . ) Clinical Trial environment, taking into consideration:

♦ Annex 14 (Blood products): Draft ready for public

consultation early 2009.

♦ the views of Hospital Pharmacists, QPs,

Pharmaceutical Companies and Phase I units

GMP related issues

♦ the current hospital practices.

♦ Introduction of QRM principles into Part II of the

GMP Guide: Public consultation just ended. Release expected early-mid 2009.

This proposal aims to ensure that the Investigational Medicinal Products are handled in optimal conditions to guarantee the quality, safety and efficacy of IMPs to enhance protection of trial subjects.

♦ Reflection paper on compliance with the

requirements of the marketing authorisation: Update ready for publication. Clarifications only, no new “QP Discretion”.

FAMHP has recognized its importance and has formed a working group with the VAPI-UPIP and pharma.be to implement this in the Belgian legislation.

♦ Format for Batch Certificate for IMPs (Directive

2001/20/EC art. 13): Awaiting publication by Commission (possibly in Eudralex volume 10).

This Belgian initiative is now extended at a European level through the EIPG. Representatives of Belgium, Denmark, Italy, United Kingdom and the Netherlands are now consulted. The EAHP has agreed to support and provide input into this initiative.

♦ QP declarations for “Atypical actives”: Q&A

published October 2008. ♦ Site Master File: To be formally integrated into EU

system once PIC/S revision is complete.

For further information contact secretary@eipg.eu. Report on EMEA GMP/GDP Inspectors working group meeting held on 26 November 2008

ICH issues ♦ Initial EU implementation strategy for ICH Q9 is

almost complete. ♦ Impact on GMP Guide and Compilation of

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

Community procedures. ♦ An initial implementation strategy for ICH Q10 is

under consideration.

The following presentations were made: 1. An update of GMP Guidelines was provided by David Cockburn Inspections Sector of the EMEA

♦ An integrated implementation strategy for ICH

Q8, Q9 and Q10 will be facilitated by Q&As prepared by the ICH-Q IWG. Mutual Recognition agreements ♦ A joint statement on inclusion of the inspection

♦ Guidelines Chapters 3&5 (Dedicated facilities):

of active substances within the operational scope of the GMP Annex of the MRA with Switzerland will be published shortly. Work is in progress on similar changes to other MRAs

Work is ongoing to prepare a supplier risk map identifying high risk physico-chemical, process and pharmacological/toxicological characteristics. ♦ Qualification of suppliers and testing of starting

materials for manufacture is held pending assessment of the impact of Commission legislation on combating counterfeits. ♦ Annex 2 (Biological): Finalisation of new text

expected February 2009. Release for further consultation anticipated and possible meeting with industry. ♦ Annex 6 (Medicinal Gases): Agreed by group for

transmission to Commission and adoption. Release in Spring 2009. ♦ Annex 11 (Computerised Systems): Public

consultation just ended. Release expected Q3 2009 together with consequential changes to Chapter 4 (Documentation). ♦ Annex 13 (IMPs): Public consultation extended to

February 2009 in view of addition of definition of “Reconstitution”.

2. Status report on the implementation of the EudraGMP database was given by Francisco Peñaranda of the EMEA Inspections Sector.

The EudraGMP database will for the first time provide an overview of authorised manufacturing sites and inspected sites subject to this common European legislation. References to EudraGMP will be provided in new applications instead of paper copies providing possibilities to aid planning, avoid duplication of resources, and assist in international co-operation. This new data base will also facilitate the issuing of GMP certificates to a manufacturer and provide access to the general public by Q1 2009, thus facilitating transparency. When complete, this database will provide Inspectors and Assessors with the latest update on the status of licenced manufacturing resources. It will also help

european INDUSTRIAL PHARMACY • Issue 2 February 2009

N E W S F RO M T H E E I P G (C o n t . ) resolve the planning difficulties and duplication of inspections, particularly for 3rd countries and the resulting non- GMP compliant and faulty manufacture information difficult to find and difficult to co-ordinate any follow up. This new database will be accessible by the public to the extent that no information will be included that can be considered as confidential within the meaning of the Annex to EMEA’s rules for the implementation of Council Regulation (EC) no 1647/2003. Information will not be disclosed where it would undermine: ♦ Protection of the public interest as regards public

security (eg. MIA/GMPc with information on controlled substances: Cannabis growing) ♦ Protection of the privacy and the integrity of the

individuals (eg. name of QPs or inspectors)

Supply chain security is to be major focus of the leadership forum, which will hold education sessions and workshops at future ISPE meetings for highlighting security issues concerning medicines. The group is actively examining other opportunities to enhance supply chain security through global standards, science and technology and are holding interactive sessions with regulators to identify additional opportunities to combat counterfeit medicines. EMEA are to publish amendments to directive 2001/83 to require full traceability of pedigree for all medicinal products, and similar regulations are to be implemented by FDA Globalisation regulations. EMEA are also liaising on control of Counterfeit with WHO working group. 5. EFPIA gave a paper on the variability in GMP inspections.

