european Industrial Pharmacy Issue 11 (December 2011)

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PLACING EXCIPIENTS AT THE HEART OF SAFE MEDICINES In the absence of comprehensive EU regulations, industry groups are developing their own GMP/GDP principles for excipients. by Iain Moore and Flavia Arce


PROGRESSION IN TABLET COMPRESSION Although many attempts have been made to make tablet compression a scientific study, fast consistent production of high-quality tablets can still be considered an art rather than a science. by Dale Natoli


SPRAY DRIED BIODEGRADABLE POLYMERS FOR CONTROLLED DRUG DELIVERY SYSTEMS Various process parameters were used to compare the morphology of different biogradable polymers in order to demonstrate the production of microspheres for controlled drug delivery using a mini spray dryer. by Cordin Arpagaus and Nina Schafroth



LOST IN TRANSLATION Whereas technical translations generally pose few problems, translation of Patient Information Leaflets (PILs) from English into other European languages needs specific expertise. by Inger Askehave and Karen Korning Zethsen

CHALLENGES FACED BY COMPANION DIAGNOSTICS Three major issues are holding back rapid growth in the market: greater cost than standard therapies, reduction of the doctor’s choice and protection of patient’s privacy. by Kenneth P Krul


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Associate Editors Belgium: Kristina Bindus, Bart de Greef Bulgaria: Valentina Belcheva

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PHARMACY Issue 11 December 2011 ISSN 1759-202X

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EDITOR Joe Ridge, MRPharmS

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


Cover picture: Scanning Electron Microscopy of spray dried microspheres of different polymer types (see page 10).

e u ro pe an I ND U STR IA L PHARMACY • Issue 11 December 2011


As we approach the end of 2011, I would like to reflect on two particular items which made an impact on me: the value of such associations such as the EIPG and the falling numbers of young Pharmacists entering this exciting but fluid sector of Pharmacy. Associations

This year EIPG has interacted with the European Commission, the European Community Pharmacy Association (aka PGEU), the European Association of Hospital Pharmacists (EAHP) and the European Federation of Pharmaceutical Industry Association (EFPIA). It was at an Interested Parties meeting organised by the European Medicines Association (EMA) that I first heard the worrying comments that "there were too many associations and that it was difficult to achieve consensus". As recent events unfold around us with respect to the European economy, it is plain to see that seeking consensus is difficult to achieve across so many member states. However, I completely disagree that Associations such as EIPG do not hold value or should not have a say or be surpassed by larger trade associations. If one is to review our statutes conferred in 1966 in Paris, one can plainly see that the EIPG was created to represent the Individual Industrial Pharmacist, to support this fine Industry and more importantly to ensure that Industrial Pharmacy continues to attract young talent (refer to: I think the words Individual Industrial Pharmacist are so important and distinct that I have emboldened and underlined them! I believe that organisations such as EIPG play a vital role when it comes to reviewing new directives or regulations. I know due to our review process that we are offering diverse but real grass roots feedback and not just the view of a small

group of large organisations. I also believe that good decision making can only occur on the richness and diversity of the data provided to make that decision – restricting data influx from a small number of organisations is clearly bad practice. Hence, I am determined to make the EIPG a more proactive voice of the Industrial Pharmacist during 2012 and we will be coordinating resources accordingly to achieve these aims.

Falling numbers of students entering the Industry

I read with some interest recently about the reasons why India has become a powerhouse for innovation. One of the reasons, and these are their words not mine, was that: "Western companies are blocking their talent pipelines. Without that route, how will tomorrow’s senior leaders emerge?" Well that's what they say. What I can say is that when I was invited to present to the European Pharmacists Students Association (EPSA) I was very pleasantly surprised to see so many students attend the event and to understand the various career opportunities open to them. To see the so many keen and eager young pharmacists to be (from Romania, Finland, Germany, Spain, UK, France, Bulgaria, Turkey, etc) was absolutely fabulous! At this forum held in Birmingham at The University of Aston in October, I was able to announce the intentions of the EIPG to offer a mentoring and career advice to students. All people have to do is to contact me or Jane Nicholson, Executive Director for EIPG, or their own national association and EIPG will link that student with an appropriate advisor or help with their enquiry directly. Without experienced Industrial Pharmacists investing their time and energy into young talent then sure enough the words from India

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willl come back to haunt us. Next year in 2012, the EIPG will forge even stronger links with EPSA to make sure we can help as many students as we can. Before I finish this editorial, I would like to thank a number of key individuals who this year have made the EIPG the success it has been. I would like to thank Jane Nicholson who has provided stalwart support to the committee throughout the year. I would like to thank Dr Claude Farrugia from Malta who has diligently updated the EIPG website and helped the committee keep abreast of the latest European Directives. I would like to thank Pär Tellner from Sweden who has worked so hard in representing the EIPG at a number of forums dedicated to Education and Training for Industrial Pharmacy. I would like to thank Carmen Castañón from Spain who made the General Assembly in Madrid a huge success. Finally, I would like to thank all the Bureau and General Assembly members who make the EIPG what it is, a fantastic and truly representative body for Industrial Pharmacists. And of course, to Joe Ridge and the team in Euromed Communciations and to you the readers who have made this Journal a success as well. I wish you all, a very Merry Christmas and a Glorious New Year. Yours sincerely

Professor Luigi G Martini, FRPharmS, MBA. EIPG President; Chair in Pharmaceutical Innovation, King's College, London




he humble excipients that go into the formulation of a medicinal product rarely capture the attention commanded by active pharmaceutical ingredients, but are critical and essential components of drugs. Their functions are many. Some excipients help to transport the API to the site in the body where it is supposed to exert its activity, protecting it so it can exert the optimal therapeutic effect. Others make sure the API is released at the right time or place, thereby avoiding potential side effects. Some help to identify a product if its authenticity is in question, while others aid patient compliance by improving the taste or appearance of a medicine. A good and consistent quality

Despite being inactive, excipients generally make up the bulk of a medicine in terms of weight and generally have well-defined functions in a drug product. Clearly, that makes it important that they are of good and consistent quality, as even minor deviations in an excipient can have a significant impact on its pharmaceutical functionality and performance. Patients rightly expect that any medicine they take has been manufactured to the highest standards and, while this is true most of the time, recent manufacturing problems affecting even the largest drugmakers are evidence that this is not necessarily assured. Moreover, there have been several cases in recent years where serious adverse reactions have been attributed to the excipients used in a drug product. Dr Iain Moore is Chair of the Global Excipient Certification Project – EXCIPACT. Dr Flavia Arce is a Board Member of IPEC Europe. Correspondence: Vicente Hernández Vázquez Email:


For example, in Nigeria in 2008, at least 84 children aged between two months and seven years died as a result of deliberate substitution of the widely-used excipient glycerin with diethylene glycol in a teething mixture. An incident in Panama the previous year led to the

deaths of 21 people after taking a cough syrup made with diethylene glycol that had again been mislabelled as glycerin. Another 38 people were affected by side effects including disorientation and kidney failure. These are all thought to be cases of economically-motivated adulteration (EMA), a phrase defined by the US Food and Drug Administration as the "fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e. for economic gain." There are plenty of examples of EMA outside the excipient arena, notably the case involving contamination of the active pharmaceutical ingredient heparin in 2008 that led to dozens of deaths around the world. In this case, a toxic adulterant was added to heparin in order to boost its apparent activity. GMP for excipients

Ensuring that the excipients used in medicines are of appropriate quality is the responsibility of the medicines manufacturer under European law. However, the increasingly complex supply chains in the pharmaceutical industry caused by globalisation in raw materials sourcing illustrate the difficulties faced by companies sourcing excipients and other raw materials. In the Panama case above, the glycerin/diethylene glycol passed from a supplier in China not registered to supply pharmaceutical grade products through the hands of several companies and traders before being bought by the pharmaceutical manufacturer. The European Commission has been looking at remedying this situation for several years. In 2005 it published a series of amendments to Directive 2001/83/EC on medicinal products for human use 1-3 to mandate the development of a Good Manufacturing Practice (GMP) system for excipients in order to bring them into line with other constituents of medicinal products. Achieving this has been a hard task, however, and even today is still some way from being completed. Overall there are more than 1,200 excipients in use in medicinal products – not including colours and flavours – but

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P LAC ING EXCIPIENTS AT THE HEART OF SAFE MEDICINES only about 300-400 have monographs in a recognised pharmacopoeia. This range of excipients – from simple sugars to complex polymers – means that ‘pharmaceutical’ GMP standards, i.e. those enshrined in Eudralex vol IV Part 2 for active pharmaceutical ingredients, are unlikely to be implemented for any but a handful of excipients. Other standards needed

