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european INDUSTRIAL

PHARMACY FEATURES 4

PHARMACEUTICAL INDUSTRY ADVANCED TRAINING (PIAT) – ACCREDITED PROFESSIONAL DEVELOPMENT FOR THE

MEDICAL AND HEALTHCARE INDUSTRIES

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The PIAT programme provides a distance learning opportunity to experience Continuing Professional Development (CPD). by Brian Lockwood

HOT-MELT EXTRUSION TECHNOLOGY: OPTIMIZING DRUG DELIVERY

Hot-melt extrusion is a new technology used to produce a variety of solid dosage forms which offer increased dissolution properties and hence improved absorption and therapeutic efficacy for poorly water-soluble compounds. by Marcia Williams, Yiwei Tian, David S Jones and Gavin P Andrews MOVING TOWARD 100% RAW MATERIAL INSPECTION WITH A HANDHELD RAMAN SPECTROMETER

Improvements in Raman spectroscopy and the development of handheld instruments makes it an attractive alternative to traditional raw material inspection methods. by Robert L Green and Christopher D Brown THE QPPV – CEMENTING THE PHARMACIST’S ROLE IN EUROPE

Why are there so few pharmacists in the UK who are Qualified Persons in Pharmacovigilance (QPPV)? The author, a pharmacist QPPV himself, urges pharmacists to consider this career. by Derek Woodcock DIAGNOSTICS AND THEIR ROLE IN PERSONALISED MEDICINE

Biomarkers and diagnostics are playing an increasing role in improving the design and probability of success of clinical trials. They are also becoming more important in improving individual treatment. by Loïc Kubitza

REGULARS

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EDITORIAL COMMENT REGULATORY REVIEW NEWS FROM THE EIPG PHARMACEUTICAL FORUM JOB VACANCIES DATES FOR YOUR DIARY

ISSUE 7 • OCTOBER 2010

www.industrialpharmacy.eu www.eipg.eu


Associate Editors

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Belgium: Philippe Van der Hofstadt Bulgaria: Valentina Belcheva

Issue 7 August 2010 ISSN 1759-202X

Czech Republic: Ales Franc

EDITOR Joe Ridge, MRPharmS

Denmark: Michiel Ringkjøbing Elema

PRODUCTION Sue Feather

Finland: Tuula Lehtela France: Jean-Pierre Paccioni

SUBSCRIPTIONS Jill Monk

Germany: Armin Hoffmann

EDITORIAL BOARD Michael Anisfeld Michael Gamlen Linda Hakes John Jolley

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

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Ireland: Anna O’Mahony Italy: Piero Iamartino Latvia: Inta Saprovska Malta: Claude Farrugia Netherlands: Ineke Kleefsman, Michiel Storimans Portugal: bastonaria@ordemfarmaceuticos.pt

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

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Cover picture: Photograph of capsules and tablets from the PIAT brochure (see p4).

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


E D I TO R I A L C O M M E N T Dear Colleagues

As I write this editorial, the Pharmaceutical Industry has entered another eventful year and a period of reflection as it deals with the many challenges that it is facing with respect to productivity, patent expiration, increased regulation and the ever increasing importance of the BRIC economies. As always, the mandate of the EIPG is to represent Industrial Pharmacists working in all areas of pharmacy with respect to Professional, Educational and Technical affairs. The EIPG is apolitical and has at its core credo that 'Pharmacists continue to enter and contribute to this important sector of pharmacy'. The EIPG website (www.eipg.eu) has been modified to allow the posting of job opportunities and we have had a major multinational company asking to use our website to post their openings. This year has seen EIPG actively engaging with the European Medicines Agency, European Federation of Pharmaceutical Industries and Associations, European Pharmaceutical Students Association, European Association of Hospital Pharmacists, Pharmaceutical Group of the European Union and the European Commission. In particular, I am proud of the role that EIPG has played in Pharmine and the

importance of ensuring that the Pharmacy Curriculum still produces pharmacists that understand how drugs are discovered, developed, manufactured, registered and regulated. More importantly, that pharmacists from year 1 of being a pharmacist understand what impacts quality and efficacy of our medicines. On September 14th, EIPG was invited by the Manufacturing and Quality Compliance group of the EMA to participate at the GMP/GDP IWG interested parties meeting chaired by David Cockburn, where a number of updates and discussions took place around: ♦ Updates to Site Master Files ♦ Implementation of 'anti-

falsification' legislation ♦ Role of the QP in supply chain

oversight ♦ Proposals to revise GMP Annex 16

for minor deviations ♦ Presentation on the use of

dedicated facilities for APIS and Intermediates risk-based auditing ♦ Survey presentation on Atypical

continue to play a role in this industry and the experiences of 'grass roots' Industrial Pharmacists can be shared with those organisations who perhaps are not as close to their core membership as they think they are. I have taken this comment on board and as President of EIPG will conduct a Strategy Day in November in Paris with an expanded Bureau to address what the EIPG of the future will look like and how it can continue to deliver its credo in these challenging times. Already, I can share with you the knowledge that there have been a number of radical suggestions for a revamped EIPG organisation but clearly all suggestions will be brought to the General Assembly for discussion and approval before their implementation. I finish this editorial by encouraging readers to visit our website and to read the various EIPG updates within the Journal which can provide more details of our activities. As always, you can contact me or my Executive Director, Mrs Jane Nicholson, through our website.

actives A report of these discussions and the GMP updates will be made available on the EIPG website: www.eipg.eu At the core of all these interactions is the belief that pharmacists

Dr Gino Martini FRPharmS President of EIPG

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PHARMACEUTICAL INDUSTRY ADVANCED TRAINING (PIAT) –

ACCREDITED PROFESSIONAL DEVELOPMENT FOR THE MEDICAL AND HEALTHCARE INDUSTRIES by Brian Lockwood

C

areer development and progression for staff in the industry and ancillary organisations is as important for employers as employees. PIAT programmes are unique in their distance learning format, and have contributed to industry success for nearly 20 years. History and delivery

The original PIAT programme was proposed in 1989 in collaboration with the UK Pharmaceutical Industry. Modules were written by experts based in major Pharma from UK, Japan, Switzerland, Thailand and academia.

BRIAN LOCKWOOD is Director of PIAT, School of Pharmacy & Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT

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Originally there were eight modules, now there is a choice of 17 modules available in the Industrial Pharmacy Programme. The modules have EU and US relevance, and are applicable worldwide due to the overriding importance of FDA and EMEA regulations. The aims of the programme were to have a flexible structure of free standing modules. These have an open and distance learning style, allowing minimum time to be absent from the workplace, which benefits both employer and student. Rigorous quality assurance is carried out by the University of Manchester. All module tutors are accredited University staff, and results are moderated by an accredited external examiner. There are a range of entry options; a minimum of an HND is usually required for a Diploma, and a degree level scientific qualification is usually needed for an MSc, most students are

science graduates. No prior learning is required for individual modules, but four credited modules with a pass mark of 50% equate to degree equivalence. Recently we enrolled students with MBAs and law degrees! Individual course modules have a workload of 150 hours per module, and the course content consists of a workbook of 150-300 pages, written assignments, and a workshop (tutorial) of 2-4 hours with the module tutor. There is a 2-hour written examination required for most modules. Other benefits include fulltime contact with a tutor, available via e-mail, and continual updates of modules on an annual basis. University awards include module credits, 15 per module, a Diploma for 8x15 credits, and an MSc is gained after the Diploma, plus Dissertation of 60 credits, making a total of 180 credits. The degree awarded for this is an Industrial Pharmaceutical Sciences MSc. Distinctions are awarded for marks of ≥70% in all the modules and the Dissertation, and 12 have been awarded over the last 4 years. Industrial Pharmacy programme

The original Industrial Pharmacy programme consists of 17 modules to date. Box 1. lists the module titles. Three

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


PHARMAC EUTIC AL INDUSTRY ADVANC ED TRAINING (Cont.) Box 1.

Box 2.

Box 3.

1 Basic Principles 2 Preformulation studies I 3 Preformulation studies 2 4 Solid oral dosage forms 5 Liquid and semisolid dosage forms 6 Sterile dosage forms 7 Controlled release dosage forms 8 Operations management 9 Quality assurance 10 Packaging 11 Regulatory affairs * 12 Pharmaceutical engineering 13 Quality control laboratory testing 14 Safety, health and environment * 15 Inhalation dosage forms 16 Product development management * 17 Medical writing*

1. Introduction to clinical trials 2. Planning, setting up, and running clinical trials 3. Phase I clinical trials 4. Phases II / III (1) 5. Phases II / III (2) 6. Statistical requirements and study design 7. Pharmacovigilance 8. Regulatory issues

1. Principles of Toxicology 2. Assessment of Toxicity 3. Biotransformation and Kinetics 4. Regulatory Toxicology 5. Target Organ Toxicology (1) 6. Target Organ Toxicology (2) 7. Mechanisms of Toxicity 8. Molecular and Cellular Methods in Toxicology 9. Integration and Risk Assessment

*Assessed by assignments only (no written examination)

of the modules do not require examination, only written assignments, see Box 1. To date there have been over 200 MSc s, and 3000 individual modules gained in the PIAT programmes. Students have come from a wide range of employers including major Pharma, biotech companies and the NHS, and have been mainly staff from Production, and R & D. Worldwide take-up of the programmes includes S. America, N. America, the Far East, and Europe. New initiatives started in 2007 include programmes in: ♦ Clinical Trials ♦ Toxicology ♦ Pharmaceutical Microbiology ♦ Pharmaceutical Business and

Development Two of these programmes were funded by HEFCE & NWRDA, and others by the University of Manchester, or via collaboration. The 1st modules were available in February 2007, and this allows for a greater selection of modules for an MSc. Currently we have 34 out of a total of 35 new modules completed

and students have started on all programmes. The benefits for students now include programmes tailored to their individual needs, particularly with the new programmes, allowing selection from all of the different programmes. The title of the award will still bear the name of the principal modules selected, provided that the following number of modules in the programme are: ♦ Certificate: 3 out of 4 ♦ Diploma: 5 out of 8 ♦ MSc: 5 out of 8

of different employers, including the UK NHS. The programme consists of eight modules in a logical development of the subject, which are shown in Box 2. Toxicology

The Toxicology Programme was set up as there is currently a severe shortage of toxicologists in the industry, and this programme aims to help this situation. The Toxicology Programme consists of nine modules which are shown in Box 3. Microbiology

Financial benefits accrue to both students and employers in terms of time and money spent, the student does not need to leave the workplace and the employer keeps and retains staff during the programme. Other benefits include improved work performance, and career development. One extreme example is that of one student who developed to become a Module author. These new modules are believed to be ideal for continual professional development (CPD), which is increasingly important to both employers and employees in the pharmaceutical industry. We currently have a range of 1-3 credit units in preparation, specifically designed for CPD.

