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contents
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Tabletability of pharmaceuticals substances Jerzy Lasota
Packaging – so easy to say… Michał Stanke
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Raman spectroscopy and its application in the pharmaceutical industry 15 Daniel Zakowiecki, Krzysztof Cal
The role of thermoforming in creating competitive advantage Honeywell
Cleanrooms Galbex Sp. z o.o.
Counterfeiting of medicinal products Marcin Weksler
Application of LC/MS in cleaning validation Robert Królicki
The serach for high-performing excipients Cardinal Pharma Trade Ltd.
The Principle of Diversity OPTIMA GROUP pharma GmbH
How promotion of OTC medicinal products affects patients’ purchasing decisions Małgorzata Matuszewska-Rembelska
Adamed
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A new laboratory
Halina Gudowska
BioCentrum
28 30 34
43 46
OPTIMA GROUP pharma GmbH Polish industry
SIMATIC IT Unilab – Siemens Solution for Laboratory – Information Management System 48 Wojciech Grzelka
Soft capsules – from a concept to a product 50
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Adamed expands its product portfolio 55
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conferences, fairs, training
Preclinical Toxicology Training Bio-Tech Consulting
Validation of Technological Processes in the Pharmaceutical Industry StatSoft Polska
Annual Registration Summit 2009 Movida Conferences
Clinical Trials Informedia Polska
Initial Batch Control – New Regulations MEDVICE
Recirculation: stop without any consequences 47
Curtis Healthcare Sp. z o.o.
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Marcin Kołakowski, Daniel Gralak
Quality Masters
Adamed
Can leaflets be understood by the layperson? 56
Initial batch control of pharmaceutical ingredients 40 Validation of a sterilization tunnel
Grasz o staż
60 60 61 62 62
reports, projects, plans
Drug invention brainstorming is on, and success will have many fathers 63 Luiza Jakubiak
Summary of medicinal product withdrawals in 2008 65 Bogdan Klimas
Dermocosmetics in Central and Eastern Europe an expanding niche market 67 Monika Stefańczyk
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R.BOSCH GmbH – Pharma Solid www.pa.bosch.com • capsule fillig machines, checkweighers, blister lines, cartoning machines ACHEMA 2009 – Hala 3.1, Stand F2-J11
R.BOSCH GmbH – Pharma Liquid www.pa.bosch.com • washing machines, sterilizing tunnels, filling lines, isolator technology, leak control of ampoules and vial ACHEMA 2009 – Hala 3.1, Stand F2-J11
R.BOSCH GmbH - SBM www.sbm-a.at • sterilizers, stoppers washing and sterilization ACHEMA 2009 – Hala 3.1, Stand F2-J11
R.BOSCH GmbH - Moeller & Devicon www.m-d.dk • inspection lines, assembly lines ACHEMA 2009 – Hala 3.1, Stand F2-J11
R.BOSCH GmbH - Pharmatec www.pharmatec.de • high purity media systems, process and bio systems ACHEMA 2009 – Hala 3.1, Stand F2-J11
GLATT GmbH, www.glatt.com • wet granulators, fluid bed dryers and granulators, coaters, material handling systems, sieves for wet and dry products ACHEMA 2009 – Hala 3.0, Stand 032-S42
MUELLER GmbH www.mueller-gmbh.com • stainless steel containers and dosing systems, material handling and mixers ACHEMA 2009 – Hala 3.1, Stoisko B5-B6
PESTER www.pester.com • packaging, robots and palletizers ACHEMA 2009 – Hala 3.1, Stoisko D2-E3
PCE Pharmacontrol www.en.pharmacontrol.de • camera image processing, code scanning, track and trace systems
ACHEMA 2009 – We are inviting 11-15 May 2009, Frankfurt am Main
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From the editors:
List of advertisers: A-TECH BEATRONIC Sp. z o.o. BIO-CHIC Sp. z o. o. DAMASZ Sp. z o.o. DRUK-PAK S.A. ECOLAB Sp. z o.o. EDELMAN POLSKA Sp. z o.o.
The Farmacom publishing house, the editorial office of the “World of the Pharmaceutical Industry” quarterly and the Honorary Host, ZF Polfa-Łódź S.A., cordially invite you to take part in “THE WORLD OF THE PHARMACEUTICAL INDUSTRY CONGRESS 2009.” This event is organised to be held on 25-26 June 2009 at the Andel’s Hotel in Łódź. Representatives of pharmaceutical manufactures and companies are invited to participate with specialists of the industry in this meeting devoted to the latest trends and technologies employed in pharmaceutical production. Experts from pharmaceutical manufacturing, universities, institutions, and organisations related to the pharmaceutical industry will ensure the high level of the Congress. The thematic scope of the Congress programme will include all of the main stages of pharmaceutical production, from supplies of raw materials to the storage of ready products and their forwarding. The next, June edition of “World of the Pharmaceutical Industry” will be a SPECIAL CONGRESS EDITION, distributed during the Congress.
ENTRO HOLDINGS Sp. z o.o.
WE ARE LOOKING FORWARD TO SEEING YOU AT THE CONGRESS !!!
FAUBEL & Co. Nachf. GmbH
More information will be soon available on our website http://www.farmacom.com.pl
GALBEX Sp. z o.o.
Programme Board:
GRUNDFOS HLP HYDROLAB POLSKA IKA POL IKA-TECHNIK Sp. z o.o. i ZMR S.C. IRTECH KRAKÓW KOMENDER TECHNOLOGIES
Leszek Borkowski DPharm
Chairman of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Andrzej Szamański President of ISPE Poland, Quality Director at Polpharma SA Pharmaceuticals
Zbigniew E. Fijałek director of the National Institute of Medicines Marcin Kołakowski head of the Supervision Department of the Central Pharmaceutical Inspectorate.
Irena Rej President of the Polish Pharmaceuticals Chamber of Commerce
LOT-ORIEL POLSKA MIKROLAB MMR CONSULT Sp. z o.o. MTZ CLINICAL RESEARCH Sp. z o.o. OPTIMA GROUP pharma GmbH PALL POLAND Sp. z o.o. POCH S.A. RAPOFARM SCHWARTE-MILFOR Sp. z o.o. STATSOFT POLSKA Sp. z o.o. SYL & ANT Instruments TRADE&CONSULT Sp. z o.o. TUSNOVICS INSTRUMENTS Polska Sp. z o.o.
Editor-in-chief Robert Miller tel./fax +48 032 455 31 61 tel. kom. +48 502 084 101 robert.miller@farmacom.com.pl Subscription and distribution Publisher FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 tel./fax +48 032 455 31 61 prenumerata@farmacom.com.pl Issue price „ŚPF” – 10 zł Annual subscription price – 35 zł
Payments may be made to the account: ING Bank Śląski O/Wodzisław Śląski 56 1050 1403 1000 0023 2091 8119 Editors Tomasz Butyński, Teresa Kubsz-Miller tel./fax +48 032 455 31 61 redakcja@farmacom.com.pl Proofreading: Maria Gniłka DTP: Wiktor Adamiec wiktor.adamiec@farmacom.com.pl Printing: Drukarnia BIMART. Number of copies printed: 2 500 Partner:
www.ispe.org.pl
The magazine is addressed to process and production engineers, automatic systems specialists, heads of production, control and quality assurance divisions, heads of logistics and procurement divisions and product development divisions at pharmaceutical companies. The magazine is also purchased by organizers of trade fairs, conferences and industry training courses, government offices, ministries, institutes, higher educational institutions offering pharmaceuticals-related courses, and design firms. The editors reserve the right to shorten and edit material. The editors are not responsible for the content of advertisements. The use of materials and publication of advertisements produced by the publisher is permitted only with the editors’ consent.
UNILOGO
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Quarterly, published by FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 farmacom@farmacom.com.pl www.farmacom.com.pl
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Tabletability of pharmaceutical substances The present article refers to an earlier publication concerning direct compression (SPF 04/2008 page 26, download www.en.farmacom.com.pl/ index.php/archives.html). The method described here is simple, precise, easy, and very useful. It dispels some important doubts regarding the direct compression technology and gives hope for a better mastering of the process. Perhaps after reading this text, a tableting technologist will be encouraged to reach for this formulation, however related to certain dangers? Jerzy Lasota
O
f the two methods of tablet production, dry and wet, the former - extremely advantageous in terms of economy and beneficial to drug quality - is winning increasing recognition among the producers. It is, however, more hazardous in application, therefore it requires thorough research. If chemical analyses may be regarded as long under control, typically mechanical studies are still underused by many tablet producers, or even by specialised service laboratories. Once a drug was successfully tableted by means of direct compression, it continues to be produced in this way thereafter. This refers especially to medicines in which the proportion of active substance is small. It is a known fact that the majority of active substances tablets poorly, which had long been the main reason for wet “kneading” and granulation. A large proportion of active substance in a tablet translates into potentially serious problems with tableting, especially if mechanical properties of the substance are not closely monitored. It has become a popular opinion, and not without reason, that the wet-processing method levels major differences in substance properties affecting the results of tableting. This refers to properties undetectable by means of chemical analysis, which however exist and reveal themselves through, e.g. tablet staining, limited hardness, capping, and other unpredictable phenomena. Allotropic varieties come into play, relating to crystalline structure, the size of molecules, their shape, etc. There are many publications on the topic. It has been known for a long time that two chemically identical substances may differ radically in terms of tabletability.
The desire to study mechanical properties of substances, as a “white mass” difficult to characterise on the basis of external features, originates directly from mechanical studies of material strength. Each structural material reveals certain strength properties determining its susceptibility to processing and transformation. Steel has a certain breaking resistance but before it breaks - studied as a laboratory sample - it displays a number of features characteristic of a specific kind. Concrete or other construction material possesses a given compression resistance, but before it gets crushed by the pressure applied during tests, it displays certain properties related to the preparation method, type of components used, etc. For a tablet technologist, pharmaceutical substances - active substances and excipients - constitute construction materials. It pays to know about them as much and as early as possible, in the research stage or earlier, at the moment of purchase. Knowledge gained only after the substance had been poured into the production machine, is water over the dam. The author, a keen promoter of the direct compression method, encourages the use of huge forces against any substance in the laboratory. It is also advisable is to put away pharmaceutical or chemical knowledge for a moment (sic!), in order to concentrate on the pure mechanics of substances, without any respect for the drug. The only rule binding us on this occasion is the care for our health and safety. Therefore, let nobody be surprised by a “formulation” defying
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all handbooks and principles, composed only of the active substance and 20% of magnesium stearate. We will try to demonstrate, on the basis of a real direct compression formulation, how to manage difficult cases, often regarded as impracticable.
Origins Here is a large tablet room with a wide assortment of drugs and machinery. A certain drug, which has been tableted for a couple of years without any problems, starts to cause technological problems. It tablets poorly, even though there were no changes whatsoever to the preparation or to the machine. Tablets are weak, which immediately brings up an idea to increase the pressures substantially. Everyone knows that there is no getting away with it but ... what if it works? It didn’t - the stamps were broken. Here is a picture from 1989 (though in some places still present - let us keep it a secret). This was the year that the author began his studies of pharmaceutical substances and a search for reasons why such situations occur. Initially, our research method was “the standard compression method,” used in civil engineering: a concrete block or a brick is compressed gradually until total destruction, while taking notes on the forces applied and the product’s displacement. In the case of pharmaceutical substances, always in loose forms, mould compression was used instead of free compression. A substance was poured into a tester with two EU-B moulds placed one above the other, which gave a column of powder about 40 mm high. In this way, the substance distortion-by-force distance
was lengthened, in order to increase the method resolution. There were expectations of finding, describing and using some characteristic points on the compression curve. The pressure was applied statically, meaning very slowly, since this is the only way to use the INSTRON hydraulic press, with a pressure of 300 tons, owned by a friendly institute. A typically research-oriented press enabled a very accurate preparation of a force-displacement graph, and even its integration. The results for many granulates and single substances were far from optimistic. It is true that there were some characteristic points for certain substances or phenomena occurring during compression, but they were not distinct. For example, we obtained a sugar tablet, made of several regular caps. We also discovered that pure magnesium stearate, compressed with great strength, can ... evaporate from the mould. The method was soon changed, and instead of slow compression, dynamic strokes were used, applied with the help of a loosely falling weight. Measurements of tablet hardness demonstrated how large is the resolution of the adopted method and how precise are the pressures applied, independent (importantly!) of the quantity of substance in the mould. And so we created a prototype of the machine shown in Figure 1, which was subsequently improved over a few years. It employs a PTB 311 hardness tester for two purposes: it measures tablet hardness, but before that it pushes them out of the mould, it accurately recorded the maximum force used. Two of such devices operate in the country in a version modified by the producer according to author’s advice. Beside it, a mechani-
Fig. 1. ELTAB gravitational tablet press, using a small tester made as a minimal tableting assembly „taken out” of a large machine. Calibrated (r2 = 0.9999) as a simulator of a KILIAN Tx-40 rotary tablet press, producing 100 000 tablets per hour. The initial and main pressures do not depend on the quantity of substance in the matrix. Ejection forces are measured using a PTB-311 hardness tester, adapted by the manufacturer to the author’s design, or a specially built mechanical hardness tester
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Procedure Product compression in the die (compacting, tableting) and testing compression effects have been used for a long time to acquire knowledge about the products processed. It is a distinctive feature that the effect of the action of the force that forms a tablet is also studied using forces. However, they are tens to hundreds of times smaller than the compression force. This may be described as follows:
Tablet deformation only, or its thickness, is measured as a distance rather than a force. The information about the product is derived from the combination of the parameters and respective calculations. This article discusses only the tests in which forces are used. Other parameters, which
include the measurement of powder flow rate, which is the “repose angle,” dynamic fluidity, internal friction, bulk density, etc., are not investigated. It is noted that tests using intense forces provide the most valuable information about products with respect to their usefulness in the formulations developed; however, they are the most difficult to execute in typical laboratory conditions. If the objective is to test the capability of a substance in forming a tablet, the first question to ask is the following: What amount of the substance should be taken to make a tablet? Realising that the products tested vary considerably with respect to their specific weight (or, in the better terminology used by pharmacists: apparent volume, since it refers to powder rather than monolith), we must bear it in mind that tablets varying in thickness are obtained from the same amount (weight) of substances. It is the thickness, expressed as the contact area with surface of the die that significantly affects the ejection force. It also determines the crushing force or hardness. In order to normalise thickness weight amounts would have to be specified for each substance tested. A more convenient and more universal method for test condition normalisation is to refer the ejection force to the contact area between the tablet and the die and to refer the crushing force to the highest tablet cross section. The mathematical expression of this relationship is as follows:
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cal hardness tester was installed, construed particularly for measuring tablet hardness, as well as “the push-out” forces. The set is completed by software making formulation designing or technological problem solving a computer assisted and recorded process. Research described here was conducted with the use of a machine with identical structure and equipment, as is shown in the photograph.
Fig. 2. Definition of the tabletability of a substance, as proposed by the author. Data acquisition, calculations and graphs are executed by a computer. Work on formula design is carried out similarly download *.pdf version: www.farmacom.com.pl
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production Fig. 3. The same active substance, from different manufacturers, tested for tablet formation without granulation. The final column contains summary results for the corresponding rows. These tests recently led to the design and implementation of a direct compression formula for a medicine which was widely believed not to allow dry tablet formation. An important advantage of these tests, after they have been reduced to a necessary and convenient minimum, is the easy control of supplies
unit ejection force = ejection force / tablet-die contact area • unit tablet hardness = crushing force / tablet cross section area at the diameter (The slash in the above formulae denotes the line of fraction). Many researchers, whose papers the author considers with respect, interpret measurements in this manner.
•
In the present method (Fig. 2), such conversions are not used, because tablet thickness is normalised at the outset, which is indicated by the text in the bottom left corner of the figure. However, the method’s advantage does not lie in the number of calculations but in the fact that forces are applied precisely in amounts needed at the moment, because they do not depend on the amount of substance in the die. In practice, the first tablet is formed using the maximum die volume (fill depth: approx. 18 – 20 mm) under a pressure of 10 kN; upon inputting the results (weight and thickness), the computer indicates the weight for all subsequent tablets in the test. When making the subsequent tablet, now using the correct amount of the substance, the weight
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can be corrected if the thickness measurement indicates to do so. From that point on, two tablets are made at a lower setting (pressure of 5 and 2 kN) and two tablets at a higher setting (pressure of 20 and 40 kN). For known and previously tested substances, the first large tablet is not made. The set and resulting tablet parameters are marked in an automatically generated plot used to calculate tabletability (trapezoidal integration). In the tabletability testing form generated, the actual apparent volume and deformation are also calculated, defined as the difference between tablet thickness for the lowest pressure and tablet thickness for the highest pressure, being the percentage of the former. On the basis of this parameter, plasticity is determined which defines capping tendency, among other things. The form also contains the results of sieve analysis and summar y tabletability result from previous forms, if the test is a sequence of logical trials for the same substance. Then the results can be reviewed and interpreted more easily. The tests are also possible when typical rotary or eccentric laboratory equipment is used. However, the relationship between pressure and substance amount in download *.pdf version:
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Application As has already been mentioned, direct formulas with a small dose of medicine in a tablet are easy to achieve, especially since ready-made placebo mixtures are available on the market. As an aside, however, it is more practical to develop one’s own placebo in place of the relatively expensive ready-made version. The situation is different when the medicine is to make up a large proportion of the tablet. It may turn out that even in the largest tablet (let’s say Ø13 with a weight of 1g) there will be no room for sufficient quantities of auxiliary substances. What do we do then? Always the same thing, and always for each formula: start by working with the active substance on its own, painstakingly investigating its tabletability. This is a difficult stage, since it is also necessary to seek suitable suppliers and sometimes negotiate quality changes with them, as in the case described below. Only if these efforts fail to give positive results do we try dry granu-
lation, or finally wet granulation. This order seems to be the correct one. The example in Figure 3 presents the results of work with a pure active substance from two suppliers, in three batches from each. One of the manufacturers is a Polish company. The chemical test certificates are almost identical, and all positive. Here, mechanical testing is shown. The addition of magnesium stearate (MgSt) proved essential, in view of the poor ejection. This is not always necessary, and it does not always have to be stearate. Each graph represents one test with variable pressures for a mixture with appropriate MgSt content. The tabletability calculated from one graph (using the formula in Figure 2) is a single dimensionless number. This number is then used as a function value in the summary graph in the last column of the table. All this together forms the product’s mechanical characteristic, from which we derive the following conclusions: 1. The substance supplied by manufacturer A has much better dry tabletability (although the manufacturer is probably unaware of this and has made no conscious effort to achieve it).
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this case may lead to extended time needed to complete tests according to the procedure.