A significant barrier to developing effective legislation has been the diffuse nature of the excipient market and the lack of a defined excipient industry, with players in the sector spanning commodity food ingredient manufacturers through to companies that specialise in functional ingredients for pharmaceuticals. Fears have been voiced that overly stringent GMP requirements – for example at the same level as those applied to APIs – could levy a disproportionate cost burden for excipient suppliers which only provide a small proportion of their overall output to the pharmaceutical industry. It has also been suggested that the cost of compliance for these companies could rise to unbearable levels, so they may choose to stop supplying their products to the industry at all and lead to shortages. Meanwhile other standards such as ISO 9001, widely used in other industries such as food, do not go far enough in their present form, so pharmaceutical manufacturers and excipient suppliers alike have been forced to rely on self-regulatory measures such as auditing, quality agreements and other business approaches to help ensure excipient quality. These considerations have been recognised by the European Commission, whose early efforts to develop a Directive on GMP for excipients focused initially on a limited list of certain high-risk excipients, such as those derived

from human or animal material, intended for use in sterile preparations or known to be associated with criminal activity, such as glycerin or propylene glycol. After reviewing an Impact Assessment report on the proposed directive 4 – which concluded that the risk posed to patients in Europe from excipients was very small, and that the cost of implementing formalised GMP would far outweigh any public health benefit – the European Commission decided to abandon the plan in 2009.5 Instead, it said it planned to develop an alternative GMP strategy for excipients based on the reform of existing legal requirements on manufacturing and quality control. EXCIPACT system

Faced once again with a regulatory vacuum, industry groups such as IPEC Europe, the European Fine Chemicals Group (EFCG) and European Association of Chemical Distributors (FECC) have taken matters into their own hands and are trying to develop a universallyapplicable scheme based on appropriate levels of not only GMP but also Good Distribution Practice (GDP). The aim is not only to help ensure medicine quality, but also to alleviate the burden of inspections and audits on manufacturers, excipient suppliers and regulatory authorities. The system – called EXCIPACT 6 – is based on the concept of thirdparty certification of suppliers to a consistent and well-thought-out set of standards covering not only GMP but also other important elements such as Good Distribution Practice (GDP). The overall aim is to develop GMP and GDP principles for excipients as an annex to the widely-used ISO 9001 Quality System, allowing excipient manufacturer and distributor companies to include certification as part of their ISO 9001 registration audits.

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Critically, the idea is to develop a network of third-party auditing companies who will certify excipients suppliers and distributors to the EXCIPACT standards, taking that task out of the hands of the pharmaceutical manufacturer or indeed the regulatory authorities, which are already struggling to meet the inspection demands of drug products and APIs, let alone excipients. If the audit is successful and accreditation is awarded, the drug maker can then purchase excipients from that supplier with a degree of assurance that the firm was providing quality materials. The EXCIPACT partners held a public stakeholder review of the standard manual during the first part of this year and aim to launch the certification scheme by the end of 2011. As progress with EXCIPACT continues, however, the legislative situation has continued to evolve, primarily as a result of the European Directive on Falsified Medicinal Products, which was published by the European Commission on July 1, 2011.7 In its initial draft this document did not cover excipients, focusing mainly on three key areas: obligations for nonwholesaler medicines distributors, obligatory safety features such as serial numbers and improved seals, strengthened regulations governing inspections and imports of active pharmaceutical ingredients (APIs). Since the initial draft in 2008, revisions by members of the European Parliament and Council of the European Union have extended the scope of the Directive to include excipients, and once again introduced the concept of a list of ‘certain’ excipients subject to tighter controls based on a risk assessment of their source and intended use. The final version has taken the approach even further, with the requirement that the authorities define how to classify excipients based on their potential risks to the patient.


P LAC ING EXCIPIENTS AT THE HEART OF SAFE MEDICINES From this analysis the excipient user can then judge if the GMP applied in the manufacture of the excipient is suitable for their application. Such a pragmatic approach is warmly welcomed, as it permits all parties to judge what is and what is not suitable in their particular set of circumstances. In this regard it seems to have been acknowledged that one size does not fit all when it comes to excipients. Tragically though, the European authorities have done nothing concerning the distribution of excipients and it will remain up to industry led initiatives like the IPEC Good Distribution Practices Guide to fill this particular vacuum on a voluntary basis. After all, the deaths associated with glycerin were not so much about failures in manufacture as in the supply chain. IPEC Europe believes that a certification scheme such as EXCIPACT has the ability to


contribute to safer medicinal products by setting minimum manufacturing standards, and minimum distribution standards which can be independently verified – this will raise standards across the industry, but without creating unmanageable administrative bottlenecks. If the three main players on the stage – excipient suppliers, pharmaceutical manufacturers and regulators – can work together to develop and agree a practical and useful approach to GMP for excipients, it can only serve to enhance patient safety. References: 1


Directive 2004/27/EC amending Directive 2001/83/EC on medicinal products for human use. cals/eudralex/vol1/dir_2004_27/dir_2004_27_en.pdf Directive 2004/24/EC amending, as regards traditional herbal medicinal products,






Directive 2001/83/EC on medicinal products for human use. cals/eudralex/vol1/dir_2004_24/dir_2004_24_en.pdf Regulation (EC) 726/2004 on medicinal products for human and veterinary use and the European medicines Agency. cals/eudralex/vol1/reg_2004_726/reg_2004_726_en.pdf Excipients Impact Assessment Report – Europe Economics, 2008. cals/pharmacos/docs/doc2008/2008_02/exci p_report_20071219.pdf DG ENTR Conclusions on Study on Pharmaceutical Excipients, 2009. cals/pharmacos/new_en.htm White Paper – International Excipients Certification Project: Minimize risks Maximize benefits. _on_Excipients_certification_Update_V3.pdf Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products. l-1/dir_2011_62/dir_2011_62_en.pdf.

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n pharmaceutical and healthcare planning sectors, a modelling environment must interrelate diverse issues such as technology development, national policy directives, organisational structure, public perception, ethical issues and educational requirements. Furthermore, it should be able to take account of global forces shaping healthcare novel emergent business models. The most common problem encountered in tablet manufacture would have to be granulation adhering to the tool face, commonly known as 'sticking'. Tablet manufacturers often have to struggle through compressing a batch of sticky product, and sometimes – due to the severity of the sticking – are unable to compress any tablets at all. Typically, sticking is unnoticed or unrecognised during product development and so will often commence and/or worsen once the product reaches production when the dynamics of weight, friction, heat, powder flow, segregation and dwell time, to name but a few, come into play. For most companies, sticking can be difficult, if not impossible to avoid. At the production level, this can affect operating efficiency and productivity, and dramatically increases manufacturing costs – not to mention the effects on tablet quality, that can affect consumer confidence and the perceived effectiveness of a product.

Dale Natoli is President of Natoli Engineering Company, Inc., Saint Charles, MO, USA. Email:

All too often, tablet manufacturers will revert to a punch coating that promises to eliminate sticking by promoting enhanced product release. In general, these coatings are costly and, in our experience, are less than 50 per cent effective. Also, adding a punch coating to the equation introduces a variable that is difficult to monitor and virtually impossible to troubleshoot. Thus, before deciding on a coating, it is better to explore the many different steel grades that can offer improved product release. These steels will typically be higher in chromium than standard tool steels and much easier to troubleshoot than a punch with a coating – when and if sticking continues.

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The most important factors for consistent tablet production are tablet press cleanliness and proper maintenance. Improperly set or maintained lower punch retainers is a common cause of variable tablet weight and hardness, whereas improper or inconsistent tool working length would typically be responsible for any deviation in tablet hardness and thickness. Improper fill cams can also be responsible for inconsistencies in tablet production; if the fill cams are too deep, excessive granulation is taken into the die, then discharged at the weight cam and re-circulated. If the feeder cannot reclaim this granulation, it will bypass the feeder and accumulate at the neck of the turret; hence, the centrifugal force of the spinning turret will propel the granulation outward and refill the dies after passing over the weight cam – resulting in weight variation. Proper product flow is also crucial to uniform tablet compression; granulation that flows evenly is conducive to higherquality tablets. Speed

The most important contributor to tableting speed – or indeed to tablet production – has been the acceptance of multi-tip tooling. This has been used for decades in the industrial, food and confection industries, but only in the last 10 years has multi-tip tooling been accepted and used in the pharmaceutical industry on rotary tablet presses. Tablet manufacturers producing micro-tabs are experiencing speeds of over 5,000 tablets per second. The main concern with using multi-tip tooling is the ability to compress consistent-quality tablets and – if not – then the ability to validate the tablet reject system to ensure that out-of-spec tablets are discharged. We expect to see faster press speeds in the future, as this is the long-term scope for virtually all premium tablet press manufacturers. Frank Stokes is believed to be the engineer responsible for designing the rotary tablet press during his employment with Parke Davis in the late 1800s. The same basic design – using cams to vertically move the tooling through the various cycles of tablet



Figure 1. Cross sections of various configurations of Fette die segments. compression in a turret, with upper and lower punches and dies – is still used today. The first rotary tablet presses produced 400 to 600 tablets a minute, whereas the modern tablet presses of today can produce more than 100,000 tablets per minute. Innovation is simply matter of time. Granulation

Having chosen a suitable excipient, proper granulation is essential for overall tablet quality. Problems such as sticking, picking, poor hardness, friability and product flow can result from improper granulating. As a consequence, excessive fines can be formed, resulting in tableting problems such as tool binding, product scorching or discoloration, and excessive tool and press wear. This seems to be a common issue with tablet manufacturers today, as dry direct compression blends have become the preferred method.


