european Industrial Pharmacy Issue 15 (December 2012) by European Industrial Pharmacists Group (EIPG)

european INDUSTRIAL

PHARMACY features 4

LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW Lactose is widely used as an excipient for dry powder lung delivery. This article reviews recently published work in the lactose spray drying field using laboratory scale spray dryers. by Nina Schafroth and Marco Meuri

LABOUR LAW AND WHISTLEBLOWING: ACCORDING TO EUROPEAN AND GERMAN LEGISLATION Whistleblowing continues to be highly contentious especially when the employee informs the general public via the press. The author, an attorney specialising in labour and medical law, seeks to clarify the situation. by Martin Wesch

DEVELOPMENT OF A NOVEL INTRA-NASAL SPRAY PRODUCT: A CASE HISTORY The problems of formulation as well as the design of the device are addressed by the authors in this detailed case history. by David P Elder, Andrew C Grant, Jim Godfrey, Anna Slater, Gavin Bone and Gary Cannon

SWOT ANALYSIS USING GENERAL MORPHOLOGICAL ANALYSIS: APPLICATION TO THE SPECIALS SECTOR FOR NEW BUSINESS DRIVERS A major improvement of SWOT (Strengths, Weaknesses, Opportunities and Threats) by a problem structuring method is described in the content of a start-up niche generic company. by Nasir Hussain, Bruce Garvey and Thomas Ritchey

HOME HEALTHCARE: IT’S PEOPLE NOT PRODUCTS THAT COUNT The effect of a medical device on a patient’s life should be one of the main considerations when designing a device. by Dan Formosa

regulars 3 21 22 23

EDITORIAL COMMENT REGULATORY REVIEW NEWS FROM THE EIPG EVENTS

ISSUE 15 • DECEMBER 2012 www.industrialpharmacy.eu www.eipg.eu

associate editors

european

INDUSTRIAL

PHARMACY

Belgium: Philippe Bollen

Issue 15 December 2012 Bulgaria: Valentina Belcheva

ISSN 1759-202X

Czech Republic: Ales Franc

EDITOR Joe Ridge, MRPharmS

Denmark: Marie Fog

PRODUCTION Dave Johnson

Finland: Anni Svala

SUBSCRIPTIONS Jill Monk

France: Jean-Pierre Paccioni Germany: Armin Hoffmann Great Britain: Shilpa Gohil, Janet Halliday Greece: Margarita Efthymiopoulou Hungary: Sylvia Marton Ireland: Anna O’Mahony Italy: Piero Iamartino Latvia: Inta Saprovska, Anita Senberga Malta: Claude Farrugia

EDITORIAL BOARD Michael Anisfeld Alexander Florence Michael Gamlen Linda Hakes John Jolley European Industrial Pharmacy is published four times a year by: Euromed Communications Ltd Passfield Business Centre, Lynchborough Road, Passfield, Liphook, Hampshire GU30 7SB Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223 Email: info@euromedcommunications.com www.industrialpharmacy.eu Annual subscription rate £70

Netherlands: Amon Wafelman

european INDUSTRIAL PHARMACY

Norway: Wenche Gordon

discussion group: www.pharmweb.net/gmp.html

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

Spain: Emma Fernández Sweden: Marianne Andersson Switzerland: Stephan Buchmann, Valter Gianesello

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

Cover picture: Whistleblowing (see pages 9-11). Image: Fotolia

european INDUSTRIAL PHARMACY December 2012

• Issue 15

editorial Dear Colleagues It is the end of another hectic year for the European Industrial Pharmacists Group and what has been another tumultuous year for the Pharmaceutical Industry. It was prophesied that 2012 in the Mayan calendar would mark a catastrophic Global event (on December 21st to be precise) – evidently the Mayans were obviously predicting the catastrophic events within the Pharma world. We have seen CEOs come and go and profit warnings combined with concerns about austerity affecting pricing and innovation! It is easy to be drawn into this gloom and doom and yet, when I talk to many young Pharmacists there is enormous interest in embarking on a career in Industry and our duty as EIPG (which is written in our statutes) is to guide and mentor such young talent. My view and that of many of the EIPG member states, is that the Pharmaceutical Industry still provides an exciting career pathway for Pharmacists but that the kind of roles and opportunities and locations will be more global and varied. In response to these changes, the EIPG has also changed and as previously reported we have redrawn our Statutes, which were constituted in 1966, to allow the EIPG to reflect the various changes ongoing within Europe and to allow greater participation of non-EEC member states to join the EIPG. I am proud to state that in 2012 we welcomed Norway to the EIPG, Germany after many years of complex negotiation was able to formalise its own Association (well done Armin Hoffman for his dogged persistence) and there have been enquiries from a number of interested parties – the EIPG has never been busier or healthier! I have to acknowledge the sterling efforts and support from the many individuals who have made

my years as President an easy one to undertake. In particular, I would like to formally thank the following individuals who have worked with me throughout the seven years: Jane Nicholson – Executive Director Claude Farrugia – Malta and Vice President Piero Iamartino – Italy and Vice President Jean-Pierre Paccioni – France and Vice President Valerie Lacamoire – France and Vice President whose enthusiasm and dedication has been unfaltering despite balancing work pressures with the challenges of supporting the EIPG often in their own time and at weekends. If I have my calculations correct, during my tenure as President these individuals would have given up 28 days of their personal time to help the EIPG become a force to be reckoned with and which represents the individual Industrial Pharmacist and actually helps more Pharmacists enter the Pharmaceutical Industry. I would also like to acknowledge Joe Ridge and his team for producing this splendid journal which I know many Industrial Pharmacists and Pharmaceutical Scientists read and enjoy. The feedback we receive is very positive and we will continue to produce a technical journal which puts pharmaceutical sciences and regulatory good practice under one title. With this, I would like to conclude this short editorial and wish you a very exciting and prosperous New Year! Warmest regards

Gino

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european INDUSTRIAL PHARMACY December 2012

• Issue 15

LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW by Nina Schafroth and Marco Meuri

Introduction Spray drying is a commonly practiced method to prepare inhalable powders and has been applied to a variety of substances, such as peptides, antibiotics, vaccines and biodegradable carrier particles1,2. The described delivery technology can be used for lung-specific applications to treat cystic fibrosis, asthma, chronic pulmonary infections, lung cancer or tuberculosis3,4. Nina Schafroth and Marco Meuri are Product Managers for spray drying at Buchi Labortechnik AG, Flawil, Switzerland. Email: meuri.m@buchi.com www.buchi.com

Lactose is one of the most common excipients used for dry powder lung delivery. The main properties of lactose are listed in Table 1. Besides lactose, leucine, mannitol, glucose, trehalose and sucrose are other carriers which have been studied over the past few years as new inhaled drug delivery formulations5,6. These excipients are approved by the Food and Drug Administration (FDA) for pulmonary delivery, and so, widely applied in aerosolisation. This is due to their non-toxic, readily degradable properties after administration. Lactose has the advantage of a low stickiness behaviour compared to other sugars (see Table 2). Moreover, its higher glass transition temperature of Tg 101°C enables easy flowing powders. This article reviews recently published scientific work in the field of lactose spray drying for inhalable applications using laboratory scale spray dryers. The adjustable spray drying process parameters are (see Figure 1(a)): l inlet and outlet temperature, l sample feed rate, l drying gas flow rate and l spray gas flow In the Mini Spray Dryer, mainly aqueous solutions are prepared by

dissolving an active ingredient (drug, nanoparticles) and excipient (lactose and others) in water at different solid concentrations. The resultant spray dried powder is separated by a cyclone and collected in a vessel. The exhaust gas is then extracted from the cyclone and filtered.

In contrast, the new Nano Spray Dryer B-90 is based on a new spray drying concept, as illustrated in Figure 1(b). A comparison with the traditional Mini Spray Dryer B-290 is given in Table 3. The drying gas enters the apparatus from the top where it is heated to the set inlet temperature, flows then through the drying chamber, and exits the spray dryer at the bottom outlet. The gas is additionally fine filtered before leaving the instrument. The inlet temperature and outlet temperature are measured just after the heater and before the fine filter. The liquid sample is fed to the spray nozzle via a peristaltic pump in a circulation mode. The generation of droplets is based on a piezoelectric driven actuator, vibrating a thin, perforated, stainless steel membrane in a small spray cap. The membrane (spray mesh) features an array of precise, micron-sized holes (4.0, 5.5 or 7.0µm). The actuator is driven at around 60kHz, causing the membrane to vibrate, ejecting millions of precisely sized droplets per second with a very narrow size distribution. These extremely fine droplets are dried into solid particles and collected by electrostatic charging and

Molecular formula

C12H22O11

Molar mass

342.3g/mol

Appearance

White solid

Solubility in water

21.6g/100mL at 25°C

Density

1.53g/cm3

Melting point

223°C

Glass transition point

101°C

Table 1: Lactose properties. Lactose (or milk sugar) is a disaccharide consisting of galactose and glucose fragments. Sugars

Hygroscopicity (relative)

Melting point (°C)

Water solubility at 60°C (w%)

Tg (°C)

Stickiness (relative)

Lactose

223

101

Maltose

165

Sucrose

+++

186

+++

Glucose

+++++

146

+++++

Fructose

++++++

105

++++++

Table 2: Physical properties of sugars and stickiness behaviour (Tg: glass transition temperature).