The Pharmaceutical Microbiology Advanced Training (PMAT) programme was planned in collaboration with Pharmig, a non-profit organisation providing a forum for microbiology in the pharmaceutical, healthcare and allied industries and was established in 1991 to meet the needs of Pharmaceutical Microbiologists.

Clinical trials

Business development

The Clinical Trials Programme has attracted students from a wide range

The Pharmaceutical Business Development and Licensing

european INDUSTRIAL PHARMACY • Issue 7 October 2010

The modules were designed to meet the needs of those responsible for and/or working in the area of pharmaceutical microbiology in the industry, and feedback from the industry highlighted the need for a flexible learning and development programme. The ten modules are shown in Box 4.

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PHARMAC EUTIC AL INDUSTRY ADVANC ED TRAINING (Cont.) Box 4.

Box 5.

1. Introduction to Pharmaceutical Microbiology and Technology 2. Water Systems 3. Microbiological Environmental Monitoring & Control (steriles & non-steriles) 4. Microbiological aspects of Sterile Pharmaceutical Manufacturing 5. Quality Assurance in Microbiology Laboratories 6. Engineering Principles for Pharmaceutical Microbiologists 7. Application of Microbiology in Biopharmaceuticals 8. Antimicrobials 9. Antibiotics and Vitamins 10. Key Management Tools

1. Introduction to the Healthcare Industry* 2. Business Development Operations 3. Financial Modelling in the Pharmaceutical Industries 4. Legal Issues in Business Development Contracts 5. Negotiation and Interpersonal Skills 6. Marketing and Commercialisation 7. Intellectual Property Rights 8. Research & Development and Manufacturing

programme was established in collaboration with UK PLG (The Pharmaceutical Licensing Group). PLG is the professional association for people in business development and licensing and again it is a not for profit organisation, industry

NEW D REVISE N EDITIO

*all modules are assessed by assignment only

based, and has no service providers. The primary role of PLG is networking and continuous professional development. In the UK there are over 200 members covering all areas of the industry pharma, OTC, biotech, drug

delivery and generics, and there are nine other PLGs in Europe plus Japan and Canada with over 1,500 members. PLG was founded in 1994, and organises a number of training courses in business professional development. The programme consists of eight modules which are shown in Box 5. University accreditation of individual modules has taken place alongside their completion, and accreditation of the complete programme is on track for late 2010. Student uptake to date is 35 modules (by 18 students), and there is demand for others when completed. Promotion of the programme is planned, including visits to major Pharma, and further presentations at learned conferences, in addition to our exhibitions at BPC 2008 and 2009, and EUFEPS 2009. www.pharmacy.manchester.ac.uk/ postgraduate/piat/

Manufacture of Sterile Products

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Quantity Discounts Packs of 10 booklets at ÂŁ80.00 per pack (plus postage at cost) minimum order one pack of 10 This handy pocket guide conveniently provides all the major sterile products manufacturing regulations. Order now for yourself, your staff and your clients. To order contact Jill Monk at +44 (0)1428 656665 or email: sales@euromedcommunications.com

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eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


HOT-MELT EXTRUSION TECHNOLOGY: OPTIMIZING DRUG DELIVERY by Marcia Williams, Yiwei Tian, David S Jones and Gavin P Andrews

H

ot-melt extrusion (HME) technology was first utilized predominantly in the plastic industry and to a lesser extent in the food industry since the 1930’s. The many advantages of HME over conventional solid dosage form manufacturing have piqued the interest of the pharmaceutical industry and academia as a novel drug delivery technology. This innovative technology has been shown to be extremely robust and a viable method of producing many different drug delivery systems, including implantable reservoirs, pellets, films, capsules and tablets. Moreover, the possibility of forming solid dispersions offering improved bioavailability renders HME an excellent alternative to other conventionally employed techniques.

Dr Gavin P Andrews is a Senior Lecturer in Pharmaceutics at the School of Pharmacy, Queen’s University Belfast, UK. Professor David S Jones is the chair of biomaterial science at the School of Pharmacy, Queen’s University Belfast, UK. Mr Yiwei Tian and Ms. Marcia Williams are PhD students at the School of Pharmacy, Queen’s University Belfast, UK. Correspondence: DR GAVIN P ANDREWS, Lecturer in Pharmaceutics School of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK Tel: +44 (0) 28 90 97 2646 Fax: +44 (0) 28 90 247794 Email: g.andrews@qub.ac.uk

This article aims to provide an overview of the technique, a basic guide to extrusion equipment and process technology, the fundamental principles of operation and to discuss the most recent applications of HME within the field of drug delivery. Introduction

Extrusion is a process that involves forcing a raw material or blend through a die or orifice under set conditions such as temperature, pressure, rate of mixing and feed-rate, for the purpose of producing a stable product of uniform shape and density1. Since the 1930’s, hot-melt extrusion has mainly been utilized in the plastic industry in the production of plastic products such as bags, sheets, and pipes2. The process is also utilized to a limited extent in the food industry in for example, extrusion cooking for the manufacture of cereals3. The technology has now found application in the pharmaceutical industry in the area of drug delivery.

The Hot-Melt Extrusion Process

At the most fundamental level, an extruder consists of a platform that

european INDUSTRIAL PHARMACY • Issue 7 October 2010

supports a drive system, an extrusion barrel, a rotating screw arranged on a screw shaft and an extrusion die for defining product shape. Irrespective of the complexity of the machine, the extruder must be capable of rotating the screw(s) at a selected speed, while compensating for the torque generated from the material being extruded. The extudate may be shaped into tablets, rods, pellets, or milled and mixed with other extra-granular excipients for different purposes. The single screw extruder is the most widely used extrusion system. It can be either flood or starve fed, high-pressure pumped and finally the molten materials are pumped to the die to form the extrudate4. The extrusion barrel may be conveniently divided into three distinct zones: feed zone, compression zone and metering zone. The depth and/or pitch of the screw flights differ within each zone generating variable pressure along the screw length (zone dependent). Due to the large screw flight depth and pitch, the pressure within the feed zone is very low allowing for consistent feeding from the hopper and gentle mixing of API and excipient. The primary function of the subsequent compression zone is to melt, homogenize and compress the extrudate so that it reaches the metering zone in a suitable form for extrusion. Consequently, products are formed through the die continuously (Figure 1). The single screw extrusion, however, does not provide the high mixing capability of a twin-screw machine, and therefore is not the preferred approach for the production of pharmaceutical formulations. Moreover, dispersing and mixing of drugs with other ingredients involve breaking the aggregates of the minor drug particles. In order to achieve this, a critical amount of force must be applied during the process5. This force cannot be achieved with the single-screw, but the twin-screw extruder with its corotating or counter-rotating screws would provide the high energy necessary. In addition, the versatility of a twin-screw extruder (process manipulation and optimisation) and the ability to accommodate various pharmaceutical formulations makes it much more

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HOT-MELT EXTRUSI ON T ECHNOLOGY (Con t.)

Figure 1. Typical hot-melt extruder.

favourable and is the preferred choice for pharmaceuticals. Another significant design variable is whether the two screws are intermeshing or non-intermeshing, the former being preferred due to the greater degree of conveying achievable and the shorter residence times. Industrially, due to process practicality and the ability to combine separate batch operations into a single continuous process, twin-screw extrusion significantly increases manufacturing efficiency. Recent FDA guidelines (FDA Pharmaceutical cGMP for the 21st Century, 2004) for the enhancement and modernization of the pharmaceutical industry has facilitated the move towards continuous manufacturing processes and the implementation of process analytical technologies (PAT) to monitor, control and understand manufacturing processes. These are achievable with HME technology. The continuous nature of HME has most recently been extended through the use of a cylindrical die and an inner rotating knife6. This design has helped to further enhance the continuity of the process through the generation of melt extruded pellets without the need for a separate spheronization step.

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Pharmaceutical applications of hot-melt extrusion: Background

Solid dosage forms in the form of tablets and capsules are by far the most popular dosage forms in use today, due to the enhanced stability and ease of use. Although comparatively more stable than liquid dosage forms, solid dosage forms do present bioavailability, stability and manufacturing challenges. Due to the significant limitations in unit operations involved in the production of these

dosage forms, as well as the need to remain competitive and maintain constant growth, pharmaceutical manufacturers are constantly seeking innovative processes to increase the efficiency of manufacturing operations whilst improving therapeutic efficacy. HME technology is one such technology that has captured the interest of the pharmaceutical industry particularly in the area of solid dispersions7. Several advantages over traditional processing methods have been identified, and some are listed in Table 17-10.

Table 1. Advantages of hot-melt extrusion. Features and benefits of hot-melt extrusion Feature

Benefit

Solvents not required

Environmentally friendly, economical; No residual solvent in final product.

Continuous process

Fewer unit batches required; Efficient scale-up from laboratory to large-scale production

Intense mixing and agitation achieved

Improved content uniformity

Compressibility not required

Useful for powders with low compressibility index

Polymers serve multiple purposes

Less number of excipients required; Cost effective.

Greater thermodynamic stability than that produced by other hot-melt methods

Less tendency towards recrystallization

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


HOT-MELT EXTRUSI ON T ECHNOLOGY (Con t.)

Figure 2. Schematic presentation of the extrusion process.