Over-blending a granulation is another concern that is generally overlooked and can occur in the tablet press itself. The rotary force feeder of the tablet press should always be considered as a mini blender. The feeder paddles aggressively move the granulation into the die bores, and if the feeders are overfilled and/or run at too high a speed, the granulation continues to be blended. This can result in the over-blending of what may have been a good granulation. Advances in technology

In the past decade – other then multi-tip tooling as mentioned earlier, the most significant advances have been the Fette Die segments, and the Courtoy die ring and die shells. Fette developed a turret configuration that eliminates the use of traditional dies and die-locks that hold the dies secure in the die table. The die segments have two

major benefits. Firstly, they increase the number of stations in a given diameter of a turret, thereby increasing the number of tablets produced per turret revolution. Secondly, they dramatically reduce tablet press set-up time by eliminating the lengthy and painstaking process of setting each die in position. Instead of handling, cleaning and maintaining individual dies, the die segments require two bolts per segment and are locked positively in place, while maintaining the proper alignment of the punches into the segment bore. The Courtoy die ring also has advantages over conventional dies and is more versatile as it allows the use of traditional dies, or alternatively a unique die configuration called die shells that are held in position without the use of traditional die locks. Unlike the Fette die segments, the Courtoy system uses a single piece

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P ROGRESSION IN TABLET COMPRESSION (Cont.) replaceable die ring that substitutes for the traditional die table of a turret. To remove and replace the die ring, the turret's upper and lower section separates allowing unrestricted access to the die ring for removal and installation. Again, increasing the number of stations in a given diameter of a turret increases the number of tablets produced per turret revolution, while use of the die ring instead of conventional dies and die locks dramatically reduces press set-up time. Tooling sizes and materials

A variety of sizes and configurations are available, with each configuration having a unique benefit. The most common configurations are the 'B' and 'D' types, which are available in the American and European cam format. The 'B' type is smaller in scale than the 'D' type and is considered the most common; it is used by virtually all pharmaceutical tablet manufacturers. In general, the different configurations are determined by the maximum available tonnage, and the output or speed of a tablet press due to fewer tooling stations in a given turret diameter. Tablet compression tooling is also available in a variety of materials. In order to maintain efficiency, it is advisable to evaluate several steel types to determine which material will be best suited for a particular product. High chromium steels tend to be preferred over standard steel for better product release, but have a tendency to be more brittle – and so are not best suited for some tablet shapes or granulations requiring excessively high compression tonnage. However, most products are suited to multi-tip tooling technology. Considerations include tablet size, compression force, product sticking, ejection force and the overall condition of the tablet press. Multi-tip tooling provides a

substantial increase in production, resulting in a highly efficient tabbing programme. In most cases, a tablet manufacturer can expect an increase in output of approximately 80 per cent for each additional tip. For example, if a press is producing 3,500 tablets per minute, then by adding an additional tip the output will be 6,300 tablets per minute, and the addition of a further tip will raise output to approximately 9,100 tablets per minute. Micro-tab punches

Micro-tab tooling is a unique tool configuration, engineered to reduce distortion or breaking of the punch tips, as occurs more commonly with the lower punch. The microtip configuration should be considered for all tablets under 4mm in diameter, and for tablets of 5mm or smaller requiring an excessively high compression force. The micro-tab tool configuration shortens the upper and lower punch tips in order to gain strength, making the punch tips more robust. In order to shorten the lower tip, a special undercut must be machined in the bottom of the die to accept a portion of the smaller punch barrel in order to have the proper tip length for tablet ejection.

“Tablet land”

Tablet land generally has the appearance of a small flat ridge around the perimeter of a tablet. Sometimes, it can be confused with poor quality tablets, which have a small raised crown around the tablet perimeter; this is commonly referred to as 'flashing'. Passing tablets through a vibrating machine called a de-duster helps to remove the soft feather edge, reducing dust accumulation during packaging and edge attrition during the coating process. The degree of flashing is dependent on punch and die clearance, tool wear, particle size and tablet design. There is a misconception regarding land as an undesirable attribute – especially for film-coated tablets, whereas in fact it is just the opposite. Designing land into a tablet design will help to strengthen the edge of the tablet, allowing for easier film coating and extending tool life. Summary

There are many factors that need to be taken into account to ensure the fast, consistent production of high-quality tablets. Tablet compression can therefore be described as more of an art than a science.


Proper cleaning of compression tooling can be a long and tedious task. Many tablet manufacturers that need to clean several sets of tooling per day have implemented expensive and automated washing systems equipped with hot air drying to reduce spotting and surface corrosion. Regardless of the method used, the most important factors to use a cleaning agent suited for carbon tool steels. The use of hot water for rinsing elevates the temperature of the tooling to aid in the immediate drying process and reducing the possibility of surface discoloration and spotting.

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Article adapted from an interview published earlier this year in Innovations in Pharmaceutical Technology.




iodegradable polymers based on polylactide (PLA) and its copolymers polylactide-co-glycolide (PLGA) were successfully spray dried with the Mini Spray Dryer B-290. Process parameters were found to prepare spherical particles with a smooth or structured surface. A literature review demonstrates the feasibility to encapsulate different drugs in biodegradable microspheres for controlled drug release. Spray dried microparticles have a suitable size and shape for new application fields in pulmonary therapy, cancer treatment or medical devices. Introduction

The glass transition temperature of the polymer depends on the glycolide content. It decreases with higher glycolide amount.

Spray drying is a successfully employed method in pharmaceutical technology to prepare micro particles for controlled drug delivery systems.1,2

Generally, the spray dried particles are amorphous because there is no time to form crystalline structures during the fast evaporation process.5

Other common methods to produce microspheres are emulsification, solvent evaporation or phase separation. Compared with other methods, spray drying is a simple, rapid, reproducible and easy to scale-up method.3 It is a one stage process, allowing mild temperature conditions.4 The spray drying technique is less dependent on the solubility of the drug (e.g. hydro solubility) and the polymer.2 The purpose of this study was to demonstrate the use of spray drying of biodegradable polymers based on lactide and glycolide acids. Materials

In this study poly-lactide acid (PLA) and poly-lactide-co-glycolide acid (PLGA) biopolymers were used. Cordin Arpagaus, PhD, is Product Group Manager for spray drying at Büchi Labortechnik AG, Flawil, Switzerland Email:


Mini Spray Dryer B-290 from BÜCHI Labortechnik AG (Switzerland).

The biopolymers are a white, amorphous, odourless powder with a neutral taste. The more hydrophilic types of polymer are indicated with a H at the end (free hydrogen bond).

Process conditions

For the preparation of micro-particles the biopolymers were dissolved in dichloromethane (DCM), which was chosen because of its high solvent capacity for PLA and PLGA biopolymers 6 and low boiling point of 40°C. It is considered one of the least toxic halogen solvents.7 Polymer type, concentration and inlet temperature were varied, with air spray flow and aspirator rates kept constant at 600 l/h and 100%, respectively. The liquid feed rate was set to maintain a constant outlet temperature during the spraydrying process. Results and discussion Polymer influences

As can be seen from the SEM pictures of spray dried microspheres of different polymer types (FFigure 1), Resomer microspheres appear in general to be spherical with a relatively smooth and closed surface, whereas the surfaces of

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Figure 2. SEM morphology of PLA R-202H microspheres prepared by spray drying at different polymer concentrations 1.5%, 5%, 10% (w/v).

Figure 3. Effect of different polymer concentrations on particle size for the R-202H biopolymer.

the Purasorb microspheres show some irregularities, incompetently formed particles and big agglomerates.

particle size distribution is homogeneous with some bigger individual particles.

This was probably due to the high molecular weight of the Purasorb polymer.4 The particles had a tendency to build up agglomerates (up to 100µg size) due to adsorption force of the small particles on the surface. This is a sign of high surface energy of the amorphous spray dried material. Concentration

Figure 1. SEM micrographs of spray-dried microspheres of different polymers, A: R202H, B: R502H, C: RG752S, D: Purasorb 50:50, E: Sample CR, F: Purasorb 53:47.