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LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW

continued

The mean particle appeared round and compact with a sizes are generally in a smooth surface. By further dilution of range of 1 to 5µm, the spray dried fluticasone and which is generally salbutamol from 10% to 1% solution, considered to be the Nano Spray Dryer B-90 appeared effective for able to produce spherical submicron pulmonary delivery. particles with smooth surface at high Blank lactose carrier yields. particles for blending Dry powder formulations were in the 50-80µm Four main strategies are range. Moreover, spray predominantly followed to formulate drying is a one-step dry powders for inhalation process with narrow applications based on lactose, as particle size illustrated below: distribution of respirable dimensions Group A: Small carrier-free drug directly from liquid particles formulations9. Aerosol powders Spray drying allows ranging from 1 control of particle to 5µm are shape, morphology considered the and density Figure 1(a): Process diagram of the Mini Spray optimum size for depending on the Dryer B-190, B-191 and B-290 models with process spray-drying deposition parameters. beyond the conditions7. increasingly Spherical particles subsequent deflection to the narrow airways into the alveoli. can be prepared which provide a collecting electrode. Finally the However, such small particles low contact area and homogeneous resulting powder is collected using a often stick together, and are very particle size distribution resulting in rubber spatula. cohesive with poor flow properties, a higher respirable fraction than Overall, spray drying is a suitable which makes physical handling of mechanically micronised drugs. alternative method for producing the particles difficult and lowers the inhalable dry powders for pulmonary fine particle fraction. Particle morphology applications. The main advantages Studies by Li et al.9,10 SEM analysis shows that most of the compared to freeze dried and jet demonstrated that the dose spray dried lactose micro-particles milled products are summarised in emission and dispersibility of spray were spherical in shape. The fine Table 4 on page 7. dried lactose particles were microparticle agglomerates Today, the market for inhalable dry powders relies on freeze dried and Nano Spray Dryer B-90 Mini Spray Dryer B-290 jet milled micronised drugs6. Main benefit for small quantities, finest for traditional spray drying, However, comparable size particles, highest established process distributions are achieved of the yields same substances with spray dried or Max. inlet temperature 120°C 220°C jet milled spray dried powders, but Water evaporation max. 0.2kg/h 1.0kg/h, higher for solvents particle morphology can more easily be influenced by spray drying than Nozzle type piezoelectric driven two-fluid nozzle by jet milling7. vibrating mesh Compared to freeze drying, spray Particle size 300nm – 5µm 2 – 25µm drying generates highly dispersible Particle separation electrostatic particle collector cyclone powders for inhalation without the Typical yield up to 90% typically around 60% use of carrier particles. The jet milling process leads to small, flat, Min. sample volume 1mL 30mL crystalline particles and stronger Max. sample viscosity 10cps (diluted samples) 300cps (viscous samples cohesive forces with poor flow and juices possible) properties. Scale-up limited by spray head and possible to scale-up to kgCompared to the crystalline electrical particle collector and tons-scale nature of jet milled lactose, the structure of spray dried lactose is amorphous8.

Table 3: Comparison of main features and benefits between Nano Spray Dryer B-90 and Mini Spray Dryer B-290

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LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW

considerably enhanced in the presence of amino acids, specifically leucine, phenylalanine and arginine. Incorporation of NaCl and its relative proportion was also efficient to control the aerosol properties of spray dried rhDNase powders11. The presence of NaCl changed the morphology and crystallinity of the co-spray dried powders, and this was paralleled by improvement in the fine particle fraction of rhDNase. In particular, in blends with about 50µm lactose carrier particles the rhDNase particles adhered apparently in the form of a monolayer to the carrier. Ely et al.3 produced inhalable effervescent powders and used a mixture of acids such as citric acid and carbonates. Different ingredients such as ethanol, polysorbate 80, L-leucine and PEG 6000 were added to the basic formulation to improve the particle size and to achieve an appropriate mass medium particle diameter. The experiments with the Nano Spray Dryer B-90 illustrate the promising potentials with high fabrication yields and very narrow size distributions. The asthma drugs, salbutamol and

fluticasone propionate were spray dried in 10% lactose solution and the resulting size distributions were shown to be in the 1-3µm range. At further diluted concentrations, the Nano Spray Dryer B-90 appeared to provide very satisfactory results for the formulation of submicron particles from small sample amounts. This novel spray drying technology offers promising perspectives for new pharmaceutical applications using spray drying. Group B: Small drug and larger carrier particles

The most common approach to overcome the cohesiveness of small particles is the use of carrier particles markedly larger than the drug particles7,11,12. The aggregation problem is solved by particle size enlargement, which involves an additional blending step of the small drug particles (active ingredients, such as budesonide and formoterol fumarate dehydrate) with large lactose carrier particles to improve their flow through the inhaler2. Lactose is the most commonly used carrier for Dry Powder Inhaler (DPI) formulations, where it is usually desired to have a size of about 50µm to 80µm for this purpose13. During inhalation, the smaller drug particles separate from the carrier particles and are deposited in the alveoli. Trehalose and mannitol are also known to improve protein stability, although the use of Figure 1(b): Process diagram of the new Nano mannitol in this regard Spray Dryer B-90 with process parameters. is limited due to its

continued

susceptibility towards crystallisation. While the spray dried trehalose was amorphous, spray dried mannitol recrystallised5. For nasal administration, an agglomeration step is successfully applied to transform primary spray dried micro-particles into spherical and flowable agglomerates, as shown by Russo et al.14 for morphine particles. Group C: Large porous drug particles

A breakthrough in inhaled dry powder aerosols research was made with the development of large porous particles (>5µm) with low mass density (<0.4g/cm3) by Edwards et al.15. It has been shown that larger particles aggregate less and disaggregate more easily. These large porous particles are specifically designed to serve as an alternative to the conventional small non-porous drug particles (Group A). They can be manufactured via spray drying because of process simplicity, cost effectiveness, and scale-up capability. By virtue of their larger size, the porous particles have better flowability and are thus capable of evading the phagocytic clearance mechanism in the lungs, which leads to an improved therapeutic efficacy of the inhaled drug. Group D: Encapsulated nanoparticle drugs in carrier particles

Nanoparticulate drugs as therapeutic carriers has become the subject of very active research8. Nanomedicine is an emerging field in the bio-medical sciences3. Nanoparticles have also been proposed for pulmonary administration to utilise their advantages in drug delivery to the lungs4. However, one issue is that their small size limits their lung deposition. Aerosolised

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LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW

1. Highly dispersible and spherical particles in a range of 1 to 5µm with narrow particle size distribution. 2. Control of particle shape, morphology and density depending on spray drying conditions. 3. One-step process directly from liquid to dry formulations. 4. Process simplicity, cost effectiveness and scale-up capability. Table 4: Advantages of spray drying compared to freeze dried and jet milled products to produce inhalable dry powder for pulmonary applications

nanoparticles have only very limited sedimentation, inertial impaction or diffusion, which causes them to be predominantly exhaled from the lungs after inhalation. Research focus is therefore on the incorporation of nanoparticles into carrier particles to produce the appropriate size for pulmonary drug delivery8. For example, Sham et al.4 incorporated gelatin nanoparticles into lactose powders by spray drying. The gelatin nanoparticles were evenly distributed throughout thelactose carrier particles. After spray drying the nanoparticles remained in the nano-range size. This promising technique was also used to incorporate biodegradable polymer and protein-based nanoparticles into lactose carrier particles. Spray dried silica nanoparticles in lactose was studied by Hadinoto et al.8 and Kho and Hadinoto5. Here, the degree of hollowness decreased as the concentration of nanoparticles increased. Spray drying of lactose in the absence of nanoparticles yielded large solid spherical particles, whereas the presence of nanoparticles led to an apparent decrease in the molecular diffusivity of the lactose solutes and produced hollow particles. Such large, hollow nanoparticulate aggregates may serve as new micron-sized carriers of nanoparticulate drugs for delivery by dry powder inhalers. Moreover, Kho and Hadinoto5 found that a multiple-excipient formulation of leucine and lactose at a 1:6 concentration ratio was capable of producing optimal results in terms of both the nanoaggregate morphology and aqueous re-dispersibility. The high

aqueous solubility of lactose facilitated the effective redispersion of the nano-aggregates, whereas the presence of hydrophobic leucine stabilised the nano-aggregates by reducing their cohesiveness. Lactose structure after spray drying

Control of the structural state of spray dried pharmaceuticals is of major importance. Spray drying is often used to produce amorphous composites which are generally attributed to the rapid drying process leaving very short time for evaporation and formation of the solid phase16. Lactose is typically 100% amorphous after spray drying because of the short residence time in the spray dryer12 and its high glass transition temperature17 (see Table 2). A drawback of the amorphous state is that this metastable form will, if not stabilised, spontaneously crystallise over time, which may result in agglomeration and caking of the primary particles so that the product becomes non-inhalable. Major factors affecting the physical instability of amorphous lactose are the physico-chemical properties of the materials; in particular the glass transition temperature of the applied materials and the crystallisation temperature, as well as the spray drying processing variables such as the drying temperature and the relative humidity of the drying air. The absorbed water has a plasticising effect on the lactose. The critical relative humidity at which the glass transition temperature falls below room temperature (25°C) is quoted in

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continued

most publications as around 48% relative humidity12. Residual moisture contents of about 2% to 11% are typically measured for spray dried powders containing lactose18,19. Co-spray drying of lactose and polyethylene glycol (PEG) was shown to promote crystallisation of lactose12,16,20. Crystallisation was favoured by a low molecular weight and a high concentration of PEG16. The presence of PEG 6000 changed the surface texture of the carrier particles from a smooth surface to a more aspirated surface20. An increase in lactose content in the feed solution resulted in a decrease in amorphous lactose percentage in the spray dried products12. Islam and Langrish20 studied the effect of NaCl and KCl salts on lactose crystallisation and obtained the most crystalline product at a lactose to NaCl ratio of 5 to 2 (w/w). The effect of varying the inlet air temperature on the degree of crystallinity for spray dried lactose powders was studied by Chiou et al.21 and Islam et al.17. A higher degree of crystallinity (from about 55% to 76%) was observed in spray dried lactose when an inlet gas temperature of 210°C was used, compared with an inlet gas temperature of 134°C21. Moreover, an insulated spray chamber was beneficial to reduce heat losses due to radiation17. Langrish et al.18 investigated spray drying of skimmed and whole milk in the MiniSpray Dryer B-290. Yield values of up to 82.7% (skimmed milk) and 18.6% (whole milk) were found. The lower yields were attributed to wall deposition due to the sticky nature of milk types with higher levels of fats and sugars, such as whole milk and lactose free skimmed milk. Conclusions Inhalable applications l

Spray drying is able to produce stable, efficient and inhalable dry lactose powder systems for respiratory delivery with adequate particle size and shape for deep lung deposition 3,4,6,7.

LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW

Spray drying versus jet milling l

Spray drying and jet milling showed insignificant differences in fine lactose particle size of the same formulations13. Spray dried particles showed higher dispersibility compared to jet milled particles due to spherical shape and smaller surface contact area7. The dissolution and inhalation behaviour of spray dried powder is even more advantageous than that of mechanically micronised powder. Spray dried particles free themselves from the large lactose carrier particles as easily as mechanically micronised particles7.

Aerosol properties and dispersibility l

The aerosol properties and dispersibilty of spray dried powders can be enhanced by incorporation of suitable excipients, such as NaCl salt11,19 or amino acids5,9,10 before spray drying, allowing the development of stable and viable formulations for pulmonary inhalation.

Acknowledgments

The rapid solidification in spray drying causes lactose in suspension to become amorphous12. Various polymorphic proportions can be manufactured by selection of the appropriate feed concentrations. Spray drying process conditions may be utilised to alter the final spray dried lactose product, where the inlet gas temperature has a significant impact on the crystallinity17,21. The presence of polyethylene glycol promotes crystallisation of lactose when the two components are co-spray dried12,16,20. Crystallisation is favoured by a low molecular weight and a high concentration of PEG16. Incorporation of nanoparticles into respirable carrier particles can be a straightforward process when formulating via spray drying4.

References 1

Nanoparticles l

BÜCHI Labortechnik AG thanks all scientists listed in the references for the research carried out on BUCHI spray dryers.

Amorphous/crystalline structure l

Spray dried nanoparticle aggregates are capable of serving as micrometer-sized carriers of nanoparticulate drugs. This facilitates the nano-particle delivery to the lung for potential inhaled drug delivery applications in Dry Power Inhalers5,8. The Nano Spray Dryer B-90 provides a novel spray drying technique in laboratory scale to prepare submicron particles for pulmonary delivery dry powder formulations.

continued

Arpagaus C, Schafroth N. Laboratory scale spray drying of biodegradablepolymers. Respiratory Drug Delivery 2009: 269-274. Arpagaus C, Meuri M. Laboratory scale spray drying of inhalable particles: a review. Respiratory Drug Delivery 2010: 469-476. Ely L, Roa W, Finlay WH, Löbenberg R. Effervescent dry powder for respiratory drug delivery. European Journal of Pharmaceutics and Biopharma-ceutics 2007;65:346-353. Sham JO-H, Zhan Y, Finlay WH, et al. Formulation and characterization of spraydried powders containing nanoparticles for aerosol delivery to the lung. International Journal of Pharmaceutics 2004;269:457-467. Kho K, Hadinoto K. Effects of excipient formulation on the morphology and aqueous re-dispersibility of dry-powder silica nanoaggregates. Colloids and Surfaces A: Physicochem. Eng. Aspects 2010;359:71-81. Seville PC, Kellaway IW, Birchall J C. Preparation of dry powder dispersions for non-viral gene delivery by freeze-drying and spray drying. Journal of Gene 2002; 4:428-437. Vidgrén MT, Vidgrén PA, Paronen TP. Comparison of physical and inhalation properties of spray dried and mechanically micronized disodium cromoglycate. International Journal of Pharmaceutics 1987;35:139-144. Hadinoto K, Phanapavudhikul P, Kewu Z, Tan RBH. Novel formulation of large hollow nanoparticles aggregates as potential carriers in inhaled delivery of nanoparticulate drugs”, Industrial & Engineering Chemistry Research 2006; 45:3697-3706. Weiler C, Egen M, Trunk, Langguth P. Dispersibility of jet milled vs. spray dried

powders. Respiratory Drug Delivery. 2008: 571-575. Li -Y, Neill H, Innocent R, et al. Enhanced dispersibility and deposition of spraydried powders for pulmonary gene therapy. Journal of Drug Targeting 2003;11(7):425-432. Li-HY, Seville PC, Williamson IJ, Birchall JC. The use of amino acids to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy”, Journal of Gene Medicine 2005;7:343-353. Najafabadi AR, Asgharian , Tajerzadeh, H, et al. The effects of fine lactose as a third component on aerosolization of cefotaxime sodium from dry powder formulations. DARU Journal of Faculty of Pharmacy Tehran University of Medical Sciences 2006;14(3):150-163. Chan H-K, Clark, A, Gonda I, et al. Spray dried powders and powder blends of recombinant human deoxyribonuclease (rhDNase) for aerosol delivery. Pharmaceutical Research 1997;14(4):431437. Chidavaenz OC, Buckton G, Koosha F, Pathak R. The use of thermal techniques to assess the impact of feed concentration on the amorphous content and polymorphic forms present in spray dried lactose. International Journal of Pharmaceutics 1997;159: 67-74. Russo P, Sacchetti C, Pasquali I, et al. Primary microparticles and agglomerates of morphine for nasal insufflation. Journal of Pharmaceutical Sciences 2006; 95:(12):2553-2561. Edwards DA, Hanes J, Caponetti G, et al. Large porous particles for pulmonary drug delivery. Science 1997;276:1868-1871. Mosen K, Backstrom K, Thalberg K, et al. The apparent plasticizing effect of polyethylene glycol (PEG) on the crystallinity of spray dried lactose/PEG composites. European Journal of Pharmaceutics and Biopharmaceutics 2006;64:206-21. Islam MIU, Langrish TAG. An investigation into lactose crystallization under high temperature conditions during spray drying. Food Research International 2010;43:46–56. Langrish TAG, Marquez N, Kota K. An investigation and quantitative assessment of particle shape in milk powders from a laboratory-scale spray dryer. Drying Technology 2006;24(12):1619-1630. Islam MIU, Langrish TAG. The effect of the salt content on the crystallization behaviour and sorption fingerprints of spray-dried lactose”, Food and Bioproducts Processing 2008;86:304-311. Corrigan O-D, Healy A-M, Corrigan O-I. The effect of spray drying solutions of polyethylene glycol (PEG) and lactose/PEG on their physicochemical properties, International Journal of Pharmaceutics 2002;235:193-205. Chiou D, Langrish TAG, Braham R. The effect of temperature on the crystallinity of lactose powders produced by spray drying. Journal of Food Engineering 2008; 86(2): 288–293.

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LABOUR LAW AND WHISTLEBLOWING According to European and German legislation by Martin Wesch

nyone who, in the public interest, discovers shortcomings in his/her employer, particularly in the state sector, earns public recognition. Unusual termination of office without notice is a particular case in point. Complaints against employers are viewed as significant grounds since these are consistent with failure on the part of the employer to comply with the employment contract until the standard period of notice has elapsed. This article seeks to clarify whether and to what extent the aforementioned behaviour adopted by employers is legally permissible and should remain devoid of sanctions in accordance with labour law. Dr. Martin Wesch is an Attorney specialising in Labour and Medical Law email: STR-law@wesch-buchenroth.com

Issues

a) The media draws widespread public attention to the fact that there are shortcomings in the treatment and care of the elderly. Those affected are looked after inadequately or not at all. This is often due to staff shortages fuelled by an overwhelming desire to make profits. In the food industry, cattle with BSE or rotten meat are used in food production. Allegations of bribery are sometimes lodged against major companies. However, violation of the employment law can also impact upon employers themselves, e.g. if an employee alleges that the Managing Director committed a traffic violation during a joint business trip in order to get the latter’s driving licence revoked.1 b) Whereas in Europe such cases give rise to disputes over the employer’s right to terminate the whistleblower’s contract without notice, the legal consequences in

the USA are entirely different. A subsidiary of GlaxoSmithKline (GSK) in Puerto Rico committed itself to criminal proceedings in 2010 and had to pay 750 million US dollars in fines and damages for the manufacture and sale of certain adulterated drugs.2 This refers to the drugs Kytril, Bactroban, Paxil CR and Avandamet, which were produced between 2001 and 2005. The whistleblower, the Quality Control Manager, was supposed to receive almost 96 million US dollars of that.3 This was based on the False Claims Act of 1863, which allowed private citizens to take civil action on behalf of the United States and participate in a productive outcome, comparative FDA press report dated 26.10.2010, the law was accepted in civil law in order to put a stop to the action of fradulent army suppliers. For 10 months she had repeatedly attempted to inform her line managers, right up to the GSK

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Chief Executive, about what was happening, but to no avail.4 Following her dismissal because of this action in 2003, she informed the FDA. c) The most famous whistleblower in the world, “WikiLeaks” fell silent at the end of 2010. The home pages were removed from the net. Numerous secret papers from ambassadors and the US military about the wars in Iraq and Afghanistan had previously been published.5 Freedom of speech in accordance with the ECHR

a) According to the European Court of Human Rights (ECHR), those Member States coming under its jurisdiction are obliged to protect the right to freedom of speech (pursuant to Article 10 of the European Convention on Human Rights) in dealings between private persons.6 In the case where an employee detected shortcomings in the treatment and care of the elderly and subsequently filed a complaint against the employer, the ECHR viewed this as a violation of the right to freedom of expression through the German courts. With the exception in the first instance of the Berlin Employment Tribunal, the courts considered the employee’s termination of contract without notice to be a legitimate outcome. b) The ECHR maintains that the employee should initially have reported the information to his/her line manager based on a loyalty or confidentiality obligation.7 Only if this approach proves impossible or fruitless should the employee bring this case into the public domain as a last resort. When weighing the extent of interest, it is important to establish whether there would indeed be public interest in such a case and whether such interest would be well-founded. Anyone wishing to pass on the information must basically check whether the details are accurate and reliable. Furthermore, the damages possibly sustained by the employer should be taken