Fig. 4. Ranking of typical excipients. Lot numbers are shown which relate results to specific products. The results are fully objective and obtained using the procedure described. If necessary, when tablets could not be ejected from the die with a force lower than 500 N, magnesium stearate (MgSt) was added as indicated download *.pdf version: www.farmacom.com.pl
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2. A large quantity of MgSt does not compromise the tablet hardness (certainly the hydrophobe impairs solubility, but this does not interest us at the moment). 3. There is a clear hardness extremum for pressures of 20 kN, and this indicates something important: the substance will “cooperate” as a binder. However, this requires that we do not lose sight of this extremum in the course of further work. When making use of these graphs for design purposes we must remember that MgSt should be treated at this stage as “lubricant and other auxiliary substances still to be used.” Of course these values of MgSt content from zero to 20% represent an artificial situation which would never occur in practice, used here only to demonstrate the behaviour of a substance subjected to various dynamic loads. In further design work, when auxiliary ingredients come into play, the main thing is to expose the previously mentioned extremum of cohesion, while now also paying attention to other properties of the tablet. This is the purpose of the next design stage, namely optimizing the formula composition and the operating parameters of the production machine. In any case, the possibility of continuous observation of the tabletability of a newly created mixture, obtained very easily (in a small beaker and mixed manually), makes it very convenient to work on the formulation. Computer-generated design sheets can be immediately added to the registration documentation. We will consider one more characteristic example. A certain manufacturer produced an active substance in micronized form, boasting of both the small size of the particles and their ability to hold fast when narrow dimensions were required. It was attempted to form tablets dry, but without success. The tablet had to contain a large amount of medicine, and it did not show sufficiently strong cohesion in any conditions similar to those shown in Figure 3. The manufacturer was then asked for a 5-gram sample of the substance, but in “unfinished” form, i.e. without micronization. It turned out that not only could the substance then be tableted dry, but – note – the release from the tablet also improved. Why? In a jet mill particles collide with huge energy, and this causes large local rises in temperature on microscopic areas. This may lead to surface melting, and hence the formation of a more durable envelope, less readily soluble in water and also impairing linking between particles. This example illustrates how much the form of the substance depends on the parameters of the last stages of manufacture, and even on the type of devices used. Having the ability to investigate the tabletability of a substance, we can come to certain arrangements with the manufacturer, measure, compare and monitor deliveries. Since we mentioned envelopes and particle size, it should be pointed out that there have been numerous papers, including by Professor Peter Schmidt of Tübingen University, which emphasize the important role of the initial pressure application in the final pressing. Initial pressing is intended to
break down the harder structure and expose many surfaces for contact with other particles. Practice shows that there are cases where the initial pressure must be exerted very precisely and in the right ratio to the main pressure. It must therefore be sound even at the testing stage, and this is a possibility not normally offered by the little “toy” rotary tablet presses present in many laboratories. Let us now consider a more general example. When preparing to introduce a new formula, we try to choose the most optimum solutions for our work: • the most carefully produced, micronized active substance; • the most accurately made, polished matrix; • the best auxiliary substance, e.g. Pharmatose DCL 14, advertised as a product “with superb compression” (quote from manufacturer). It may be found, however, that in order to achieve success we need somewhat “inferior” products: • ad. 1. active substance without micronization, as has already been commented on; • ad. 2. matrixes which are not polished but merely ground, with inferior coarseness, to which the substance used adheres less (such cases exist, but there is no space here to describe them in detail); • ad. 3. „inferior” auxiliary substance, e.g. Pharmatose DCL 11, which nonetheless forms tablets much better (compare nos. 25 and 31 in Figure 4) than the much praised DCL 14. Here we can see that we can get to know our way around the jungle of auxiliary substances, not always relying on the information supplied by manufacturers. In summary: once we have the results of tabletability testing, we know what we want. Many more examples could be given. Tabletability testing is very detailed, as has been seen. It is worth quoting here the old saying: the devil is in the detail. Industrial technology, like probably every strategy, depends on skilful mastery of the details. Having sufficiently detailed knowledge, it is possible for example to confidently eliminate the wet production line in a large plant, as has been done in the past. And this is no longer just a detail.
Summary The pharmaceutical technology that can yield good tablets inexpensively is called mechanics. The statement may be considered slightly perverse, but indeed, without advanced mechanical tests, direct compression formulations cannot be designed in difficult cases. Substance tabletability tests perfectly match quality assurance. While the tests are carried out using modest means, they provide strong arguments for large-scale savings. The benefit achieved sometimes seems improbable, and the immense gain can only be assessed in hindsight.
All those interested are kindly invited to the course OPERATION OF TABLETING MACHINES led by the author in Konstancin, March 26-27, 2009. Details and registration: www.polfarmed.pl
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The wealth of pharmaceutical products on the market is growing month after month. These are complex products with difficult and demanding production processes. They differ in terms of their composition, their intended uses, and the doses of active substances. Most of them have one common feature, however – they are sold in packaging.
Packaging
– so easy to say…
Michał Stanke Head of Quality Management, Edelmann Poland Sp. z o.o.
W
hen we enter a pharmacy we may note that there are as many different medicines as there are packages in which they are sold. Only by observing that picture do we start to become aware what purpose packaging has, what is needed in order to create it, and what work is required to design and produce what would seem a small and unnecessary component of the product which is the medicine we desire. And only then does the thought enter our minds that it is the packaging that carries the most essential, sought-after information which helps us to keep the most precious thing we have – our health. We must bear in mind that all of us require absolute perfection of manufacture from our medicines. The packaging, as a component of that product, must also be of the highest quality. In order to make that happen, a simple package must go through a multi-stage process, during which every action should be performed with the greatest care about the smallest detail. Successful completion of this process is a difficult art for those involved in the printing work. The basis for the manufacture of packaging is a good graphical design, for both the packaging itself and the leaflet. This is usually complex and difficult, because the design must contain all the essential information. It must be remembered that the more detail it contains, the greater the risk of error. For this reason, checking at the stage of preparation for printing involves many levels and many persons: correcting the proofs,
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checking the layout, checking the files before the material is recorded on the printing plates, and compliance checking of the plates after they are made. Next comes the stage which is the main factor in the success of the packaging – the printing. This places not insignificant demands on the people supervising the process. They have to check the correctness of the colours, the matching of individual graphical elements, and the compliance of the lacquer applied to the cardboard after printing. Next it is time for the most magical and elusive element of modern pharmaceuticals packaging production – stamping and die-pressing. We may wonder wherein lies the magic of stamping. It is at this stage where the Braille text is produced. The precision with which this is done is a true art in machine control. After all, the dots must be in the right place, have the right convexity and form the right characters. Not everyone is able to evaluate the quality and correctness of the text printed, so once a pattern is accepted it requires absolutely ideal repeatability, which is not easy to achieve. For this reason operators must display professionalism and a feel for the task. Folding the printed medicine leaflets is another difficult art which needs to be mastered to perfection. The larger the leaflet, the more times it needs to be creased before folding. Remember that this is done with a soft and sensitive material, normally the paper with the smallest possible weight. Paper has a memory and its own caprices download *.pdf version:
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wipe a box clean when it has already been printed. If the graphics preparation or the printing is incorrect, there is no point in stamping or gluing it. There are two aspects to the work of the quality control department – monitoring, which is generally recognized by all staff, and the “creation of ideals”. The latter mainly involves creating a pro-quality organizational culture – a culture which ought to teach and stimulate a feeling of responsibility not only for one’s own work, but also for that of others. This education not only makes us aware of the effects of undesired actions, but also allows us to understand what is meant within the organization by cooperation, joint solving of problems, and above all the avoidance of all possible defects. It also teaches effective communication between production departments, which increases the efficiency of each one of the actions performed. It is important that the personnel responsible for quality are willing and able to talk to people, giving them a sense of their importance in the overall production chain. The quality process is therefore a kind of philosophy of behaviour for the entire team of people producing packaging from start to finish. And it is the result of that work, done by a whole group of trained and specialized people, that we pick up when we buy medicines in a pharmacy. One of many which are no doubt situated close to your home and workplace. We hold the packaging in our hands, look at it, sometimes admire it, and read important information from it. But what we are holding is the fruit of the work of a huge number of people. Remember this the next time an empty medicine box lands in the rubbish bin.
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– it is plastic and does not always do what is expected of it. On the one hand there are many ways of folding it, but on the other it can get folded in many undesirable ways, apparently following its own agenda. It tries to escape the control of the operators, who have to pay attention to every movement controlling the machine. This means that the operator’s responsibility involves mainly his or her expertise and, again, a feel for the task. Every movement by the operator must be thought out in terms of the effects that it brings. Before the product can be called finished, one more stage is needed. This is the gluing of the box which has now been printed, cut out and stamped. There are different types of gluing, each requiring a different setting of the machine. There are also types of packaging that are so complex that in each of them several different types of gluing need to be used, or for example additional elements stuck in as informational inserts or to hold the packed product in place. Operators and those assisting them must pay special attention to the correctness of the construction after gluing. This is important in terms of the packing of the end product, and above all the efficiency of that packing. Thus the production process ends, and the logistical processes begin. We must not forget, however, about something that does not affect the product directly, but is omnipresent in the process – quality control. Clearly, this must serve to ensure that each of the described steps is performed correctly. Remember that in a multi-stage process, if something is done wrong at the start, later steps will not be able to put it right. Moreover it is not possible to
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Raman spectroscopy and its application in the pharmaceutical industry Daniel Zakowiecki, MSc
Preformulation Department Pharmaceutical Works Polpharma SA
Krzysztof Cal, PhD, MSc
Department of Pharmaceutical Technology Medical University of Gdansk
Raman spectroscopy is a versatile and universal technique, which has experienced a renaissance since the introduction of lasers in the 1960s. Recently, its advantages have also been discovered by the pharmaceutical industry. The method has many applications, ranging from characterizing active drug substances and excipients, through structural analysis, to in-depth studies of the final drug product.
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t is successfully used, not only in examining solid dosage forms, but also in studies on semisolids and liquids. Raman spectroscopy can also be applied in vivo - provided that strict safety requirements are met due to the use of laser beams, particularly in studies on the skin penetration and permeation [1-4]. The present paper presents research involving Raman spectroscopy conducted in the early stages of drug development, particularly in the preformulation stage.
Fig. 1. Outline of the formation of dispersive Raman spectra
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Position (micrometers)
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Fig. 2.
Position (micrometers)
Spectral map of a tablet fragment with active drug substance marked in red
Theoretical background The effect of inelastic scattering of photons by substance molecules was theoretically envisaged by A.G. Smekal as early as in the 1820s, and it was empirically proven in 1928 by the subsequent winner of the Nobel Prize, Indian physicist C.V. Raman. The phenomenon, named “the Raman effect” after its discoverer, had long had no application. This was largely due to the lack of appropriate research and measurement equipment that was capable of inducing and detecting high-quality spectra containing Raman bands of high intensity. The rapid development of Raman spectroscopy began with the introduction of using laser beams as a source of excited radiant energy. A laser light is characterized by high monochromatic and very intensive beam. Furthermore, laser radiation is polarized, which makes it possible to determine the depolarization level of Raman bands. The use of laser light to induce molecules, together with the use of highly sensitive signal detection systems, such as Coupled Charge Detectors (CCD), enabled a simultaneous recording of the whole Raman scattering spectrum of high spectral resolution and high intensity [5, 6]. Today’s Raman spectrometers are wholly integrated units, compliant with safety standards and computer-controlled. There are calibration
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procedures devised to meet the stringent requirements of the pharmaceutical industry [5]. When a monochromatic laser beam falls on a substance, it interacts with its molecules in many ways, resulting in the absorption, reflection, or scattering of light. If the energy of the exciting light does not correspond to the difference in energy between stationary quantum states of the molecules, light scattering occurs as a result of inducing the dipole moment of the molecule, which itself becomes a source of radiation that is scattered in space in all directions. Some of scattered photons reach the detector, which results in creating a Raman spectrum containing information on vibrations characteristic of a given molecule [7-11]. A Raman spectrum represents the relationship between intensity of scattered radiation and its frequency [6]. During scattering, the photons falling on the tested sample may interact with its molecules in three ways (Fig. 1): they may decrease their energy (Stokes Raman scattering), increase their energy (anti-Stokes Raman scattering), or remain unchanged (Rayleigh scattering). The most useful information is contained in the Stokes and anti-Stokes bands, but due to the fact that the antiStokes band is a few or several times less intensive than the Stokes band, it is precisely the latter one that is mainly studied by Raman spectroscopy [11]. Typical Raman download *.pdf version:
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Depending on the type of material, a direct analysis through glass or polymer containers is possible, which further restricts the influence of external factors. The lack of interference caused by bands coming from water or carbon dioxide enables the analysis of water systems, and excludes the necessity of isolating the examined substances or providing special conditions, such as a nitrogen atmosphere, or other neutral gas atmosphere. All this makes this kind of analysis non-invasive, non-destructive, and relatively easy to conduct. In practice, two types of apparatus are used: a dispersive Raman spectrometer and a Fourier Transform (FT) spectrometer. Each of these devices has its advantages and disadvantages. Dispersive Raman spectrometers are very sensitive, but their main flaw is the possibility of exciting a fluorescence of sample contaminations during the measurement [10]. On the other hand, FT-Raman spectrometers are less sensitive, but their use of Nd:YAG neodymium lasers (Nd:YAG = neodymium-doped [Nd3+] yttrium aluminum garnet) of low intensity with near-infrared exciting light (ë=1064 nm) allows the avoidance of fluorescence which hampers the observation of Raman spectra [6]. In examples given below, A Thermo Scientific’s Nicolet Almega XR dispersive Raman spectrometer was used, equipped with an exciting laser with a wavelength of 780 nm, a microscope with a 50x lens, and a CCD detector.
Position (micrometers)
spectra cover the range of 0 to 3500 cm-1; although in practice, bands situated so close to the excitation wavelength are rarely analyzed. The location and the intensity of bands are characteristic of the molecule under examination and reflect the movements of its atoms [1]. Raman spectroscopy is more and more widely used in the pharmaceutical industr y, and its applications include, among others, the identification of active drug substances and excipients for quality control, examining the polymorphism of substances and the processes related to changes in polymorphic forms, the monitoring of solvation and hydration processes, etc. Raman spectroscopy is also used in testing final drug products in terms of the distribution of the active drug substance and excipients, the formation of agglomerates, changes in polymorphic forms, quality, and repeatability of the tablet coating process, and in stability tests [1, 8, 9]. An unquestionable advantage of Raman spectroscopy is the ease of preparing samples for examination: The samples usually require no special preparation, the use of supplementary reagents is not necessary, no grinding, pill-forming, nor mixing with dispersing agents required (just as in IR spectroscopy). Therefore, there is no danger of polluting or changing the physical or chemical structure of the sample. Moreover, the study requires only a small amount of the sample material, and in the case of microscopic systems, this is limited to just a few crystals of the sample.
Fig. 3. Spectral map of a tablet coating fragment
Position (micrometers) Position (micrometers)
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Raman Intensity
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Raman moving (cm-1)
Fig. 4. Comparison of Raman spectra in two polymorphous forms (Form 1 - purple line, Form 2 - blue line) of a substance used in treating hypertension and a spectrum of active drug substance in tablets (red line) within the region from 2820 cm-1 to 3010 cm-1
Visualization - mapping Raman microspectroscopy, i.e. the combination of Raman spectrometer with a microscope, enables the visualization and analysis of heterogeneous systems, such as tablets, powders, creams, ointments, suspensions, etc. One technique of visualization is mapping, which consists in recording a series of spectra in subsequent points of the studied area by means of pre-programmed microscope lens movements. The laser beam is focused on the surface of the sample placed on a mobile microscope table, and the spectrum is recorded by the spectrometer, which enables simultaneously obtaining of spectral and spatial information on the studied sample. The spatial resolution is limited to the light beam size , i.e. about 1 µm. The obtained spectra are calculated by relevant programmes and transformed into correlation maps, which are very illustrative and comprehensible, even for persons only vaguely familiar with spectroscopic techniques [1, 12]. Such experiments are time-consuming, but the use of new-generation Electron Multiplying Coupled Charge Detectors (EMCCD) allows for a considerable reduction in the time of analysis. Because a typical spectral image consists of thousands of spectra, the time of recording a single spectrum is critical, and it usually lasts from a few seconds to a few dozen seconds. The use of EMCCDs limits the time of recording a single spectrum even to 760 µs, which may shorten the time of recording the whole spectral map even to a few minutes [13, 14]. Application of the mapping technique enables the analysis of the distribution of the active substance and excipients in a given dosage form (e.g. tablets or capsule contents). It is possible to identify the active drug substance and excipients and to locate them within the studied sample [8]. It can be determined
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if the substances become agglomerated in the production process or if a change occurs in the polymorphic form of the active drug substance. Parallel to analysis using an optical microscope, it is possible to determine the size of molecules of the active drug substance and excipients. Figure 2 presents a spectral map of the distribution of the active substance in tablets applied in hypertension treatment. One can clearly see the places of active substance occurrence, regularly distributed over the whole visible space. Because the molecules do not form agglomerates, it is possible to estimate the size of drug substance crystals with fair accuracy. In the sample under examination, molecules smaller than 25 µm prevail. Also, the very small molecules are visible (5 µm and smaller), but to determine their size with higher accuracy, measurements with a higher spatial resolution should be conducted. The examined tablets were made of an active substance whose crystal size was estimated earlier by means of a Malvern Mastersizer particle size analyzer , and it amounted to d(0,9) – 21.04 µm, which means that the size of 90 per cent of molecules was below the given value. Evidently, the results of measuring the molecules of an active substance in the form of powder and in tablets are very well correlated. In the development stage of coated tablets, it is crucial to determine the optimum parameters of the coating process - the thickness and uniformity of the coat is often very important to the stability and effectiveness of the drug. By creating a correlation map with a characteristic spectrum of titanium dioxide (in one of the polymorphic forms - anatase), which is a frequent component of the coating, one can determine the thickness of the coating in various parts of the tablet. Figure 3 shows a spectral map of a tablet coating fragment, whose thickness ranges from 37 µm to 55 µm. download *.pdf version:
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Another significant phenomenon in the pharmaceutical industry is the problem of polymorphism, i.e. the occurrence of substances in many crystalline forms. In the process of dosage form preparation, i.e. during granulation, drying, forming tablets, and then storing the drug, what may occur is a change in the polymorphic form of the substance, or hydration, solvation, etc. Polymorphs of an active substance differ in physical and chemical properties, e.g. solubility, which may directly influence the biological availability of the drug. What is also important is to analyze the polymorphs in terms of patent protection assessment and the possibility of using reserved forms of the active drug substance in the final dosage form. The most popular instrument used for measuring polymorphism is an X-ray diffractometer, and because most samples occur in a powdered form, the powder method is the one most frequently used. In the case of drugs with a very small active substance content, or when the influence of the excipients is so high that analysis through X-ray diffraction becomes impossible, Raman spectroscopy turns out to be an inestimable solution. It allows developmental research with an objective to determine the optimum parameters in the processes of granulation, drying, selecting an appropriate solvent and optimal excipients, demonstrating no physical or chemical incompatibilities with the active drug substance. Figures 4 and 5 present a comparison of Raman spectra in two polymorphs of a substance used in treating hypertension and a spectrum of active drug substance recorded in commercially available tablets. In the two regions shown (from 2820 cm-1 to 3010 cm-1 and from 1510 cm-1 to 1780 cm-1) the bands differentiating the two polymorphs were marked. Evidently, the substance contained in the tablets is identical to form 1.