Figure 2 shows the influence of concentration (1.5%, 5% and 10% w/v) of R-202H at 55°C inlet temperature on the morphology. The pictures reveal completely formed microspheres with spherical shape and smooth surfaces. The

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Moreover, increasing the concentration from 1.5 to 10% resulted in a bigger particle size (FFigure 3). Dichloromethane evaporates quickly and renders microspheres more spherical.8, 9 Temperature influence

The surface of the spray dried particles at 55°C was spherical and smooth, whereas at higher temperatures the treated particles had a shriveled surface, small craters and collapses (FFigure 4). It was concluded that the inlet temperature has to be sufficiently low to allow solvent evaporation (boiling point of dichloromethane is 40°C) but not too high to prevent


S PRAY DRIED BIODEGRADABLE POLYMERS (Cont.) Lactide to glycolide ratio

Figure 6 illustrates spray dried particles of the same molecular weight but different lactide to glycolide ratio produced at 5% polymer concentration. No significant difference in shape was noticed between the microspheres of different ratios. However, the ratio has influence on the drug release properties.4 With a higher glycolic acid content, both the amorphous and hydrophilic properties increase and facilitate the release of a loaded drug.10 Reported drug release rates

Data in the literature revealed that the drug release profile typically exhibits two phases. At the beginning there is a steep increase (so called “burst effect”), followed by a second sustained release period. The “burst effect” in the first 12-24h is attributed to the release of drug from the more superficial area of the microspheres.2,9,11 Initial bursts of 20 to 60% are reported in the literature.7-9 Figure 4. SEM observation of the PLA (R-202H) spray dried powders obtained at 55°C, 65°C and 75°C inlet temperature.

Figure 6. SEM pictures of spray dried biopolymers with different lactide to glycolide ratio. R-202H (PLA, 100:0), R502H (PLGA 50:50) and RG752S (PLGA 75:25).

destruction of the polymer. The outlet temperature in the drying chamber has to be kept below the glass transition temperature of the polymer. Viscosity

Figure 5 shows the influence of the viscosity and molecular weight on the morphology of Purasorb biopolymers (PDLA, 50:50) at a constant concentration of 1.5%. A higher viscosity was seen to increase particle size, which was also found by Schöttle5 and Pavanetto et al.4

Figure 5. SEM pictures of Purasorb polymers (PDLA, 50:50) at two different molecular weights and viscosities (0.2 and 1.05 dl/g).


At high molecular weights, the forces needed to break up the liquid filament into droplet are insufficient, which leads to incomplete formation of particles and big agglomerates.2

The second phase of release is determined by the diffusion of the drug through small pores or channels in the polymer matrix.12 Drug release data clearly prove retarded profiles compared to pure drug samples. The high loading efficiency from 50% up to 100% is typical for spray drying.13 The reason for this is that the drug cannot separate into an external phase, as is the case with solvent evaporation.12 Highest encapsulation efficiencies are obtained with the lowest amount of drug added to the polymer.4 In vitro drug release from the particles can be altered by selection of the used copolymer.13 Drug release studies from the literature revealed typically lower drug release rates at higher inlet temperature (denser polymer matrix), higher air flow rate (smaller particle sizes), lower polymer concentration (reduced porosity) and lower drug loading (less pores, less diffusion).

e u ro pe an I ND U STR IA L PHARMACY • Issue 11 December 2011


An average yield of 46% was achieved. These values are comparable with results obtained by other authors of 37-49% 9, 30-40%8 or 40%.1 Most of the product loss was found as a deposit in the spray chamber and in the outlet filter after the cyclone. Product deposition on spray chamber walls can result from semiwet particles or from sticky deposits caused by the nature of the product which has a high affinity to the glass walls. Small particles less than about 1 micron may go directly to the filter from the separation cyclone.

Spray drying is promising to be the method of choice in preparing powders for new application fields in pulmonary therapy, cancer treatment or medical device applications.

the air spray flow from 400 to 800 l/h reduced the mean particles size from 8 to 4µg. Conclusions

The development of biodegradable microparticles by the spray drying of polymers such as polylactide (PLA) and its copolymers polylactide-coglycolide (PLGA) appears to be an attractive alternative to conventional micro-encapsulation techniques, like phase separation or solvent evaporation.

References 1

2 3 4

Spray drying is a one-step method, allowing fast processing of small batches at reasonable yields.

An aspirator rate of 100% gave good results. A high spray air movement through the dryer enhances the separation efficiency in the cyclone.

Spray dried microparticles have a suitable size and shape for inhalation applications. Process parameters are found for the production of spherical particles with a smooth or structured surface.

A higher air spray flow through the nozzle reduces the mean droplet size. A higher relative velocity between gas and liquid produced smaller droplets due to the increased shear force. This higher atomizing energy consequently led to smaller particles and narrower particle size distributions. Increasing

The feasibility of the Mini Spray Dryer models B-190, B-191 and B290 is further demonstrated by results from several literature studies. The collected data show the possibility to encapsulate different drugs in biodegradable microspheres for controlled drug delivery systems.


6 7 8 9


11 12 13

Conte U, Conti B, Giunchedi P, Maggi L. Drug Development and Industrial Pharmacy. 1994; 20(3): 235-258. Bodmeier R, Chen H. J. Pharm. Pharmacol., 1988; 40, 754-757. Masters K. Spray Drying Handbook, 5th ed. New York, John Wiley & Sons (1991). Pavanetto F, Genta I, Giunchedi P, Conti B. J. Microencapsulation, 1993; 10(4): 487-497. Schöttle I.A. Spray Drying of PLA and PLGA micro particles for controlled release of pulmonary dosage forms, Dissertation, University of Mains (2006). Youan B.C. Drug delivery, 2004; 11, 209-214. Fu Y.J, Mi F.L, Wong T.B, Shyu S.S. J. Microencapsulation, 2001; 18(6): 733-747. Wang F.J. Wang C.H. J. Microencapsulation, 2002; 19(4): 495-510. Blanco M.D, Sastre R.L, Teijon C, Olmo R, Teijon J.M. J. Microencapsulation, 2005; 22(6): 671-682. Rivera P.A, Martinez-Oharriz M.C, Rubio M, Irache J.M, Espuelas S. J. Microencapsulation, 2004; 21(2): 203-211. Wagenaar B.W, Müller B.W. Biomaterials, 1994; 15(1): 49-54. O’Hara P, Hickey A.J. Pharmaceutical Research, 2000; 17(8): 955-961. Lee L.Y, Wang C.H, Smith K.A. Dspace at MIT, online available, (2007)

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www.euromedcomm e u rop ea n I N DU ST RI AL PHARMACY • Issue 11 December 2011


LOST IN TRANSLATION? When patient information crosses borders by Inger Askehave and Karen Korning Zethsen


his article deals with an aspect of patient information that differs somewhat from the traditional scope of this journal; namely the linguistic and translational aspects of Patient Information Leaflets (PILs). During the past decade much work has been dedicated to making the English PILs as informative and lay-friendly as possible. However, much of the good work is ruined when the PIL is translated. Why is this so and what can be done about it? A general note on translation

Native speakers of English may well think: “Is translation such a big deal?” But as Danes (coming from a small country of 5 million people who speak Danish) we know for a fact that translation is very important, and part of our everyday lives. A study from Finland shows that about 40% of what is read by a person during a day has been translated (ranging from the latest bestseller to the list of ingredients on the back of a product).1 In spite of this, translation has only become professionalised very recently and is not considered a high-status job. In fact, translation is often not considered an expert function and in many countries ‘translator’ is an unprotected title. Add to this that translation comes last in the production chain of documents and you are asking for trouble. Three types of translation

Karen Korning Zethsen is Professor at the School of Business and Social Sciences, Aarhus University, Denmark, where she heads the Research Group for Translation and Interpreting. Inger Askehave is Pro-rector and Professor in Professional Communication at Aalborg University, Denmark


Translation is much more than translating from one language into another, and when we talk about PILs, there are three types of translation that are all relevant to the production of PILs in Danish and other EU languages. Drawing on the work of the famous linguist Roman Jakobson,2 we will refer to these types of translation as:

• Intralingual translation • Interlingual translation • Intersemiotic translation Intralingual translation is a question of

rewording within the same language: Example:

“Keep out of reach of children” is translated or reworded into: “Keep your tablets where children cannot see or reach them” Interlingual translation or translation proper is a question of translating from one language into another: Example:

“Keep out of reach of children” is translated into Danish: “Opbevares utilgængeligt for børn” And, finally, intersemiotic translation is a question of replacing a verbal message with a picture or drawing: Example: “Keep out of reach of children” is translated into a pictogram:

Thus, although translation in its many forms is really essential for patient information leaflets, it is not often recognised as essential! Why is translation problematic in relation to PILs?