Formation of solid dispersions

Not only is HME an efficient manufacturing process, additionally it may enhance the quality and efficacy of manufactured products4. Of particular interest is the use of HME to disperse active pharmaceutical ingredients (APIs) in a matrix at the molecular level, thus forming solid solutions (see Figure 2). HME is an approach commonly utilised in the delivery of poorly water-soluble, class II compounds due to the increased dissolution achievable, and hence improved absorption and therapeutic efficacy12. Whilst the formation of solid solutions may significantly enhance drug dissolution rate of class II compounds in vivo, the presence of a metastable state, high internal energy and specific volume of the amorphous state leads to a tendency during storage (thermal and/or humidity stress) towards recrystallization. Interestingly, extruded solid solutions offer greater thermodynamic stability than those prepared by alternative processes such as spray drying, solvent evaporation and other hot-melt methods11. The polymers used in the extrusion process may function as thermal binders, drug stabilisers, drug solubilisers and/or drug release controlling excipients with no compressibility requirements. Typical examples of pharmaceutically approved polymeric materials include vinyl polymers (polyvinylpyrrolidone (PVP), PVPvinyl acetate (PVP-VA)), polyethylene oxide (PEO), EudragitÂŽ (acrylates), PE glycol (PEG) and cellulose derivatives. While residence time within the extruder and high

processing temperatures (required to melt the polymeric carrier) were initially projected as significant disadvantages of this technology, the ability to modify screw configuration and the high-shear forces generated within the extruder allow for processing at lower temperatures. Additionally, the use of plasticizing agents and the introduction of twin-screw extruders, removed such concerns. Typical plasticizing agents for HME include PEGs, triacetin, citrate esters, citric acid, and the API’s themselves in some cases12. A recent development is the use of surfactants to improve the release profile of solid dispersions14. The surface activity improves the solubility and aids in preventing precipitation and also protects the fine crystalline particles from agglomeration. High levels of solubility improvement have been achieved using this approach. The ability to predict the suitability of a polymer for the process should be viewed as another favourable advantage. Using small quantities of drug and polymer, thermal, spectroscopic and rheological methods may be used to determine drug/polymer miscibility thus providing information on the probability of forming a suitable dispersed (down to the molecular level) drug polymer platform8. Dosage forms prepared using HME technology

This technology has proven useful in the design of a number of drug delivery systems such as immediate and modified release tablets, granules,

european INDUSTRIAL PHARMACY • Issue 7 October 2010

pellets, implants, matrix systems, transdermal drug delivery systems and ocular inserts, and targeted delivery such as enteric matrix tablets and capsules1,15,16. De Brabander et al.17 described the use of HME in the preparation of matrix mini-tablets that minimise the risk of dose dumping, reduce inter- and intra-subject variability and provide highly dispersive formulations within the gastrointestinal tract. Miller et al.18 have demonstrated the ability of HME to act as an efficient process for the wettability and hence improve drug release properties of engineered particles. Additionally, the coating of hot-melt extruded tablets with suitable polymers has been shown to significantly delay the onset of crystallization during dissolution and storage19. Future developments

The pharmaceutical industry is going through a period of unparalleled change that has been brought about by a number of factors. In particular, globalization of the industry, increased risk/cost associated with the development of new drug compounds and patent expiry on numerous high revenue drugs are the most compelling factors. As a result of such dramatic changes, the demand for new drug compounds to bridge the gap in lost revenue within shorter timeframes is increasing significantly. This undoubtedly means that the industry can no longer focus on projects that do not provide early promise. Furthermore, it is well accepted that the major changes being implemented within the pharmaceutical industry will result in focus on areas that will offer significantly high growth potential. This will involve the development of

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HOT-MELT EXTRUSI ON T ECHNOLOGY (Con t.) dormant pharmaceutical compounds that have been abandoned prior to FDA approval or approved but never commercialized. Due to the implementation of high throughput screening over the last decade these compounds have been designed for the treatment of conditions that have more difficult and complex targets. Although this may provide enhanced clinical outcomes and reduce adverse effects, these drugs commonly exhibit poor solubility in gastrointestinal fluids and hence are often not absorbed after oral ingestion. Hot-melt extrusion (HME) is an emerging drug delivery technology that is currently being investigated by the industry as a suitable method for the production of solid drug dispersions exhibiting enhanced solubility in gastrointestinal fluids. To date, the development of solid dispersions using HME has been empirical and the rationale for the selection of polymers is unclear and the prediction of the stability of the resultant drug delivery platform has not been addressed sufficiently. Therefore in order for the industry to reduce the time required to develop and release new products on to the market a greater understanding of the formulation and engineering

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aspects of this process is required to ensure that stable solid dispersions may be both predicted and prepared. This will undoubtedly be the focus of both industrial and academic research in the foreseeable future so that bio-enhanced formulations with improved efficacy may be developed. References 1. Breitenbach J. Melt extrusion: from process to drug delivery technology, European J of Pharmaceutics and Biopharmaceutics, 2002; 54: 107–117. 2. Kaufman HS, Falcetta JJ. Introduction to Polymer Science and Technology: An SPE Textbook, 1977; John Wiley & Sons, New York. 3. Guy R. Extrusion Cooking – Technologies and Applications 2001; Woodhead Publishing. 4. Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology 2003; Marcel Dekker, New York. 5. Douglas P, Andrews GP, Jones DS, Walker G. Chemical Engineering Journal, 2010, doi: 10.1016/j.cej.2010.03.077. 6. Radl S, Tritthart T, Khinast J. Science Direct – Chemical Engineering Science 2010; 65(6): 1976–1988. 7. Forster AH, Rades T, Hempenstall J. Selection of Suitable Drug and Excipient Candidates to prepare Glass Solutions by Melt Extrusion for Immediate Release Oral Formulations. Pharmaceutical Technology, Europe 2002; 14(10): 27–37. 8. Chokshi RJ, Sandhu HK, Iyer RM et al. Characterization of Physico-Mechanical Properties of Indomethacin and Polymers to Assess their Suitability for Hot-Melt Extrusion Process as a Means to Manufacture Solid Dispersion/Solution. J Pharmaceutical Sciences 2005; 94(11): 2463–2474.

9. Andrews GP, Jones DS, Abu Diak O, et al. Hot-Melt extrusion: an emerging drug delivery technology. Pharmaceutical Technology, Europe 2009; 21(1). 10. Forster A, Hempenstall J, Tucker I, Rades T. The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion. Drug Development and Industrial Pharmacy, 2001; 27: 549–560. 11. Rades T, Patterson JE, James MB, et al. Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int J Pharmaceutics. 2007; 336: 22–34. 12. Ford JL. The current status of solid dispersions, Pharmaceutica Acta Helvetiae 1986; 61(3): 69–88. 13. McGinity JW, Zhang F, Repka M, Koleng JJ. American Pharmaceutical Review 2001; 4: 25–36. 14. Bley H, Fussnegger B, Bodmeier R. International Journal of Pharmaceutics 2010; 390: 165–173. 15. Mehuys E, Remon JP, Vervaet C. Production of enteric capsules by means of hot-melt extrusion. European J Pharmaceutical Sciences 2005; 24: 207–212. 16. Andrews GP, Jones DS, Abu Diak O, et al. The manufacture and characterisation of hotmelt extruded enteric tablets, Eur J Pharmaceutics and Biopharmaceutics. 2008; 69(1): 264–273. 17. De Brabander C, Vervaet C, Remon JP. Development and evaluation of sustained release mini-matrices prepared via hot-melt extrusion, J Controlled Release 2003; 89: 235–247. 18. Miller DA, Jason TM, Yang W, et al. Hot-Melt Extrusion for Enhanced Delivery of Drug Particles, J Pharmaceutical Sciences 2007; 96(2): 361–376. 19. Bruce D, Fegely KA, Rajabi-Siahboomi AR, McGinity W. Drug Development and Industrial Pharmacy 2010; 36(2): 218–226.

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MOVING TOWARD 100% RAW MATERIAL INSPECTION WITH A HANDHELD RAMAN SPECTROMETER by Robert L Green and Christopher D Brown

P

harmaceutical manufacturers are facing mounting pressure to reduce costs, improve quality control, and increase productivity. Since inspection of incoming raw materials is a significant portion of manufacturing costs, companies are exploring opportunities in this area. In addition to minimizing costs, companies need to perform even more tests to accommodate increased production volume and regulatory requirements.

ROBERT GREEN is an analytical chemist with expertise in an array of spectroscopic/optical methods and chemometrics. He is currently a Research Scientist at Thermo Fisher Scientific. CHRISTOPHER BROWN, PhD is currently the Director of System Analytics & Applications at ThermoFisher where he leads the development of the embedded analytics and chemometrics software for the company’s analytical devices. Correspondence to: Alyssa Knightley email: aknightley@ahurascientific.com

An assessment of the workflow associated with incoming raw material inspection reveals numerous opportunities to improve both the efficiency of the process and the quality of results. For the majority of raw materials, containers are opened for sampling. Samples are then transferred to QC for analysis. While awaiting results, incoming materials are not available for production. Additionally, this process carries risks of contamination caused by sampling, mislabelling of test samples, and production delays if the QC laboratory has a higher than normal work load. In recent years, the availability of portable and handheld instruments has created the potential for moving analytical testing from the laboratory to the manufacturing floor. Current instrumental techniques

The most common analytical techniques used for identification of raw materials are HPLC (high performance liquid chromatography), NIR (near infrared) and mid-IR (mid-infrared) spectroscopies, plus wet chemical methods. Raman spectroscopy is also effective and efficient for raw material identification, in-process analysis, and final product authentication1.

european INDUSTRIAL PHARMACY • Issue 7 October 2010

The Raman light scattering effect has been historically difficult to detect because the scattering phenomenon is very weak. The increased availability of longer wavelength diode lasers, charge coupled devices, and Rayleigh rejection filters has increased its sensitivity and decreased nuisance signal contribution from fluorescence. Today, Raman spectroscopy is a practical laboratory technique, and modern Raman instrumentation is faster, more robust, and less expensive than earlier versions. Additional advances in component miniaturization and embedded software algorithms have enabled development of decision-capable handheld Raman solutions for environments beyond the laboratory. Operational attributes of infrared and Raman spectrometers

A significant advantage of handheld spectrometers is their ability to quickly verify material identity at the point of need. The ability to acquire Raman spectra through transparent packaging, such as plastic bags1, 2, eliminates the risk of contamination created by traditional sampling. While both Raman and NIR spectra can be acquired through transparent packaging, NIR measurements can produce markedly different spectra as a result of subtle variations from one container to another. In comparison to solids sampling with Raman and NIR, mid-IR techniques require direct contact with the material being tested. Raman is unique amongst the three techniques in its ability to measure liquids through a container in a backscattering geometry. This negates the need for additional transmission optics or immersed sensors wetted by the sample, as in NIR or mid-IR. Analytical characteristics of infrared and Raman spectrometers

Every chemical compound with covalent bonds produces a characteristic pattern of Raman shifts and Raman spectra offer a high degree of selectivity, making them particularly effective for identity testing. For example, the Raman spectra of acetyl salicylic acid and acetaminophen

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MOVI NG TOWARD 100% RAW MATERIAL I NSPECT ION (C on t.) comprise distinct peaks that can be used to chemically fingerprint each compound.

––––– Glycerin ––––– Glycerin Contaminated with DEG

r = 0.96 p-value = 3.2 x 10–3

400

600

800

1,000 1,200 1,400 1,600 1,800 2,000 Raman Shift (∆cm–1)

Figure 1. Raman reference spectum of pure vs contaminated glycerin.