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Identification of polymorphic form of a drug substance
Confocal analysis The combination of a Raman microscope with confocal optics opens the possibilities of depth-selective sample measurement and creating depth sample profiles. Confocal analysis is best conducted with the use of a dispersive Raman spectrometer with shorter wavelengths, provided that no sample fluorescence occurs. The capacity of confocal analysis may be exploited in studies of packaging materials (blister packs) in order to confirm their identity. Packaging materials usually consist of multi-layered polymer laminates. Through applying appropriate distances between which particular spectra are recorded, one can determine the number and thickness of foil layers in a blister pack and identify them [5, 15].
Summary Apart from the examples mentioned above, the range of the applications of Raman spectroscopy is much wider. The technique is mostly used in qualitative analyses; however, through exploiting the direct proportion of substance band intensity and substance concentration, one is also able to conduct quantitative analyses, including those involving final drug forms [10, 16]. Not only in vitro but also in vivo research is conducted, such as research on the skin penetration and permeation of drugs [2-4]. Raman spectroscopy is also popular in detecting counterfeit medical products that fail to meet the quality requirements and are dangerous to patients, e.g. because of a high contamination content or the use of an inadequate polymorphic form of the active drug substance [17]. The usefulness of Raman spectroscopy in an R&D laboratory is invaluable, and the range of possibilities is not limited to the ones presented above, and the ways of application seem almost infinite.
Bibliiography in polish part (page 22)
Fig. 5.
Raman Intensity
Comparison of Raman spectra in two polymorphous forms (Form 1 - red line, Form 2 - blue line) of a substance used in treating hypertension and a spectrum of the active drug substance in tablets (yellow line) within theregion from 1510 cm-1 to 1780 cm-1
Raman moving (cm-1)
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The Role of Thermoforming in Creating Competitive Advantage Honeywell
This paper examines the trends and issues currently facing packaging stakeholders in the pharmaceutical industry and looks at how companies are utilizing thermoformed primary packaging to create a competitive advantage.
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eeting regulatory and quality needs are a basic standard and a “given” requirement for any primary packaging solution. However, in order to meet the challenges of today’s pharmaceutical marketplace, many companies are now looking beyond these basic technical needs – for these, pack presentation is now considered a competitive differentiator. It is against this background that Honeywell commissioned RM Consulting (RMC) to research and better understand the needs and future aspirations of a broad spectrum of pharmaceutical stakeholders who need effective packaging solutions to deliver mission critical goals for their company’s ongoing success. A major finding of the research was that in order to meet marketplace demands, packaging stakeholders now need ever increasing flexibility in design options – an issue well-addressed by thermoformed solutions.
Introduction
Dr. Thomas Dries is European Healthcare Marketing Manager for Honeywell Specialty Films. He has 18 years’ experience in the packaging sector with 6 years exclusive experience in supplying solutions to the pharmaceutical industry.
Charles Rowlands and Amy Morgan are founding partners of RM Consulting, an international business consultancy focused on providing management support services to the global pharmaceutical, biotechnology, chemical and healthcare sectors. Jointly they have more than three decades’ experience and have worked on numerous strategy development and market assessment projects in both developed and developing economies.
As a world leader in pharmaceutical packaging materials and manufacturer of Aclar ® fluoropolymer film, Honeywell Specialty Films is working to develop industry leading packaging solutions which can deliver increased competitive advantage to the pharmaceutical industry. The objective of the research conducted by RMC was to gain an understanding within both ethical and generic producers of the current trends and evolving role of thermoformed primary packaging solutions in drug development. Research was based on 40 in-depth interviews conducted with a broad range of key functional stakeholders across 19 leading pharmaceutical companies – marketing, clinical trials, pharmaceutics as well as packaging professionals and operations.
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Figure 1: The above value curve was constructed by rating the importance of each of the criteria in the choice of primary packaging material as reported by study respondents. It is a reflection of the issues that are currently considered important to stakeholders and on how these might change over time.
Study Findings Packaging decisions are increasingly being made by multi-functional teams that follow a candidate from “proof-of-concept” through to transfer to manufacturing operations. As such the packaging choice and design must meet the needs and expectations of all team members. The relative importance of various criteria in the decision making process for primary packaging and the role of thermoforming was discussed with stakeholders during interviews - study findings are visually represented in Figure 1.
Barrier Properties Study respondents were unanimous in reporting that barrier requirements drive the choice of primary packaging material. Meeting regulatory requirements for stability and selecting a primary packaging material that affords adequate shelf-life is the primary concern – notably with the push into developing markets. Additionally, formulation is becoming an increasingly important tool in drug development and product lifecycle management. Formulators are being asked to develop more novel or more sophisticated dosage forms to improve marketability or to compete with other products presenting formulators and packaging developers with unique challenges. It was reported that more potent and complex formulations are driving the need for increased barrier protection – not only against moisture, but also O2, heat and light. Consequently, some respondents highlighted the benefits of employing a high barrier material from the start in order to avoid unnecessary and costly repeat stability testing. The study revealed that thermoforming offers the flexibility to use the level of barrier required – with a range of films available from low moisture barrier PVC to the high moisture barrier and chemical stability offered by PVC /
Aclar ® UltRx 4000 for example. An additional advantage is that thermoforming does not limit the option to migrate the packaging platform to a lower cost material over the product lifecycle.
Cost of Materials While cost of materials is an important issue, it was not found to be the key driver in the choice of primary packaging material - respondents reported looking for the optimum cost solution which provides the required level of barrier protection. Nevertheless, judgments are made on cost – particularly where it is a case of weighing up the cost of one (potentially more expensive) standard against the cost of keeping several materials for different climate zones. When considering costs it was found that up-front cost per square metre was the primary concern. However, many respondents noted the need to start looking at costs beyond the initial cost of material – i.e. at the total costs of packaging over a product lifecycle including not only the cost of primary packaging but also that of secondary packaging, labour, machinery, maintenance, consumables, material usage, scrap, etc. It was reported that a total cost understanding would not only assist manufacturing operations to better predict the costs of running various materials, but it would also help stakeholders in early decision making – by bringing more informed cost arguments into the earliest stages of packaging design.
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For this reason Honeywell designed the Aclar ® Value Calculator which allows packaging stakeholders to evaluate the potential total cost advantages that thermoforming can offer for pharmaceutical packaging. Thermoforming for example has the capability for higher tablet density thus reducing the level of primary and secondary packaging required. The calculator is based on accessible information and allows stakeholders to input their own internal parameters (e.g. tablet size, shape, quantity, etc) and cost numbers in order to evaluate total packaging costs.
Complexity Reduction The pharmaceutical industry now operates on a worldwide basis – increasing heterogeneity in market and end-user requirements results in many companies running multiple pack variations to suit specific market preferences and requirements. Operational Heads reported that running multiple variants increases the rate of changeover – which can result in a struggle to maintain operational efficiency. Complexity is now a major contributing factor to increased development costs and time. Addressing complexity is a prime concern and there is much effort within the industr y to standardise primar y packaging as much as possible. Pharmacos are drawing up lists of “harmonised” or default solutions suitable for various levels of barrier protection. Criteria for inclusion in lists differ by company, but in general take into consideration the need to overcome stability issues as well as costs, in-house resources and capabilities, security of supply, etc. Respondents reported that the ideal solution would be the same primary packaging for all markets; which could be achieved by standardising on a high barrier thermoforming option. Alternatively, thermoforming can provide increased flexibility as the same machines can be utilised to run different materials – thus facilitating changeover and maximising machine utilisation.
to package more tablets per machine stroke. This can increase the effective capacity of each packaging line and offer a direct reduction in: • Scrap • Labour • Energy • Tooling & Consumables • Capital equipment needed In addition, “clear” thermoforming films can lead to improved process control and quality inspection options – through the ability to see the tablets. In summary, the increased production capacity and flexibility offered by thermoforming impacts on the bottom-line and can lead to increased manufacturing efficiency and flexibility – key issues against a backdrop of increasing operational efficiency targets and tightening plant budgets.
Ease of Use for Patients Meeting the needs of patients and other end-users (care-givers, pharmacists) is forcing the Pharma industry to become more creative. Packaging materials can have a huge impact on the size of the finished pack and the ease with which patients can remove medication. As such, it was reported that packaging has become integral to the patient experience and has an important role to play in influencing behaviour – notably with respect to patient retention and compliance with the recommended or prescribed therapy. More attention is now being paid to developing patient friendly packs in terms of look, functionality and portability as well as ones that take into account the needs and capabilities of the widest possible range of potential users. The challenge is to get better access for seniors while maintaining safety for children. Respondents reported that thermoforming allows greater flexibility in design in order to meet end-user needs – for
Maximisation of Plant Increasing complexity within the industry has brought about more challenges in manufacturing operations for cost effective production and good machine utilisation - hence minimizing the number of materials used while maximizing interchangeability was cited as a potential solution in limiting production downtime. It was noted that there is an increasing need for operational flexibility in Europe and the rest of the world. Here shorter campaigns and many changeovers make it difficult to maintain operational efficiency. In contrast, the US is still characterised by dedicated long production runs – giving rise to different operational needs for Pharmacos in different geographical regions. Many respondents cited a technical preference for thermoforming – machines can be used interchangeably, the process has the capability for higher tablet density as well as the ability
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Addressing the needs of end-users can lead to improvements in both patient retention and patient compliance - which in turn can be measured in terms of: • Increased revenues by Pharmacos • Cost-reduction by healthcare providers • Reduced patient visits by doctors • Increased market pull at the pharmacy Thus meeting end-user needs can provide an important revenue-enhancing advantage and can be likened to consumerisation with the OTC sector. It is becoming increasingly important for prescription medicines pitching the drive for user-centric packaging versus simple regulatory satisfying packs.
Marketing Needs The role and influence of marketing needs was found to vary greatly from company to company and by geographical region – European marketing groups reported generally providing “direction and guidelines” while having less control over the “actual choice of material” as long as it fits their general criteria; while US marketing groups have a much stronger influence in the decisionmaking process. Marketing input frequently places more demands on the choice of primary material and requirements often tip the balance in favour of one packaging material over another. Marketing stakeholders reported that pack aesthetics can be improved by thermoforming – it is a more flexible technology offering more design possibilities. For the more forward-thinking Pharmacos, packaging now represents value creation which in turn represents market share; hence occasions do arise where shelf-life might be
compromised in favour of pack aesthetics or more userfriendly designs on the basis of sound marketing arguments. Brand recognition is an important marketing feature – visual recognition of the drug product in particular. In this respect clear thermoformable blister film was noted to have an advantage – “After investing so much in the look of the dosage form, why hide it in an opaque barrier?” From a patient compliance perspective, transparent film allows multiple tablet colours to be visible and provides clear evidence of medication taken. Colourcoding can also be useful in chronic diseases or where dosage sequences are important. However, the use of clear blister film is prohibited in some countries on the basis of child resistance – leading to many companies testing clear and opaque films in parallel in order to cover all options. The pharmaceutical industry is under great pressure to deliver new products to market and to “squeeze” the most out of product assets while still on patent – it is becoming far more challenging to sustain the “blockbuster” model. Increasing marketplace demands continue to place more pressure on Pharmacos to look for means of differentiation: • Increasing competition • Generic erosion • Declining pipeline productivity • Increasing numbers of “me-too” products • Escalating R&D costs
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example, the small form factor involved leads to a smaller footprint and increased portability, while the option of transparent packaging can offer a therapy compliance advantage.
Industry challenges are forcing Pharmacos to incorporate commercial arguments earlier on in product development. Respondents anticipate that the impact for pharmaceutical packaging will be: • Increased marketing input in material choices • Greater emphasis on the role of packaging in patient outcomes
Brand Protection With increasing exports of pharmaceutical products to emerging markets robust IP protection measures are gaining in importance. Anti-counterfeiting now represents a major area where packaging has become a strategic issue for pharmaceutical companies – while optical security features can already be incorporated into some thermoformable films many respondents indicated that they would be keen to see more initiatives from the packaging industry in this area. The flipside to this argument is that innovation can sometimes be seen to represent an increase in costs, “Anti-counterfeit initiatives would drive up material costs.” However, many respondents believe that cost has to be taken in context with the added value conveyed and as such many Pharmacos now view anti-counterfeit measures as an investment in brand and revenue protection as well as in patient safety. Nevertheless, while the financial benefit of such technologies is generally felt in the sales organisation, the implementation cost is felt on the ma-
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Figure 2: Examples of where thermoforming can provide an advantage to the packaging task as reported by study respondents.
nufacturing side, so this message can sometimes get lost. Recent high-profile cases of Big Pharma being caught out by counterfeit products are now expected to drive further investment in this area.
Conclusions Study findings highlighted the fact that packaging is no longer considered purely functional, but increasingly it must demonstrate value both internally and to the end-user (patient, care-giver and pharmacist) and that thermoforming has a role to play in creating competitive advantage [Figure 2]. Packaging has evolved to become an integral and fundamental part of product development – and given that the primary pack is what ends up in the hands of the user, it has the potential to exert the ultimate influence on behavior. The study concluded that meeting regulatory and quality needs are a basic standard and a “given” requirement for any primary packaging solution. However, in order to meet the challenges of today’s pharmaceutical marketplace, the more forward-thinking Pharmacos are looking beyond these basic technical needs – for these, pack presentation is now considered a competitive differentiator and thermoforming affords greater flexibility not
only in design but also in manufacturing operations. In order to move forward, these companies are now debating some key issues: • What is the real value of packaging to our company? • How can packaging help us compete? • What should we focus on from a packaging perspective? • Are we really maximizing our opportunities through packaging? • How can we use packaging to protect and defend our products? In recent years, issues such as ease-of-use, patient compliance and anti-counterfeiting have really brought packaging into the limelight and while barrier requirements will remain the major factor driving the choice of primary packaging material, spiralling R&D costs are anticipated to bring the total cost argument more into the fore. In summary, it is believed that the demands and expectations on packaging in terms of features and performance will continue to increase, as will its role in the patient experience and outcomes – the study confirmed that thermoforming remains strategically well-suited to meeting these challenges.
Honeywell is American multinational conglomerate company that produces a variety of consumer products in four major sectors: Aerospace, Automation and Control Solution, Transportation Systems and Specialty Materials which are global leader in processing fluoropolymers. One of Honeywell Specialty Materials products are ultra high barrier Aclar® films used in pharmaceutical industry.
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Galbex Sp. z o.o.
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Cleanrooms A cleanroom is an area with a defined system of controlling contamination from particles and microbes, built and used as to limit the intrusion, generation, and accumulation of contaminants.
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ecree of the Minister of Health of 1 October 2008 on the requirements of Good Manufacturing Practice, with reference to the requirements for production rooms, asserts as follows: “ … in rooms in which blank materials, direct packaging materials, intermediate products, or loose products are subjected to contact with the surroundings, the interior surfaces of rooms (walls, floors, ceilings) should be smooth, scratch-, crack-, and open weld-free, they should not constitute a source of solid particles, and should be convenient for efficient cleaning and, if necessary, disinfection” and “pipelines, lighting and ventilation points, as well as other installations, should be designed and installed in a way that would not create hard to clean recesses.” If possible, they should be accessible from the outside of production rooms for maintenance purposes.
Classification of cleanrooms Cleanrooms in which sterile products are manufactured can be classified according to the required characteristics of the environment. For every production activity there is a required level of cleanliness of the environment, which aims at minimising the risk of contaminating the product or materials used. In order to meet the air cleanliness requirements in such rooms, one must determine which requirements are applicable to “on-duty time” and “off-duty time.” “Off-duty time” refers to a situation when all production devices are installed and ready for use but the operators are not present in the workrooms. “On-duty time” refers to a situation when all devices work properly and are operated by an adequate number of employees. In manufacturing sterile products, four classes of air cleanliness zones can be distinguished: Class A: This is a distinct and separated zone in which highest-risk activities are performed, such as filling, corking, making aseptic joints, as well as a place for keeping
open ampoules and vials. Usually the required conditions are enabled by laminar air-flow. Laminar air-flow systems should provide a uniform air-flow speed in the workplace over the open product in the range of 0.36 to 0.54 m/s (recommended value). Maintaining these parameters should be verifiable at any desired moment. A one-directional air-flow and its reduced speed may be applied in closed isolators and gloveboxes. Class B: In aseptic production and filling, this zone constitutes the surrounding environment for Class A. Classes C and D: These are cleanrooms in which less critical stages of sterile product manufacturing are conducted. Cleanrooms are virtually always composed of two basic and inseparable parts: • A space separated by means of systemic elements, so as to isolate it from the external environment; and, • An HVAC system (for heating, ventilating, and air conditioning) equipped with elements for required processing of air compressed into the chamber.
Room construction - systemic panels Usually the system is based on modular construction made of smooth layered boards 48 to 75 mm thick, 1 200 mm wide, and 2 200 to 5 000 mm high. Layered boards may - depending on the client’s needs - be filled with Styrofoam, polyurethane foam, mineral wool, or the “honeycomb” structure which is used particularly in constructing cleanrooms for the electronics industry.
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The filling is laminated on both sides with galvanised sheets of metal 0.6-0.9 mm thick, powder-coated in a colour selected by the customer, or a standard RAL 9010. Metal plates must have a hygienic certificate issued by PZH for use in the food and pharmaceutical industry, as well as certificates for use in the building industry, and relevant fire-resistance certificates. The plates are joined with each other by means of ready-made hidden locks, and, where doors or glass sets are mounted, the plates are joined with aluminium closed profiles fixed in C-profiles in the sides of the plates (biscuittype joints). The plates are fastened to the floor by means of socles, which enables the floor to be rounded in accordance with GMP guidelines. Another way is to fasten the panels to the floor is with C-profiles. They are trimmed on the floor with an adequate PCV panel or a floor overlapping the socle. The glass sets are made of safety glass and are level with the wall panel surface on both sides. Doors, 900 to 1600 mm wide, are level with the plate surface. The door leaves are partly glazed and equipped with seals whose function is to limit the amount of air coming out of the room through the gap between the door and the floor. The joints between plates are sealed with hygienically certified and scrub-resistant silicone. Ceilings are made of layered board filled with mineral wool (they can bear the weight of a human body) or of tinplate coffers, powder-coated, 600 by 600 mm, mounted on a grate and joined with each other by means of clip-in latches. Joints between boards or coffers are sealed with silicone. The wall-to-wall and the wall-to-ceiling joints are finished with rounded PCV moulding, powder-coated tinplate or painted aluminium profiles. Below a few samples of construction outlines are given.