Patient information leaflets have the largest and most varied target group possible, namely potentially the entire population of a country. This means that people with all kinds of backgrounds should be able to read, understand and act upon the information provided, as the law requires. However, the fact that PILs not only involve text production but also at least two aspects of translation in their production process, makes the task of producing readable, understandable and lay-friendly PILs even more complex. Consider the production process of a Danish PIL (FFigure 1). Often problems begin to appear already at the stage of intralingual translation when the English PIL is created on the basis of an English Summary of Product Characteristics (SmPC). The problem is that the intralingual translation (which in this case involves going from an expert text to a lay

e u ro pe an I ND U STR IA L PHARMACY • Issue 11 December 2011

LOST IN TRANSLATION (C ont.) direct translation and writes “kwinder i den fødedygtige alder”, but also introduces the synonym “fertile kvinder” (in English “fertile women”). This means that in the Danish version patients may be in doubt as to whether the two expressions refer to exactly the same group of women – as they clearly do in the original. Passive voice Figure 1: Representation of the production process of a Danish PIL.

text) does not always take place to a sufficient degree, and so the PILs may end up with:

• Medical terminology transferred without explanation • Inconsistent use of synonyms • Extremely complex sentence structure • Too many passives, etc. The above are a few of the problems we have identified in our research through the years and which may have a very negative impact on layfriendliness. However, in this article our main focus is on interlingual translation, or translation proper, where we move from one language to another. This is because our research has shown that the quality of Danish PILs (and many other translated PILs we assume) suffers not only from the intralingual translation but also from the translation proper. In other words, even in cases where the English PIL is in fact very lay-friendly and has been successfully reworded for a lay audience, the Danish version is not. EMA’s notion of translation

The European Commission, in its guideline to applicants for marketing authorisations3, appears to indicate that a lay-friendly text in English will lead to a lay-friendly target text in the other 22 European languages.. This is supported by the fact that only the English original has to be user tested in order to be approved, but there is no systematic testing of the 22 translations. From the point of view of Translation Studies this is a dangerous assumption.

Furthermore, the Danish translation (made on the basis of the English original) is provided by the marketing applicant and is mainly checked by European Medicines Agency (EMA) for technical correctness. In other words, this is a system which strongly favours very direct translations: i.e., translations which do not take into consideration the different languages involved but which are easy to check from a technical point of view. Danish PILs are typically translated by pharmacists, i.e. people with medical backgrounds and no translational skills. This is unfair on Danish patients, as well as on pharmacists who struggle with a task for which they are often illequipped. The result of this lack of translation competence is that these de facto translators do what research shows people do when they are translation novices; they make very direct translations – often at the expense of lay-friendliness. Let us give you a few examples of authentic PIL translations which go against the overall goal of layfriendliness. Inconsistent terminology

It may be easy for an expert reader to recognise that two different words may in fact be synonyms. But this is not as easy for a lay person: Example:

An English PIL uses the expression “women of childbearing age”. The Danish translator makes use of a

e u rop ea n I N DU ST RI AL PHARMACY • Issue 11 December 2011

The direct and active voice in many English leaflets is unfortunately often replaced by a passive and indirect voice in Danish, derived from much more formal language: Example:

Source text: “If you feel tired, do not drive a motor vehicle or operate machinery” Target text: “Forsigtighed tilrådes ved bilkørsel og maskinbetjening” Literally: “Carefulness is recommended at car driving and machine operation” In this way the agent, that is the person who is supposed to act in the leaflet, is hidden. Focus on the doctor, not the patient

The English originals are generally much more interactive: Example:

If the English leaflet says “Why you have been given…” it is often (in Danish) rendered as “Why the doctor has prescribed…” Latin – a true lingua franca ?

The vocabulary of the Danish translations is much more formal than in the English originals. One aspect in particular — Latin-based terminology, is a very frequent source of expert terminology finding its way into the texts for laymen. It is a well-known phenomenon for those working with PILs that expert medical terminology should be avoided as far as possible. But it is less well-known that Latin-based


LOST IN TRANSLATION (C ont.) terminology plays a very different role in different languages and may, when translated directly, pose significant problems to the layreader in another language. This is certainly the case between English and Danish.

When Latin-based medical terms, understood by all English people, are directly transferred into Danish, the level of formality is drastically raised and lay-friendliness suffers greatly. When laymen are involved, Latin is simply not a lingua franca.

In English-speaking countries the Latin expressions of e.g. body parts or illnesses have in many cases merged with common language to such a degree that no Anglo-Saxon alternative exists. But to the ordinary Dane such Latin words and expressions are either incomprehensible or very formal. A Danish doctor may well use the word “appendicitis” (with a Danish pronunciation) when speaking with his colleagues. But the average Dane would not have a clue what “appendicitis” means. The table below gives some examples of Latin-based English terminology being replaced by typical Danish layman expressions:

A fast and smooth approval procedure

The development of new pharmaceutical products takes many years and the approval procedure is the last step before the product can be marketed and start making a profit. The need to obtain marketing approval as quickly as possible means that the approving authority becomes the immediate recipient of the translation and the two purposes of the translation: correct and layfriendly consumer information and fast marketing approval, are likely to be in conflict.

Latin based English term

Common Danish term

Literal/direct translation



“Body mother”

Ulcer (stomach)


“Stomach wound”

Varicose veins


“Vein knots”

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As illustrated by the examples above, it is important to create awareness of the fact that the translation of PILs often plays havoc with all the efforts invested in the improvement of the English original. A lay-friendly English original, as well as a professional translation, are prerequisites for improved understanding and adherence among the general public. If translators were seen as experts and their function on a par with medical expertise in connection with the development of PILs the two purposes of the translation may not be in conflict. Proper translators would be employed (as they undoubtedly are by some of the major international Pharmas), there would be enough time and money allotted to their work. There would be time to co-operate with pharmacists and other medical experts and there would be time and money to properly user-test all versions. Trained translators would also be able to remedy defects in the original – remnants of unsuccessful intralingual translation (when translating the SmPC into a PIL). Otherwise lay-friendliness may be “lost in translation”.


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References 1 Salmi, Leena: “Translations around us – the amount of translated text in everyday life” 2010.pdf (accessed 12 Oct. 2011). 2 Jakobson, Roman “On linguistic aspects of translation”. In: Venuti, Lawrence (ed.) (2000): The Translation Studies Reader, London and New York, Routledge, pp. 113118. 3 en.pdf

e u ro pe an I ND U STR IA L PHARMACY • Issue 11 December 2011


Despite these promising benefits, the use of companion diagnostics for personalized medicine applications will not have an easy passage to and through the market.



s the field of nucleic acid therapeutics emerged, the link between genomic data and therapeutics grew stronger, and so did the idea that therapeutic problems can be solved by genomics and related biomarker testing. The pairing of a diagnostic test to a therapeutic agent, the essential element of companion diagnostics or “theranostics”, a combination of the terms “therapeutics” and “diagnostics”, as it has become to be called, is in some cases already a reality and predictions are being made for its future success. Theranostics are considered the pathway to what is often called personalized medicine. This has given the diagnostics field a huge boost in terms of publicity/public attention, revenue potential and investment interest. Yet, questions exist as to how extensive such testing will be and how soon we will see its growth in clinical practice. There are many hurdles to overcome. Researchers are confident, however, that these can be handled. It is now possible to characterize diseases such as cancer by their molecular profile. Historically, the diagnostic classification of cancer has been based on the organ or tissue location where it originated in the body, e.g. pancreas, lung, stomach. These days, cancers can be classified by the genes that are expressed, the tumour's cell surface proteins and other molecular attributes. Such information may lead to understanding how cancer may spread and which therapeutic route may be the most effective.

Kenneth P Krul, PhD, is a senior analyst for Kalorama Information. Email: kkrul@kalorama

Challenges facing companion diagnostics

Many experts believe that if such testing is included in clinical practice, we could be looking at an entirely new era of health care delivery. Such testing may provide substantially more information about a patients’ condition, including disease susceptibility and progression and likely drug responses. Due to the potentially predictive nature of such testing, the expectation is that it may form the basis for preventive interventions.

e u rop ea n I N DU ST RI AL PHARMACY • Issue 11 December 2011

First, the molecular diagnostic tests associated with companion diagnostics face the challenge of a healthcare finance system that has become dependent on visible disease symptoms and gross clinical classifications. Simultaneously, the ability to classify diseases into distinct molecular subcategories challenges traditional pharmaceutical business models that focus on one-size-fits-all drugs. As a result, the economic rationale for personalized medicine in healthcare decisions needs to be based on the cost savings that result from proactive and preventive interventions.

Physicians’ attitude

Physicians have an uneasy relationship with clinical diagnostics as it is. Despite the fact that they need this information to properly diagnose their patients, it is an aspect of their practices that is beyond their control. Physicians, by their very nature, must feel in control of the patient's care. What companion diagnostics and personalized medicine are asking them to do is to accept direction in prescribing for their patients. If that direction is contrary to their experience, it raises conflict.


Currently, the legal picture in the USA regarding medical privacy issues that may affect personalized medicine and companion diagnostics is a patchwork of federal, state, and local laws. The Health Insurance Privacy and Portability Act (HIPPA) not withstanding, these offer various levels of protection against the misuse of genetic information.