Table 1. Common pharmaceutical raw materials used for reference spectra and their average measurement times using handheld Raman spectrometers. Material

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Titanium (IV) oxide, anatase a-Lactose monohydrate Polyvinylpyrrolidone Dextrose anhydrous Dextrose monohydrate Sodium bicarbonate Potassium bicarbonate Calcium carbonate Cellulose Ethyl cellulose Hydroxypropyl cellulose Dextrin from corn Calcium stearate Magnesium stearate Stearic acid Citric acid Potassium citrate tribasic monohydrate Sodium citrate (+)-Sodium L-ascorbate Sulfanilamide Acetaminophen Sodium phosphate monobasic Sodium phosphate dibasic Calcium phosphate dibasic Trimagnesium phosphate Zinc sulfate Calcium sulfate Calcium sulfate dihydrate

* rounded to nearest second

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Average Measurement Time(seconds)* 1 15 69 11 18 9 11 6 36 284 390 49 79 54 42 22 21 21 8 1 5 15 29 35 124 4 14 7

Compared to Raman spectra, NIR spectra are less distinct, with broader peaks resulting in poorer selectivity. Computationally intensive methods may be necessary to detect differences. Additionally, when using NIR, physical attributes of the sample can affect the spectrum and interfere with the identification. Variability in the optics and other components of NIR instruments can result in spectral differences of the same order of magnitude as the compounds being tested. Transferring an NIR method from one instrument to another may require a multitude of reference spectra and/or tuning of method parameters. Methods of quantifying spectral differences

The most common approach to spectral comparison is to calculate the wavelength correlation. The resulting correlation coefficient equals –1 when the spectra are in perfect correspondence and 0 when they are orthogonal. The correlation coefficient provides some indication of the similarity between two spectra but is not particularly sensitive to discrepancies between spectra, and values other than 0 or 1 have no direct interpretation. Despite these deficiencies, regulatory guidance states, “Unless otherwise justified, a [correlation] threshold below 0.95 is not acceptable …”3. An example of how using a correlation threshold to compare spectra can yield erroneous results is shown in Figure 1. A Raman reference spectrum of pure glycerin is compared to the spectrum of an “unknown” substance composed of glycerin contaminated with 20% diethylene glycol (DEG). In spite of clear differences in the highlighted areas of the spectra, the correlation

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


MOVI NG TOWARD 100% RAW MATERIAL I NSPECT ION (C on t.)

1

2

3

1 2 3 4 51 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

4

5

6

7

8

9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

§ §

p<10–15

10–15≤p<10–4

10–4≤p<0.01

0.01≤p<0.1

p>0.1

§ Material 10 (fail, pass, fail); Material 11 (fail, pass, pass); all other categorisation (pass/fail) same across all three units Figure 2. p-values for each sample-method measured across all three test devices.

coefficient at 0.96, would identify the unknown as glycerin if a threshold of 0.95 were used. The Raman units used in this study employ an alternative approach to wavelength correlation, evaluating whether the measured spectrum lies within the specified multivariate domain of the reference spectrum (or spectra). The multivariate domain is defined by the uncertainty characteristics of each measurement, including exposure settings, instrument and environmental properties (eg. temperature, dark current, ambient light) and the optical properties of the sample itself. Rather than comparing the bulk spectra, this approach looks for spectral features that contradict the reference spectrum given the uncertainties of the measurement.

Like most statistical tests, the analysis is distilled into a p-value, which in this case is the probability that the observed differences between the sample and reference spectra arose simply by chance. High p-values signify a high probability that spectral differences arise only from the uncertainty of measurement, meaning that the measured spectrum is consistent with the reference. In such cases the instrument returns a “PASS” result. Low p-values (0.05 is the PASS/FAIL threshold for the device) indicate a low probability that discrepancies between spectra arise solely from measurement uncertainty, meaning that the test sample is spectrally and chemically different from the reference. In Figure 1, the p-value is 3.2 x10–3, which results in the instrument returning a “FAIL” result.

european INDUSTRIAL PHARMACY • Issue 7 October 2010

Experimental design

Six handheld Raman spectrometers were used in this work. Three reference devices were used to acquire spectra from 32 common pharmaceutical raw materials to evaluate the applicability of the technology. For each of the 32 raw materials, a single reference spectrum was acquired by one of the reference devices. The spectra were then consolidated upon a single master unit for method development. Using a web-based software utility, a method for each material was generated. A method is a statistical comparison of a known reference spectrum versus a sample spectrum to verify the identity of the incoming material. The final method library was then cloned to the two remaining reference devices.

13


MOVI NG TOWARD 100% RAW MATERIAL I NSPECT ION (C on t.) Samples of approximately 2g of each test material were sealed in 2ml thick polyethylene bags in an effort to emulate expected-use scenarios. Three measurements of each sample were made, one with each of the test devices. To thoroughly evaluate the specificity of the Raman spectrometers, each sample spectrum from each of the three test devices was evaluated against the entire method library of 32 raw materials. For example, the cellulose sample was evaluated against the cellulose method and against the methods for all other raw materials. Using the probability approach described previously, each of the three test devices calculated a unique p-value for all of the 32 sample-method pairs. Results and discussion

During the collection of reference spectra, it was determined that colloidal silica, talc, sodium carboxymethyl cellulose, and hydroxypropylmethyl cellulose did not produce an adequate signal to acquire spectra in a practical period of time for handheld deployment. The remaining 28 materials and their average measurement times are listed in Table 1. The variations in measurement time are functions of characteristics of the material (Raman cross section, etc.) and range from 1 second to more than 6 min, with the average being less than 1 min. As indicated above, a p-value for each sample-method pair was generated for measurements across all three test devices. The p-values were averaged for presentation purposes. Figure 2 shows the pvalues for each averaged pair, ranging from p<10–15 to p>0.1. The default threshold for “PASS ” is p≥0.05. The values along the diagonal represent cases where the sample was tested against its own corresponding method, which should produce a “PASS ” result. All other values arise from the sample

14

being tested against one of the other raw material methods, which should produce a “FAIL" result. With the exception of ethyl cellulose and hydroxypropyl cellulose (items 10 and 11 in Table 1), the p-values along the diagonal are all greater than 0.1, indicating these materials are consistent with the method reference spectrum. For ethyl cellulose and hydroxypropyl cellulose, p-values were between 0.01 and 0.1, which are very close to the default threshold of 0.05. As a result, the three test devices returned different PASS-FAIL results for these materials. Further inspection of the spectral data revealed subtle features in the unknown samples that were not found in the reference materials. Examination of a polyethylene bag found bands corresponding to the extra peaks in the unknown spectra. This suggests the weak Raman signals and long measurement times for these cellulose materials created subtle interference from the polyethylene bags. Examination of the off-diagonal elements confirms the excellent selectivity of the technology as evidenced by p<10–15 for the overwhelming majority of unknown-methods pairs. The only materials lacking acceptable selectivity are the alkali metal stearates. Both calcium and magnesium stearate are readily differentiated from stearic acid (p<0.01), but they cannot be differentiated from each other. While smaller molecules differing only in their cation can be easily differentiated with the handheld Raman system (eg. bicarbonate and sulfate), the large stearate molecule produces the majority of the Raman signal, which minimizes spectral differences caused by the cations. In this case, Raman spectroscopy would verify that the incoming material was stearate, and secondary testing would determine the cation.

Conclusion

Handheld Raman spectroscopy is an excellent alternative to traditional incoming raw material verification methods. The excellent specificity of Raman spectroscopy, coupled with intelligent on-board algorithms, reduces the time and effort to develop and validate methods. Furthermore, methods loaded onto different Raman systems produce consistent data and material verification without loading additional spectra or performing other customization. In addition to their analytical characteristics, today’s Raman solutions are environmentally robust and can be used by nontechnical personnel. This is in contrast to Raman instruments of the past, which were bulky, slow, expensive, and delicate. Based on this study of common pharmaceutical materials, the handheld Raman spectrometer offers an attractive option for achieving 100% inspection of most raw materials used by pharmaceutical manufacturing facilities. References 1. Compton DAC, Compton SV. “Examination of packaged consumer goods by using F-T Raman spectrometry”, Applied Spec., 1991; 45(10): 1587–1589. 2. Skoulika SG, Geurgio CA. “Rapid noninvasive quantitative determination of Acyclovir in pharmaceutical solid dosage forms through their poly(vinyl chloride) blister packages by solid-state fourier transform Raman spectroscopy”, Applied Spec., 2003; 57(4): 407–412. 3. European Medicines Agency (EMEA), Note for guidance on the use of near infrared spectroscopy by the pharmaceutical industry and the data requirements for new submissions and variations (London, UK, 2003).

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


THE QPPV – CEMENTING THE PHARMACIST’S ROLE IN EUROPE by Derek Woodcock

I

n the June 2010 issue of European Industrial Pharmacy, Jane Nicholson stated in the editorial comment “…The mantra of EIPG is always focussed on ensuring that pharmacists continue to play a pivotal role in the European Pharmaceutical Industry and as such we are keen champions of education, professional competencies and in particular the role of the Qualified Person”. Of course, this is a reference to The Qualified Person who is responsible for certifying the suitability for release of every batch. Perhaps now is the time to add the role and responsibilities of the Qualified Person in Pharmacovigilance (QPPV) to this mantra? Pharmacovigilance has grown significantly over recent years, both in terms of number of professionals employed and also in its importance to the success of an organisation. A number of factors have been driving this; growing numbers of adverse drug reaction reports, some high profile safety issues with widely used drugs and greater regulation and enforcement. Whilst the primary goal of post-marketing surveillance is to identify serious and unexpected risks (not detected during the clinical trial phase), and evaluate these signals against the reference safety information (e.g. SPC), more recent developments have raised the contributions a drug safety team can make.

DEREK WOODCOCK is a Pharmaceutical Consultant as well as a Qualified Person in Pharmacovigilance email: derek.woodcock@crossoakpharma.co.uk

A recent survey in US found that 54% of patients say they do not consistently take their prescription medicines as instructed even though 87% believe it is important to do so. Of patients not following their instructions, 37% gave concern about side-effects as their main reason1. Pharmaceutical companies are increasingly developing proactive risk minimisation strategies, with more sophisticated tools, to help overcome this

european INDUSTRIAL PHARMACY • Issue 7 October 2010

type of problem. Increasingly, good pharmacovigilance practice is being seen as the conduit for crucial data on a product’s use in medical practice. Companies are seeing that improving compliance and promoting more effective use of medicines can widen accessibility (good for marketing) and also reduce risk of costly liability litigation. This means that pharmacovigilance professionals are now also helping guide future drug development and provide key contributions to new marketing authorisation applications – and so, if harnessed properly, good PV should be seen as being an asset rather than solely from the perspective of Regulatory Compliance. What are the responsibilities of QPPV?