LABOUR LAW AND WHISTLEBLOWING

into account together with the reasons for providing the information and the type of sanction. A complaint against shortcomings in the workplace can be justified when there are no grounds to reasonably expect that in-house grievances will lead to an investigation and corrective action. Evidence must be substantiated and should not be knowingly or deliberately falsified. Further to inconclusive in-house grievances, the employee in the case dealt with by the ECHR could assume that a complaint would be the last resort in any attempt to improve the care situation. Public interest in shortcomings in the care of the elderly in state-run nursing homes attracts so much attention that it actually outweighs the company’s interest in protecting its good reputation in terms of business connections and business interests. c) Violation of Article 10 of the European Convention on Human Rights by the German courts did not lead to the reinstatement of the care assistant. Pursuant to Article 41 of the aforesaid Convention, Germany was instructed to pay legal compensation to the person who filed the complaint. In this particular case, this amounted to €10,000.00 to compensate for non-pecuniary damages and €5,000.00 in costs and expenses. Germany had to pay the damages within three months but the person who lodged the complaint lost her job. The consequences of jurisdiction in Germany

a) National jurisdiction has already been adjusted in line with ECHR decisions. In the case of so-called whistle blowing, the German Bundesarbeitsgericht (BAG – Federal Labour Court) states that, on constitutional grounds, an employee must not be disadvantaged in accordance with civil or labour law if he/she is

continued

exercising civil rights within the scope of preliminary penal or regulatory proceedings providing that no untruths are knowingly stated and information is not deliberately falsified.8 The constitutional rights of the employee (in accordance with Article 2 para. 1 of the said Constitution and the fundamental right to general freedom of action, in conjunction with the due process of law) resonate with the employer’s obligation to provide protection and consideration (in accordance with § 241 para. 2 BGB). In filing a complaint with the Publication Prosecution Department and contacting the Bundesanstalt für Finanzdienstleistungsaufsicht (BaFin – Federal Financial Supervisory Authority), the employee has adopted approaches that are approved and permitted by the legal system. He/she should highlight the proceedings which, in his/her opinion, constitute grounds for complaint, to the employer in conjunction with organisational involvement and allow them to be investigated by competent state bodies.9 Civil rights have been exercised by sending the employer’s documentation to these authorities. b) The case of the announcement against the managing director who allegedly committed a traffic violation was viewed differently. In this case, the employee wanted to have the managing director’s driving licence revoked. This was viewed by the BAG as tantamount to destroying any basis for trust between the parties to the contract. Extraordinary termination of contract without notice was therefore considered justified.10 c) An employee who is responsible for the safety of operating devices, e.g. in a nuclear research plant, must raise safety objections to the competent state authorities in an appropriate format.11 The employee’s termination of

contract on this basis was ineffective. d) In Germany, the threat of a complaint against the employer is sometimes viewed as sufficient grounds for termination of contract.12 The employee is not even covered if he asks a third party to deliver the threat on his/her behalf. If the employee has initiated or at least approved of the threat, termination of contract without notice may be justified.13 International legislation and endeavours to this effect

a) Ways of improving protection for whistleblowers is under discussion in many countries. One Canadian woman provocatively suggested that it was a case “of breaking the silence of the lambs”14. In Great Britain15, Australia16, recently in Ireland17 and even in Romania18 there are certain laws to protect whistleblowers when they are employees. Whistleblower protection in Belgium19, the Netherlands20, France21 and Germany22 only falls under general bans on discrimination. b) Germany is still wrestling with appropriate protection for whistleblowers. The Federal Government sees no need for whistleblower legislation.23 A ban on disciplinary measures is already in force, according to which an employer cannot discriminate against an employee because the latter is exercising his/her rights in an appropriate manner (§ 612 a BGB). Recommended behaviour

Employer The employer can facilitate anonymous in-house reporting by the employee. A secure site must be provided where the employee can voice his concerns without fear of sanctions. Companies often appoint an “Ombudsman” for this purpose. The latter must be bound by secrecy. Anonymous reports can also be received by ombudsmen. In this way, the employer is made

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LABOUR LAW AND WHISTLEBLOWING

aware of in-house shortcomings. It is easier for employees to make themselves known to the employer. They do not have to reveal their personal data. This can also easily lead to unjustified reports against line-managers or unpopular colleagues (“black-listing”). The ombudsman will have to weigh up whether the charges are justified and directed against individual people. This will depend on the nature, severity and frequency of the violation as well as the level of accuracy in terms of presenting the evidence. The ombudsman will then decide which procedures the employer should introduce in order to clarify the situation and initiate corrective measures. The introduction of an ombudsman, “ethics hotline” or “whistle blowing systems” in Germany is not devoid of problems from a data protection perspective. Personal data must only be used by the employer when needed to justify, implement or terminate a working process. This is sometimes permitted only when there is a binding obligation in Germany or the EU to record and monitor data and not when it concerns compliance with an in-house company policy based on legal proceedings in other countries. The extent to which personal data should be collated and processed must be carefully weighed by the ombudsman and the in-house complaints office. Necessity will be based on the extent, severity and frequency of the violation and the accuracy of the presentation. Employees In any case, whistleblowers are advised initially by the employer and in-house to seek corrective measures in an appropriate manner and without threats. Whether shortcomings are pointed out to the employer anonymously or with disclosure of identity is irrelevant. It is, however, crucial for the shortcoming to be reported to the employer via relevant channels. The

continued

shortcoming must also be presented in sufficient detail with accompanying evidence where possible (especially witnesses, documentation or visual inspection of locations or objects). Employees must have an opportunity to consider individual shortcomings. General complaints that have no sound basis and which may lead to violation need not be pursued by the employer. However, if the employer does not take action despite substantial evidence and in situations where the employee cannot reasonably expect his/her inhouse complaint to generate an inspection and corrective measures, a complaint against shortcomings in the workplace is justified. It is open to debate as to whether the employee is also entitled to inform the general public via the press. The inevitable damage to the employer’s reputation is quite simply justified on the basis of freedom of speech pursuant to Article 10 of the European Convention). Such considerable impacts on the rights of the employee are weighed in terms of public interest only in the severest of shortcomings in the workplace where human life and health are at risk or the environment is under threat. This does not, however, apply when the employee wishes merely to pursue personal gain or desires revenge. Employees should therefore exercise particular caution when reporting to the press. Public interest in the information will occasionally oppose termination of the employee’s contract but only in the severest of cases. References 1

3 4

Comparable Bundesarbeitsgericht (BAG) dated 18.12.1980, Practice in accordance with Labour Law, BAG (Federal Labour Law) Reference Work No. 4 to § 174 BGB (German Civil Code). Food and Drug Administration (FDA), Office of Criminal Investigations, Press report dated 26.10.2010, www.fda.gov. http://en.wikipedia.org/wiki/Whistleblower. Simon Goodley in “The Guardian”, 28 Oct. 2010, www.guardian.co.uk.

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Available at: www.canadianlawsite.ca/whistleblower.htm

ECHR, judgement dated 21.07.2011 – 28274/08, Neue Zeitschrift für Arbeitsrecht 2011, 1269.

See in the following: ECHR, judgement dated 21.07.2011 – 28274/08, Principles.

BAG, Judgement dated 14.12.2011 – 10 AZR 283/10 Text reference 23.

BAG, at the specified location.

BAG dated 18.12.1980, Labour Lawrelated practice No. 4 to § 174 BGB.

BAG dated 14.12.1972, Labour Lawrelated Practice No. 8 to § 1 Kündigungsschutzgesetz (Legislation providing Protection against Termination of Contract) Verhaltensbedingte Kündigung (Behaviour-related Termination of Contract).

Mueller-Gloege im Erfurter Kommentar zum Arbeitsrecht (Discussions on Labour Law),11th Edition2011, Kennzahl 230, § 626 BGB Marginal Number 64.

Essen Court of Employment dated 15.05.2009, Neue Zeitschrift für Arbeitsrecht- Rechtssprechungs-Report 2010, 75.

Rosella Melanson in the New Brunswick Telegraph Journal May 2001. Available at: www.canadianlawsite.ca/whistleblower.htm#f; little store is set by protecting whistleblowers in this article. Available at: http://en.wikipedia.org/wiki/Whistleblower.

Public Interest Disclosure Act 1998 (PIDA). Available at: www.cipd.co.uk/hrresources/factsheets/whistleblowing.aspx.

Whistlesblowers’ Protection Act 2001. Available at: www.austlii.edu.au/au/legis/vic/consol_act/ wpa2001322/ (accessed 23 October 2011).

Whistleblower Protection Law since January 2012. Available at: http://en.wikipedia.org/wiki/Whistleblower.

Act on the Protection of Whistleblowers (Law No. 571/ 2004, Priority on other national laws). Available at: www.europarl.europa.eu/document/activit ies/cont/201105/20110524ATT20164/201 10524ATT20164EN.pdf.

Klokkenluidersdecreet in the Vlaamse Ombudsdienst, see footnote No. 18.

Civil Servants Act, see footnote No. 18.

Loi n° 2007- 1598 relative à la lutte contre la corruption (French law No. 2007-1598 relating to the fight against corruption), see footnote No. 18.

Law on the Status of Civil servants, see footnote No. 18.