Biomarker discovery is another issue. Companion diagnostics have largely been the product of biomarker discovery. The identification of biomarkers, however, has mostly been a Continued on p19








Since the publishing of the Human Genome in 2003 researchers and companies have been scrambling to commercialize affordable technologies that will allow every person to have a copy of his/her genome. As the technology progresses the goal is to have people own a flashcard with their genome sequence that will help establish personalized medicine. The 1000 Genomes Project (, an international research consortium was launched in January 2008. It involves sequencing the genomes of at least a thousand people from around the world to create the most detailed and medically useful picture to date of human genetic variation. The project is supported by the Wellcome Trust Sanger Institute (Hinxton, UK), the Beijing Genomics Institute (BGI Shenzhen, China), and the National Human Genome Research Institute (NHGRI), part of the U.S. National Institutes of Health (NIH). Data from the 1000 Genomes Project will be made available to the worldwide scientific community through freely accessible public databases. With current technology, the cost of sequencing is now estimated to be approximately $50,000 and the time of sequencing can take several weeks. But companies are promising to bring the time down to minutes or hours and the price to $1000 in the near future and $100 eventually. Why the $1000 target? It is expected that once costs drop under $1,000 per sequence, more people will have their genome done. Once this is correlated with demographic and medical information, researchers will gain a much better understanding of the relationship between genetics, diseases and drug metabolism. A number of companies, reference labs and DTC test services have been developing sequencing technology that may make faster, inexpensive DNA sequencing a reality. Much of the research is performed using Affymetrix’s (Santa Clara, CA) GeneChip Human Genome U133A 2.0 Array, a bioarray representing 14,500 well-characterized human genes that can be used to explore human biology and disease processes. Affymetrix continues to perfect its human genome sequencing offerings. In November 2008, Affymetrix acquired Panomics Inc. (Fremont, CA) that offers a suite of assay products for a wide variety of low to mid-plex genetic, protein and cellular analysis applications. Affymetrix reported that the acquisition will strengthen its position in high-growth validation and routine-testing market segments. The combination will also enable a more complete customer workflow, beginning with whole-genome Affymetrix microarray studies and then focusing on genes and proteins of interest with the Panomics products. Panomics’ products run on an installed base of more than 5,600 instruments worldwide. The first to jump in are several direct-to-consumer test services. 23andMe, Inc. (Mountain View, CA) offers the Personal Genome Service. Knome (Cambridge, MA) offers a test service that costs $350,000. It includes wholegenome sequencing and a comprehensive analysis from a team of leading geneticists, clinicians and bioinformaticians. Navigenics (Red Shores, CA) and Affymetrix formed a collaboration to provide consumers with an understanding of their genetic predisposition for developing certain medical conditions. The sequence will be done in Affymetrix’s CLIA lab. Then, Navigenics will provide the genetic-predisposition analysis to the customer via a secure, private web portal and offer genetic counseling. Agilent Technologies (Santa Clara, CA) and BioNanomatrix (Philadelphia, PA) are developing technology and an instrument platform that enables nanoscale single molecule identification and analysis of the entire genome. BioNanomatrix and Complete Genomics (Sunnyvale, CA) formed a joint venture that will share an $8.8 million grant from the U.S. National Institute of Standards and Technology to develop technology that will be able to sequence a human genome in eight hours for less than $100. The proposed sequencing platform will use Complete Genomics’ sequencing chemistry and BioNanomatrix’ nanofluidic technology. The companies said they plan to adapt DNA sequencing chemistry with “linearized nanoscale DNA imaging” to create a system that can read DNA sequences longer than 100,000 bases quickly and with accuracy “exceeding the current industry standard.” October 2009, Kaiser Permanente and the University of California, San Francisco entered into an agreement with Affymetrix to conduct genome-wide analyses of DNA samples from 100,000 Kaiser Permanente members for a large-scale research program designed to create a new resource for studying disease, health, and aging. Scientists from the program will use the Axiom Genotyping Solution, which delivers high-throughput, automated technology enabling researchers to find novel and common genetic variations associated with complex disease. Pacific Biosciences (Menlo Park, CA) has reported that it has technology, now in development, needed to complete a high-quality sequence of the human genome in 15 minutes.


e u ro pe an I ND U STR IA L PHARMACY • Issue 11 December 2011




• Abacavir and HLAB 5701 HAS • Carbamazepine and HLAB 1502 SJS • Cetuximab/Panitumamab and KRAS • Clopidegrel (Plavix) and 2C19 resistance • Imatinib and Kit, GIST • Maraviroc and CCR5 and (tropic) HIV-1 • Nilotinib and UGT hyperbilirubin • Tetrabenazine and 2D6 dosing • Trastuzumab and HER2+ Br Ca • Warfarin and 2C9/VKORC1 dosing Source: Kalorama Information As is usually the case technology is outpacing regulatory guidance on the use of pharmacodiagnostic tests that are already available. Authorities in the major markets are still developing regulatory oversite for these tests, and payers have not yet embraced reimbursement of pharmacodiagnostic tests for routine testing. A survey of US-based health management organizations and payers found that all the tests shown above require pre-approval for reimbursement.

Continued from p17 one-at-a-time approach. Many of the well-known biomarker assays have been identified based on clear biological insight from genetics, physiology or biochemistry. As a result, only a few markers at a time have been considered for development. While genomics and proteomics are providing strong bases for biomarker discovery, the process is still a laborious one that has significant technical difficulties. Finally, at a time when the healthcare system is seeking cost containment, companion diagnostics introduce new complexity into successful diagnosis. Complex genetic relationships (i.e., multiple affected genes) and rapid mutational states present key problems for companion diagnostics. Market factors and estimates

The number of companies actively engaged in development, manufacture and marketing of companion diagnostics is large –

somewhere on the order of 150 companies or more, and may continue to increase over the next few years. Their number may then fall as some cannot find alliances that allow them early access to proprietary genetic data from pharmaceutical firms; some will merge; and some will be acquired (or at least their technology will be bought out), by therapeutics firms wishing to maintain proprietary testing technologies.

product. Therefore, since the industry is just now planning the complete companion diagnostic paradigm and entering the co-operative development process, it is likely that it will not be before 2015 or 2016 that any major surge in these markets will be seen. Some readers may have seen larger projections, but we believe these are unwarranted at this time. These figures are probably not what the diagnostics industry is hoping for. To increase companion diagnostics revenues to the diagnostics companies, it is suggested that they use a strategy of royalties associated with the sales of the therapeutics their tests target. Because of the subordinate role that diagnostics has in the companion diagnostic relationship, such a strategy will show greater promise than some of the companion diagnostic marketing strategies commonly advanced. While the promises of theranostics for modern medicine are great, developing models that work in the reality of today's healthcare marketplace will serve companies better than a completely futuristic view.

Kalorama Information's forecast for companion diagnostics presents what we believe to be the potential market for companion diagnostics in the US, and the actualized markets, including today's ad hoc associated testing transitioning to the true companion diagnostic paradigm by 2015 or 2016. The worldwide market for companion diagnostics is estimated to be $50 million in 2009, projected to $200 million by 2014. This is a conservative forecast based on the estimates of pharmaceutical industry executives who project a seven-year development period for each companion diagnostic

e u rop ea n I N DU ST RI AL PHARMACY • Issue 11 December 2011

"Companion Diagnostics: Kalorama Information’s Markets" is available at


Project Management for the Pharmaceutical Industry

HEADING STYLE The targets for this book, as stated in the Preface, by Laura Brown and Tony Grundy Reviewer: Paul Butler

include senior and middle management engaged in strategic projects and ‘pharmaceutical professionals managing projects within their own roles’. This would appear to cover all types of projects within a pharmaceutical environment but, in fact, the book concentrates on two very different types – clinical trials and strategic business development. There is very little about the many other types of projects typically handled within pharmaceutical companies. It is unfortunate that the title does not make it clear that such a narrow field of projects is addressed in the book. The backgrounds of the two authors, the one being a Clinical Trials expert and the other a Management Consultant, are very apparent throughout the book. There is very little connection between the two different types of project that are the main subjects of the book. This is typified in the penultimate chapter ‘Project Management Checklists and Cost-management Project Case Study’. This contains a very detailed and excellent Checklist for Multicentre Clinical Research Trials’ that would be a wonderful tool for any manager organising such a trial. The remainder of the chapter deals with the totally different requirements for what are described as ‘Organic Business Development Projects’ and ‘Organisational Change Projects’, as well as ‘Checklists for Acquisitions and Alliances (Joint Venture) Projects. The final sets of checklists are ‘Checklists for Operational Projects’, but these are then divided into ‘Operations expansion’ and ‘Cost management and efficiency’. The subject of ‘Operations expansion’ merits less than half a page, despite being one of the commonest type of project in the industry. The section on Cost Management, whilst of interest to a small number of financial managers, would be of little interest or relevance to production, quality management, clinical trial, or engineering management, who constitute the majority of management within the pharma industry. The earlier chapters of the book give clear and excellent descriptions of the many tools now available for defining and managing projects. Many of these are relevant to almost all types of projects (and not only in the pharmaceutical industry). The danger with having so many tools is determining which ones to apply to a


particular project, and this is not really described in any detail. Again, because the book only really describes two types of project, and the tools described are largely relevant to business development projects rather than clinical trials management, the objectives of the book seem very confused. This book would be best split into two completely separate volumes. There is an obvious need for a good textbook for aspiring Clinical Trials Managers, but this is not that book. From the relevant sections in this book, it is apparent that Laura Brown has the knowledge and experience to write such a book. Her section in Chapter 3 “Defining Pharmaceutical Projects” on the selection and contracting of CROs is very comprehensive, and clearly shows her experience in running this type of project. Similarly, there is probably a niche market for a good book on managing business development projects, and, from his bibliography and cv, Tony Grundy should be able to write this. Let us hope that any future corroborative efforts between these two will be better coordinated and targeted to a more specific readership. Reviewed by Paul Butler, a pharmaceutical consultant at PJB Pharma Consulting Services. Email:

Published by Gower Publishing, UK, 2011 Price: £65 298pp hardback ISBN: 978-1-4094-1894-8

e u ro pe an I ND U STR IA L PHARMACY • Issue 11 December 2011


Review of developments in GMP and the regulation of Medicines October – November 2011

by Malcolm Holmes

United States of America

Incorporation of Physical Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting. New Guidance to pharmaceutical manufacturers wishing to use physical-chemical identifiers (PCIDs) in solid oral dosage forms as anticounterfeiting measures. A PCID is a substance or combination of substances possessing unique physical or chemical properties that unequivocally identifies and authenticates a drug product or dosage form. This guidance provides:

• design considerations for

incorporating PCIDS into Solid Oral Dosage Forms (SODFs).