♦ Protection of commercially confidential nature

(eg. name of products under evaluation) ♦ Protection of commercial interests of a natural or

legal person (eg. non-compliance)

They stated that this is a complex situation with many players involved and requested an opportunity for: ♦ Increasing transparency of GMP inspections

♦ The effective management or operations of the

NCAs (eg. API GMPc) (ie. to avoid an unnecessary huge volume of requests for inspections where competitors have an API GMPc available) ♦ EU National Competent Authorities (NCAs) have

full read/write access to the EudraGMP database.

carried out by National authorities. ♦ The industry to ensure appropriate interpretation

of inspection findings while reducing the regulatory burden yet ensuring patient safety. ♦ Regulators to apply greater consistency in the

standards of GMP required and an increased in the harmonisation between member states.

– Inspectors have currently full read/write access.

♦ Rapid Alert notification to include

– Assessors/EMEA staff have full read access.

suspected/confirmed alerts on IMP &API and a contact list of partners to be prepared and released by the appropriate National authority.

♦ Read/write access to MRA partners agreed. ♦ Restricted access to general public has been

agreed.

6. Other items

♦ General public will have access in Q1 2009 ♦ Non-restricted read access has been agreed with

some non-EU competent authorities (FDA, WHO and EDQM). 3. A status report on the European Pharma Excipient Certification (EPEC) Project was given by Tim Boelke, BASF Care Chemicals & EFCG and Iain Moore, Croda & IPEC Europe

An ambitious European pharma excipients certification project has been defined and launched, with the global intent of issuing Certificates of suitability for all active pharmaceutical ingredients and major excipients that have been assessed by third part auditors (IPEC).

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

EMEA Inspectorate informed the meeting of a pilot project to rationalise international GMP inspection activities.

Notification was given that cooperation will be arranged between TGA, FDA and EMEA inspectors so that evidence of local inspections can be used to verify GMP compliance. PDA representatives provided an update on the technical reports published by PDA

Report prepared by John DR Jolley

eur opean INDUSTRIAL PHARMACY • Issue 2 February 2009

DATES FOR YOUR DIARY

M A R CH

18 March 2009 – London, UK Combating counterfeiting – current status of the new technologies and raising public awareness email: events@rpsgb.org www.rpsgb.org/worldofpharmacy/events 18-19 March 2009 – Frankfurt, Germany 1st European Annual Conference on clinical trial supplies email: apv@apv-mainz.de www.apv-mainz.de 23-25 March 2009 – Berlin, Germany EuroMeeting Berlin 2009 email: EuroMeeting2009@diaeurope.org www.diahome.org 23-25 March 2009 – Nottingham, UK APS Inhalation 2009 www.apsgb.org 23-26 March 2009 – Dublin, Ireland Pharmaceutical GMP www.DBA-global.com 23-26 March 2009 – Manchester, UK Practical aspects of pharmaceutical validation www.DBA-global.com

20-21 April 2009 – Manchester, UK Achieving operational excellence: how to simplify and improve your batch record review process www.DBA-global.com

9-11 May 2009 – Athens, Greece 14th Panhellenic Pharmaceutical Congress: Pharmaceutics in the 21st Century www.pepharm.gr

22-24 April 2009 – Nice, France Biotechnology for the nonbiotechnologist email: registrations@managementforum.co.uk www.management-forum.co.uk

17-21 May 2009 – Cambridge, UK The Eleventh Advanced Level Workshop on pharmacokineticpharmacodynamic data analysis: a hands-on residential course using WinNonlin email: events@rpsgb.org www.rpsgb.org/events

23 April 2009 – London, UK Impact of ICH Q8, Q9 and Q10: Quality by design: fact or fiction? email: events@rpsgb.org www.jpag.org 27-29 April 2009 – Barcelona, Spain Out-of-specification results with postcourse workshop on failure investigation email: info@gmp-compliance.org www.gmp-compliance.org 28-29 April 2009 – Prague, Czech Republic Product quality review – compliant, reasonable, efficient email: info@gmp-compliance.org www.gmp-compliance.org

A P RI L 1-2 April 2009 – London, UK Nasal drug delivery – Annual International Conference email: registrations@managementforum.co.uk www.management-forum.co.uk

JU N E 8-12 June 2009 – Nice, France 2nd PharmSciFair email: pharmscifair.programme@congrex.com www.congrex.com 11 June 2009 – London, UK Biosimilars and analytical challenges email: events@rpsgb.org www.jpag.org 15-18 June 2009 – Manchester, UK Key topics in sterile products manufacture www.DBA-global.com

M AY

S E P T E M B ER

7-8 May 2009 – London, UK Pre-filled syringes email: registrations@managementforum.co.uk www.management-forum.co.uk

3-8 September 2009 – Istanbul, Turkey FIP 2009 – Responsibility for patient outcomes – are you ready? email: registration@newbrooklyn.nl www.fip.org/istanbul2009

World Leader in GMP gap analyses, seminars and individual GMP training Hard hitting web-based GMP training in the comfort and convenience of your office or home (save on expensive and inconvenient travel: These seminars are offered as web-based learning:

GMP and Quality System Consulting: With over 200 clients in 27 countries, we pride • ourselves that every single one of our clients has passed an FDA inspection the very first time through (when they have listened to us)

• Passing an FDA Inspection – Guaranteed • Managing the QC Lab in a GMP Manner • Fundamentals and Essentials of Validation • Effective Investigations and Corrective Actions • Effective Quality Assurance Auditing

We have wide expertise in evaluating GMP and • Quality Systems at your facilities and in

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

Let us assist you. Speedily and cost effectively. Contact us at: consulting@globepharm.org

performing third-party supplier and contract manufacturer audits

european INDUSTRIAL PHARMACY • Issue 2 February 2009