System component joints scheme
Fastening the panel to the floor on a socle
PCV floor moulding on a socle
Joints between plates
Structure of a panel Door mounting scheme
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Panel trimmed with a PCV socle
Panel-to-wall joint scheme (with rounding)
Material hatch mounting scheme (central mounting and one-side compatible mounting)
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The ventilation/air conditioning system (HVAC) An adequately designed system of cleanrooms plays a significant role in the production process or in a laboratory. The key element of cleanroom equipment is the air conditioning system. This system performs a few important functions: It conditions the air, maintains a required cascade pressure configuration and prevents cross-contamination. The system is usually composed of an air-preparing unit (ventilation centre), in which the air is cleaned and prepared in terms of temperature and humidity, an air-distribution system, which is usually in the form of ventilation channels made of tinplate with a proper tightness class, and an air- separation system (ventilators and vent openings). It is often the case that User Requirements force us to employ additional elements for accurate air processing, such as dryers or humidifiers. The key elements of the filtration system are the HEPA filters. The final ventilators are usually equipped with HEPA filters with a class similar to the cleanliness class of the room, eliminating other types of contaminants. Devices placed inside the cleanrooms must be so designed as to generate no additional contamination. Elements of the room construction system constitute a thermal and acoustic insulation because of the filling (mineral wool, Styrofoam or polyurethane foam). This facilitates maintaining adequate temperature in the rooms. In designing the arrangement of ventilation devices in cleanrooms, the rigour of the “dead zone” exclusion and of the avoidance of excessive outlet speed should be observed, especially with regard to weighing rooms. Elements that are often used in cleanrooms are devices used for the protection of the product or personnel, namely the laminar ventilators. As a result of using a laminar air-flow, the contaminants are being removed through their equal displacement by means of a stream of air towards the vent openings. Depending on the type of final filters used, an adequate class of air cleanliness is obtained, e.g. with the use of H-14 HEPA filters we obtain cleanliness class A (100).
The element that determines the formation of a homogeneous air stream is the separator (laminariser). Another feature necessary for obtaining the proper effect is the speed of the air-flow, which is 0.3 - 0.45 m/s (in special performance 0.2 - 0.9 m/s). In the case of frequent movement of personnel or elements of machines near the ventilator, which might disturb the laminar flow, short, transparent strap PCV curtains are installed. The ventilator has a compact and rigid housing made of stainless steel, forbidding the unfiltered air to get out of the ventilator. The main elements of the ventilator are the housing, including the expansion box, the fan, the HEPA filter, and the control system. Laminar ventilation may be suspended, standing, or mobile. One also should not forget about elements of light sources. Usually, lamps are mounted flush with the ceiling. Lamps are mounted in custom-cut holes in the board and sealed with silicone to obtain the proper tightness of the room. Depending on the requirements and the place of application, lighting should be produced in a tightness class of at least IP54 or IP65. Each construction of a cleanroom with equipment should be concluded with a validation process. A detailed description of cleanroom testing methods can be found in P.F. No 3/2008.
Legal basis: •
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Decree of the Minister of Health of 1 October 2008 on the requirements of Good Manufacturing Practice (Dz. U. of 2008, No. 184, item 1143); Act of 6 September 2001 - Pharmaceutical law (Dz. U. of 2008, No 45, item 271).
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sponsored article
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Counterfeiting of medicinal products an increasing threat to public health and safety
Marcin Weksler
Business Development Manager, Faubel
How to protect products and brands against fraud?
The fraud of medicinal products has always been a serious problem, not only because it has been bringing losses to the pharma business, but more so because it poses a serious threat to patients’ health. The scale of the problem is increasing alarmingly: according to EU statistics, 2, 711410 fake drugs were seized by European customs in 2006, which is 384% more than in 2005. And this figure is expected to rise even further in the years to come.
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o prevent further damage, the European Commission has introduced a regulation program to establish tighter and more effective control. It involves security measures which are designed to make packaging tampering and consequently drug fraud - impossible. In this respect, holograms, Data Matrix codes, product tracing in supply chains and mass serialization are solutions worth mentioning. Faubel is well positioned to meet forthcoming requirements in this field: as a manufacturer of self-adhesive labels, Faubel has already completed several projects involving security seals. Holograms are being increasingly used as reliable security marks on products or as seals applied on packages. Self-adhesive holograms have also proved their worth in labeling.
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Faubel also completed the installation of a new machine capable of printing Data Matrix codes with a variable data option which we believe will be the preferred solution when it comes to security issues.
Optimizing safety To ensure adequate and optimal product safety, we offer a comprehensive range of security elements. However, optimal protection is mostly achieved by combining various state-of-the-art techniques such as special papers, modern printing methods, special security colors, hidden information and diffractive security features. Diffractive product authentication features of the TRUSTSEAL® type meet high functional security requirements. Once applied on the product, on the packaging or as sealing elements, optical security features can also include
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an optional self-destruct mode to defeat tampering. As attractive eye catchers, OVD’s (optically variable devices) are easy to recognize and remember. The high recognition value and the striking appearance of OVD’s are achieved through extreme brilliance and dynamic design elements.
TRUSTSEAL® technology Even though holography is already an effective counterfeit deterrent, it cannot always defeat experienced forgers. However, the patented TRUSTSEAL® -solution represents a technological advance that cannot be easily caught up. The diffractive optical structures of the extremely hard-to-copy TRUSTSEAL® are computer-generated and replicated in a sheet polymer structure. These striking structures can be easily recognized even under unfavorable lighting conditions such as twilight or scattered light. Additional security elements, such as hidden images or information that can only be read with a special reading device or the so-called ‘nanotext’ (a microscopic text inserted in graphic elements, which is only legible if extremely magnified) can effectively enhance the level of protection against fraud. TRUSTSEAL® -technology can also be used to implement diffractive bar codes, thereby allowing automated authenticity verification. Thanks to the microscopic structures of the bar code generated by TRUSTSEAL® -technology (in nano-range) any kind of holographic forgery would be easily detectable.
2D-DataMatrix Code The 2D-DataMatrix Code is gaining momentum as a real alternative. Thanks to this new device, it is possible to store large amounts of data on minimum space and personalization is feasible, too. 2D codes can store thousands of alphanumerical signs and not just the manufacturer’s name or batch numbers. Indeed, they can reveal the entire supply chain of a particular drug. It is essential to be able to trace back a supply chain with an “easy-to-read” solution: once a counterfeit pro-
duct has entered the original supply chain, it gets “laundered” and is no longer traceable. With 2D-DataMatrix codes, it is possible to store vital information as a kind of manufacturer’s seal. In practice, mass serialization implies that every item, e.g. a label featuring a 2D code, has an individual mark, e.g. a number stored in the code, which makes every package and product unique. This is indeed a new approach to security and product distribution.
New machinery for printing and checking variable data Having switched from thermal transfer to inkjet printing, Faubel is now able to print variable, customized data and codes on labels in a quicker, cleaner and safer way. Thanks to this new technology, Faubel is now able to print variable data on the top side of booklet labels containing as many as 81 pages. Inkjet printing is – by industrial standards – a key technology which serves our purpose, i.e. printing labels and even those with special coating on their surfaces. DataMatrix, bar codes, graphics and texts are reproduced in a perfectly legible manner. In terms of product safety and protection against counterfeiting, Faubel’s printing systems offer a variety of new options. Customization and personalization techniques will make your products safer and unmistakable. All in all, the best protection against product counterfeiting is always to be one step ahead of potential forgers from a technological point of view.
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Application of LC/MS in cleaning validation Robert Krรณlicki, PhD BioCentrum, Krakow, Poland
Cleaning validation of manufacturing equipment is a key factor for minimizing the risk of cross-contamination of drugs. It is based on producing sound, science-based evidence that the cleaning procedure is fit for the purpose. In practice, this task implies much effort on drug manufactures. Performing a risk analysis in order to set product and detergent limits, group equipment as well as to establish acceptance limits for microbiological contamination is now mandatory. Nonetheless, it is the development and validation of analytical methods which seems to be the most time and resource consuming, as the methods must be sensitive enough to deal with traces of APIs.
Fig. 1. LC/MS apparatus. High performance liquid chromatograph (working pressure up to 800 bar) equipped with both UV-VIS and MS detectors. BioCentrum laboratory in Krakow, Poland
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Robert Królicki, PhD graduated in chemistry from the Jagiellonian University in Krakow, Poland. He holds a PhD in physical chemistry/spectroscopy. During his doctoral studies he conducted research on solvation dynamics using ultrafast laser spectroscopy. He was then appointed at Case Western Reserve University (USA) as a research associate. While at Case, he investigated novel nanomaterials with potential applications in photodynamic cancer therapy. After this stay he joined pharmaceutical industry, where he gained several year experience in qualification, validation and compliance issues. Since October 2008 he has been with BioCentrum, a Krakow’s biotechnological company. His main duties involve development and validation of HPLC and LC/MS analytical methods. He is a member of ISPE (Polish Affiliate)
Fig. 2. Molecular structures and molar masses of acetaminophen and caffeine
Fig. 3. MS and UV chromatograms of product A and the identification of its components by means of MS
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Fig. 1. Parameters used for setting the limits of cross-contamination of product B by product A and the limits itself Minimal batch size of product B Maximum daily dose of product B Safety factor Surface of manufacturing installation Minimal therapeutic dose of product A Maximum allowable carryover Amount of product A on standard surface
The most common analytical methods used within the pharmaceutical industry for quantification of API rely on classical high performance liquid chromatography (HPLC) techniques with UV-VIS detection. A technique which offers superior sensitivity and specificity is a combination of HPLC with a mass spectrometer (MS) as a detector (LC/MS). Such apparatus is depicted in figure 1. LC/MS is nowadays commonly used in pharmacokinetics, proteomics, drug development studies and forensic sciences. Due to its sensitivity and the possibility of mass detection LC/MS push the frontiers of drugs identification on the trace level. As a case study, the application of LC/MS in cleaning validation will be demonstrated on the example of a common pain reliever, product A.Product A contains two active pharmaceutical ingredients, namely acetaminophen and caffeine. Molecular structures of the APIs and their molar masses are given in figure 2. In cleaning validation, the allowable limits of API residues in the manufacturing equipment/installation are set on the basis of the following criteria taking into account the worst case scenario: • MAC, i.e. the maximum allowable carryover of API A which could be transferred to the next manufactured product B, calculated on the basis of pharmacological data, • MAC calculated on the basis of toxicological data (LD50), • Empirical „10 ppm” (or Eli Lilly) criterion - the maximum concentration of API A in the next manufactured product. The complete description of cleaning validation methodology is beyond the scope of this article, therefore the discussion will be restricted to surface sampling only. As it was mentioned before, the final limit setting is a complex task and it depends on numerous factors. For the particular purpose of the demonstration of the LC/MS method, we assume that the limits have been set using “pharmacological” MAC, which in turn is calculated according to the following equation:
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MBSB (kg) DDB (mg) SF S (m2) TDA (mg) MAC (mg) CS (mg/25 cm2)
50 6000 1000 40 Acetaminophen 60 500 0,031
Caffeine 10 83 0,0052
In this equation TDA is the minimal therapeutic dose of product A, DDB corresponds to the maximum daily dose of product B, MBSB is the minimal batch size of product B and, finally, SF stands for a safety factor. The parameters which are necessary to calculate MAC for installation, where the surface between shared products A and B equals 40 m2, are given in Table 1. From the calculations shown it follows, that the amounts of acetaminophen and caffeine which can be transferred to product B are 500 and 85 mg, respectively. Assuming the worst case scenario, i.e. the transfer of the whole amount of product A residues to product B during manufacturing of B, it has to be proven that the residues of product A in the whole installation are below 500 mg for acetaminophen and 85 mg for caffeine. For surface sampling method these values transfer to 0.031 mg of acetaminophen and 0.0052 mg of caffeine per standard surface (usually 25 cm2). Consequently, if one takes into account the way the swabs are taken, sample preparation itself and the recovery value, a sensitive and specific analytical method should be employed to enable quantification of acetaminophen and caffeine at the level of 10 and 2 ppm, respectively. The results of LC/MS analysis performed on product A are shown below. The studies were conducted for a solution containing 5.3 ppm of acetaminophen and 0.7 ppm of caffeine in 25 °C. A 100 × 3.0 mm C18 column was used with particle size of 1.9 µm. 0.1 % v/v water solution of formic acid and methanol (60/40) were employed as mobile phase. The flow was isocrtatic and was set at 0.6 ml/min. Two channels of the UV detector were used (249 nm and 272 nm) and the masses were registered in the range of 50-600 m/z. It should be pointed out that each data point on the chromatogram corresponds to one mass spectrum. To sum up, it has been shown that the LC/MS technique is a method of choice when the quantification and simultaneous identification of trace amount of drugs is necessary, as it is the case in cleaning validation. A great advantage of the method is its specificity. In addition, LC/MS enables one to observe a mass spectrum for each data point on the chromatogram, which makes it possible to distinguish between substances with similar retention times.
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The search for high-performing excipients Cardinal Pharma Trade Ltd.
Nowadays tablets and capsules seem to be the most predominant form of providing medicines to patients. They can be dosed accurately, they are ease to manufacture and the cost associated with the production is relatively low. Because of their popularity among patients, scientists, clinicians and producers, the manufacturing process details have become a science on its own, encompassing many different branches of knowledge. Basically there are two ways to create a tablet: granulation or direct compression. The latter – based on compacting dry blend of powders comprising a drug - gained large popularity mainly due to the simplicity of the whole process and costeffectiveness compared to other methods.
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ue to large technological progress, modern high-performance tableting machines have capacity of more than 1.000.000 tablets/hour. These performance gains also put bigger stress on the correct choice of materials than can be used according with stability requirements. Due to high demands, the choice for excipients is becoming more and more narrow as their manufacturers try to cope with more stringent requirements. Modern dry blends represent a mixture of different substances and excipients chosen with their distinctive physicomechanical properties in mind: flowability, compressibility, dilution potential. Most formulations have a higher percentage of excipient that the active drug in the whole formulation, and this fact also puts bigger stress on excipients’ properties. The most sought-after characteristics of a good excipient, like good flowability, low or no moisture sensitivity, good compressibility, low level of sensitivity to lubricant, lead excipient designers to develop new high-functionality excipients.
Road to new excipients It is precisely this increasing appreciation of the excipients’ role in solid dosage forms that has triggered their metamorphosis from “inert ingredients” to “functional components” of the formulation . Most of the substances lack some important characteristics of an ideal excipient. Coprocessing is a novel concept of altering excipient functionality by retaining the favorable attributes and supplementing with newer ones,
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by processing the parent excipient with another excipient (7-9). This allows production of high-functionality excipients to the formulator’s advantage. The high functionality can be in terms of improved process ability such as flow properties, compressibility, content uniformity, dilution potential, and lubricant sensitivity, or improved performance such as disintegration and dissolution profile. The proceeding sections discuss the intensive efforts to harness greater benefits by developing high-functionality excipients targeted at specific formulation needs. Increasing importance of excipients made them a functional component of the formulation. Driven by formulation departments around the world, the demand for new and better excipients has been mainly shaped by the industry using them. However, due to large cost associated with excipient discovery and development, we have seen not a single new chemical excipient introduced to the market in recent years. So what factors are shaping the search for new excipients: • Growing performance expectations in addressing issues such as dissolution, disintegration • The ability to influence stability, solubility of drug molecules • Addressing the shortcomings of existing excipients, such as agglomeration, sensitivity to moisture, loss of compaction • Ability to work well with high-speed, high-performance tableting machines (good compressibility)
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The search for excipients combining best features of two or more single excipients in one However one might find plenty of excipients, most of them lack important characteristics of an ideal. To retain the basic excipient functionality and supplement it with needed favorable properties, a coprocessing concept was introduced.
How to create new excipient There are three levels of solid state for solid substances: molecular, particle, and bulk level. They are closely linked to each other and changes at one level have implications on another level. Molecular level defines arrangement of individual molecules in the crystal lattice. This level is responsible for pseudo-polymorphism, polymorphism and amorphous state. The particle level defines such particle properties as surface, porosity, size or shape. The last level – bulk – is formed from a combination of particles and defines properties such as flowability, dilution potential or compressibility. Because the dependencies are bottom-to-top and particle properties such as morphology, particle size, shape, porosity, surface area or density influence excipient functionalities like flowability, disintegration and lubrication potential or compactability, the creation of new excipient with demanded functionalities must start at the particle level. Particle engineering of single excipient can already yield substantial results. Avicel 101 and 102 (microcrystalli-
ne cellulose) and spray-dried lactose are examples of this approach. There is even more room for improvement if more than one excipient is manipulated at the particle level. This is called coprocessing and it is based on the concept of two or more excipient interacting together at a subparticle level. The aim here is to: • provide functional improvements (get the “best of both worlds”) • mask undesirable properties of certain single excipient Thanks to large amount of excipients available, the platform for manipulation is substantial and paves the way to create “designer excipients” with exactly the properties that are needed for certain applications. The first step is to identify your target – a group of excipients that will be coprocessed. The choice should be made upon the studies of their material characteristics and functionality requirements. Next step involves selecting the proportions of the excipients that will be combined. After that we should asses the particle size required for coprocessing and select a suitable process of drying (eg. spray-drying). The whole process should be monitored and findings and observations from subsequent iterations should be taken into account in order to improve it. The first coprocessed excipients can be dated back to 1980s with introduction of coprocessed microcrystalline cellulose and calcium carbonate, followed by Cellactose by Meggle in 1990 – a coprocessed combination of cel-
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lastose, which involves coprocessing 75% of lactose (which is brittle) and 25% of cellulose (plastic material). Due to such combination, storage of excessive elastic energy during the compression phase is prevented. This improves the properties of dry blend resulting in small stress relaxation and reduced tendency for capping and lamination. There are also examples where the proportions are reversed – SMCC is combined from a large amount of MCC, a plastic material, and small amount of silicon dioxide (CSD), which is brittle. As we can see, combining two excipient exhibiting different elastic properties can create synergistic effect, improving major functional characteristics such as compaction performance, flow properties, lubricant sensitivity, strain-rate sensitivity, sensitivity to moisture or reduced hornification.
Coprocessing methodology
lulose and lactose. Also one of the most commonly used excipient nowadays – silicified microcrystalline cellulose SMCC was developed in a similar way.
Elastic, Plastic and Brittle Materials – consideration Generally based on their behavior demonstrated when mechanical force is applied, solid materials can be classified under the following three categories : elastic, plastic and brittle. The elastic property means that any change in shape can be completelly reversed and original shape of the material will return once the stress is released. Platic property means a permanent change can be introduced to material due to applied stress. Examples of plastic materials : MCC, sodium chloride or corn starch. Third category, brittle, means the structure will be broken upon application of stress, ie. a rapid propagation of crack throughout the meterial can be observed. Examples of such materials are : sucrose, sodium citrate, mannitol and lactose. The predisposition of a material to deform in a particular manner depends on its lattice structure, in particular whether weakly bonded lattice planes are inherently present. However, most of the materials share characteristics of more than one category. Pharmaceuticals in particular exhibit all three characteristics – and usually one predominant response – making it difficult to clearly evaluate which property favors the compressibility. Using coprocessing introduces new possibilities to achieve the perfect combination of above characteristics. Generally both plastic and brittle excipients are combined – fine example is Cel-
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brittle material is preventing the formation of coherent lubricant network by forming newly exposed surfaces upon compression, which breaks up the lubricant network Better dilution potential. Dilution potential can be defined as the ability of the excipient to retain its compressibility even after diluting with another material. Most API’s are poorly compressible, which is why excipient must exhibit good compressibility to retain good compaction after it is diluted with poorly compressible active drug substance. Again, coprocessed excipient like Cellactose shows higher dilution potential compared to a simple physical mixture of the excipients that it stems from.