Every Marketing Authorisation Holder (MAH) must have an effective pharmacovigilance system in place and have appointed a suitably qualified person to oversee this – the QPPV. He or she is responsible for: ♦ Establishing, maintaining and

overseeing the MAH’s entire PV system. ♦ Preparation and submission of

suspected serious adverse drug reaction reports (ADRs) and periodic safety update reports (PSURs). ♦ Acting as a single contact point for the

Competent Authorities on a 24-hour basis. ♦ Having an overview of the safety

profiles and any emerging safety concerns in relation to all of the products of the MAH. Depending on the number of Marketing Authorisations, the product portfolio and the size and nature of the organisation, the execution of these responsibilities can vary greatly between companies. The QPPV can delegate specific tasks to others – but only under supervision. Every QPPV must have access to a medic (if not themselves medically qualified). It is almost a certainty that the MHRA’s PV inspectors will pay you a visit – inspections are planned according to a formal risk assessment which takes into account the factors mentioned above as well as results from previous inspections and evidence of

15


T HE QPPV – C EM ENT ING T HE PHARMACIST ’S ROLE I N EUROPE ( Cont .) non-compliance (eg. late reports being submitted to them). Putting a company’s pharmacovigilance system into practice requires a systematic, practical, logical and pragmatic approach: ♦ How are ADRs captured by the

company? ♦ How is safety information

exchanged between departments, affiliates, co-marketing partners and distributors? ♦ How are ADRs evaluated, data-

based and aggregate data reports produced? ♦ How is the published literature

searched for safety information? ♦ How is use data collected (eg.

paediatric use, off-label use, abuse/misuse, overdose, population exposure, etc.)? ♦ How effective is the Risk

Management strategy? ♦ How is compliance monitored

(eg. in relation to the quality, completeness and timeliness for submission of reports)? ♦ How is the system quality-assured

(eg. through audits and training)? ♦ Is there adequate back-up and

disaster-recovery in place? The QPPV ensures the system will detect, evaluate and report any possible safety signals and must be in a position of sufficient authority to instigate a change in the labelling that will promote its safer use (or possibly other urgent safety actions or regulatory activity – including a possible product withdrawal). Such responsibility can produce considerable pressure – especially when one considers today’s transparency with the Competent Authorities. The QPPV is open to personal prosecution in respect of the numerous EU and UK Pharmacovigilance Offences, so this may not be regarded as a position for the faint-hearted.

16

Proposal for a QPPV register

effective arrangement for a company.

It is widely recognised and well accepted that to become a QP for batch release, specialised training and experience is necessary. There is no equivalent formal system or recognition for a QPPV and yet the scale of responsibilities is comparable. The expectation is that the QPPV should have an in-depth knowledge of applicable PV legislation gained through several years’ experience and have a relevant biological sciences, pharmacy or medical degree. Some Member States have produced “clarifying” guidelines, for example in Belgium, the QPPV must submit a copy of his/her diploma “…either of pharmacist or of master of pharmaceutical sciences, either of physician or of master of medicine…or the persons who are legally exempted from this” [sic], as part of a formal recognition. Additionally, there are still National regulations that overlap with the responsibilities of the QPPV, such as the Stufenplanbeauftragter in Germany (who must possess a degree in medicine, human biology, veterinary medicine or pharmacy) and the Pharmacien Responsible (who must be a pharmacist) in France. In such cases, a “doublingup” of local and EU responsibilities for one person may be the most

In the absence of a formal qualification and register, it is the responsibility of the Marketing Authorisation Holder to satisfy itself that the person named as QPPV is suitable, and then hope that the relevant inspectors of the Competent Authorities will be similarly satisfied when they carry out their inspection. The only absolute requirement is that the person must be an EU resident. Pharmacists have all the skills which are pre-requisites for an effective QPPV, and should play a leading role in championing levels of education, professional competencies and formal recognition of the role and its responsibilities. Qualifications of QPPVs

A search for QPPVs (and deputies) and their qualifications was conducted through web-based professional forums (see Table). The results showed that about half of the QPPVs are medics. Just over a quarter are pharmacists, with the highest proportions in Poland (63%) and France (43%). Numerically, pharmacists were least well represented in Germany; of 13 QPPVs found only one is a pharmacist.

Table. Qualifications of QPPVs. First qualification

Number (%) All

UK

Country with highest

Country with lowest

Medical degree

55 (50)

18 (42)

Germany 10 (77)

Italy 2 (25)

Pharmacy degree

28 (25)

6 (14)

Poland 5 (63)

Germany 1 (8)

Chemistry or biological science

24 (22)

17 (40)

UK 17 (40)

France, Poland, Denmark 0 (0)

3(3)

2 (5)

Nursing/vet

sample too small

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


T HE QPPV – C EM ENT ING T HE PHARMACIST ’S ROLE I N EUROPE ( Cont .) Although this is a limited survey and there may be other regional factors (e.g. distribution pattern of companies by size, participation in professional web forums), clearly there is an opportunity to enhance the position of pharmacists engaged in drug safety throughout Europe. Most member states, including the UK, take a pragmatic approach – “any person who is capable of competently performing the specified duties would meet the requirement”, but there are others, as previously mentioned, where a

more formal approval is required. The consequence is that different member states may have different views on the suitability of an individual put forward as a QPPV. The opportunity exists for a more formalised programme, as applies to the QP for manufacturing and quality issues, which would ensure high and consistent application of standards. Bodies representing the professional bodies of pharmacovigilance professionals, including EIPG, may have a role to play in this.

References 1. National telephone poll was conducted October 22-25, 2009 by Opinion Research Corp. on behalf of Prescription Solutions and NCPIE. http://news.moneycentral.msn.com/ticker/a rticle.aspx?Feed=BW&Date=20091112&ID= 10694915&Symbol=UNH

Further reading

Good Pharmacovigilance Practice Guide: Compiled by the Medicines and Healthcare Products Regulatory Agency (MHRA). Published by The Pharmaceutical Press. VOLUME 9A: The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. Published by the European Commission; Enterprise and Industry.

Clean Air and Containment Review This new quarterly journal under the editorship of John Neiger, is aimed at users, specifiers, designers, manufacturers, installers and testers of contamination control facilities and of clean air and containment equipment. It contains articles of topical, technical and historical interest, updates on standards and regulations, news, views and information on relevant events, especially training.

Visit our website to subscribe now – Issue 4 due out in October 2010

www.cleanairandcontainment.com european INDUSTRIAL PHARMACY • Issue 7 October 2010

17


DIAGNOSTICS AND THEIR ROLE IN PERSONALISED MEDICINE by Loïc Kubitza

C

ollaborations between diagnostic and pharmaceutical industries are expected to grow, driven by the development of personalised medicine. This trend is evidenced by Pfizer’s August 2009 collaboration with Abbott’s diagnostics division to develop a test to screen non-small cell lung cancer tumours for gene rearrangements. Pfizer has developed a novel investigational agent, PF-02341066, that selectively targets cancer-causing genes implicated in the progress of many cancers. The test will be used for patient selection for future clinical trials of the agent. The future of pharma is inextricably linked with smart diagnostics The molecular level of personalised medicine

Personalised medicine – or the use of information about a person’s genes, proteins and environment to prevent, diagnose and treat disease – has been much talked about in recent years. And some observers are wondering what the excitement is all about. In the words of Roche’s CEO, Severin Schwann: “Personalised healthcare is nothing new. Doctors have always tried to fit the therapy to the patient if possible. But what’s happened more recently is that we’ve begun to go a level deeper. We’re now exploring the biology of disease and treatment at the molecular level.”

LOIC KUBITZA is a life sciences expert at PricewaterhouseCoopers, Luxembourg and can be contacted at: loic.x.kubitza@lu.pwc.com

18

Molecular medicine does not per se define personalised medicine but molecular tools are important as they should enable greater relevance in the information provided by diagnostic tests. Personalised medicine as a spectrum

As personalised medicine means different

♦ Early diagnostics: diagnostic products

permitting the detection of a disease at very early stages of its development thus giving more treatment options (eg. early lung cancer detection allowing surgery). ♦ Prognostics: diagnostics that provide

a prediction or estimate the risk of developing a particular condition based on – phenotypic (e.g. transcriptomic, proteomic or metabolomic) parameters; or – genomic (e.g. hereditary or gene based) characteristics.

things to different people, additional complementary ways of characterising diagnostics may further help distinguish different shades of grey in the personalised medicine spectrum. In the strictest sense, personalised medicine diagnostics may consist exclusively of companion diagnostics, which are by definition geared towards supporting a therapy decision for a particular drug, patient by patient. At the more permissive end of the spectrum, personalised medicine tests may include also early diagnostics, prognostics and possibly all other types of diagnostics. You may indeed argue that if a diagnostic were not designed to inform treatment decisions for individual patients – one way of defining a personalised medicine diagnostic – it would not have much sense. Companion diagnostics and the future of pharma

The concept of companion diagnostic (CD), and its role in the future of healthcare, was also mentioned in Pharma 2020: Marketing the future, a report published by PricewaterhouseCoopers (PwC) in February 2009. This report discusses the key forces reshaping the pharmaceutical marketplace and the changes required to create a sales and marketing model that is better adapted to the stakeholder priorities expected for 2020. Of particular relevance to the diagnostics industry is the move from mass market therapies to

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


D I A G N O S T I C S A N D T H E I R R O L E I N P ER S O NA L I S E D M E D I C I N E ( C o n t . ) specialist therapies, which is highlighted in the report. Many specialist therapies are very costly (eg. almost $300,000 annually for Fabry’s or Gaucher’s disease) and are used to treat smaller target patient populations with specific disease subtypes. In this context, there is thus a growing imperative, both clinical and budgetary, to accompany therapies with diagnostic tools of increasing sensitivity and specificity to better enable the identification of those patients in the relevant disease subtype and most likely to benefit from the therapy. The marketing model foreseen for most specialist therapies in 2020 will include a companion diagnostic as a key component. Highlighting a movement towards personalised medicine is not straightforward as a concept as it is so widely open to interpretation. It is however important that we try as the response rates on drugs are still unsatisfactory, varying widely from 20% to 75%. Companion diagnostics partnerships with the pharma industry

If diagnostics are so important to improving the value of therapeutics to patients, we should expect the

pharmaceutical industry to be entering significant CD partnerships with the IVD industry. However, this is not yet the case and diagnostics collaborations with pharma have yet to become an established practice Only seven partnerships were announced in 2008 between pharmaceutical and diagnostic companies to develop a companion diagnostic. This represents a significant drop from the 14 collaborations announced in 2007 but there is no clear up or downward trend over the period 2004-2008, with annual deal numbers varying between 6 and 14 throughout. Companion diagnostics partnerships with pharma have yet to become an established industry practice (Figure 1). Most 2008 deals focused on cancer and involved a big pharma partner