Publication in the Frankfurter Allgemein Zeitung (FAZ Online) dated 31.05.2012: “Ausplaudern erwünscht“ (Whistleblowers wanted).

DEVELOPMENT OF A NOVEL INTRA-NASAL SPRAY PRODUCT – A CASE HISTORY by David P Elder, Andrew C Grant, Jim Godfrey, Anna Slater, Gavin Bone and Gary Cannon

ntra-nasal spray products contain active ingredient(s), which are dissolved/suspended in vehicles comprising a variety of functional excipients, such as isotonicity agents, preservatives, suspending agents, viscosity modifying agents (bio-adhesives), buffering agents and emulsifiers. These products are presented in nonpressurised dispensers that deliver metered dose sprays of the active ingredient, as either multi-use or single dose products1. The container-closure system is comprised of the container, closure, metering pump, and any secondary packaging; the formulation and container-closure system comprise the drug product. David P Elder and colleagues are in the R&D Division of GSK in Ware, Hertfordshire, UK. Email: david.p.elder@gsk.com

Intra-nasal products deliver a spray of droplets into the nasal cavity for either local (topical), or systemic action for direct delivery to the brain. There is a relatively short nasal residence time (up to 20 to 30 minutes) before mucociliary clearance mechanisms will drain the administered dose down the nasopharyngeal tract2. The pump design influences the actuation force, pump valve design, metering chamber design, length of actuator and nozzle orifice design. The FDA guidance states that with respect to droplet size and particle size distribution, that this ‘is an important property influencing the nasal deposition of aerosols and sprays’. This is because droplets less than 10µm can potentially enter the lungs; whereas, excessively large droplets will be deposited at the front of the nostril and ‘run-off’ from the nasal cavity. The majority of nasal medicines achieve maximum

therapeutic effect when droplets are deposited between the nasal valves in the posterior two-thirds of the nasal cavity3. Intra-nasal spray products have some unique aspects that can impact on both stability and performance. These aspects include: the physicochemical nature of the formulation composition may be critical in describing both the stability (chemical, physical and microbiological aspects) and performance characteristics of drug products. These physicochemical properties together with the potential for agglomeration, sedimentation or flocculation on storage can be crucial to the performance of the drug product, influencing suspendability and particle characteristics as well as device delivery performance. Similarly, the potential for interaction of the formulation with internal contact surfaces, particularly elastomeric materials, can influence

delivery properties as well as generating leachable impurities. For multi-use products the efficacy of the preservative system needs to be evaluated during the product’s in-use period as well as over its entire shelf-life. Container-closure systems The design of the container-closure system can have significant impact on the dosing performance of the drug product. The design attributes of the device need to address the potential for operator-dependent actuation, particularly if paediatric/geriatric use is being considered. Both the metering and spray producing attributes (e.g. orifice, nozzle, etc) components are used to generate reproducible drug delivery. These constituents are constructed from many plastic sub-components that need to be precisely controlled both in terms of dimensional attributes (impacting on manufacturability and operational performance) as well as composition (impacting on leachable profile). This review will focus on the development of an intra-nasal spray product, which utilised a novel sideactuated device that was developed in parallel with the formulation. Design attributes of an intra-nasal spray product A Quality by Design (QbD) riskbased approach was applied to the development of an intra-nasal spray4. The drug product should provide a consistent dose to the patient with respect to: (i) amount of drug delivered, (ii) DSD (Droplet Size Distribution) of the nasal spray, and (iii) amount of small droplets (<10µm) which should be minimised (this reduces potential for inhalation into lungs). Structured-risk based methods were applied, which are aligned with ICH Q95. The drug product was designed to meet appropriate quality standards in routine manufacture at commercial scale. Qualitative studies using external consultants were used to identify patient/physician’s dissatisfaction with currently marketed nasal sprays (see Table 1).

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DEVELOPMENT OF A NOVEL INTRA-NASAL SPRAY PRODUCT

Risk analysis

Container closure system The intra-nasal product was developed by first-intents to mitigate the following potential risks associated with the delivery system: – Potential instability of the formulation due to inadequate protection during shelf-life (chemical, physical and microbiological effects) – Potential change in formulation composition and performance arising from moisture loss/uptake – Potential incompatibility of formulation and product contact materials (novel degradation and/or leachable/extractables ) – Potential variability of in vitro/in vivo performance as a result in variation of key device component attributes (ex-device spray characteristics) – Potential variability of in vitro/in vivo performance due to inability of device to maintain prime between doses (ex-device spray weight characteristics) Container Type I glass was selected to minimise the potential for leachables and adsorption of the drug product and to minimise moisture loss/uptake or adsorption of other components. Amber glass was selected to provide protection from ambient light as there was a slight increase in impurities observed after exposure of unprotected drug substance to high intensity light. The bottle was shaped to minimise the overall size of the device with a nominal fill volume consistent with the target fill weight for the commercial product.

continued

Table 1. Patient/carer/physician’s preferences for new intra-nasal steroid spray Patient/carer/physician’s preferences

Novel intra-nasal spray desired attributes

1. Reduced post-nasal drip

Dose volume (100µL) will be half that of the established gold-standard market leader (200µL)

2. Scent-free

Removal of scented additives

3. Removal/reduction of additives that might cause nasal stinging/burning

Removal of phenyl ethanol and minimisation of BKC (benzylkonium chloride)

4. Device is easy to use correctly and is suitable for use by paediatrics

The novel side-actuated device is designed for self-administration by patients of 7-years and older (see Figures 1 and 2). Specifically, with respect to ergonomic design and lever force. The device is designed to have the minimal number of steps to use (shake, open, actuate, close). The device is designed to have features preventing accidental actuation

5. Easy to use correctly by carers for administration to young children (>2 to <7-years)

Side-actuated device facilitates carer administration (see Figure 1). Actuation of device by carer (or patient) does not require contact between fingers/nose, as with currently marketed devices (see Figure 2).

6. Shorter, smaller device nozzle. Less opportunity to irritate/damage nasal membranes of children, particularly very young children (>2 to <7-years)

Re-designed nozzle (see Figure 3) and actuation mechanism

7. Product retains prime once actuated

Flexible stopper inside cap seals the nozzle, preventing drain back and loss of prime

8. Consistent dose

The pump is actuated with a consistent force, and it is not dependent on the actuation force (7-year child vs. 25-year old man). This minimises potential operator variability.

9. Ability of patient to assess volume of remaining product (reduces ullage)

There is a level indicator window incorporated into device

Intra-nasal pump Critical Quality Attributes (CQAs) were identified to assure that the pump provided the required performance for the product. The pump must be capable of metering a consistent volume of the formulation throughout the life of

the product (50µL). The pump must be manufactured to appropriate dimensional controls to assure a reproducible fit to the neck of the bottle and between the pump stem and the nozzle. The pump was constructed using materials selected to have low potential to leach into aqueous formulations. Formulation development risk strategy

Figure 1. Side actuated device (left) facilitates carer administration, compared to top actuated devices (right)

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The formulation was developed to mitigate the anticipated risks associated with a low dose suspension formulation: – In-homogeneity of drug product arising from manufacturing process or sedimentation/surface enrichment of API over time – Variability of spray characteristics

DEVELOPMENT OF A NOVEL INTRA-NASAL SPRAY PRODUCT

continued

development holistically (from both formulation and device perspective) significant efficiencies were introduced and problems could be assessed and addressed rapidly and effectively.

levels, to minimise irritation, particularly in paediatrics. Conclusion

Figure 2. Side actuated (left) and standard top actuated (right) nasal sprays.

– As a result of changes in key excipient attributes – Inadequate protection against microbial contamination, e.g., during ‘in-use’ dosing – Patient discomfort (part of design intent) These risks were addressed by inclusion of a suspending agent that is sufficiently well characterised/controlled to prevent variation in the DSD of the drug product, an isotonicity agent that adequately controls the tonicity and a robust, broad spectrum preservative system that has been optimised at the minimal effective

Using a combination of Quality by Design (QbD) and specific regulatory guidance, a novel side actuated intra-nasal product was rapidly developed and subsequently commercialised. Extensive focus on the design intent and in particular, patient/physician’s dissatisfaction with currently marketed nasal sprays allowed issues to be anticipated and addressed at the design stage. By approaching the

References 1

Guidance for Industry. Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products. Chemistry, Manufacturing and Controls Documentation. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2002. Soane, R.J., Frier, M., Perkins, A.C., Jones, N.S., Davis, S.S., Illum, L. Evaluation of the Clearance Characteristics of Bioadhesive Systems in Humans, Int. J. Pharm., 178, 1999, 55-65. Kippax, P., Huck, D., Levoguer, C., Virden, A., Suman, J. Characterising a nasal spray Formulation from Droplet to API particle size, Pharm. Tech. Europe, February 2011, 34-39. Guidance for Industry, ICH Q8(R2) Pharmaceutical Development, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), November 2009. Guidance for Industry, ICH Q9 Quality Risk Management, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), June 2006.

Figure 3. Carer administering product using side actuated device (26-month old child).