Some more examples
Advantages and disadvantages of coprocessed excipients So after the brief introduction to the topic of coprocessing I’d like to point the number of advantages this process has to offer. It is important to remember that due to the process no chemical changes occur during coprocessing, and the changes exhibit themselves only in the physical properties of the particles. Improved flow properties. Due to ability to control the particle size and its’ distribution, a superior flow can be achieved without the need to use extra glidants. Good example again is SMCC in comparison with MCC. The particle size range of the parent and child excipient are mainly the same, however the flow of coprocessed excipient was superior to the one of a simple physical mixture. Another example is Cellactose, which was found to have better flow properties than simple mixture of Cellactose and lactose. The flow was party improved by the spherical shape and even surfaces of the compound. Lack of chemical change. The studies on coprocessed excipients proved no chemical change occurs in the process. The studies run mainly on SMCC – X-ray diffraction, NRM, IR spectroscopy and C13 NMR spectroscopy have all confirmed no chemical change occurred. This fact has implications on the regulatory concerns during development phase. Lower sensitivity to lubricants. Due to a mixed properties of coprocessed excipient stemming from it being a combination of brittle and plastic materials, the sensitivity to lubricants is lower. It is because of a large amount of
Various reports describe improved excipient functionality after coprocessing, with multiple advantages. Roller drying of a solution of anhydrous lactose (95%) and lactitol/sorbitol (5%) resulted in a DC excipient with good tablet strength . A free-flowing, compressible powder was obtained by spraying a 4.5% aqueous solution of poly(vinyl pyrrolidone) (PVP) onto a fluid bed of starch and PVP admixture (48:1) . Statistical optimization of a coprocessed product of lactose and MCC by various product evaluation parameters such as bulk density, Carr’s index, percentage friability, percentage fines, tensile strength, flow rate, and angle of repose resulted in a directly compressible product (with 9:1 composition) with satisfactory flow, compressibility, and friability . Coprocessing of lactose monohydrate, PVP, and croscarmellose sodium (79:15:6) by melt agglomeration resulted in a multifunctional DC adjuvant with satisfactory dilution potential, and superior flow ability and compressibility than those of lactose monohydrate . Spray drying of rice starch with jet-milled MCC (with volumetric mean diameter of 13.57 um) in the proportion of 7:3 resulted in spherical composites of a directly compressible excipient with high compressibility, good flow ability, and self disintegration
Conclusion There are also more advantages coming from using coprocessed excipients. While it may seem tempting to create physical mixtures of certain excipients yourself, you have to be aware that as many studies show, coprocessed excipients will be superior in terms of major functionalities due to process taking place at particle level. And although the coprocessed excipients might be a bit more costly, the increased functional properties will decrease the overall production cost in the long run. Also there should be less test requirements compared to individual excipients. Coprocessed excipient can sometimes “make or break” formulation due to its’ specific characteristics. This is where tailor-made designer excipients come into play, often resulting in shorter formulation development time. Last but not least, coprocessed excipients can also be used as a tool to protect intellectual properties of pharmaceutical companies when proprietary combinations are created, which can be patented and made hard to reproduce.
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Excipient table
Excipient Advantose FS 95 Avicel CE-15 Captisol
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Composition Fructose, starch Microcrystalline cellulose, guar gam Modified cyclodextrin, sulfobutylether-beta-cyclodextrin
Comments
Manufacturer
Co-processed; chewable tablets; high flowability
SPI Pharma
Co-processed; less grittiness; creamier mouth-feel
FMC
New chemical entity; improved water solubility
CyDex
Cellactose
Lactose, cellulose powder
Co-processed; high compressibility
Meggle
Di-Pac
Sucrose, dextrin
Co-processed; low hygroscopicity; directly compressible sugar
American Sugar Refining
Eudragit RL and RS
Methacrylic acid polymers
Modified existing polymer; coating for sustained release
Evonik Industries
Kollidon CL, CL-F, CL-SF, CL-M
Crosslinked water-insoluble polyvinyl pyrrolidone
Size modified to application for disintegration and solubility enhancement
BASF
Ludipress
Lactose, Kollidon, Kollidon CL
Co-processed; directly compressible; high powder flowability; tablet hardness; disintegration functionality
BASF
MicroceLac
Microcrystalline cellulose, lactose
Co-processed; high flowability
Meggle
PanExcea MCC333G
Microcrystalline cellulose, hydroxypropyl methylcellulose, crosspovidone
Co-processed to form spherical particles with unique morphology; directly compressible; high flowability; high compressibility; high API loading and mixing; composite particle with binder filler and disintegrant functionality
Mallinckrodt Baker
Pharmatose DCL 40
B-lactose, lacticol
Co-processed; high compactibility
DMV
Plasdone S630
Vinyl acetate, vinyl pyrrolidone
Tablet binder; improves compressibility of other binders and fillers
SPI
Prosolv
Microcrystalline cellulose
Co-processed; directly compressible; silicon dioxide suitable for wet granulation; high compressibility; high flowability
JRS Pharma
Ran Explo-C
Mircrocrystalline cellulose, silica, crosspovidone
Co-processed; directly compressible; improved flowability; superdisintegrant
RanQ Pharma
Ran Explo-S
Mircrocrystalline cellulose, silica, sodium starch glycolate
Co-processed; directly compressible; improved flowability; superdisintegrant
RanQ Pharma
StarCap 1500
Corn starch, pregelatinized starch
Co-processed; wet and dry binder; enhances functionality of other binders
Colorcon
StarLac
Lactose, maize starch
Co-processed; high flowability; disintegration
Meggle
Xylitab 100
Xylitol, polydextrose
Co-processed; directly compressible sugar with improved mouth-feel
Danisco Sugar
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References •
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J.L. Czelsler and K.P. Perlman, “Diluents,” in Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C. Boylan, Eds. (Marcel Dekker, Inc., New York, NY, 1990), pp. 37-83. R.F. Shangraw and D.A. Demarest, “A Survey of Current Industrial Practices in the Formulation and Manufacture of Tablets and Capsules,” Pharm. Technol. 17 (1), 32 44 (1993). E. Hines, “Restocking the Excipient Superstore,” www. pharmaquality. com/excipient.html (accessed on 16 January 2003). R.F. Shangraw, Compressed Tablets by Direct Compression in Pharmaceutical Dosage Forms: Tablets, H.A. Leiberman, L. Lachman, and J.B. Schwatz, Eds. (Marcel Dekker. Inc. New York, 1990), pp. 195-246. P. York, “Crystal Engineering and Particle Design for the Powder Compaction Process,” Drug Dev. Ind. Pharm. 18 (6,7), 677-721 (1992). N.A. Armstrong and L.P. Palfrey, “The Effect of Machine Speed on the Consolidation of Four Directly Compressible Tablet Diluents,” /. Pharm. Pharmacol.^, 149-151 (1989). M. Steinberg, L. Blecher, and A. Mercill, “From Inactive Ingredients to Pharmaceutical Excipients,” Pharm. Technol. 25 (7), 62- 64 (2001). IPEC Americas, “Why IPEC-Americas is Needed,” http:// www. ipecamericas.org/public/whyneeded.html (accessed on 16 January 2003). L. Blecher, “Pharmaceutical Excipients—Producers and Users Strengthen their Voice,” Pharm Technol. 17 (2), 38-39 (1993). M.J. Tobyn et al., “Physicochemical Comparison between Microcrys-talline Cellulose and Silicified Microcrystalline Cellulose,” inf. /. Pharm. 169, 183-194 (1998). R.C. Moreton, “Tablet Excipients to the Year 2001:A Look into the Crystal Ball,” Drug Dev. Ind. Pharm. 22 (1), 11-23 (1996). A.K. Bansal and S.K. Nachaegari, “High Functionality Excipients for Solid Oral Dosage Forms,” in Business Briefings: Pharmagenerics (World Markets Research Centre, London, UK, 2002), pp. 38-44. CyDex, “Innovative Drug Delivery Technologies,” www. captisol.com (accessed on 16 January 2003).
www.farmacom.com.pl
1_2009_pl_en_spf.indd 39
• •
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•
• •
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•
• •
•
•
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CyDex, “Captisol,” www.cydexinc.com/CaptisolProductApprovals.pdf (accessed on 16 January 2003). R.F. Shangraw, J.W. Wallace, “Morphology and Functionality in Tablet Excipients for Direct Compression: Part I,” Pharm. Technol. 5 (9), 69-78 (1981). R.F. Shangraw, “Emerging Trends in the Use of Pharmaceutical Ex cipients,” Pharm. Technol. 21 (6), 36-42 (1997). D. Reimerdes and K.P. Aufmuth, “Tableting with Coprocessed Lactose-Cellulose Excipient,” Manufacturing Chemist. 63 (12), 23-24 (1992). D. Reimerdes, “The Near Future of Tablet Excipients,” Manufacturing Chemist, 64 (7), 14-15 (1993) J.J. Modliszewski and D.A. Ballard, “Coprocessed Galctomannan-Glucomannan,” US Patent No. 5,498,436 to FMC Corporation (Philadelphia, PA) 1996. K.M. Dev et al., “Coprocessed Microcrystalline Cellulose and Calcium Carbonate and Its Preparation,” US Patent No. 4,744,987 to FMC Corporation (Philadelphia, PA) 1988. G.K. Bolhius and Z.T. Chowhan, “Materials for Direct Compaction,” in Pharmaceutical Powder Compaction Technology, G. Alderborn and C. Nystrom, Eds. (Marcel Dekker Inc., New York, NY, 1996), pp. 419-500. K.V.D.V. Maarschalk and G.K. Bolhius, “Improving Properties of Ma terial for Direct Compaction,” Pharm. Technol. 23 (5), 34-46 (1999). L. Casahoursat, G. Lemagen, and D. Larrouture, “The Use of Stress Relaxation Trials to Characterize Tablet Capping,” Drug Dev. Ind. Pharm. 14 (15-17), 2179-2199 (1988). P.M. Belda and J.B. Mielck, “The Tableting Behavior of Cellactose Compared with Mixtures of Celluloses with Lactoses,” Eur. J. Pharm. Biopharm. 42 (5), 325-330 (1996). B.E. Sherwood and J.W. Becker, “A New Class of High Functionality Excipients: Silicified Microcrystalline Cellulose,” Pharm. Technol. 22 (10), 78-88 (1988). J.D. Allen, “Improving DC with SMCC,” Manufacturing Chemist 67 (12), 19-20,23 (1996). P.C. Schmidt and C.J.W. Rubensdorfer, “Evaluation of Ludipress as a Multipurpose Excipient for Direct Compression Part I: Powder Characteristics and Tableting Properties,” Drug Dev. Ind. Pharm. 20 (18), 2899-2925 (1994). J.N. Staniforth and M. Chatrath, “Towards a New Class of High Func tionality Tablet Binders, I: Quasi-Hornification of Microcrystalline Cellulose and Loss of Functionality,” Pharm. Res. 13 (9),S208 (1996). L.E. Flores, R.L. Arellano, and J.J.D. Esquivel, “Study of Load Capac ity of Avicel PH-200 and Cellactose, Two Direct-Compression Excipients, Using Experimental Design,” Drug Dev. Ind. Pharm. 26 (4), 465-469 (2000). Prosotv Technical Report: Tableting Binder Improves Production (Pen-west Pharmaceuticals, New York, NY, 2001). R.C. Moreton, “Cellulose, Silicified Microcrystalline,” in Hand Book of Pharmaceutical Excipients. A. Wade and P.J. Weller, Eds. (Pharmaceutical Press, London), pp. 110-111. PT.
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Due to increasing demand for high-performance, highspeed tablet manufacturing, direct compression tableting is the path of choice for most Pharma manufacturers. The excipient industry trying to keep up with the increased demands has to offer excipients that far outpace presently available counterparts in terms of its functional parameters, while retaining the same quality and safety. What can be a slowing factor in the adoption of such compounds is sometimes lack of inclusion of their monographs in pharmacopoeias – a factor often discouraging formulation scientists from using them. However with the recommendations from IPEC (International Pharmaceutical Excipients Council) – an international organization which harmonizes requirements for purity and functionality testing of excipients – they will probably appear in pharmacopoeias, either as mixtures or as single-bodied excipients.
39 2009-02-23 16:42:23
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Initial batch control of pharmaceutical ingredients Marcin Kołakowski, Daniel Gralak
Official batch control is an additional national control mechanism applied in European Union countries. The scope of official batch control is laid down in each country’s national law. In Poland, firms are obliged to carry out controls pursuant to Article 65 of the Pharmaceutical Law (Dz.U. 2008 no. 45 item 271 and no. 227 item 1505).
A
rticle 65 of the Pharmaceutical Law of 6 September 2001 (Dz.U.08.45.271) lays down that medicinal products may be in circulation on condition that they have undergone initial batch control at the cost of the responsible entity. However not all medicines are subject to such control. The obligation applies to ingredients used to make up general or individual prescription medicines, as well as: 1) immunological products for humans, which include: a) vaccines containing live microorganisms; b) vaccines for newborns or other risk groups; c) vaccines used in public vaccination programmes; d) new immunological medicinal products or immunological medicinal products made using types of technology which are new, altered or new for the manufacturer in question during the period indicated in the licence for bringing into circulation; 2) veterinary immunological medicinal products; 3) blood-derived products. The above rules have been in force since May 2007, with the coming into effect of the Act of 30 March 2007 amending the Pharmaceutical Law and certain other Acts. The most revolutionary change would appear to be that relating to the obligation to perform initial batch control on pharmaceutical ingredients used to make up prescription medicines. The Order of the Minister of Health of 28 October 2008 on initial batch control (Dz.U.08.197.1224) specifies a closed list of me-
40
dicines quality control laboratories which are authorized to issue decisions concerning the completion of controls. These include: 1) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Gdańsk; 2) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Katowice; 3) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Kraków; 4) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Łódź; 5) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Opole; 6) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Poznań; 7) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Rzeszów; 8) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Wrocław; 9) the Medicines Quality Control Laboratory of the Provincial Pharmaceutical Inspectorate in Białystok. Initial batch control includes quality tests involving testing a sample taken from each batch of a medicinal product in order to confirm its identity and compliance with specified quality requirements contained in the documentation on the basis of which the licence to bring into circulation was issued.
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The Order of the Minister of Health states that the responsible entity shall present for initial batch control a sufficient quantity of samples to allow the performance of a double quality test in accordance with the documentation on whose basis the licence to bring into circulation was issued and with the control procedures applied by the testing institution. The testing institution may, in view of the type and form of the tested medicinal product or the testing method, and having given reasons in writing, require an additional quantity of samples of the medicinal product. A sample of a medicinal product or a sample of an ingredient for the making up of prescription medicines supplied for initial batch control testing must be delivered in packaging compliant with the documentation on whose basis the licence to bring into circulation was issued. The regulations referred to above do not apply to active substances (APIs) used as starting materials for the production of medicinal products or auxiliary substances used in the production of medicinal products. Activity involving supplying APIs is covered by the statutory definition of Article 2(42a), according to which production of active substances used as starting materials for the production of medicinal products includes any action leading to the formation of active substances, including the import of active substances used as starting materials for the production of medicinal products from outside the territor y of EU member states or members of EFTA being party to the agreement on the European Economic Area, as well as distribution, packing, repackaging and relabelling. According to the guidelines contained in the Order of the Minister of Health of 26 July 2002 on the procedures of Good Distribution Practice (Dz.U.02.144.1216), the obligations of a pharmaceutical wholesaler dealing in medicinal products include establishing, when purchasing pharmaceutical ingredients intended for the making up of general or individual prescription medicines, whether they have undergone initial batch control. This implies that a manufacturer of ingredients intended for pharmacy dispensing should, whenever requested by a licensed wholesaler of medicinal products, present not only a certificate releasing the ingredient batch into circulation given by a qualified person, but also a decision of a medicines quality laboratory concerning the results of initial batch control. A draft amendment to the Pharmaceutical Law, which has been through the community consultation stage, would abolish the obligation to obtain a licence for bringing into circulation in the case of ingredients intended for medicine dispensing. Moreover, businesses who under present regulations are engaged exclusively in the manufacture of ingredients would be released from the duty to hold a licence for the manufacture of medicinal products and would no longer be subject to the standards of Good Manufacturing Practice (GMP). Should the two houses of Poland’s parliament adopt such a measure, it seems that it will be necessary for the competent national authorities to propose regulations which would make it possible to protect patients from ingredients of substandard quality.
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Moreover, in accordance with the above-mentioned regulations, the research and development institutions authorized to carry out initial batch control will exempt a given batch of a medicinal product from initial batch control if it has been subjected to such tests by the competent authorities in a member state of the European Union or a member state of EFTA being party to the agreement on the European Economic Area, provided that a document confirming the performance of such tests is presented. It should be remembered, however, that the possibility of exemption does not apply to ingredients used to make up prescription medicines. As has already been mentioned, initial batch control is carried out at the cost of the responsible entity, which according to Article 2(24) of the aforementioned Act is a business within the meaning of the Act of 2 July 2004 on freedom of business activity (Dz.U. 2007 no. 155 item 1095 and no. 180 item 1280) or else an entity carrying on business activity in a member state of the European Union or a member state of EFTA being party to the agreement on the European Economic Area, applying for or having obtained a licence to bring the medicinal product into circulation or a licence obtained under Article 20 of the Pharmaceutical Law (accelerated registration of ingredients). The entity may appoint a representative to discharge its obligations and exercise its rights in Poland. A representative is appointed by way of a dated and signed written contract. The contract lays down the rights and obligations of the representative. The responsible entity must submit the contract, and any subsequent amendments to it, for the information of the Chairman of the Office and the Chief Pharmaceutical Inspector without delay.
41 2009-02-23 16:42:25
Sophisticated requirements? Safety in detail.
The fastest and safest delivery for your new product: Filling and packaging technologies of Optima Group pharma. After approval, time-to-market brings economic success. With Optima Group pharma, you are on the safe side. The brands Inova, Kugler, and Klee, offer a unique range of machines for pharmaceutical filling, packaging, and freeze drying, including both upstream and downstream processes and
automation software. All machines meet the highest requirements with regard to process safety, output, and flexibility. Optima Group pharma has implemented many large turnkey projects for pharmaceutical and biotechnical liquids and powders - successfully and reliably. But no matter if the projects are large or small – our service is always perfect.