Three key themes were reflected in the partnerships announced in 2008: ♦ Cancer attracted strong interest

as the disease area of choice for the development of companion diagnostics. In 2008, all deals focused on diagnostics for cancer. ♦ Big pharma was dominant as

pharmaceutical partner for collaborations with the

15

Number of deals

12

14 12

diagnostics industry. In 2008, all pharmaceutical partners were top 20 companies by sales of prescription pharmaceuticals (2008 ranking from IMS Health). OSI Pharmaceuticals was the only exception but big pharma company Roche was a co-partner in OSI’s collaboration with Abbott’s diagnostics division to develop a pharmacogenomic test to identify patients most likely to respond to cancer drug Tarceva (erlotinib) for non-small cell lung cancer. In this study, we counted any deals involving Genentech as a big pharma deal due to Roche’s majority ownership in Genentech at the time of the deal and which became a full ownership during 2009. ♦ Niche specialists dominated as in

vitro diagnostics partner for collaborations with the pharmaceutical industry. In 2008, Abbott was the only IVD major involved in collaborations with third-party pharmaceutical companies for companion diagnostics. None of the other diagnostics partners announcing deals in 2008 – Aureon, Celera, Dako and DxS – were ranked among the ten largest in vitro diagnostics companies. Similar themes emerge when we analyse the pharmaceutical and diagnostics partners involved in companion diagnostics licensing deals over 2004-2008 in more detail. The pharma partners

9 7 6

6

6

2005

2006

3 0 2004

2007

Figure 1. Companion diagnostics partnerships with pharma in 2004-2008. Source: PricewaterhouseCoopers analysis using Windhover data

european INDUSTRIAL PHARMACY • Issue 7 October 2010

2008

Roche, Pfizer and Merck were the most active pharma partners over 2004-2008. Roche’s pharmaceutical division, including Genentech, stands out as the most active thirdparty pharmaceutical licensing partner for the diagnostics sector over 2004-2008 with ten announced deals – an average of two deals per annum. Pfizer, Merck and AstraZeneca followed Roche with 6,

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D I A G N O S T I C S A N D T H E I R R O L E I N P ER S O NA L I S E D M E D I C I N E ( C o n t . )

10

10 9

6

6

5

4

3

3

Ipsen

3

3

Schering-Plough

3

Lilly

3

BMS

2

Biogen Idec

3

Amgen

Number of deals

8

Single Deal doers

AstraZeneca

Merck

Pfizer

Roche

0

Figure 2. Companion diagnostics partnerships by pharma partner in 2004-2008. Source: PricewaterhouseCoopers analysis using Windhover data

5 and 3 diagnostics partnerships respectively over the same period (Figure 2). The position of Roche as the leading pharmaceutical partner for collaborations with diagnostics companies is remarkable if we consider that none of the other pharmaceutical companies with a major IVD affiliate – Abbott, Bayer and J&J – announced more than one partnership with a third party diagnostics company over 20042008. However, the full picture about these diagnostics majors is not available as there is little visibility about any intra-group diagnostics collaborations with their respective pharmaceutical divisions. The diagnostics partners

The most active diagnostics partners for deals with pharma were all niche players. Serial deal making for companion diagnostics was limited amongst diagnostics companies. Only four diagnostics companies announced at least two partnerships with pharmaceutical companies over 2004-2008 and they were all

20

niche diagnostic specialists: Celera, Dako, Epigenomics and Perlegen. Dako is the largest among these diagnostic companies with $322 million of net sales reported in 2008. Three observations follow from this analysis and our discussions with selected industry players: 1. The pharmaceutical industry is not currently a priority market for large diagnostics companies. The development risk and time to market associated with drug candidates make the development of a companion diagnostic significantly less attractive to major diagnostics manufacturers than the revenues currently available from its more traditional target market of clinical laboratories. 2. The limited deal flow by company suggests that even for niche diagnostic companies, the prospective economics of developing a companion diagnostic may not always be attractive. Key factors that impact the net present value expected

from companion diagnostics projects include the strength of the intellectual property, the pricing and reimbursement coverage and the extent of testing required by regulators to obtain key marketing authorisations. Achieving a positive net present value from a companion diagnostics development project will be a challenge unless some of these factors become more favourable. For those diagnostic companies that do target the pharmaceutical industry, some are developing companion diagnostics without entering a partnership with a pharmaceutical company. When diagnostics companies have the required funding and access to sufficient, high-quality biological samples to conduct such development work without partnering with pharma, this approach can help keep more of the value in-house. In due course, however, it can be helpful to have some form of public support from the targeted drug’s marketer to underline the validity of the test as

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


D I A G N O S T I C S A N D T H E I R R O L E I N P ER S O NA L I S E D M E D I C I N E ( C o n t . ) a companion diagnostic for the drug. Biomarker testing requirements

Drug approval agencies, including the FDA and EMA, are encouraging greater use of biomarkers and diagnostics in drug development and prescribing decisions, thus promoting the concept of companion diagnostics for drugs. The FDA recently started reporting a list of genomic biomarkers that it considers valid to guide the appropriate clinical use of approved drugs. The list is being updated on a quarterly basis and counted 32 valid genomic biomarkers in mid September 2009. Most drug labels in the list provide pharmacogenomic information with no immediate recommendation for genetic testing. However, testing is “recommended” or “required” in a few cases. At 20 March 2009, only four biomarkers were “required” to be tested for – three for cancer. Thus we are still at the start of the

process if we consider that only four biomarkers are “required” to be tested for. However, the FDA was prompted to publish its list following a marked increase over the last decade of approved drugs labels containing pharmacogenomic information. The FDA estimates that 10% of approved drug labels now contain pharmacogenomic information and this is expected to continue increasing. The EMA’s communication on the requirement for biomarker testing is less transparent than the FDA’s but its initiatives should not be overlooked. For example, the European agency played a key role in requiring biomarker testing for Amgen’s Vectibix, following the FDA’s accelerated approval without specific testing requirements. The EMA also has a larger number of drugs for which biomarker testing is required – in mid 2009, we counted at least 11 drugs with the requirement. We expect greater harmonisation between different regulatory agencies to develop over time

through greater consultation but also following pressure from clinician communities as stakeholders in one country push to implement practices already included in drug labels in other countries. Moving towards personalised medicine

Increasingly, pharmaceutical companies will not move a drug candidate to the clinical development stage without a clear biomarker development program. These companies understand the contribution of biomarkers and diagnostics in improving the design and probability of success of clinical trials. In addition, pressure from healthcare payers is putting more emphasis on the availability of a companion biomarker test when deciding on a drug’s reimbursement. These factors will combine to accelerate the development of new diagnostics for personalised medicine. We anticipate that alliances and collaboration will be inevitable as the market need expands.

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21


REGULATORY REVIEW

Review of major developments in GMP in the EU and USA, June to August 2010

by Malcolm Holmes Introduction

The current review period has seen a number of changes in the regulation of medicines and regulatory guidance in both the USA and in the EU. The most significant of these are noted below. United States of America

The Drug Safety and Accountability Act of 2010 (S.3690) was introduced by Sen. Michael Bennet. The Act seeks to strengthen industry standards to ensure the quality and safety of drugs made for the US market, and to improve the US Food and Drug Administration’s (FDA) oversight abilities, such as the power to order a drug recall.

inspections in an effort to evaluate industry’s compliance and understanding of Part 11. FDA also intends to take appropriate action to enforce Part 11 requirements for issues raised during the inspections that do not fall under the enforcement discretion discussed in the Guidance. Europe

The European Commission has • Issued a further public consultation targeted on specific issues related to in vitro diagnostic medical devices. This is in the form of a questionnaire aimed at revision of Directive 98/79/EC. MHRA

The FDA has issued new and updated guidance covering the following topics:

• Created a specific area on its website dealing specifically with disputes over regulation of medicines and the Regulation of Medicines Review Panel which deals with such issues.

• Post-approval manufacturing changes reportable in annual reports. This is part of the FDA’s initiative to ensure that its CMC regulatory review should be based on an understanding of product risk and how best to manage such risks. • Guidance for Industry – label comprehension studies for nonprescription drug products. • Questions and Answers (Q&A) on cGMP Good Guidance Practices, Level 2 Guidance Holding and Distribution – Human Drug Recalls. • Draft recommendation for the revision of the permitted daily exposure for cumene according to the maintenance procedures for ICH Q3C impurities: residual solvents. FDA has announced

• That it will be conducting a series of

22

• Following 6 months experience with the new variations legislation, published details of experience to date and an audit of submissions made in June 2010. They have also updated the FAQs. International

New and updated regulatory guidance

• The latest in a series of FDA guidances addressing the risk of CJD and vCJD transmission by blood and blood products. The Guidance amends the 2002 guidance.

be removed from the MA by submission of a Type 1A Variation.

The MHRA has

• Provided a set of frequently asked questions (FAQ) relating to the EU GMP Guide Part I, Chapter 1 and Annex 20, in which the GMP expectations and requirements for integration and use of Quality Risk Management in pharmaceutical quality systems are defined. The purpose of the Q&A is to help industry understand how the expectations of EU GMP will be interpreted by MHRA inspectors. • Published a new enforcement strategy (Inspection, Enforcement and Standards Division). The strategy aligns UK Government better regulation initiatives, the Hampton review and the Regulators Compliance Code • Issued guidance for Marketing and Manufacturing Authorisation holders requiring that all named sites are fully maintained as approved suppliers and thus available for use. Redundant sites / suppliers should

EMA/US FDA

• Continue to seek potential candidate companies for a joint GMP pre-approval or re-inspection pilot programme for manufacturers of medicinal products. The objective is to see whether greater international collaboration can help to distribute inspection capacity allowing more manufacturing sites to be monitored and reducing unnecessary duplication. PIC/S

• International collaboration on the quality of APIs (European commission concept paper / PIC/S role). WHO

• World Health Organization (WHO) has issued as part of Technical Report Series, No. 957 significantly revised documents – Annex 3 good manufacturing practices for pharmaceutical products containing hazardous substances and Annex 5 Good Distribution Practices (GDP) for pharmaceutical products. ISPE

• Has announced the release of the Baseline Guide® Risk-based Manufacture of Pharmaceutical Products (Risk-MaPP). For further information on these and other topics we suggest you refer to current and past editions of “gmp-review News” published by Euromed Communications. (www.euromedcommunications.com)

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


NEWS FROM THE EIPG Strategy Meeting

As envisaged during the General Assembly in Milan, a Strategy Meeting will be held on 5th November in Paris which will map our aims and activities for the next 5 years. What does it mean when we say “we are the EIPG”? The simple answer is the membership! As a member, please tell us what you want from EIPG. Anyone wishing to propose subjects for debate, please e-mail your Association’s delegate or one of our Bureau members via the website. Professional Qualifications Directive

EIPG and the European Associations of community and hospital pharmacists are waiting to comment on the results of a questionnaire from the EC. This questionnaire, evaluating the Professional Qualifications Directive, has been sent to all Competent Authorities in pharmacy and the responses are being coordinated by the Ordre des Pharmaciens in Paris. Pharmaceutical Education PHARMINE Project

Outcomes for the education and training of pharmacists have been divided into “Foundation level” (Day 1 of registration as a pharmacist) and “Specialisation and advanced level practice”. For the “Foundation level” testing for validity is the next step in establishing recommendations for a core scientific set of competencies to equip a newly qualified pharmacist for his/her early career years. The working group responsible for the review of the undergraduate course will test these competencies via the pharmacy students of EPSA and the young pharmacist members of the three professional groups.