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PHARMACEUTICALS

HEALTHCARE

AND

Edited by Tim Sandle and Madhu Raju Sag hee

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SWOT ANALYSIS USING GENERAL MORPHOLOGICAL ANALYSIS Application to the Specials Sector for new Business Drivers

(GMA), a problem structuring method, which we have reported before in this journal4 that permits the structuring and analysis of highdimensional problems. Such problem complexes are often nonquantifiable, contain ineradicable uncertainties and cannot be causally simulated or modelled in a meaningful way.

by Nasir Hussain, Bruce Garvey and Thomas Ritchey

Process description using a pharmaceutical case study

To test the validity of SWOT-MA™ process, an actual case example involving a start-up niche generic firm was considered for the following focus question: “What are the most important factors to secure drug approvals within funding time frame of 3 years”. In most cases, regulatory authorities require clinical testing in human volunteers of the generic drug against the original innovator medicine whose patent (or more correctly data exclusivity period) has expired, i.e. bioequivalence studies. In rare circumstances, drugs of ‘wellestablished use’ and those that meet certain criteria (BCS Class 1) are given ‘biowaivers’ particularly if reference can be made to original drug dossier5. Figure 1 shows a SWOT we generated to address the problem. In all, 22 factors were identified in the four parameters. This would necessitate that 840 unique

he humble SWOT (Strengths, Weaknesses, Opportunities and Threats) is a remarkably simple problem structuring framework. Ubiquitously taught in business schools, it is often the first port of call in many organisations to map out tactical approaches for short to near term projects. Since its introduction by Albert Humphrey1 in the 60s, however, it has surprisingly undergone little revision – the lack of facilitation of constructing a SWOT in the business setting, particularly the haphazard way of inter-relating the various elements within each quadrant, has failed to realise the technique’s true potential. The authors are Founding Partners of Strategy Foresight, London, UK. Email: hussain@strategyforesight.org

In their seminal paper, Hill and Westbrook2 from London Business School cited that seasoned strategy professionals displayed similar deficiencies when performing a SWOT analysis — “long lists (over 40 factors on average), general (often meaningless) descriptions, a failure to prioritize and no attempt to verify any points.” Most worrying was the universal finding that noone subsequently used the outputs in the later stages of the strategy formulation. The more pertinent question remained: what, if any, was the output? In this paper, we report a major improvement of how a SWOT should be constructed and analysed by using the process of Cross Consistency Assessment (CCA), transforming it into an actionable framework. Here, each and every suggestion from each quadrant is compared pairwise to test for compatibility. The CCA is similar to a cross impact analysis except that no

directional or causal linkage is assumed but merely mutual consistency in the arguments. CCA is actually an essential element of General Morphological Analysis3 Strengths 1. Low overheads (e.g. head count) 2. Specialist testing outsourced 3. 4. 5. 6.

Simple dosage forms (solutions, creams) Fixed private funds Strong marketing & distribution network Generating income from Specials dealing which funds R&D 7. Contracted out Specials manufacturing Opportunities 1. Further increase Specials operations 2. Diversify into more high-risk, highreward dosage forms (e.g. suspensions) 3. Seek new indications of existing drugs 4. Ability to raise funding

Weaknesses 1. Agency theory… 2. Limited experience of team in securing the full process of licensing 3. Limited staff – spread too thin 4. Licensed manufacturing 5. Limited monthly budget/lack of flexibility 6. Limited key equipment e.g. HPLC

Threats 1. Regulatory guidelines being more strictly interpreted 2. Same drug licensed by another company – reduced market share 3. Bioequivalence trial costs escalate 4. More data required for biowaivers by regulators at Day 105 5. Difficult to obtain original dossiers

Figure 1: A SWOT analysis examining internal and external factors to be taken into account by a niche generic drug firm to ensure drug approvals within fixed funding timeframe (of three years).

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SWOT ANALYSIS USING GENERAL MORPHOLOGICAL ANALYSIS

continued

configurations be considered by the working group, an onerous task given the lack of time in many organisations and, more importantly, the lack of a dedicated computer software able to capture the pairwise assessments (there are 279 unique pairs for the SWOT alone). Since a 3-dimensional problem (pitting three dimensions against each other) can be represented as X Y Z columns, the four dimensions of a SWOT can easily be converted into a 4-fold morphological field as shown in Figure 2. The reader will Figure 2: The four parameters of a SWOT displayed as a 4-fold morphological field – or notice, however, an 5-fold if one adds the output. In this example, there are 267 unique pairs and 3,360 additional output simple configurations (a configuration is a string of cells with each cell only appearing parameter, namely the once – one shown). Ansoff’s Matrix has been bolted onto the threat” (e.g. increased Figure 3 displays the CCA – SWOT. This is an essential step to governmental regulation but lack intersecting cells denoted by ‘X’ make sense of what one is trying to of regulatory personnel within the were deemed incompatible as achieve with the SWOT-MA™ firm) assessed by the working group exercise, i.e. the output – the – Weaknesses and Opportunities: whereas blank cells signified that principal objective of this paper, and “How can we circumvent an either the two conditions were indeed of the SWOT. In this external threat to the project or compatible, or operated in two instance, the workshop team organisation given an internal different spheres of activity without concluded that of the wide variety of weakness?” impacting on each other. The role of management models available6, the Cross-analysing some conditions objective facilitation and the product/market diversification can become cathartic – for example meaning afforded by comparing model of Ansoff best suited the is it meaningful to compare internal different parameter blocks cannot company’s near term aims and strengths and weaknesses, be over-emphasised. In this context, current activities (of specialised particularly when such conditions some of the questions asked during provision of unlicensed medicines are mirror images that can offset the CCA included: and product registration). A more each other? For example, having – Strengths and Threats: “Can we mature company in its business low fixed costs (strength) tolerates overcome a potential threat in the lifecycle may well have considered the weakness of possessing limited external environment with our another output such as the (specialist) equipment (as such internal strength?” Horovitz’s framework, which assets are relatively illiquid, and – Strengths and Opportunities: evaluates cross-market/sector require maintenance and service “Can we exploit an opportunity in expansion strategies by pitting the contracts). In other instances, such the external environment with our dimensions of the ease of entry vs. as pitting weaknesses against internal strengths?” cultural fit7. opportunities, it becomes a concern: – Weakness and Threats: “Given For the CCA, the CARMA® “What is the impact of having our internal weaknesses, how can software reformats the limited equipment (a weakness) on we circumvent external threats?”, morphological field into a matrix the ability to exploit a particular or “What is the impact on the that easily allows a facilitator (e.g. organisation if the internal opportunity?” In the first situation, it the project manager) to conduct the weakness reinforces the external there is no impact because each exercise with the project team.

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continued

Figure 3: The entire problem space identified in a morphological field can be dramatically reduced by Cross Consistency Assessment. Whereas in a morphological field the number of configurations increases exponentially with each additional dimension (for example SWOT alone gives 840 configurations cf. 3,360 with the addition of the Ansoff column), the number of Cross Consistency Pairs does not increase in proportion (179 vs. 267). For a relatively small morphological field, few tens of pairs need to be ‘knocked out’ to obtain a manageable solution space.

condition operates in separate set or universe (i.e. the conditions are uncorrelated), whereas in the latter case, there is a meaningful comparison to be made. Note that a third level of output was also achieved with the use of user-defined keys (K, S, and F), which considered empirical constraints (i.e. conditions that

would be possible if one only had enough time, resources, etc). This is an important facet as SWOT is an evolving, dynamic framework that needs to be revisited on a periodic, basis. Using dedicated software, notes can be taken for each intersecting cell such that an electronic audit trial of how the decision was arrived is available for

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sake of transparency, auditing, due diligence, and timeline analysis. Picking the winning strategy

Performing the CCA resulted in 23 unique configurations out of a possible 3,360 combinations, a reduction of over 99% of the entire problem space – previous projects have seen a reduction in over 99.9%

SWOT ANALYSIS USING GENERAL MORPHOLOGICAL ANALYSIS

with much larger morphological fields that have contained 105 – 106 configurations. A deeper analysis of strengths and opportunities yielded some expected and more significantly unexpected results. The principal strength was in fact the ability to fund company operations from income being generated from wholesaling and brokerage arm i.e. 7 of the 23 configurations contained the cell ‘Specials income funds R&D’ – not particularly surprising given that ‘cash is king’, especially when a company has a fixed amount of (private) funding. However, at the start of the company’s founding, this activity was too readily dismissed, as the market for dealing in Specials (see Box) was considered highly volatile and uncertain8. The ability to generate cash naturally allowed all outputs to be considered except ‘Product Development’, a totally unexpected result (diversification was expected to fall out). The point here is that multiple scenarios can be considered, the dynamic model can be driven from the desired output (and what would the required inputs to get to the desired output state, i.e. reverse engineering) and more importantly the contrast, i.e. those cells which do not show up. When the inference model was considered in its entirety, a hitherto unconsidered opportunity emerged. Whilst applying for a market authorisation of an unlicensed product, it can be supplied as a Special – this selffunds the submission procedure provided it is within the same disease indication. Such gap analysis is only possible using a very structured and facilitated framework, to which GMA is fully attuned. Mapping and connecting the entire landscape

Assessing multi-dimensional sociotechnical problems amongst stakeholders without experienced facilitation and purposeful software, leads to sub-optimal decisionmaking and waste of resources. This is not surprising when one considers

how teams make decisions without mapping out the entire ‘messy’ problem landscape. As observed by Michael Pidd in his book Tools for thinking 9: “one of the greatest mistakes that can be made when dealing with a mess is to carve off part of the mess, treat it as a problem and then solve it as a puzzle, ignoring its links with other aspects of the mess.” Early stage companies face three principal types of uncertainties – commercial feasibility, technical feasibility and the managerial ability to execute, particularly when the management team has not worked together before10. In such situations, the non-linear connectivity of innumerable factors in a rapidlychanging environment and the subjective judgments when interrelating even the most marginal of factors are rarely captured or facilitated in any meaningful manner.

continued

SPECIALS Some patients have special clinical needs that cannot be met by licensed medicinal products. So that these special needs may be met, UK law allows manufacture and supply of unlicensed medicinal products (commonly known 'specials') subject to certain conditions, e.g. Viagra liquid suspension is given to neonates with pulmonary hypertension – the original manufacturer, Pfizer, only produce a tablet form, and for a very different condition!

competitive potential) can assess the internal Strengths and Weaknesses. The various configurations that emerge within a smaller solution design space can subsequently lead to the development of possible scenarios, which is the desired output in business analysis and decisionmaking frameworks.