Kalimpex OPTIMA GROUP pharma GmbH Otto-Hahn-Str. 1, 74523 Schwäbisch Hall, Germany www.optima-group-pharma.com
BIURO INFORMACJI TECHNICZNO-HANDLOWEJ ul. Lazurowa 8, Sękocin Stary, 05-090 Raszyn tel. (48-22) 720 70 64 , -65, fax: (48-22) 720 70 66 e-mail: dorota@kalimpex.pl, www.kalimpex.pl
INOVA KUGLER KLEE download *.pdf version:
Optima Group is global: In the USA, Mexico, Brazil, France, the United Kingdom, Italy, Japan, Korea, China and Germany
1_2009_pl_en_spf.indd Image Pharma 2009_englisch42für Polen mit altem Motiv.indd 1
2009-02-23 16:42:27 12.02.2009 09:57:31
production
57:31
Validation
of a sterilization tunnel Quality Masters
A
During the manufacture of sterile forms of medicines, one of the most important devices in the production chain is the sterilization tunnel. In order to ensure repeatable and effective sterilization results, a number of validation tests are required to be carried out.
mong the guidelines laid down in European requirements are the following: • sterilization with hot air is preferred over other types of sterilization; • confirmation of the effectiveness of sterilization takes place before the first use of the device; • the effectiveness of sterilization should be confirmed for each type of charge (bottles, ampoules, vials) used; • each type of charge must be identified and its position validated; • the temperature during sterilization must be monitored, the monitoring record being a required document for the release of a given batch of a product;
• •
it is necessary to monitor air purity in the chambers used for initial heating, sterilization and cooling; in each of the sterilization chambers (heating, target sterilization, cooling), HEPA filters (min EU13) should be used.
Sterilization with hot dry air is one of the sterilization processes by which we can eliminate microorganisms and also – specifically to this type of process – neutralize pyrogens. Sterilization tunnels are used mainly for the sterilization and depyrogenation of glass packaging (bottles, vials, ampoules). The tunnel consists of an initial chamber, where
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the material is heated to around 50°C, followed by a chamber for target sterilization (the minimum temperature is 160°C for sterilization and 250°C for depyrogenation). The final chamber is a cooling chamber, where the material is cooled to below 40°C.
The acceptance condition for the speed of air flow is the same as for traditional LFs, namely 0.45 m/s (±5%). For uniformity and homogeneity of the flow the condition must be satisfied that RSD (relative standard deviation) ≤ 15% and the qualification index CRa≥1.
A sterilization tunnel is a fairly complex device in terms of validation tests. Installation validation should include, among other things: • checking the completeness of documentation relating to the device (technical and operational documentation, operating instructions, material certificates, etc.) • checking the correct installation of the device in its final position • checking the correct connection of supplied media and support systems • evaluation of the functionality of the device • identification of measurement and monitoring apparatus for the device, and drawing up of procedures for its calibration.
The following computational formulae are used: a) Average velocity
The principal tests included in operational validation include: • functional tests of the device, • test of integrity and tightness of fitted HEPA filters. A 0.5 µm aerosol particle generator should be used for the test. For the initial heating zone and sterilization zone, a maximum penetration of 0.1% of aerosol concentration should be confirmed; similarly 0.01% for the cooling zone. • measurement of quantity of particles in each zone of the tunnel (class C for the heating zone and class A for the sterilization zone) The quantity of particles is measured by scanning each of the zone surfaces as for normal tunnel operation. During scanning of the sterilization zone, a suitable system is used for cooling the air at entry to the particle counter. The air should be cooled to min. 50°C. Acceptance conditions for quantities of particles are as follows: ≥ 0.5 µm: max. 3500 particles/m3 ≥ 5 µm: max. 1 particle/m3 • measurement of maintenance of the correct pressure difference in the sterilization zones Using a pressure difference sensor, for various states of the device it is necessary to confirm the excess pressure of the sterilization zone over the heating and cooling zones. •
44
Where: VL is the average air flow velocity (m/s) V i is the average velocity at the ith sample point (m/s) N is the number of sample points b) Standard deviation S
c) Relative standard deviation RSD
d) Qualification index
Where: Kconfidence(n) is a tabular parameter D is a difference parameter D= min {│VL- upper limit │,│VL – lower limit │} temperature distribution test for an empty tunnel The test is performed three times in a row for a given sterilization process. The positions of the sensors recording the process should be varied, in order to locate cold spots. At the coldest point on the tunnel charge, the value FH≥120 min must be attained for Z=20° C and T=160°C for the sterilization process. The difference of temperatures in the system chambers must not exceed 25° C for the time of 75% of the cycle. •
measurement of the speed of air flow and the uniformity and homogeneity of the flow
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Where: FH = killing effect, i.e. the relevant time of sterilization with hot air T i = temperature measured at time ti Tref = reference temperature for sterilization with hot air (160°C) Z = coefficient of temperature for degree of microbiological degradation (20°C) ∆ti = change at time ti. For the process of depyrogenation FD≥30 min, for Z=46.4° C and T=250°C. The value FD can be computed from the following formula:
Where: FD = depyrogenation effect, i.e. the relevant time of depyrogenation T i = temperature measured at time ti Tref = reference temperature for sterilization with hot air (250°C) Z = coefficient of temperature for degree of microbiological degradation (46.4°C) ∆ti = change at time ti. Temperature distribution test for a charged tunnel The distribution test must be performed for each established charge. During this test it must be remembered that the recorders are to be placed inside the charge being sterilized and must not be in contact with elements of the sterilization tunnel. Also, the test must be performed at least three times.
•
Pre- and post-calibration of temperature recorder sensors Before and after the temperature distribution tests, the external temperature sensors used in the test must be calibrated. •
• • • •
Acceptance conditions are as follows: for pre-calibration accuracy ± 0.6°C stability ± 0.2°C for 3 minutes linearity ± 0.6°C at three points
production
The value FH can be computed from the following formula:
Pre-calibration should be performed for at least 3 points (the sterilization or depyrogenation temperature should cover one of the calibration points) for post-calibration – accuracy ± 0.6°C – stability ± 0.2°C for 3 minutes Post-calibration need only be performed for one temperature; usually this is the sterilization or depyrogenation temperature. •
test for neutralization of microorganisms (using Bacillus Subtilis biological indicators) The purpose of the microbiological control is to prove that the sterilization cycle ensures reduction of microorganisms by a minimum of 6 log. The indicators are placed in the charge being sterilized (inside ampoules or vials), then after completion of the sterilization cycle the indicators are transferred to a growth medium and incubated. A correct cycle shows a 100% reduction in microorganisms. A depyrogenation cycle should ensure reduction of endotoxins by a minimum of 3 log. The methodology used during the test is the same as in the test for reduction of microorganisms, except that in this case the charge is infected with endotoxins. •
Tunnel validation is completed with a validation report, which must include conclusions that briefly and clearly summarize the result of the validation as a whole. It must be stated explicitly whether the process of sterilization/ depyrogenation fulfilled the set acceptance criteria. The report should also contain recommendations relating to the completed validation, e.g. concerning revalidation, monitoring of operating parameters, and calibration. It is also important to be aware that the validation completed at this stage is the first step in ensuring the proper functioning of the device. Validation is an ongoing process, and continuous monitoring and periodic revalidation are required in order to ensure that the process remains standard.
Quality Masters provides consulting and services to the pharmaceutical industry. It specializes in preparing documentation and carrying out certification of devices, premises and systems and validation of processes and cleaning. More information is available on our website. www.qualitymasters.pl, info@qualitymasters.pl
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sponsored article
46
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2009-02-23 16:42:35
Ad
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sponsored article
Special filling system for suspensions
Recirculation: Stop without any consequences Even short machine stoppages and interruptions can be problematic when dispensing suspension products. When restarting the line after a machine stop it was typical and inevitable to reject the first syringe tubs, since the intended product composition of solid or liquid components could not be guaranteed (suspensions can separate). The recirculation technology of the Optima Group Pharma avoids this and furthermore provides a time saving. When restarting the line it is now possible to change directly into the “production mode” without product loss. The filling and packaging line is equipped with a reaction path. The tubs, which are protected by plastic bags, are sanitized by means of alcohol and then enter the laminar flow zone. The Inova debagger and the Inova
Filling suspensions without any product loss, regardless of any stops. Filling process of the filling and closing machine
TRR robot remove and dispose of the plastic bag and the Tyvek lid and liner. The Inova SV 125 is perfectly suited to be combined with these two upstream tub-handling machinery. The whole syringe nest is lifted out of the tub and placed into the filling position. The syringes are then by means of the rotary piston pumps filled at five positions row by row.
Directly thereafter, the finished syringes are provided with a plunger rods that are fed from an automatic sorting bowl and positioned exactly in the syringe barrel. The nest with the filled and closed syringes are placed back into their original tub. The tubs are marked with batch data for product identity and tracking.
Here also the recirculation system waits to be activated: The high-precision recirculation valve is located directly in front of the filling needles. In case of an interruption in the filling and packaging process, even the smallest suspension quantities can be recirculated.
The specified, restricted sterile area, which has virtually been fitted into the line, was one of the challenges for this project. The smooth product flow, the clear arrangement of the line and compact dimensions complemented each other in an optimum way.
OPTIMA GROUP pharma GmbH Otto-Hahn-Str. 1, 74523 Schwäbisch Hall, Germany www.optima-group-pharma.com
Kalimpex
BIURO INFORMACJI TECHNICZNO-HANDLOWEJ ul. Lazurowa 8, Sękocin Stary, 05-090 Raszyn tel. (48-22) 720 70 64 , -65, fax: (48-22) 720 70 66 e-mail: dorota@kalimpex.pl, www.kalimpex.pl
INOVA KUGLER KLEE
USA, Mexico, Brasil, France, Italy, England, Japan, Korea, China
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Anz_inova_dt_eng_franz_polnisch.indd 1
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2009-02-23 16:42:37
Polish industry
SIMATIC IT Unilab
Siemens Solution for Laboratory Information Management System Wojciech Grzelka Siemens Sp. z o.o., Sector Industry, IA AS
Pharmacy – an industry, in which the quality of the manufactured product plays a key role, due to the safety of the patients. Manufactured products Quality Control Process management thus poses a serious challenge. LIMS (Laboratory Information Management System) supports and helps to coordinate, supervise and improve the quality of work done by quality control labs.
SIMATIC IT Unilab LIMS System by Siemens SIMATIC is, first of all, a well known name of a range of automation products manufactured by Siemens for the industry, including programmable logic controllers, products and systems for visualization, complex control systems. Siemens decided to use the SIMATIC name also for its range of Manufacturing Execution Systems (MES); they are referred to as SIMATIC IT. As part of the solutions provided by SIMATIC IT, Siemens offers a system for managing the workflow of a laboratory - LIMS, called the SIMATIC IT Unilab. This system can either be a part of a complete SIMATIC IT MES implementation or an independent system for plant(s) lab(s) management. SIMATIC IT Unilab offers complete functionality, defined by the Quality Operation model of the MES ISA-95 industry standard.
SIMATIC IT Unilab Main Tasks Since the system is LIMS, it is used mainly for execution of a complex quality control, service and R&D labs workflow management. One thing worth mentioning is the fact that the laboratory workflow model (from generating to the release of a sample / generating a report) can be custom-configured in the system, enabling adapting the system workflow to the particular lab’s specifications and a given environment & staff’s requirements. SIMATIC IT Unilab gathers, analyzes and reports quality control data on the quality of raw materials, intermediate products, finished goods, commissioned and environmental tests. The system manages lab personnel’s qualifications as well as the equip-
48
ment, enabling it to check whether a device was calibrated at the time of analysis, or whether an analyst was properly qualified to perform the analysis. System Architecture SIMATIC IT Unilab system utilizes a client-server architecture. The application can either be run on a PC computer connected to a wire structural network, a laptop or a “tablet PC” with wireless network connection, or a client terminal (when using a terminal server). It can also be used with “Pocket PC” devices via docking station when working remotely in the field, e.g. when creating samples at remote locations. It is also possible for users to use www technology and work with the system via web browser. Simatic IT Unilab System supports all languages (Unicode) and time zones. When implemented in Poland, the user interface is, of course, in Polish.
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Polish industry
SIMATIC IT Unilab has a SAP-certified SAP QM module interface for the ERP SAP system. It enables a direct data exchange between the SIMATIC IT Unilab system and the SAP QM module (e. g. downloading test specifications to Unilab and sending processed results to SAP QM). It is possible, of course, to integrate SIMATIC IT Unilab with other ERP (Enterprise Resource Planning) systems. As for coupling the SIMATIC IT Unilab system with laboratory test and analysis equipment, there is a Uniconnect module designed specifically for connecting lab equipment to the Unilab system. The device has to be, of course, equipped with a communication por t (e.g. RS232 serial port, USB, Ethernet). It is also possible to create the data exchange between laboratory equipment and Unilab based on transfer of files.
Creating Reports Reports are created using the SIMATIC IT Report Manager, which is a tool that is fully integrated with SIMATIC IT Unilab. It allows intuitive “drag & drop” report templates generating directly by the user. The process does not require any knowledge of IT systems. SIMATIC IT Unilab system can perform automatic reporting based on time (e.g. daily rejected samples sheets) or events (e.g. printing a certificate after all samples have been approved).
Meeting the Requirements regarding Electronic Records and Electronic Signatures SIMATIC IT Unilab meets FDA (Food and Drug Administration) requirements stated in 21 CFR Part 11, regarding electronic records and electronic signatures. Siemens delivers an appropriate compliance response (21 CFR Part 11).
System Implementation in Poland SIMATIC IT Unilab is implemented on the Polish market by a “Siemens Solution Partner Automation” certified partner – ASKOM Sp. z o.o. from Gliwice. Implementation is performed by Polish engineers from ASKOM, with the help from Siemens, if necessary.
Summary – Benefits From Using SIMATIC IT Unilab system
Laboratory Administration • Shorter sample analysis times • Easier decision making and results viewing • Higher work and Customer Service standards • Compliance with regulations Analysts • Easier repetitive activities workflow • Less errors when inputting data Manufacturing Staff • Instant access to analyzed samples results IT staff • Industry standard software and hardware • Open data exchange interfaces • Scalable architecture and licensing Company image improvement & quality standards compliance amongst: • Own staff • Clients and agents • Suppliers and co-operating parties
Note: SIMATIC IT Unilab system will be presented during EuroLab 2009 trade fair in Warsaw on 4-6 March, 2009 (ASKOM C4 booth).
Siemens Sp. z o.o. Sektor Industry Industry Automation, AS simatic.pl@siemens.com www.siemens.pl/simatic
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Soft capsules are a form made of specially developed gelatine combined with a plastifying substance, in which medicinal products of other substances in the form of a solution or a suspension are contained. Their development was triggered by the fact that numerous new medicinal products had an unpleasant bitter taste or smell. This form of capsule allows the elimination of these inconveniences.
Soft Capsules From a concept to a product Curtis Healthcare Sp. z. o.o.
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ne of the advantages of capsules over tablets is a fact that their production does not require the use of any cementing or releasing substances. The active substance itself can be used in smaller quantities. The research has shown that active ingredients contained in capsules require less time to achieve maximum concentration released in the bloodstream. A soft capsule may also be a perfect alternative for many oral liquid medications. It allows enclosing them in the form of a single dose, retaining the bio-equivalence of the substance. The capsule is a perfect solution for producing dietary supplements. Many of them have the form of oil or substances that are sensitive to light or to the technological process. Technological possibilities are practically limited only by equipment. Presently, it is possible to encapsulate powders or even gases. Soft capsules can be widely used in the production of medications and dietary supplements for the following reasons: • Faster release of the active substance; • Faster results; • A form attractive to patients and easy to swallow; • The possibility to mask the colour, taste and smell; and, • The possibility to extend shelf life in the case of non-durable raw materials. Soft capsules are available in various shapes, sizes, and colours. Curtis Healthcare has produced OTC medications and dietary supplements since 1989.
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In 2009, it launched a new Soft Capsules Line, offering R&D and production services at all stages of manufacture, from the purchase of raw materials to the packaging process. Our assets include the following: • Provision of services from developing the concept to achieving the final product; • Experience in R&D; • Specialisation in difficult products; • The possibility to produce smaller batches, which allows reducing the costs of storage and adjusting stock to sale; • Series for clinical studies; and, • Meeting ISO 9001: 2000 standards, which guarantees the highest quality of services. The experience and knowledge of our team are at your disposal.
Curtis Healthcare Sp. z o.o. ul. Żeromskiego 9, 60-544 Poznań tel. +48 061 847 51 47 Barbara Różańska brozanska@curtish.com.pl
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„Grasz o staż” Adamed – a Polish pharmaceutical company, is participating for the second time in the „Grasz o staż” (Compete for Internships) competition, funding internships in various fields of its business operation. Five winners of this year’s edition will have the opportunity to gain experience in one of the following departments at the company: Research & Development, International Projects, Human Resources and Grant & Funding Acquisition.
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n search of the best graduates of biology, pharmacy, biotechnology as well as management and marketing, Adamed for the second time is participating in the „Grasz o staż” competition. The company has funded month long, fully paid, internships which may be extended to three months in its key departments. Adamed’s focus is research on innovative therapies. Research and development are the base for the company’s strategy in 2009. Adamed’s advantage in this area are state of the art research laboratories, which can facilitate highly advanced work on a level which is comparable to other internationally known research centers. Two finalists of the competition will have an opportunity to participate in research on innovative therapies for countering cancer and metabolic diseases. They will learn methods of optimizing and controlling gene expression, methods of analyzing patent documentation and bioinformation data as well as the use of molecular biology methods in biomedical research. Adamed is dynamically developing on the domestic as well as foreign markets. Exports are constantly rising to satisfy global trends in the pharmaceutical industry. Patented medicine is being exported to fifteen European markets. Three finalists of the „Grasz o staż” competition will be able to learn about exporting medical products, possibilities of receiving grants for research and development projects as well as gain experience in human resource management.
„The positive outcome of last year’s edition of „Grasz o staż” convinced us to once again participate in the project. We want to allow participants to familiarize themselves with the latest advancements and technology. This time we want to also invite those who will work in marketing and management fields and offer them a chance to gain experience - says Małgorzata Korpusik, R&D Director. We understand what key role individuals play in finding new therapies – whether they are renown researchers or young people just beginning their professional career and who in the future may achieve success” adds. Adamed actively cooperates with educational institutions, which allows to hire the best specialists such as: doctors, pharmacists, biologists, biotechnologists, to work on developing innovative therapies. The „Grasz o staż” competition gives an opportunity to add to our teams the best graduates of universities. Another opportunity for this were meetings held at schools as part of Adamed’s project „In Search of the Golden One – National Research Project Competition”. The company invited young researchers from medical universities to share their experience and ideas. Authors of the best ones were offered a chance to realize them. Individuals who are interested in participating in internships at Adamed must solve at least one of three assigned problems and submit them to the organizers of the competition in the allotted time.
„Grasz o staż” competition is organized by Gazeta Wyborcza (Poland’s leading newspaper) together with PricewaterhouseCoopers (PwC). It is open to 3rd, 4th and 5th year students as well as university graduates born in 1979 or earlier. Winners have an opportunity to receive paid internships in leading companies as well as win other prizes. The competition gives participants a chance to gain valuable experience and learn new skills. Individuals who are interested in putting their skills to the test must solve at least one of three assigned problems and submit them to the organizers of the competition in the allotted time. Rules and conditions for participating can be found on www.grasz.pl download *.pdf version: www.farmacom.com.pl
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How promotion of OTC medicinal products affects patients’ purchasing decisions Małgorzata Matuszewska-Rembelska Ministry of Health
Processes occurring in the market for over-the-counter (OTC) medicines have an effect on the behaviour of pharmaceutical companies. Growing competition and incoming foreign investment encourage firms to improve their efficiency, the quality of their products and their position in the marketplace. The promotion of medicinal products is one of the basic instruments by which firms achieve success and vigour. Without it it would be hard to persuade people to buy OTC products and increase the size of one’s market. In order to increase sales of OTC medicines firms can use many different tools, including advertising, sales promotion, public relations, direct marketing, personal promotion and merchandising. This article deals with the subject of marketing activity policy in the pharmaceutical market. Such activities have for a long time been used as a strategic option by firms operating in market economies in the pharmaceutical sector. More and more often we can observe a significant intensification of OTC product promotion in the press and media. All this means a growth in the importance of promotion and its tools in the pharmaceutical market, and a deepening of interest in the theory of these tools among both theoreticians and practitioners in the pharmaceutical sector.