For the advanced level framework, the “expert professional practice” will be sector specific. However, the working group has reasoned that “building working relationships, evaluation and innovation, management, leadership and continuing education, training and development” are common to all sectors of pharmacy practice. However, competencies for the various disciplines in which industrial pharmacists work once they specialize in an area of industry are under review. Supply Chain Security

The European Commission’s progress report on the prevention of counterfeits into the legal supply chain which was discussed during our EIPG General Assembly was officially released in May. However, the date for discussion in the European parliament has been delayed and is currently not expected until this December. European Medicines Agency

Gino Martini and John Jolley represented EIPG at the Manufacturing and Quality Compliance meeting with interested parties on 14th September at the EMA in London. The topics discussed are the subject of the Editorial in this issue of the Journal and progress reports will be provided to Member Association contacts. EuroPharm Forum

The chairman of Pharmadanmark, Antje Marquardsen, will represent EIPG at the General Assembly of the EuroPharm Forum on 2nd October. Their General Assembly in Copenhagen is organised to come after the Joint WHO and EuroPharm Forum Conference on the role of pharmacists in individual patient care.

european INDUSTRIAL PHARMACY • Issue 7 October 2010

Annual Symposium of the Pharmaceutical Group of European Union (PGEUGPUE), Bruges 14/06/2010

Roland Schots from our Belgian member association represented EIPG at a Symposium in Bruges. His summary report is shown below: The key question arising from this community pharmacists’ Symposium was whether community pharmacists will still be needed within the next 20 years? If yes, what will be their role and tasks in the healthcare system? The traditional role of the community pharmacist to dispense medicinal products is declining due to the cost limiting policies of all EU countries. However, the role of the community pharmacist is changing from a dispensing function to that of a public health adviser. The historical role of "responsibility for the quality of the dispensed medicine" is no longer realistic and today this role has been taken-over by the Qualified Persons of pharmaceutical companies. In all countries, community pharmacists are acting as healthcare advisers (pharmaceutical care) for patients and, particularly, for patients with “at risk” pathologies such as diabetes, hypertension and blood lipid deviations. In the future, all countries will need to devise multidisciplinary protocols, supported by appropriate financial incentives. The meeting concluded that despite major changes in pharmaceutical practice, the pharmacist will remain an essential actor in the healthcare system. Jane Nicholson, Executive Director EIPG

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PHARMACEUTICAL FORUM observed impurities can be shown to have been present all the time – then the combination of new data and old data can be used to support a reasonable retest interval. This might or might not be three years of course…

The following questions and responses are a selection of those published on an open online discussion group www.pharmweb.net/gmp.html. The Forum serves as a means of exchanging views on international regulations affecting the pharmaceutical industry. Readers are invited to contribute to the Forum.

Response 5 – Monographs are specific to the processes used, both for the drug substance and the drug product. For the drug substance, the USP monograph will explain how to compare it to the USP Reference Standard, called USP RS. You have to decide for yourself if that is appropriate. Similarly, the USP Drug product monograph may describe a 20mg tablet, but you may want to register a cream. That’s an extreme example, but the same considerations apply even if you want to register a 15mg tablet.

Retest period and stability testing

I have two cycles of stability studies for a Q certain active substance. The second cycle was launched when the PhEur monograph was changed and this change was major as the limit for impurity X and the method of examination have been changed. The retest period was established as 3 years for the first cycle of studies (before the monograph had been changed) but the new cycle does not cover such time and the retest period is shorter. The problem is that our client wants us to keep the 3-year retest period – how should I manage this problem?

Laboratory log books and notebooks

I have always been under the impression Q that all notebooks need to be hard-backed, bound and page-numbered. Is this still a correct assumption and if it is, is there a specific regulatory requirement or is it simply an accepted solution?

Response 1 – I suggest you consider registering this

material as two different active substances according to the registration specifications: one that conforms to the old specification and the other that conforms to the new specification. Selecting according to a specification is common practice for particle size distributions, for example. Your marketing team may like this because of the potential pricing flexibility, even though your regulatory team may not like the extra work. Response 2 – Not entering into the

technical/scientific details, I would say that a retest period of three years is quite a long period. How long is the material kept in a facility warehouse before it is used? Will a company pay for keeping an active two years in stock?

Response 3 – If the old stability data shows the impurity X below the new EP monograph limit and the method of analysis is a validated and accepted one, a retest date of three years may be claimed with the earlier data supporting it and a commitment to provide the ongoing data every year.

I assume the impurity X was being monitored in the earlier cycle and maybe the earlier method also quantifies it.

Response 4 – A combination of accelerated nad real time studies can be used – see the ICH stability guideline and the relevant CHMP guidelines. Combined with the original data – and assuming that any newly

24

Response 1 – I share your opinion that a logbook should ideally be solid as a book. However, I have no knowledge of a guidance that describes such a model of log.

What I know (but I deplore it) is that a number of companies use “flying sheets” that, when filled in, are collected in a binder (sometimes even bound). These companies call these sytems “logbooks” too. And I know from my experience that a number of inspectors and a number of auditors do accept this solution worldwide. In my personal practice as an auditor, I only DEMAND bound logbooks for the record of the sterility testing results. I ACCEPT “flying sheets” for most other situations althouguh I am not really supporting them.

Response 2 – We recently had an audit and the auditor recommended we used controlled loose-leaf sheets in place of our current bound notebooks, perhaps not for everything, but to improve efficiency and reduce potential non-compliance for tests that are performed many times, by removing the need to continuously write down headers and raw data in the lab books. this is something we have used in the past and we moved to notebooks as that seemed to be the industry standard then, but now it seems that controlled loose-leafs are much more acceptable.

Response 3 – In my experience, auditors accept flying logs provided the control is through QA. Some QC labs also

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


P H AR M A C E U T I C A L F O R U M ( C o n t . ) have flying sheets to record the analysis and analytical results and it is accepted by regulatory auditors. My personal view is that bounded books should be used.

Response 4 – I have just done a search through various appropriate guidances and it does seem that both are now acceptable – summarised maybe by this APIC statement: “The QC laboratory should use laboratory notebooks (bound notebooks prenumbered) or an equivalent system (one option is the use of loose sheets pre-numbered, the printing has to be controlled and also the storage as control records) to record the raw data at the time they are produced”.

In the Eudralex and PIC/S the statement is: “Testing procedures and records (including analytical worksheets and/or laboratory notebooks).” So, yes it seems that I am old-fashioned, although I feel that issuing dedicated notebooks is an easier compliance and control than pre-pnumbered controlled loose sheets including storage and retrieval. I would add that there is a PIC/S Inspection Aide Memoire which states: “Recorded/attached directly into relevant laboratory notebooks data (no scrap or loose paper) which is a bit the other way. Also I checked through the various 483s from the FDA and certainly it would appear that in those reports the notebook is still commonly found (and not infrequently mentioned). Diisopropyl ether

Q

What limit should we define for Di-isopropyl ether in one of the API we intend to manufacture, as the same solvent has insufficient toxicity data and no standard ppm levels is mentioned in ICH guidelines?

Response 1 – As per the ICH Q3C(R4) page 1 the substance can be considered as an impurity: “Supporting safety data in a marketing application for a new drug product containing a new solvent may be based on concepts in this guideline or the concept of qualification of impurities as expressed in the guideline for drug substance (Q3A, Impurities in New Drug Substances) or drug product (Q3B, Impurities in New Drug Products), or all three guidelines.”

I found the following toxicology data to be helpful if you want to calculate the PDE (Permissible Daily Exposure) and the allowed specification: www.epa.gov/IRIS/pdfs/Litsearch_Diisopropyl-ether.pdf. The published information is based on Pharmaeuropa, Vol 9, No 1, Supplement, April 1997 so you have to calculate the limit based on the current toxicology data available. Response 2 – We’ve had the same problem. For

the assessment of safety and toxicity on the basis of available knowledge or appropriate tests. We’ve gathered some information from the literature and used a method for establishing the exposure limits described in PhEur (chapter 5.4). Some widely used methods for establishing exposure limits are also mentioned in this chapter if you assess the factors and NOEL or LOEL you will also calculate the PDE value. You can always tighten the limit. In my example the calculated PDE was about 300ppm but we performed tests on several batches of API and the limit was tightened to 170ppm. Change in granulation process

If we need to change the approved wet Q granulation process, what kind of submission do we need to do to satisfy the US FDA? We wish to granulate our API with some excipients and granulate some other excipients separately. Then mix the granules and compress the tablets. We are not changing any excipient nor their quantity – we are just changing the order and style of granulation to avoid the formation of certian degradants. SUPAC and Guidance for changes in the approved NDA/ANDA do not address this change.

Response 1 – Considering there are no guidelines, you will have to go by following worst case scenario.

1. Firstly is the end product quality the same as the ealier approved product. 2 Assuming you have validated the new process the new product formed has to match the earlier product. 3. Since some degradation was taking place in the earlier (this must have been noted in the dossier), by the new process there is a better quality and technically the stability of this would entail detailed studies again. Looks like you will have to work again and prove that the new process and product is safe. Response 2 – It seems that your change in process, that is, the sequence of granulation, should be regarded as a Level 3 change in manufacturing. Though there is no change in the excipient, the change in style of granulation may have an effect on the product quality and safety. This kind of change should be pre-approved by US FDA. Readers are invited to send their Q&As to www.pharmweb.net/gmp.html

these kinds of solvents it is recommended to perform

european INDUSTRIAL PHARMACY • Issue 7 October 2010

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job vacancies sponsored by:

Contracts Manager – CRO internazionale La posizione menzionata e presso una CRO internazionale situata a Milano. Location: Milan, Italy Salary: €30000–€45000 Reference: JL/6255/EIPG Contact John Lavarino: +44 207 940 2106, ricerca.clinica@nonstop-pharma.it

Senior Account Manager: A Medical Communication Giant A global Medical Communication Company that keeps the global healthcare community updated with the ongoing pharmaceutical development, as a result of the expanding business is currently looking for a Senior Account Manager. Location: Netherlands Salary: A highly competitive base salary + bonus Reference: PD/47140/EIPG Contact Paurush Dhiman: +44 20 7940 2105, p.dhiman@nonstop-pharma.com

Senior QA PM API’s Switzerland, German Speaker A cash rich Biopharma have an interesting opportunity for a Senior QA Project Manager experienced in API manufacturing. Location: Switzerland Salary: 140,000CHF Reference: SK/46607/EIPG Contact Stephen Kenny: +44 20 7940 2105, s.kenny@nonstop-pharma.com