Conclusion

In this paper, we have attempted to describe how problem-structuring methods such as GMA can vastly improve analytical tools, such as SWOT, in the context of business management. GMA, however, functions upstream in mapping the totality of the problem space by developing an exhaustive inventory of all its possible solutions. By using the CCA procedure, the synthesis of internally consistent multiple solution concepts (i.e. the design space) can be isolated and tested against possible outputs, intended, and unintended, ahead of time. We believe that such an approach can be applied to other commonly applied business management tools where multiple parameters must be considered. For example the PESTEL framework (an analytical tool to identify different environmental factors affecting business strategies) can be worked in the manner described here to develop the Opportunities and Threats of the SWOT, and the VRIO12 concept (resource capability of the firm that determines its

References 1

SWOT Analysis. Available at http://en.wikipedia.org/wiki/SWOT_analys is (accessed 10 September 2011). 2 Hill T, Westbrook R. SWOT Analysis: It’s Time for a Product Recall. Long Range Planning 1997; 30: 46-52. 3 Ritchey T. Problem Structuring using Computer-Aided Morphological Analysis. J Operat Res Soc 2006; 5: 792-801. 4 Hussain N, Ritchey T. Wicked Problems. Eur J Ind Pharm 2011; 31: 4-7. 5 Gupta E et al. Review of global regulations concerning biowaivers for immediate release solid oral dosage forms. Eur J Pharm Sci 2006; 29: 315-24. 6 Van Assen M, Van den Berg G and Pietersma P. Key Management Models. London: FT Press; 2009. 7 Horovitz J, Kumar N. Strategies for retail globalisation. Editors: HEC, IMD, Templeton College and Oxford Mastering Global Business. London: FT Press; 1998. 8 Colquhoun A. Special measures – time for a healthy debate on specials procurement. Pharm J 2010; 285: 481-88. 9 Pidd M. Tools for thinking: modelling in management science. 2nded. Chichester: John Wiley & Sons; 2003. 10 Improving the quality and quantity of investment grade deal flow. City University Research & Enterprise Unit; 2010.

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HOME HEALTHCARE – it’s people not products that count by Dan Formosa

ealthcare is not about the products that companies create – it is about the ultimate effect the product or service will have on someone's life. While this may sound obvious, many medical companies seem to know much more about their products than they know about the patients their products are meant to treat. This isn’t because they don't care or consider it unimportant. But many (and it’s probably fair to say “most”) medical researchers and engineers are not trained in even the basic elements of human behaviour, perception and physical ability. This significantly limits the opportunity to fully realise the benefits of the pharmaceuticals or medical devices that companies create. Dan Formosa, PhD is a founding member of Smart Design, Barcelona, Spain, New York and San Francisco, USA. e-mail: dan.formosa@smartdesignworldwide.com. www.smartdesignworldwide.com

In view of the staggering statistics on non-compliance and dropout rates, everyone would benefit if more attention were paid to these human-centred issues. Two topics are of special interest in my design research in the field of healthcare: the impact of design on behaviour, and the ways in which people behave under stress. The impact of design

Pharmaceutical companies rarely consider the ability of design to influence patient behaviour for purposes of improving the efficacy of their medications or treatments. Yet this presents tremendous opportunity for companies that have traditionally focused solely on the formulation of a medicine. Drug delivery devices and packaging represent two critical touch-points for patients that can contribute to improved compliance. This not only helps the patient, it ensures continued sales, a stronger brand presence and better health outcomes. Skimping on either the device or the package can be a costly mistake. Our design group sees lots of examples of products and

packages that we call wellengineered-but-not-well-designed. Which means, yes, it may work technically, but that accomplishes little if patients are unable or unwilling to use it. Design in some cases can be the most influential component in adherence to a regimen and improvement in personal health. This is important in view of the fact that, for some people, even fear of death may not be a sufficient motivator. One example of “design for compliance” that our firm Smart Design created involved the design of a new syringe for use with Cimzia, a biologic medication for rheumatoid arthritis (RA) patients. Because RA patients have limited strength and dexterity, self-injection can be difficult. While our design team was enlisted to help re-design both the syringe and the packaging, we re-directed the assignment. We set our focus not on the syringe and package themselves, but on compliance. We asked ourselves what could we add to the design of Cimzia's delivery system to help patients take their medication successfully?

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This shift in focus made a considerable difference in the questions we asked ourselves and patients, and on the design solutions we conceived. The packaging, for instance, isn't simply a box to protect the medication – it is an opportunity to walk patients through the steps required to take the medication properly. We opted for a format reminiscent of a storybook, with left and right flaps. Rather than simply empty the contents on the table, our format put us in “design control” of the components as the package is opened by the patient, using an organised and easy-to-understand left-to-right sequence. Also rare, even when design is being addressed, is a good understanding of usability and behaviour under varying levels of stress. Even simple tasks such as taking a blood pressure reading can create anxiety in some people, the so-called “white coat” effect. Under stress, the mind and body work differently. So for all the thought and logic that may have been put into a task flow for medical devices, that development often takes place without any realworld context. This means a designer’s or engineer's logical explanation of how a product works and how it is supposed to be used can make perfect sense in the lab – but not once the product is at home in a kitchen or bathroom. Its use may sound simple enough in theory, but unfortunately for the patient a medical company won’t be sending a suitably trained nurse or technician to every single home to explain how simple that product is to use! Behavioural aspects

From the many pleasant or annoying examples in our daily lives we all know that our behaviours are influenced, for better or worse, by the products, services and environments that surround us. Home healthcare products are no different. A patient's actions will determine to what extent a product or service will work. His or her ability and willingness to operate the device or

HOME HEALTHCARE

perform a task will ultimately determine the reputation of that product, service or brand and, more importantly, whether the patient is likely to comply with the treatment. Medical devices that look like medical devices can be intimidating. While the patient may be the only person to use the device, he or she may not be the only person to see it. The same is true of packaging. Visual impact should not be ignored. A badly designed package or medical device can make a patient feel sicker than he or she actually is, or it can give that impression to others around him or her. It can also prompt a patient to hide the device in a drawer or cupboard instead of keeping it in a more accessible location that could encourage use. Visual appearance can also affect the willingness of the patient to bring the device along when travelling. Many medical conditions are serious, of course, and the appearance of a product or service should reflect that – but medical products and services also need to integrate neatly into peoples' homes and lives. An illness does not define a person. He or she is very much the same person he or she was before the illness. This is one of the reasons why it is advisable when developing medical products to meet and get to know patients personally. Without that, it’s easy to fall into the trap of imagining a patient, and grouping him or her into an average that can unnecessarily conjure up stereotypical and misleading images. The first six months

Soon after the diagnosis of an illness comes awareness of the products, services or brands that are available. As a patient's need arises so does the willingness to use those products. Healthcare companies are in a unique position to initiate emotional connections with patients during the first few

continued

months of an illness. This relationship can be long term and truly meaningful. Patients will be most interested, curious and apprehensive after being diagnosed or started on a new treatment. That start-up period, up to the point where the patient is on “cruise control,” where it has been worked into their regular routine, deserves special attention. That is, extra special care should be taken early on, when patients may be avoiding use, reacting according to individual preconceptions of how they think a product may work, or concerned about what effects they believe they might experience. The so-called out-of-box experience – literally the first 20 minutes of use – is critical to establishing a relationship between the patient and the product, service or brand. Failing to get started within this time window, due to difficulty of use or confusion, can lead to product returns or refusal to use the device or take the medicine. For example, the number of returned sleep apnoea products can account for one-third of total sales! The product may work as designed, but the design was just too difficult for patients, who were confused about how to use it. The days, weeks or months immediately following first-time use are also critically important in shaping behaviours and attitudes. Establishing proper behaviour early is a project unto itself, and it should be addressed accordingly. Usability

I have identified the following pattern, a hierarchy of usability. People first respond according to instincts, then preconceptions – the latter being somewhat unpredictable. Following that, people will react to physical cues, making three-dimensional design a powerful tool. Communicating proper use through 3-D design is a much stronger driver than printed words. A day-to-day example is a door handle, a problem we have all

experienced. We are likely to pull on a handle if it is shaped like a pull handle, even if it is clearly marked "push" – especially true when we are in a hurry. Following that, simple graphics, simple text and other types of colour coding can be effective in directing behaviour and usability. As for printed instruction sheets or user guides – calling a friend, a doctor or a toll-free number may precede that option for many people. Home healthcare: It’s not you, it’s us

There are many good reasons to move healthcare tasks from hospitals and clinics to the home. Cost and convenience are at the top of the list, and technology continues to make this possible. However, the move to the home will be most effective when those technologies are extremely usable. The future of home healthcare, and the speed and extent to which it will develop in the next decade, will depend on the ability of patients to successfully use and understand the products we provide. Our ultimate goal is extreme usability, allowing untrained people to use the advanced-technology medications and devices we make available. Companies have an opportunity to help patients comply with health regimens by realising that design affects behaviour. Good design takes into account both the physical and psychological needs of the patient. The fact that design can heavily affect success or failure means that influencing the attitudes and behaviours of patients should be well within the definition of responsibilities of a product development team. While this approach should be followed whenever a new technology becomes available, there is also opportunity to apply it to existing medical products and technologies – a move that can make us all healthier now.

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regulatory review The current review period has seen a number of changes in the regulation of medicines and regulatory guidance in the EU, International markets and the USA.