Promotion as one of the elements of the marketing mix1 is an instrument used by firms to communicate with the consumer and others around them. It is associated with a flow of information in two directions. Consumers are informed about the firm and its products or services, which is intended to persuade them to accept and then to buy those products. In its contacts with consumers the firm also obtains important information about the needs and preferences of its potential customers. Marketing communication policy aims not only to inform, but also to persuade of the attractiveness and benefits accruing from buying and using the recommended product. It involves making appropriate use of tools, information and methods in order to best present products or services to potential purchasers and to maximize sales. P. Kotler defines promotion as a set of means by which a firm informs the market about itself or its products, shapes the needs of purchasers, and stimulates and directs demand.
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Marketing communication refers to a set of information coming from different sources which the firm conveys to intermediaries, wholesalers, suppliers and competitors, as well as information which a firm collects from the market, usually relating to the likes and preferences of customers. The process of marketing communication in the pharmaceutical market comprises three main elements: • the originator of the message; • the content of the message; • the recipient of the message. Originators of messages include drug manufacturers, prescribing doctors, medical representatives, and wholesale firms, pharmacies and other wholesale and retail points. The content of a message should include properties of the medicine, such as pharmaceutical dosage, description of its action, adverse effects, etc. The recipients of the message are doctors, pharmacists, competitors, and above all patients. Marketing communication is understood as a set of tools, which include informing recipients of the message through elements of the marketing mix, such as price, product and manner of distribution, as well as tools of promotion: advertising, sales promotion, personal promotion, public relations or direct marketing. The set of these tools is assigned to various forms of communication, among which we can distinguish indirect (mass) communication and direct (interpersonal) communication. Indirect communication includes advertising and sales promotion, as well as certain actions of products. Marketing communication in the pharmaceutical market is conditioned by many factors, such as the features of the medicine itself as a product (Rx or OTC), legal regulations, the financial resources of the firms operating in those markets, as well as purchasing habits and customs. The system of marketing communication comprises the following instruments: • advertising – a form of presentation and promotion of the goods and services of a particular sponsor; • direct marketing – use of electronic advertising, the Internet, phone or fax to communicate directly with potential or existing purchasers in order to stimulate reactions and establish dialogue; download *.pdf version:
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sales promotion – so-called supplementary promotion aimed at encouraging people via various stimuli to try or purchase a product or service; personal sales – the direct presentation of a firm’s products to a potential purchaser in order to bring about a sale; public relations – the building of a good image for the firm.
Promotion is a means of competing which goes beyond price. Its importance for the firm depends on the following factors: type of market, reach, type of products, type and quality of packaging, nature of the target group, legal restrictions, purpose of the promotion, costs of reaching one target customer, ability to determine the effects of the promotion, competition in the marketplace, and the firm’s marketing plan. Consumption is a process in which the following stages are distinguished: arising of a need, planning of purchase, taking of a decision to purchase, making of the purchase, and post-sale behaviours which may or may not lead to another purchase. Compared with the purchasing process in relation to products in general, the process in the pharmaceutical market is similar: arising of a medical complaint, planning of a purchase independently or in consultation with a doctor or pharmacist, making of the purchase, and behaviour which may lead to a repeat purchase of the medicine for the same complaint or else its removal from the household medicine cabinet. The process of making a purchase is affected most often by the following factors: recommendation of a product or brand by a trusted person, purchase of a known advertised brand, loyalty to a brand giving satisfaction, one’s own motivation, increased awareness, one’s own experience, preferences regarding price, forms and dosage. The essence of pharmaceutical marketing is maximization of profit through the best possible satisfaction of the needs of a selected group of patients. In order to satisfy those needs, it is necessary to identify them by making an analysis of the environment and resources, and then determine a composition of marketing instruments. Purchasers’ choices are often guided by motives which are hard to predict. because the same consumer need might be satisfied by different products, or one product may satisfy different consumer needs. It is therefore necessary to make a segmentation of customers. Pharmaceutical companies have a MAP (marketing activity policy) which regulates in detail the principles of promotion and advertising. The MAP contains: • a description of product activities; • conditions for application; • procedure for realization; • documentation (e.g. a form for settling up for samples distributed). Each advertisement or promotion is accepted in accordance with a relevant procedure, i.e. they must be approved by the Marketing Director and by persons performing the functions of Registration Manager and Medical Consultant, and controversial advertisements are also the subject of consultation with lawyers. Different OTC medicinal products have different channels of distribution, and each of them is associated with specific forms of promotion and advertising. Promotion often needs to be adapted to the season, some medicinal products being of a more seasonal nature than others. Promotion is based to a large extent on a system of priorities, which leads to different types of support being given for leading products and for niche products.
Because of its nature, the medicines market is subject to special legal regulations. A key role is played by the act of parliament called the Pharmaceutical Law, which regulates the principles and procedure for allowing medicinal products into circulation, conditions of manufacture, the advertising of medicinal products, and conditions for the functioning of pharmacies and pharmaceutical wholesalers. According to Article 52(1) of the Pharmaceutical Law, advertising of a medicinal product is an activity which involves informing and persuading to use a medicinal product, aimed at increasing the number of prescriptions, delivery, sale or consumption of medicinal products. Instruments of promotion of medicinal products and purchasing decisions by patients regarding medicines issued without the need for prescription. The effectiveness of promotion of medicinal products in the Polish pharmaceutical market is varied. There is ever greater rivalry in the area of promotion on the medicines market, with manufacturers constantly seeking new ideas for effective ways of advertising and promoting their products which do not violate legal restrictions or ethical principles. Competition in the pharmaceutical market now means that creative ideas are required for presentation in new promotional campaigns. Below I present the results of a survey which I have carried out. The sample is not representative in a statistical sense. The survey involved 100 persons aged over 16.
Figure 1.
Breakdown of respondents by place of purchase of OTC medicines Source: own data. The survey showed that 70.80% of patients most commonly purchase OTC medicines from pharmacies. Moreover 13.30% of patients buy such medicines in shops, 12.40% at petrol stations and 3.50% via the Internet. Other sources were not mentioned in responses (Figure 1).
Figure 2.
Breakdown of respondents by effect of price promotion on purchasing decisions Source: own data. Of the total number of patients, 46% replied that price promotions do not affect their decisions to purchase OTC medicines, while 28% stated that they believe price promotions on such medicines encourage them to buy products which they had not planned to purchase. Another 26% of patients replied that price promotions on OTC medicines
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encourage them to buy, but they try to resist such encouragement (Figure 2).
Figure 5.
Figure 3.
Breakdown of respondents by location of most frequently encountered information materials on OTC medicines Source: own data.
Breakdown of respondents by factors affecting choice of OTC medicines Source: own data. When choosing among different brands of OTC medicines offered by the pharmacist, 33% of patients are guided by the effectiveness of the medicine. Another 28.34% of patients responded that price shapes their choice. Around 24.50% stated that they generally buy the medicine they had planned to buy earlier, while 13.38% of patients are influenced by the ability to buy OTC medicines without the need to visit a doctor. Only 0.79% suggested that when buying OTC medicines they are guided by the opinion of a doctor (Figure 3).
Figure 4.
Breakdown of respondents by source of information affecting their decision to buy OTC medicines Source: own data. To my question concerning the main sources of information affecting decisions to buy OTC medicines, more than 26% of respondents replied that they are guided by their own experience when they buy a medicine, 22.20% by the pharmacist’s suggestions, and 20% by a doctor’s recommendation. As regards instruments of promotion, 12.20% replied that their decisions are most often influenced by television advertisements, which confirms the effect on OTC medicine purchase decisions by media advertising as the main source of information. Ten percent replied that their decisions to buy OTC medicines are affected by the opinions of friends, 3.30% took account of the information found on leaflets picked up at pharmacies, and 2.25% of information on leaflets picked up at medical centres. Magazine advertisements were indicated by 2.25% of respondents, and radio advertisements by 1.70% (Figure 4). Patients become familiar with information materials on OTC medicines most commonly in pharmacies, as indicated by 23.77% of respondents, or at medical centres (11.47%). As many of 55.74% of patients gave television as the location of the most commonly found information materials, while 5.74% pointed to information materials in shops, and 3.28% information received by radio (Figure 5).
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Medicine manufacturers recognize the role of advertising in the decision-making process regarding purchases of medicines. This is evidenced by the increasing financial expenditure on the production and broadcasting of advertisements. Over recent years activity in the promotion of medicinal products has rocketed. In conditions of strong competition in the medicines market, ever greater use is made of promotional instruments to gain competitive advantage, these being a method of achieving dynamic growth in sales, and thus improving the performance and financial liquidity of a pharmaceutical company. Medicine manufacturers are battling each other in the marketplace to an ever greater extent, but it is those that best make use of promotional instruments which gain prestige and renown among customers. Analysing the results of my research, and by the same token reviewing the promotional instruments used to promote OTC medicines, it can be concluded that it is information remembered from advertisements that is decisive in the purchasing process. Nonetheless, when taking decisions on the purchase of OTC medicines, respondents are most often guided by their own experience or information obtained from specialists in the field. The engagement of pharmaceutical firms and the costs incurred in relation to the promotion of OTC medicinal products are paid back by achievement of the intended benefits and still more, which indicates the need to take financial risk and build a brand image for one’s products.
Bibliography: [1] A. Czerw, Specyfika promocji produktu leczniczego (leki etyczne), Zeszyty naukowe Nr 51, Kolegium Zarządzania i Finansów, SGH, Warszawa 2005. [2] L. Garbarski, Zachowania nabywców, PWE, Warszawa 2004. [3] Ph. Kotler, Marketing. Analiza, planowanie, wdrażanie i kontrola, Wyd. Gebethner & Ska, Warszawa 2002. [4] J. Pindakiewicz, Podstawy marketingu, AGH, Warszawa 2000. [5] T. Sztucki, Encyklopedia marketingu, Agencja Wydawnicza Placet, Warszawa 1998. [6] Ustawa Prawo Farmaceutyczne (Dz.U.04.53.533, ost. zm. Dz.U.08.45.271, art. 52).
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Marketing mix means a set of marketing tools which a firm uses in order to achieve its intended marketing goals in a target market. It should shape production, goods turnover and services from the point of view of market needs.
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Adamed expands its product portfolio Adamed – one of the leading pharmaceutical manufacturers in Poland has added to its product portfolio one more therapeutic group – ophthalmology. The new drug Rozalin – a new Polish drug used in ophthalmology to treat glaucoma and ocular hypertension – gives an opportunity to lower the costs of therapy for over one hundred thousand patients.
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p to now, drugs produced by Adamed were available in such therapeutic areas as: cardiology, pulmonology, psychiatry, gynecology and treatment of urinary tract infections. In these groups Adamed is the leader on the Polish market in new generation drugs. Introducing the drug in the new therapeutic group gives us an opportunity to develop and increase revenues. Until now, only one drug was available in this group, produced by a foreign manufacturer. The market for this medicine is approximately fifty million zloty per year. Rozalin is a drug which lowers intraocular pressure in the eye, used in treating glaucoma and ocular hypertension. Over 800,00 people suffer from this disease in Poland, and only one out of eight are undergoing treatment. Treatment with Rozalin allows to lower the costs of treatment for patients with this disease by 30 percent when compared to the drug already available on the Polish market. Adamed’s advantage and opportunity is innovation. Already today, most of the medicines manufactured by Adamed are innovative drugs with the added value in the form of own patents. Adamed is systematically developing its portfolio of drugs and on a regular basis enters new foreign markets with its drugs.
„We are successfully striving to expand our portfolio of drugs. In 2009 we plan to enlarge our portfolio by about five new drugs. These will be mainly in therapeutic groups which Adamed is already present in, which are cardiology, pulmonology, psychiatry, etc.” – comments Mrs. Anna Czajkowska, Adamed’s Member of the Board. The company’s priority is research and development of innovative therapies. Currently, Adamed is leading a project to develop innovative therapy to be used in treating type 2 diabetes as well as a project to develop a drug which will be a Polish answer to central nervous system diseases. Furthermore, research is underway to develop an effective anticarcinogenic therapy, selectively acting on affected tissues. In order to meet the needs of patients and the medical society, Adamed invests in research and development of new, effective, safe and at the same time easily accessible therapies. These are to be the answer to the so called unsatisfied needs of today’s medicine and giving the biggest benefits to patients. This requires an ongoing dialog with the medical society and with patients, in order to better assess their needs from therapy. Thanks to innovative drugs which Adamed plans to develop during the course of research, many patients all over the world can count on improving their health and quality of life.
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Patients have the right to information about their medicines, subject to the condition that the information is comprehensible to them. There is one way to achieve this – by writing good leaflets!
Can leaflets be understood by the layperson? Halina Gudowska
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ased on readability testing of many leaflets carried out by us at Pharmbicon, I can observe that most of them do not meet the needs of patients, particularly those who are elderly or have had only a basic or vocational education. A separate problem is patients’ neglecting to read leaflets carefully. Many of them do not read them as a rule, either because they assume in advance that they won’t understand the contents, or because they are frightened of side effects and prefer not to know about them, since otherwise they wouldn’t take the medicine. Some patients read only selected fragments which they find interesting or consider important. The leaflets supplied with medicinal products should, by assumption, be addressed to patients, who are non-specialists having different levels of knowledge about medicines. The information should be comprehensible to those people. In practice, however, this is not always the case. The content of most leaflets is unclear to patients who, having no medical or pharmaceutical training, might have problems understanding or – worse still – using the medicine properly. Leaflets contain a huge amount of completely useless information, including many medical terms which are not explained (like angioneurotic oedema, thrombocytopenia, granulocytopenia, bradycardia, orthostatic hypotonia). Another obstacle to the understanding of leaflets is the use of names of pharmacological groups of medicines (non-steroidal anti-inflammatory drugs, sympathicomimetic medicines, anticholinergic drugs, calcium antagonist, etc.) as well as complicated rules on dosage. Most importantly of all, leaflets are lacking in detailed practical information written in simple language. A good leaflet should contain: • Explanations of specialist medical terminology; • A readable description of indications and contraindications to use of the medicine; • A comprehensible description of warnings; • The description of adverse effects should provide practical information, not lead to unnecessary fears which discourage the patient from taking the medicine. It should instruct the patient what to do should particular symptoms occur.
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Precise information on interactions between drugs and the combining of drugs with food or drinks; A description of adverse effects including comprehensible information on their frequency of occurrence; Clear information on the method of dosage.
Access to medical information has improved significantly over recent years, mainly thanks to its being published on the Internet. Nonetheless the medicine leaflet remains the most common method of receiving medical information. This means that high leaflet quality is a key component of patient education. Of course it cannot take the place of doctors (or pharmacists in the case of over-thecounter medicines), who have a duty to clear up in a thorough manner any doubts the patient may have about the action of the prescribed drug. However these are the reasons why such great emphasis is placed at present on the readability and accessibility of leaflets to patients. To meet these requirements, appropriate legal regulations have been put in place which aim to encourage the spread of standards with regard to patient medical education. These regulations vary between different countries – those of the European Union, Australia, the United States. There is a common principle, however: the content of the leaflet accompanying a medicine must be comprehensible, accurate and useful to the patient and designed in a transparent manner which encourages the patient to read it. In the European Union these issues are regulated by Directive 92/27/EEC, issued by the European Commission in 1992 [1]. These guidelines were later included in Directive 2001/81/EEC, and then amended in Directive 2004/27/EEC [2]. Since January 1999 all medicine packages have had to be supplied with information leaflets that patients will be able to understand. The leaflets are composed by the manufacturers, but their content and layout are subject to detailed legal regulations, titled Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use, commonly known as “the Guidelines”. These include not only requirements that information be presented in a way which is clear and comprehensible for patients. They also regulate the appearance of a leaflet, i.e. the way in which the content download *.pdf version:
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Testing of readability is not carried out on such a large scale in Poland as it is in the United Kingdom, for example. It is essentially obligatory only in two cases: when a new medicinal product is brought into circulation or when the registration documentation is updated (harmonization). In practice many responsible entities submit incomplete applications for permission to bring medicinal products into circulation. Rather than submit a report on leaflet readability testing (which is an integral part of the application for permission to bring a medicinal product into circulation – Module 1.3.4), they undertake to supply one at a later date. To date this has been acceptable to the Office for Registration of Medicinal Products (URPL), in view of the absence of a Health Minister’s Order on leaflet readability testing and the huge workload associated with the harmonization of documentation. Many entities wait for the information materials to be accepted by the URPL, and only following this acceptance begin testing the readability of the leaflets for their medicinal products. This situation seems to be gradually starting to change. Work was completed on document harmonization at the end of 2008, and so it can be expected that the URPL will begin to draw attention to the missing reports on leaflet readability testing. 1
Medicines and Healthcare products Regulatory Agency
And how do things look in other EU countries? The United Kingdom was the first to complete leaflet readability testing, in July 2008. All medicinal products allowed into circulation since 2005 carry tested leaflets, although the process of evaluating the reports has not yet finished. The other “old” EU member countries will complete readability testing this year, the Czech Republic and Hungary are working on it intensively, but Lithuania, Latvia and Romania – like Poland – do not have executive orders in place from their health ministers and restrict leaflet testing only to cases of absolute necessity.
What is the essence of leaflet readability testing?