QA Compliance Manager, Leading Biopharma Experienced QA Manager required to manage a Quality compliance team. Location: Switzerland Salary: 130,000 CHF Reference: SK/46484/EIPG Contact Stephen Kenny, +44 20 7940 2105, s.kenny@nonstop-pharma.com

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Formulations Sales Manager: An Impressive Generic Pharma A generics pharmaceutical based in Netherlands, as a result of the ongoing business expansion, is now looking for a Sales Manager who would be in charge of all the commercial operations in Netherlands. Location: Netherlands Salary: Very competitive base salary + highly motivating bonus structure. Reference: PD/46561/EIPG Contact Paurush Dhiman: +44 20 7940 2105, p.dhiman@nonstop-pharma.com

Ingegnere Meccanico – Compagnia Farmaceutica Una compagnia farmaceutica internazionale ha contattato NonStop per una selezione molto importante. Questa compagnia e’ in cerca di un ingegnere meccanico che abbia un background nella manutenzione di stabilimenti di produzione. Location: Italy Salary: €45000–€60000 per annum car, relocation package Reference: JL/6245/EIPG Contact John Lavarino: +44 207 940 2106, ricerca.clinica@nonstop-pharma.it

Sei un Medico Junior con una specializzazione in oncologia? NonStop sta collaborando con una compagnia farmaceutica internazionale che ha un grande reparto di farmacologia che sta crescendo moltissimo. Location: Italy Reference: JL/ 6272/EIPG Salary: €35000–€55000 Contact John Lavarino: +44 207 940 2106, ricerca.clinica@nonstop-pharma.it

Senior CRA – Leading International CRO! An exciting opportunity has come up with one of the leading, international CRO with their offices in Germany. This role will ideally fit to an experienced CRA who is fluent in both German and English. Location: Germany Salary: up to €55,000 Reference: MS/ 47127/EIPG Contacting: Marketa Smelhausova, +44 207 940 2103, germany@nonstoppharma.com

PM Internazionale Gentili Signori, sono alla ricerca di un Brillante PM Internazionale che Regione Toscana Location: Italy Salary: €41000–€48000 Reference: NS/43724/EIPG Contact Sabrina Nifosi: +44 207 940 2105, s.nifosi@nonstop-recruitment.com

Ecotoxicologist – Germany, Netherlands or Cardiff Our client is amongst the fastest growing Chemical consultancy in Europe with 200 staff members recruited in just over a decade. Given a surge in demand for their services and strong brand image, joining this organisation is clearly a desirable career path. Location: Germany, Netherlands or Cardiff Reference: AK/45611/1/8/EIPG Salary: €55000– €70000 Contact Abid Kanji: +44 207 940 2108, a.kanji@nonstop-recruitment.com

Clinical Project Manager – Frankfurt An exciting opportunity has come up with one of the small sized CROs with their offices based in Frankfurt. They are looking for a German speaking clinical professional who will take on the post of Clinical Project Manager. You will be responsible for managing the clinical studies in Germany and in the future expand your responsibilities to other European countries too. Location: Germany Salary: Up to €70,000 Reference: MS/47340/EIPG Contact Marketa Smelhausova: +44 207 940 2103, germany@nonstoppharma.com

Senior CRA – Germany – 2-years contract! A challenging role has come up for a Senior CRA with one of the leading, international pharmaceutical company with their headquarters based in Germany. This is an English speaking role. Location: Germany Salary: up to €55,000 Reference: MS/44507/EIPG Contact Marketa Smelhausova: +44 207 940 2103, germany@nonstoppharma.com

eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


JOB VAC ANC IES (C ont.) Global QA Auditor, Blue Chip Pharma A top 10 Pharma have an opportunity for a Quality professional to take on a role as a Global GxP Auditor. Location: South East, UK Salary: £50,000 Reference: SK/47287/EIPG Contact Stephen Kenny: +44 20 7940 2105, s.kenny@nonstop-pharma.com

Human Health Safety Expert/ Toxicologist – BASEL Our client is a leading research organisation with an established history in offering high quality service and contribute in helping companies discover a solution to a certain medical need. Location: Switzerland Reference: AK/45945/7/EIPG Salary: €60000–€70000 Contact Abid Kanji: +44 207 940 2108, a.kanji@nonstop-recruitment.com

Klinikreferent – RheinlandPfalz /Nordrhein-Westfalen Our client is an international company specialising in developing and producing new diagnostic test procedures to improve the diagnosis, and the treatment of illnesses.unmet therapeutic areas. They are looking for experienced Sales Representatives to cover areas of Rheinland-Pfalz /Nordrhein-Westfalen. This challenging role requires willingness to travel and fluent knowledge of German language. Location: Germany Salary: Up to €60,000 + bonus Reference: MS/46042/EIPG Contact Marketa Smelhausova: +44 207 940 2103, germany@nonstop-pharma.com

Gastroenterology Translational Medicine Director An excellent opportunity to lead the Translational Medicine Department for the developments of Gastroenterology projects and initiating the Proof of Concept strategy and early Clinical Development Plans. Location: Switzerland Salary: €100000– €200000 per annum Reference: AL/47156/01/EIPG Contact Antony Lambrou: +44 207 940 2105, a.lambrou@nonstoppharma.com

Senior and Junior positions in QA Global activities and QA Belgian operations GlaxoSmithKline Biologicals is one of the world's leading vaccine producer and the fastest growing business within the GSK group today. Headquartered in Rixensart & Wavre, Belgium, GSK Biologicals employs approximately 9,000 people worldwide, including over 6,000 in Belgium. GSK Biologicals’ global production network is in the midst of becoming the largest in the entire vaccines industry. 13 sites on three continents manufacture, formulate, fill, pack, check and deliver over a billion doses of about 30 different vaccines. The Global Quality Department of GlaxoSmithKlineBiologicals is looking to fill several junior and senior positions in QA Global activities and QA Belgian operations. Candidates should have: 1. Experience in the pharmaceutical area (preferably in biotechnology) 2. Experience in one of the following areas • product/raw materials release – global staff & local operational positions; • deviation handling; • QA systems; • internal auditing; inspectors • QA co-ordinators/supervisors • validation managers Profile • pharmacist or scientific university degree • 3 to 15 years experience according to the position • experience in manufacturing and/or quality is a must • GMP background • quality mindset • experienced with Health Authorities inspections • team leader skills • investigation skills • capacity to take decisions • Lean Thinking • capacity to work in a changing environment At GSK we provide a supportive working environment, and a range of development challenges and opportunities. We also offer competitive benefits and compensation packages designed to attract and retain the very best. Feel free to apply for a role by visiting our website at

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european INDUSTRIAL PHARMACY • Issue 7 October 2010

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JOB VAC ANC IES (C ont.) sponsored by:

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Working for a global CRO you will audit study sites in Germany to ensure complete compliance with ICH-GCP requirements. Location: West Germany Salary: €60-70K Contact: CK Clinical – Jim Gleeson: +44 (0)1438 870027 jgleeson@ckclinical.co.uk

This role will be based at The Netherlands offices of a leading global pharmaceutical company. You will audit investigator sites and third parties around the world to ensure GCP compliance. Fluent English and the ability to travel extensively on an international basis is essential. Location: The Netherlands Salary: Up to €66K Contact: CK Clinical – Jim Gleeson: +44 (0)1438 870027 jgleeson@ckclinical.co.uk

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A leading Pharma has various opportunities for a SAS Programming professionals. Location: Switzerland Salary: €Negotiable Contact: CK Clinical – Priya Mukherjee: +44 (0) 1438 870028 / pmukherjee@ckclinical.co.uk

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A home-based role with a large, international CRO. You will oversee a number of study sites in the Stockholm region. The company is expanding it's Swedish operation, so there will be very good career development opportunities. Location: Sweden Salary: SK42K per month Contact: CK Clinical – Jim Gleeson: +44 (0)1438 870027 jgleeson@ckclinical.co.uk

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eur opean INDUSTRIAL PHARMACY • Issue 7 October 2010


DATES FOR YOUR DIARY

N OV E M B E R

D E C EM B E R

8-10 November 2010 – Köln, Germany Innovative pharma distribution 2011 www.pharma-iq.com/events

1-2 December 2010 – London, UK Cold chain challenges, risk management and lessons learned: case studies www.smi-online.co.uk

9 November 2010 – Zurich, Switzerland Drug & device combination products – finding the right regulatory strategy www.diaeurope.org 15-17 November 2010 – Berlin, Germany Pharma track & trace www.pharma-iq.com/events 17-19 November 2010 – London, UK Serialisation & traceability 2010 www.pharma-iq.com/events 22-24 November 2010 – Cambridge, UK Tabletting technology for the pharmaceutical industry www.rpsgb.org/events 25-26 November 2010 – London, UK Qualified Person forum 2010 www.qp-association.eu 29 November-1 December 2010 – Geneva, Switzerland World Orphan Drug Congress 2010 www.terrapinn.com 30 November-1 December 2010 – Manchester, UK Practical application of quality by design www.DBA-global.com

1-3 December 2010 – Nice, France 11th Conference on European electronic document management www.diahome.org 2 December 2010 – London, UK Characterisation of active product ingredients www.jpag.org 6-7 December 2010 – London, UK EMA Review of the year and outlook for 2011 www.topra.org 6-8 December 2010 – London, UK Developing IP strategies for crystalline forms www.pharma-iq.com/events 8-10 December 2010 – Edinburgh, Scotland Drug delivery to the lungs www.aerosol-soc.org.uk

JANUARY 2011 24-25 January 2011 – London, UK Amorphous pharmaceutical materials www.visiongain.com

24-26 January 2011 – Rotterdam, The Netherlands Cool Chain Europe 2011 www.pharma-iq.com/events 26-27 January 2011 – London, UK Social media in the pharmaceutical industry www.smi-online.co.uk 26-28 January 2011 – Rotterdam, The Netherlands Clinical trial supply Europe www.pharma-iq.com/events 30 January-2 February 2011 – Brussels, Belgium 3rd Annual disposable solutions for biomanufacturing www.pharma-iq.com/events

FEBRUARY 2011 3 February 2011 – London, UK Measurement challenges in the analysis of topical products www.jpag.org 15-17 February 2011 – Copenhagen, Denmark Nordic pharmaceutical distribution www.pharma-iq.com/events 23-24 February 2011 – Barcelona, Spain Revision of bioavailability requirement for modified release products www.eufeps.org

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european INDUSTRIAL PHARMACY • Issue 7 October 2010

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european Industrial Pharmacy Issue 7 (October 2010)  

European Industrial Pharmacy is the electronic journal of the European Industrial Pharmacists Group (EIPG). The journal contains articles, n...

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