• supporting documentation to be

submitted in new drug applications (NDAs) and abbreviated new drug applications (ANDAs).

• supporting documentation to be submitted in post approval submissions to report or request approval to incorporate PCIDs into SODFs.

• procedures for reporting or

requesting approval to incorporate PCIDs into such products as a post approval change.

PCIDs include inks, pigments, flavours, and molecular taggants. Radiofrequency identification for drug products or the incorporation of a PCID into packaging or labelling is outside the scope of this guidance. Europe

EMA has published two important Concept papers that will have far reaching effects on the industry. 1. Concept paper on Revising Annex 16 of the EU GMP: Certification by a Qualified Person and Batch Release. Complexity of Supply chains/new threats/modern control techniques and many other initiatives mean

that a thorough review of Annex 16 is needed. Problem statements are raised, such as: What is the minimum a Qualified Person (QP) must personally carry out when certifying a batch? What are the pre-requisites for relying on statements from persons other than fellow QPs? How is the Control Strategy/batch certification release process linked? What are the expectations for QPs reviewing batch records manufactured by third parties in third countries? What knowledge should a QP have about the site(s) involved in the manufacturing of a batch? What actions are expected from the QP when a batch cannot be certified and therefore released? Comment by 31 January 2012. Adoption of a revised annex proposed by November 2013. 2. Development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities. Toxicological data are not always used in establishing limits for crosscontamination. Often arbitrary limits e.g. 1/1000th of the lowest clinical dose are used as limits for cleaning validation. Such limits do not take account of pharmacological/ toxicological data/duration of exposure and may be too restrictive or not restrictive enough. A scientific approach based on current available pharmacological and toxicological information is required to establish threshold values to be used as part of the overall Quality Risk Management in shared facilities. Comment required by 31 January 2012. Proposed final text by March 2013 with a 6 month implementation deadline.

• • • • • •

e u ro pe an IN D US TR IA L PHARMACY • Issue 11 December 2011

Pharmeuropa now available online and free. The intention is to publish Pharmeuropa articles and draft texts for comment as early as possible. news/information, etc., and access to 3 databases is provided:

• Texts for Comment • Bio & Scientific Notes • Pharmeuropa Archives Products

Duplicate marketing authorization submissions. The Commission notes that requests for duplicate marketing authorisations under Article 82(1) of Regulation (EC) 726/2004 have increased and consider this trend likely to continue as the use of the centralised procedure rises. A document update provides examples of applications that fall under the scope of Article 82(1). International PIC/S

The Slovenian Agency For Medicinal Products And Medical Devices will join the Scheme as from 1 January 2012. Japan confirmed its intention to apply for membership and South Korea appears likely to do so. Two draft PIC/S guidelines on Quality Risk Management are ready for formal adoption.

• Recommendation for Risk-based GMP Inspection Planning.

• Aide-Memoire on Assessment of Quality Risk Management Implementation.

For further information on these and other topics please refer to the websites of relevant regulatory bodies and to the monthly “GMP Review News” published by Euromed Communications and available only to subscribers to GMP Review. To subscribe, contact:


PHARMACEUTICAL FORUM The following is a selection of the questions and answers taken from recent exchanges in the PharmWeb GMP Discussion Group. This Forum is held on the Internet at and sponsored by the publishers of Industrial Pharmacy and GMP Review. The Forum is free of charge and open access. It serves as means of exchanging views within the context of international regulations affecting the manufacturing side of the pharmaceutical industry. Your own questions and answers are very welcome. Send them to but please remember to write your name and email address at the bottom of your message.


I have seen different approaches for analytical transfer. The more complete one is described in the ISPE guideline. But, do you think it acceptable to transfer an analytical method within the same organisation (even building), between two different labs with similar equipments and practices? The strategy for that is to use and compare (with an acceptance criteria) the data generated by both laboratories for the reproducibility of the method during its validation?

Response: 1 In your case I feel no need for method transfer because reproducibility in both the labs is proven during the method validation.

Response: 2 There are very many pitfalls. For example, do both labs have the same SOPs? That could be a problem if they do not. Often what happens in companies is that there is a lab that “develops” the method and a lab that “validates” the method. The roles of these two laboratories must be very carefully defined as it is sometimes not obvious. Again, are the staff in the two laboratories equal? That is, are they trained in the same way on the same issues? Remember, analytical methods are very often extremely poorly defined – that may come as a shock to many but as an example ask yourselves how many different ways there are of complying with the instruction “mix thoroughly”. For labs in the same building the best solution in my opinion is joint validation.


I work in the pharmaceutical industry (specials) and am in the process of writing a Quality Assurance SOP for end of line quality checks and batch release


for produced products. I am making the SOP as detailed as possible giving step-by-step guides of exactly what checks to perform and also have specified that the SOP must be used as a working guide each time checks are performed. I have done this to avoid the need for a checklist stating what parameters to check which would mean having to transcribe the batch details and other information onto the checklist and then perform the checks (and attach the checklist to the batch document). I have been told that a checklist must be used as it is standard pharmaceutical practice but I do not agree. We check and release around 300 batches per day and I believe a more user-friendly approach where all actions are covered step-by-step within the SOP is a more streamlined approach allowing the user more time to perform adequate checks.

Response: 1 For batch records verification there are specific requirements in the EU and in the FDA. 211.188 and 211.192 are very specific on the content and review process. The EU GMP also provides specific requirements on releasing or certifying batches. So, in my opinion, a checklist in a table format will facilitate the work for the person verifying and releasing the batches’ paper work. Maybe for another task your step guide approaches might be appropriate.

Response: 2 A check list is not compulsory but it does provide written evidence that the checks were made. If you reply on an SOP how will you record the checks? User-friendly – will the operator have to read through the whole SOP each time a check is applied? What about training? I suggest you get the best of both worlds with a detailed SOP to make sure you cover everything for training purposes, and then a short, simple, effective and user-friendly check list. You should be able to print off some of the data (e.g. a spare label or a spare pack) to attach to the check list to avoid some of the hassle of copying out details.

Response: 3 1. Manufacturers need an SOP that defines what checks must be performed for each batch of every product formulation, at what point, and by whom. 2. Product spec. needs to state acceptance limits for each check. 3. Each check must be recorded and retained for a defined period of time, based on shelf life. It does not matter on what piece of paper or specified digital field the check is recorded as long as it is secure, accessible and tied to the lot.

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PHARMACEUTICAL FORUM (Con t.) 4. It is not sufficient to simply repeat that “all checks were performed according the SOP” without recording each result as it is obtained during the checking process. FDA is very clear on this.

Response: 4 So you have a written detailed SOP, all the details of which are committed to memory by the QA personnel? So when the QA is completed what record do you have that each of the critical items was checked and none omitted? My best suggestion is to do both. Use the SOP as for both training and covering all the necessary details of what has to be done. Create a template list as well, make it an attachment to the written SOP. Make it a requirement that a copy be used and attached to the documentation. If you need more than one check list, make more than one. I cannot imagine you will ever be sorry you have a checklist, but would guarantee that without one you risk a serious problem and will regret not having one. In my physical pharmacy laboratories, where data are collected and included in reports to the FDA, our management decided that every SOP would have reporting data sheets that guaranteed compliance with the conduct and the reporting of all experiments. Not quite a check list, but it was the same in that it forced a compliance in reporting and conduct, which is what an SOP is all about.

Response: 5 We too follow the system of having a checklist as an annexe to the SOP with reference to the SOP mentioned in the checklist to ensure they both are updated together. However, can the mixing of the 300 batches into smaller number batches (validation will be a must) of larger size be an answer if the checklist is too exhaustive and seems impractical to follow for the number of batches at hand. Response: 6 I am of the view that says you verify and record operator understanding. In addition, when deploying that procedure on LIVE manufacturing, you supply unambiguous signed evidence (check sheet) that completion was performed 100% as defined by your SOP. Your QA has to be delighted with this on two counts. The training histories of your operatives are maintained AND your inspectable batch documentation is defined at the detailed level and verified by trained operator signature.

batch record), there are never any problems. Incidentally, managing the QA batch release this way allows the “QA batch release” checklist to be customised for each product.