United States of America Contaminated steroid injections – USA Multistate Fungal Meningitis Outbreak The Centers for Disease Control and Prevention (CDC), in collaboration with state and local health departments and the FDA is investigating a multistate fungal meningitis outbreak among patients who received contaminated steroid injections. Several patients suffered strokes that are believed to have resulted from their infections. The investigation also includes fungal infections associated with injections in a peripheral joint, such as a knee, shoulder or ankle. FDA has confirmed that implicated medication has not been exported to any EU country.

Europe Guideline (for comment) on quality of oral modified release products This guideline concerns quality aspects, especially pharmaceutical development and in vitro testing, of dosage forms in which the release of active substance is modified. It is restricted to gastro-resistance and prolonged release oral dosage forms. Pulsatile and accelerated release dosage forms and delayed release dosage forms with other principles are not covered. However many principles discussed will be relevant to other modified release dosage forms intended for oral administration or via other routes. Reflection paper on medicinal product supply shortages caused by manufacturing/GMP Compliance problems This Reflection Paper is concerned with public health crises that arise due to unforeseen disruptions within the

manufacturing process, caused by manufacturing/GMP compliance problems. While control and supervision of the national market remains a national responsibility, the Network is increasingly looking to the European Medicines Agency (EMA) to develop and communicate appropriate risk management measures arising from unexpected shortages in supply. This Reflection Paper summarises the lessons learned from previous crises where the EMA had a supporting or co-ordinating role, and presents short and mid-term actions that may allow the Network to prevent, mitigate, and manage shortages of important medicinal products. EU GMP Guide The European Commission has proposed changes to the EU GMP Guide. These include: Draft Concept paper on revision of Annex 15

The need for this revision arises from significant changes in the (GMP) environment via ICH Q9 and Q10, the updating of the guideline on process validation, advancement in manufacturing technology through process analytical technology and the continuous manufacture concept plus many changes to other chapters and Annexes. Draft Concept paper on revision of Annex 17

Originally the main foreseen application area for Parametric Release was sterility testing. Changes in GMP consequent to the adoption of ICH Q8, Q9, Q10 and Q11 and the recently published guideline on real-time release testing have broadened the scope of the Annex. MHRA Public consultation (MLX 379): Transposition of Directive 2011/62/EU (“the Falsified Medicines Directive”) into UK legislation The Falsified Medicines Directive substantially changes the European framework concerned with the supply of medicines, and may capture

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businesses that have traditionally not been directly regulated e.g. internet platforms based in the UK offering medicines for wholesale or retail supply, which may be considered to be brokering or offering “sales-at-adistance”. MHRA wins High Court case on wholesaler dealing MHRA has written to all those holding wholesaler dealer’s licences reminding them of the regulations following a recent High Court case. The core of the judgment is that in order to comply with legislation holders of wholesale dealer’s licences (even if they also operate as a pharmacy) must only obtain medicines from another wholesale dealer licence holder or from a licensed manufacturer. Notification of imminent request for active substance information MHRA is contacting UK-based MA holders to request data on active substance imported into the UK for manufacture. The aim is to minimise the risk of potential shortages of human medicines by identifying high risk suppliers which may need to be inspected by an EU authority as they cannot meet the requirements for certification by competent authority of the exporting third country that the plant manufacturing active substances operates in compliance with EU GMP or with equivalent rules

International Revised PIC/S GMP Guide

The revised PIC/S GMP Guide (PE 009-10) will enter into force on 1 January 2013, as will the corresponding changes to the EU GMP. The revision concerns Chapter 4 & Annexes 6, 7, 11 and 13. For further information on these and other topics we suggest you refer to the websites of relevant regulatory bodies and to current and past editions of “GMP Review News” published by Euromed Communications. To subscribe to this monthly news service contact: info@euromed.com

news from the EIPG Welcome to our new Swedish delegate

Regional Pharmacy Union of Sofia Meeting in Bulgaria.

Following the move by Pär Tellner to work for EFPIA in Brussels, the Board of the Swedish Pharmaceutical Association has appointed Marianne Andersson, Regulatory Affairs, AstraZeneca as the new contact person for EIPG in Sweden. We welcome Marianne and bid farewell and thanks to Pär and wish him every success in his new job. Marianne’s email address is: Marianne.andersson@astrazeneca.com).

Claude Farrugia delivered a lecture co-authored with Gino Martini to a large meeting of pharmacists in Sofia (of 900 registrants, 8-10% were industrial pharmacists). During Claude’s visit, Evgeni Grigorov and Valentina Belcheva set up a series of meetings with academics including the Dean of the Faculty of Pharmacy and the ProRector (who is a member of staff of the Pharmacy Faculty), as well as with leading members of the pharmacy profession in Sofia from the Regional Pharmacy Union of Sofia (the largest of 7 chapters of the Bulgarian Pharmaceutical Union.)

The PHAR-QA (Quality assurance in pharmacy education and training in Europe)

The second stage of the PHARMINE project has been funded by the EU and Nuno Moreira attended the “kick off” meeting of the Consortium in Brussels on 30th October. The management of the 5 working parties and networks for this exercise were agreed. LifeTrain (An Innovative Medicines Initiative (IMI) Education and Training Project)

In November, employers, course providers and professional scientific bodies were brought together with the aim of producing an agreed position paper on a European Common Framework for continuing professional development. As a member of a regulated profession, Jane Nicholson was asked to speak on Developing a Competency Profile for industrial pharmacists. On-Course, another IMI initiative, is now the most comprehensive biomedical and medicines research and development postgraduate course portal in Europe (www.oncourse.eu)

European Medicines Agency’s (EMA) Meeting with Interested Parties 28th Nov.

The main topics of discussion were the medicinal product shortages due to manufacturing and quality issues and the implementation of the Falsified Medicines Directive. The EMA update on their work plan provided a summary of the present position on GMP and GDP guidance: Final & Upcoming final guidelines l GMP Guide Chapter 2 (2012Q4) l GMP Guide Chapter 7 l GMP Guide Annex 2 l GDP Guideline – FP (EC-2012Q4) Upcoming public consultations l GMP Guide Chapters 3 & 5 + SWP toxicological guideline (dedicated facilities) (EC-EMA-2013Q1) l GMP Guide Chapter 6 (EC-2012Q4) l GMP Guide Chapter 8 (EC-2012Q4) l GMP Guide Annex 15 (EMA concept paper) (EMA-2013Q1) l GMP Guide Annex 16 (EMA drafting on going) (EMA-2013)

GMP Guide Annex 17 (EMA concept paper) (EMA-2012Q4) GDP Guideline – API (draft to be adopted Nov 2012) (EMA2012Q4/2013Q1) Proposal to include definition of importer and apply guidance to importers, EC to consult Standing Committee GMP Risk Assessment Guideline – excipient (draft to be adopted Nov 2012) (EMA-2012Q4/2013Q1) API Inspection Trigger document – revision (draft to be adopted Nov 2012) (EMA-2012Q4/2013Q1)

EudraGMP database l

New Module: GDP (FP & API) and API registration (26 Feb 2013) – regulators and users of API New Module: 3rd countries inspections planning (Dec 2012) – regulators only

The GDP guideline (FP) is being updated to reflect current practice. The GDP guideline has been completely revised based on numerous comments received during the public consultation. The chapter on transport remains. The wholesale requirements for transport have been revised. The final GDP guideline (FP) will come into force 6 months after publication in the Official Journal. Bureau meeting in January 2013

An EIPG Bureau meeting will be held on Saturday 13th January. For any items that members wish to raise with Bureau members, please contact me at: jane@nicholj.plus.com

Jane Nicholson

Visit the website: www.industrialpharmacy.eu for PharmaTV and Quality by Design videos, Regulatory Review, Financial Pharma News and other current items concerning Industrial Pharmacy

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events JANUARY 23 & 24 January 2013 – London, UK Social Media in the Pharmaceutical Industry www.social-media-pharma.com 28 & 29 January 2013 – London, UK European Pre-filled syringes www.prefilled-syringes.com 28-30 January 2013 – Cambridge, UK Stability testing of pharmaceuticals www.rpharms.com/courses

18-19 February 2013 – London, UK Advances and progress in drug design www.drug-design.co.uk

26 February-1 March 2013 – Berlin, Germany Pharmaceutical Microbiology www.europe.pda.org/Micobio2013

19-20 February 2013 – London, UK Real world outcomes strategy for pharmaceutical products www.healthnetworkcommunications .com/evidence

MARCH

26-27 February 2013 – Barnard Castle, UK Cleaning validation www.honeyman.co.uk 26 February-1 March 2013 – London, UK The business strategy of affordable medicines www.healthnetworkcommunications .com/generic

30-31 January 2013 – London, UK Pharmaceutical Microbiology www.smi.online.co.uk

FEBRUARY 5-6 February 2013 – Lyon, France Modern biopharmaceutical manufacturing www.europe.pda.org/Biopharm2013

26 February-1 March 2013 – London, UK Innovations in development for the biosimilar industry www.healthnetworkcommunications .com/biosimilarseu

6-7 February 2013 – London, UK Parallel Trade www.parallel-trade.com

26 February-1 March 2013 – London, UK World Generic Medicines Congress www.healthnetworkcommunications.com

7 February 2013 – London, UK Assuring the Quality of Medicines www.jpag.org

3-7 March 2013 – Sorrento, Italy 3rd International Conference on Multifuncational, Hybrid and Nanomaterials www.hybridmaterialsconference.com 4-6 March 2013 – Copenhagen, Denmark 7th Annual FEI EMEA Front End for Innovation www.IIRUSA.com/FEIeurope 12-14 March 2013 – Barnard Castle, UK Cleanrooms: Principles in Practice www.honeyman.co.uk 21 March 2013 – London, UK Progress and challenges in pharmaceutical harmonisation www.jpag.org 31 March-3 April 2013 – Lisbon, Portugal 9th World meeting on pharmaceuticals, biopharmaceutics and pharmaceutical Technology www.apv-mainz.de

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