According to 21 CFR Guidance, “A usage log of major equipments shall be maintained”. Should we consider in-process test equipment/instruments such as a friability machine, an auto hardness tester as major equipment? Is it mandatory to keep log books for these machines?

Response: 1 If any equipment’s usage is cGXP-related then it is mandatory. Thinking of it as a single or series of link/s in a long chain – get it wrong anywhere along the GXP chain and the chain breaks. Response: 2 21 CFR 211.182 is not a guidance. It is code of federal regulations (FDA GMP). The equipment you have listed is generally not considered as major equipment and no usage is maintained. However, records for calibration and prevention maintenance for the equipment must be maintained. Response: 3 A usage log should also be considered an aid to the company during investigations, such as Corrective Action investigations. If the equipment fails, or is found to be out of tolerance at the beginning of a routine maintenance, then an investigation must determine the impact on material already produced. A usage log helps to identify which batches of products have been released using that equipment since it was last known to be performing properly, which is probably the date of the previous maintenance. This usage information may also be recorded in notebooks or batch records, but a dedicated log book is much easier to follow than reading every batch record or log book. The double entry of information into both the log book and the notebook is sometimes a point of contention, which is sometimes resolved by recording part of the information in each, such as the daily calibration of a pH meter in the log book, along with the batches tested; and then putting the test results themselves by batch into the notebook. (The two recordings can cross-reference each other).

This is unlikely to attract adverse audit comment.

Response: 7 I have found that the most efficient method of QA Batch Release is to have the last batch of the production batch record as the “QA Batch Release Checklist”, and of course as it is issued as part of the batch record (and paginated as part of the

Readers are invited to send their Q&A to:

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NEWS FROM THE EIPG 1. Innovative Medicines Initiative (IMI)

EIPG was represented at a LifeTrain workshop run by the Innovative Medicines Initiative Education and Training projects on 4-5 October 2011. The following is a press release from the meeting: “In order to make Europe more competitive, a broad group of European Professional/Scientific bodies came together to develop a common framework for Continuous Professional Development (CPD). This enhanced guidance will support scientists working in all aspects of medicines’ discovery, development, processing and usage to maintain their professional competence in a rapidly changing environment. There was tremendous enthusiasm from all participants to combine forces for the good of R&D in Europe. In parallel with the development of a common framework, work is underway with a range of employers and with academia/course providers to ensure that there is close alignment between: the individuals’ and employers’ needs; the guidance from the scientific bodies; and the provision of flexible, high quality courses. For more information see" 2. European Association of Faculties of Pharmacy (EAFP)

Discussions have been held with representatives of EAFP on the next steps for PHARMINE, a project looking at competencies for industrial pharmacists. Anyone interested in involving their company (large or small) in a potential training project which will involve a person in 3 meetings and some e mail correspondence should please contact Jane Nicholson at:


3. Student contact

Following the presentation by Luigi Martini, to EPSA students during their Autumn Assembly, Philippe Bollen (a Board member of VAPI/UPIP, Belgium) met with the President of EPSA, Guilherme Monteiro Ferreira Santos during his recent visit to Brussels to discuss how best to advertise careers in the pharmaceutical industry to the student membership. Bojan Davinic, EPSA Vice-President of External Affairs also participated in the discussions. 4. European Medicines Agency – Inspectors Working Group (IWG)

A meeting with Interested Parties to discuss various aspects of good manufacturing practice (GMP) was held on 23rd November. The inspectors stated that the updated texts of Chapters 1, 2 and 5 would be issued during the 1st quarter 2012. The IWG is awaiting guidance from the Safety Working Party (SWP) before revised Chapter 3 can be finalised. Text updates for other Chapters of the GMP Guide remain “work in progress”. Various omissions and inconsistencies between terminologies in different chapters of the Guide were brought to the attention of the inspectors. Also, perceived differences between inspectors on the handling of GMP aspects during inspections were highlighted by interested parties. The concept paper on revising Annex 16 (Certification by a Qualified Person (QP) and Batch Release) has been released for consultation and it is hoped that all QPs will consider the questions raised in the “problem statement” (comments should be sent in the first instance to Jane Nicholson at: EIPG will be submitting a response to this and the Good Distribution Practice

Guide. Any final comments on the latter should be sent to Claude Farrugia at: during the next three weeks. During the meeting, EFPIA presented a paper outlining the major changes in GMP resulting from implementation of the Falsified Medicines Directive 2011/62. This will require additional safety features for medicines, greater oversight of supply chain, greater control in production of APIs and excipients as well as control of internet sales. It was stated that additional Security of the Pharmaceutical Supply Chain will be required and the representative from the European Commission listed their three priorities as; importation of APIs (a public consultation is to be issued shortly); authentication of all prescription medicines dispensed from pharmacies; and on-line pharmacies. 5. European Medicines Agency – First EMA Workshop on Ophthalmology

EIPG was represented by Dr José Manuel Massó, Coordinator of the Clinical Trials Working Group of AEFI Central Section, Spain, at this initial EMA ophthalmology workshop. His report of the meeting follows: On 27 and 28 October 2011, the European Medicines Agency assembled for the first time some 200 experts in eye diseases from Europe, Australia, Japan and the United States of America in a twoday workshop. The attendees reviewed regulatory and scientific challenges in developing medicines for eye disorders. New treatments in ophthalmology are rapidly evolving, with the recent breakthrough of new medicines for continued on following page

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wet age-related macular degeneration. Research is also ongoing in new eye diseases where no treatment is yet available, such as retinitis pigmentosa and dry agerelated macular degeneration. The workshop participants, who included European regulators, the pharmaceutical industry, doctors and patient representatives, discussed methods for measuring visual function in clinical trials, developing stem cells and gene therapy for retinal diseases, treatment for macular diseases and inflammation in the eye, repairing the corneal surface with stem cells and treatment for dry eyes. The participants also tackled the development of treatment in childhood eye disorders such as retinal diseases in premature babies, childhood glaucoma, eye inflammation and relief of pain

after eye surgery. Particular challenges relate to measuring outcomes in children, the absence of good-quality information on existing treatments used in areas such as eye inflammation, and the need for long-term safety data. The workshop was successful in developing interactions between European regulators, doctors and patient representatives and pharmaceutical industry in this area. The Agency will now move forward with regulatory guidance in areas such as dry eyes and macular oedema. Further discussion and research is needed before the Agency can provide guidance in other areas such as trial designs and endpoints in inflammation of the eye, and advanced therapies in corneal and retinal disease. The workshop identified the need for future submissions for endpoints



16-17 January 2012 – London, UK Biomarkers summit

20-21 February 2012 – London, UK Advances and progress in drug design

18-19 January 2012 – London, UK European pre-filled syringes

29 February – 9 March 2012 BioBarriers 2012 – International conference and workshop on barriers in vitro and in silico tools for drug delivery and nanosafety research

18-19 January 2012 – London, UK Forced degradation for pharmaceuticals

HEADING STYLE 1-2 March 2012 – Vienna, Austria 22-25 January 2012 – Maryland, USA 26th International forum: process analytical chemistry

24-25 January 2012 – London, UK Social media in the pharmaceutical industry 26-27 January 2012 – Rome, Italy 2nd Annual pharmacovigilance & risk management strategies: new dimensions in global drug safety macovigilance-risk-strategies


2nd Annual global vaccine forum – challenges in the world of novel vaccines 11-14 March 2012 – West Point NY, USA 47th AAPS Arden conference – nanoscience in pharmaceuticals: translating fundamental understanding to practical application in drug and device 12 -13 March 2012 – Bangkok, Thailand 2nd Annual international conference on advances in biotechnology (BioTech 2012)

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and biomarker qualifications from companies, academia or consortia and the Agency is looking forward to receiving these. Companies developing eye products are encouraged to discuss their development plans with the EMA at an early stage. The Agency will continue its public dialogue with academia, regulators, pharmaceutical industry, doctors and patients’ representatives on ophthalmology medicines. 6. EIPG Bureau Meeting

The Bureau will be holding a meeting on 21st January 2012 and any items which members wish to raise should be sent to Jane Nicholson at: by 10th January.

Jane Nicholson November 2011

13 March 2012 – Manchester, UK Deviation and CAPA systems – best practices 14-15 March 2012 – Manchester, UK Human error prevention 19-22 March 2012 – Istanbul, Turkey 8th World meeting on pharmaceutics, biopharmaceutics and pharmaceutical technology 20-22 March 2012 – Archamps/Geneva, France 15th Industrial symposium and 6th trade fair on microencapsulation 21- 23rd March – Milano, Italy 17th Congress of the European association of hospital pharmacists (EAHP) 28-29 March 2012 – London, UK Controlled-Release – advances in nanomedicine for oral and non-oral drugs