Testing of the readability of information leaflets for patients was first introduced in Australia. That country’s regulations have been in force since January 1993, and came into being as a result of cooperation between professionals, the government, the pharmaceutical industry and patients. Experts have the task of assessing a leaflet in terms of its substantial content, evaluating scientific accuracy and ensuring that it is consistent with research results. In turn, patients express an opinion on how easy or difficult the information in the leaflet is to read and understand, and to what degree it is significant and useful. They also evaluate the appearance of the leaflet, how it is laid out and the how the typeface looks. The methodology for leaflet readability testing in the EU is similar, and involves face-to-face interviews in two rounds, each including a minimum of 10 volunteers. These are classical quality tests. The aim of the interviews is to obtain confirmation of whether, after reading the leaflet, interviewees are able to find the required answer, understand the content of the leaflet and take appropriate action (these being the three main aspects covered by the MHRA guidelines). Tests must be conducted by experienced and properly trained interviewers. All interviews are recorded. The respondent reads the leaflet once, and may look at it throughout the test. The interviewer reads a series of questions, and the respondent has the task of finding the information in the leaflet and answering the question in his or her own words. Respondents are asked to assess the difficulty of each question and to indicate whereabouts in the leaflet they found the answer. A questionnaire is drawn up on the basis of the contents of the leaflet. It should contain 12–15 key questions (or more in certain specific situations) and 3–4 questions about the appearance of the leaflet. Each respondent is asked the questions orally by the same interviewer. The questions must be open, enabling interviewees to imagine that in the future they will be using the medicinal product being tested. They relate to, among other things, important information concerning the safe use of the
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is presented, in terms of such elements as print size, colour and even graphical layout. Moreover a leaflet should comply with the medical product description as given during the registration process [3]. In the EU, leaflets are quality assessed and approved by a unit set up by the MHRA1 called the Patient Information Unit, which verifies compliance with the guidelines laid down in the Directive [6]. Since July 2005 it has been obligatory for patients/users of medicines to be involved in the process of preparing information leaflets. This is laid down in Article 59(3) of Directive 2004/27/EEC: “The package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use.” In Poland, all responsible entities have been obliged to test the readability of leaflets since November 2006. This is stated in the Article 10(12) of the Pharmaceutical Law of 6 September 2001 [4]. Testing is necessary when a responsible entity brings a medicinal product into circulation under any of the applicable procedures, and also in the case of changes should they affect the content of the leaflet. • Testing is always required when: • a new molecule is brought into circulation; • there is a change to the availability status; • medicine is introduced in a new form; • in the case of “hazardous” medicines.
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product. They should be worded in a way that differs from the leaflet text itself, in order to avoid getting an answer identical to the leaflet’s own wording (volunteers are stimulated to use their own words). The questions are placed in random order – they should not be in the same order as the information appears in the leaflet. One interview should last for not more than 45 minutes. After the end of each round of testing an analysis is made of the results, and on this basis changes are proposed and the leaflet is modified. When the leaflet is altered, the changes must be tested on a new group of 10 volunteers (in order to prove their readability) until the required criteria are satisfied. This means that for all questions 90% of interviewees (18 out of 20) properly located the information, and of these 90% another 90% (16.2 out of 18) were able to understand and explain the content of the leaflet and take appropriate action.[7] It is very important that the respondents be selected appropriately[8]. The “Guidelines” lay down precise criteria for enrolment. Ideal respondents are those who: • Have not taken part in tests of this type in the past 6 months. • Are not employees of medical or pharmaceutical establishments and do not work in the media. • Their level of education should be mixed (primary, vocational, high-school; but college and university graduates are not recommended).
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Have not used the tested medical product at all or in the past 12 months.
If a positive result is obtained in the second round of testing, work begins on the final stage – the report, drawn up in the form of a summary explaining how the testing was carried out and how it influenced the final content and appearance of the leaflet. The report is prepared in CTD format ready to accompany the application for permission to bring the medicinal product into circulation in Module 1.3.4. Testing of a single leaflet lasts on average between 6 and 10 weeks. Leaflet readability testing requires a great deal of knowledge and commitment on the part of the responsible entity. They often have this research carried out by firms with experience in leaflet readability testing. It is important that their subcontractors employ staff with experience in the pharmaceutical industry, and particularly in the authorship of leaflets. The absence of a Health Minister’s Order on leaflet testing makes the work of the responsible entities more difficult. They base what they do mainly on the “Guidelines”, which they translate for themselves from English. The consequence of this may be incorrect interpretation and consequently rejection of reports by the URPL. In this situation, we are left reliant on the understanding of URPL personnel. After all, both sides learn from their own mistakes. It would be very useful if consultation were available to firms during the readability testing. This would make it possible to avoid having to make corrections to leaflets and reports at a later stage, which is time-consuming for both parties. Especially since our efforts have a common objective – an accurate leaflet that the layperson can understand. The author is the owner of the firm Pharmbicon, which specializes in readability testing of patient information leaflets. www.badanieczytelnosciulotki.com
Bibliography
CONTACT US FOR A FREE CONSULTATION!
Halina Gudowska hgudowska@pharmbicon.com Phone:
+48 22 21 54 107 +48 22 42 42 890 Mobile: +48 502 67 1964
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info@pharmbicon.com
Headquarter: PHARMBICON Sloneczna str. 105 B, lok. 72 05 – 500 Piaseczno 1 (near Warsaw) POLAND
1. Council Directive. Council Directive 92/27/EEC – Dyrektywa Rady 92/27/EWG z dnia 31 marca 1992 r. dotycząca oznakowania i ulotki informującej o środkach medycznych przeznaczonych dla ludzi. 2. Dyrektywa 2004/27 /WE Parlamentu Europejskiego i Rady z dnia 31 marca 2004 r. zmieniająca Dyrektywę 2001/83/WE w sprawie wspólnotowego kodeksu odnoszącego się do produktów leczniczych stosowanych u ludzi. www.doc.ukie.gov.pl 3. Prawo Farmaceutyczne – www.gif.gov.pl/ustawa_prawo_farm_a2_html 4. Dz. U. z 2004 r. nr 53, poz. 533, z późn. zm.) 5. Raynor DK, Britten N: Medicine information leaflet fail Concordance test. British Medical Journal, 2001; 322 (7301): 1441. 6. Always read the leaflet – report of the Committee on Safety of Medicines Working Group on Patient Information. MHRA. 7. MHRA – www.mhra.gov.uk 8. Regulatory Rapporteur – TOPRA, Nr 5. 2008; 18.
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Polish industry
A new laboratory BioCentrum
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On the 10th December 2008, Krakow’s BioCentrum biotechnology firm set up a new R&D laboratory located in the buildings of III Kampus Uniwersytetu Jagiellońskiego (3rd Campus of the Jagiellonian University) in Krakow, Poland.
he laboratory, with the area of 150 m2, will make it possible for BioCentrum to expand its activity scale and the scope of the previous service offer. At present, the total area of all BioCentrum laboratories is 200 m2, and it will be enlarged by additional 60 m2 in the near future. Moreover, the new laboratory enables BioCentrum scientists to conduct advanced biochemical studies and work with cell lines. Such studies are used during the process of designing innovative drugs as well as various kinds of analyses for pharmaceutical and chemical companies. BioCentrum’s scope of research for pharmaceutical companies and scientific institutions is as follows: • ADME preclinical studies (adsorption, distribution, metabolism and elimination); • Pharmacodynamic studies of drugs (cell line assays); • Protein chemistry (protein sequencing, protein isolation from biological sources);
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Developing methods for the determination of non-standard protein antigens (chromatographic analyses); Constructing monoclonal antibodies; Crystallography; and, Chemical syntheses.
The value of BioCentrum’s capital expenditure for laboratory adaptation and equipment has been 1 900 000 PLN. The sources of funds for this investment were the following: their own financial means earned by the company, capital brought in by Selvita sp. z o.o. – a strategic investor of BioCentrum from March 2008, a subsidy from Europejski Fundusz Rozwoju Regionalnego (European Regional Development Fund – ERDF), as well as the national budget awarded by Polska Agencja Rozwoju Przedsiębiorczości (Polish Agency for Enterprise Development) within Program Operacyjny Innowacyjna Gospodarka (Operational Programme: Innovative Economy). As part of the laboratory equipment, the following analytical devices have been purchased: a mass spectrometer, a high-pressure liquid chromatograph, a spectrofluorimeter, a spectrophotometer and equipment for chemical syntheses, and a cell laboratory. The heart of the new BioCentrum laboratory is the STARLIMS lab management system, which provides company clients with a remote access to data from research projects. At present, in BioCentrum laboratories projects associated, among others, with antineoplastic and antipsychotic drugs, and with immune system diseases are run. Furthermore, BioCentrum produces novel enzymes used in the studies of new vaccines.
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conferences, fairs, training
Preclinical Toxicology Training
StatSoft Polska Bio-Tech Consulting
Media Partner:
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Validation of Technological Processes in the Pharmaceutical Industry
reclinical Toxicology Training, that was a name of training event, targeted to companies in biopharmaceutical sector, aimed at expanding their products for the European market and to research institutions, which would provide toxicological studies for these companies. Event was organized by Bio-Tech Consulting Ltd. company from Lodz in Poland, within the framework of the project – Academy of Innovative Biobusiness. Ivana Šurova, Aleš Brejcha, Jiří Marhan and Martin Šlais, professionals from Czech laboratory BioTest s.r.o., 20th January 2009 in Krakow conducted a workshop for representatives of pharmaceutical companies and research units from across Poland. There were discussed aspects such as: the role of toxicological studies in the development of pharmaceuticals, essence of the legislation, testing the layout and of course, stages of testing the short and long-term, the role of GLP, bioavailability. The next training carried out within the framework of the Academy of Innovation Biobiznesu can be found on www.biotechnologia.pl/szkolenia.
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etween the 11th and 13th February 2009, the fifth edition of the training titled “Validation of Technological Processes in the Pharmaceutical Industry” was held. It was organised by StatSoft Polska, a company that has been supporting the pharmaceutical industry for many years, providing STATISTICA analytical tools and training employees of production, quality assurance and R&D departments on using modern techniques of data analysis and data mining. The training was divided into two parts. During the first one, participants became familiar with methods and procedures applied in the validation of technological processes. The discussion covered issues of requirements and recommendations valid in Europe and in the United States as well as individual stages of validation and method of work organisation. Validation documents were also reviewed, and their format, protocol, and validation report elements were described. A Validation Department Manager of one of the largest pharmaceutical plants in Poland shared his knowledge and experience in this field. The second part of the training was entirely devoted to statistical methods used in process validation. Individual analytical methods and techniques were discussed step-by-step, in order to enable the participants to successfully employ them in their day-to-day work. In all analyses, the STATISTICA package and a dedicated tool named STATISTICA Process Validation, an element of the STATISTICA Pharmaceutical Set solution, were used. The fact that these two days devoted to statistics were not merely a lecture was of immense significance with regard to effective knowledge acquisition. The workshops enabled the participants to perform tasks independently, acquire practical knowledge, and have a possibility to ask questions related to doubtful issues. Such an interactive way of taking part in the training guarantees acquiring practical knowledge that the participants will be able to easily use after the course. We encourage all persons interested in deepening their knowledge on using data analysis in pharmacy to take part in the second “Practical Data Analysis for the Pharmaceutical Industry” Conference – more information on the meeting is available on the website http://www.StatSoft.pl. The “Świat Przemysłu Farmaceutycznego” quarterly extended its patronage over the conference.
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conferences, fairs, training
Annual Registration Summit 2009 On February 10 and 11, 2009, the third edition of the Annual Registration Summit took place – a yearly conference addressed to representatives of pharmaceutical companies’ registration departments.
This year’s meeting gathered over 130 people from nearly all of the relavent pharmaceutical companies. The scope of topics, which included the most important issues pervading our Guests’ minds, as well as our expert lecturers, representing primarily the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (URPL), have turned the conference into a very interesting event. The animated discussions and exchange of different opinions provided answers to many questions which arise in the participants’ daily work practice. Some of the issues raised at the conference were as follows: • Systemic changes in decision-making with regard to medicinal products, and the new authorities of URPL President; • Changes related to the amendment of Pharmaceutical Law and executive regulations;Practice and perspectives in MRP and DCP procedures, and in national Polish procedure;New regulations of the post-registration and re-registration change procedures;Research on the
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comprehensibility of drug information leaflets - URPL practical interpretations and guidelines; The monitoring of medicinal product safety, especially in relation to planned changes in Polish and Community law; The introduction of eCTD to URPL; Perspectives in Polish legislation concerning the increasing problem of drug counterfeiting prevention;New regulations (ECJ jurisdiction) on parallel import; and, The functioning of competition on the pharmaceutical sector in relation to the EC decision of 28 November 2008.
Each of the lectures was thoroughly based on the URPL practice, and the lecturers made every effort for the information to be explanatory with regard to audience’s doubts and helpful in teaching how to avoid practical mistakes and prepare for oncoming changes. The very high quality of the lectures’ essence, the lecturers’ openness to discussions, and their exhaustive answers to questions from the audience resulted in an exceptionally favourable assessment of the lectures. Some speeches were even awarded with applause, for example, the lecture on informational publications conducted by Anna Wachnik-Święcicka, Manager of URPL’s Unit for Product Information Evaluation. The 2010 edition of the Annual Registration Summit will take place near the end of January or the beginning of February.
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Media Partner:
One can easily say it is the most important meeting of people occupied with broadly conceived registration of medicinal products in Poland and a permanent item on the annual agenda.
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conferences, fairs, training
Clinical Trials
Media Partner:
– New Regulations
Informedia Polska
The Conference on the subject of „Clinical Trials” was organized by Informedia Polska on 15-16 December 2008 in the Polonia Palace Hotel in Warsaw. An excellent body of speakers, just to name a few Wojciech Masełbas, The Association for Good Clinical Practice in Poland, dr. Wojciech Przybyś, Quintiles Poland, Anna Petriw, PPD Poland and Rafał Zyśk, National Health Fund (NFZ) presented the major challenges and limits concerning the development of clinical trials in Poland.
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Initial Batch Control
he main part of the program was dedicated to discussing the forthcoming changes in the clinical trials law – the cases were presented by excellent lawyers Ewa Rutkowska from Lovells and Hubert Tuchołka from Tuchołka i Wspólnicy law firms. Furthermore, delegates could also learn about the details of the clinical trials registration procedures (presented by Agnieszka Krywoniuk –Zielińska, Lovells), how to draw up contracts in clinical trials (presented by Katarzyna Bondaryk from Hogan&Hartson Jamka) and were given the opportunity to find out about the standards of trials taxation (presented by Piotr Augustyniak, Hogan&Hartson Jamka). In addition, during that conference Rafał Zyśk, representant of National Health Fund together with Jerzy Gryglewicz from Institute of Rheumatology presented transparent procedures of conducting clinical trials based on the Institute of Rheumatology case study. Due to great interest in the subject of clinical trials Informedia Polska has announced the next edition of the conference for 2009.
MEDVICE
On the 20th of January 2009, a Krakówbased company, MEDVICE, organised a training titled: “Initial Batch Control – New Regulations,” which included lectures by the representatives of the Polish Main Pharmaceutical Inspectorate – Daniel Gralak, Head of GMP Inspection Department, and Marcin Kołakowski, Head of the Department of Supervision.
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mong training participants there were the representatives of the Kraków Institute of Biotechnology, Sera and Vaccines BIOMED S.A., Eucerin Factory Pharmaceutical Laboratory “COEL”, Pharma-Cosmetic, Galfarm, Wrocławbased Hasco-Lek, and ZF Amara. During the training, conditions, procedure and the manner of performing an initial batch control was discussed in detail. Special attention was drawn to the immunological products for people, immunological veterinary medicinal products, hematogenous products, and raw materials used to produce compounded or galenic drugs before their distribution with this purpose. Another issue tackled at the training was the role and scope of the activity of R&D units and medicine quality control laboratories authorised to carry out batch controls. OCABR, the basic controlling mechanism, was also subjected to detailed discussion. The issues of the role and tasks of the responsible entity, the importer and entities running wholesale in terms of initial batch control, were also discussed. The last element of the training was a workshop – a case study.
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2009-02-23 16:43:07
brainstorming is on, and success will have many fathers Luiza Jakubiak
Last year, there were a few confrontations between major players, combing through the market in search for a profitable takeover, merger, or purchase of licence for a promising medicinal product. Top mergers include, for example, Eli Lilly and the purchase of the ImClone Systems biotechnological company, or Novartis which paid 11 billion dollars for 25% of Alcon stock.
reports, projects, plans
Drug invention
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espite offering 43.7 billion dollars for 44% of stock, Roche has not yet accomplished the takeover of Genetech, a tycoon in biotechnology. But company mergers are only one in many trends which shaped the pharmaceutical industry in 2008.
Mergers and takeovers Last year also witnessed the continuation of a trend of big players taking over companies with promising drug portfolios in different stages of development or with the purpose of entering new therapeutic fields. That was the case with the Japan-based Takeda company, which took over the biotechnological Millennium last April, and, for the sum of 8.8 billion dollars, it purchased Millennium’s 15 products in oncology and infectious diseases, along with the right to commercial sale of bortezomib, used in multiple myeloma treatment, on the American market. Eli Lilly also went into oncology by winning the fight against other pharmaceutical giants for the 6.5-billiondollar purchase of ImClone Systems at the end of the year. Due to this fact, it obtained cetuximab, a blockbusterstatus monoclonal antibody used in colorectal cancer treatment, as well as three other oncology-dedicated biological products in stage II or III of clinical tests.
Team spirit at work Last year, many pharmaceutical companies engaged in cooperation with academic institutions in search for discovery and development of interesting ideas, which in some cases resulted in substantial organisational changes in these companies.
GSK introduced a new R&D process organisational model. Researchers working in smaller teams are rewarded on the basis of the results of their work, i.e. creating a valuable project assessed in terms of therapeutic and cost efficiency. Today, cooperation means more than just providing funds for academic institutions. R&D costs are so high similarly to investment risk - that companies tend to unite in their efforts. This is why the success of a single innovative drug, from its invention to commercial implementation, has
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many fathers. Also, the sponsors accustom the producers to team work. The Goldman Sachs investment bank has offered hundreds of millions of dollars for the financing of interesting projects in research Stage I or II, provided that these would be team projects of cooperating researchers, chemists, or clinical tests experts.
Oncology out-of-focus What is noticeable is the shift of focus away from certain therapeutic areas. One of our interlocutors admitted that, for many years in his company, oncology was outside the main circle of attention. Gradually, this falling behind had to be made up for in order to catch up with other firms which had earlier discovered the potential of this market. Last year was full of news concerning oncology related genetic research and so the focus of companies shifted that way, along with their funds. A few firms have also moved their funds to research on Alzheimer disease drugs. On the other hand, companies reduce or give up research on, for instance, circulatory system diseases.
Generics are saving the business The European trend has reached the USA. Last year, Merck became the first American company to announce plans for setting up a department for biogeneric drugs, that is, copies of biotechnological drugs. The scheme may be modelled on the example of Novartis whose lucrative generic stream is instituted by the Sandoz Company. This year the phenomenon will gain even more ground, especially with generic use supporters coming into greater prominence. Soon the American Congress will consider the possibility of biogeneric drug registration, which was one of the elements of Barack Obama’s election plan.
Efficient and cost-effective Increasing support is won by the trend of developing payer cost-effective drugs. Companies adjust their scientific research and clinical test programmes to meet this requirement. There are also more and more examples of risk sharing agreements. One of most frequently mentioned examples of such company-payer agreement is the Velcade drug (bortezomib). This year a similar agreement will probably be concluded. Last year, NICE rejected some renal cell carcinoma drugs - bevacizumab, sorafenib, sunitinib, and temsirolimus - as cost-ineffective. Currently NICE is negotiating with one or two producers of these drugs in order to enter a similar agreement. Source: www.rynekzdrowia.pl
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reports, projects, plans
Summary of medicinal product withdrawals in 2008 Bogdan Klimas
At the end of the year we decided we would analyse and summarize the decisions taken by the Chief Pharmaceutical Inspector in 2008 regarding withdrawal of medicinal products.
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he total number of decisions leading to withdrawal (up to 23 December 2008) was 62, and these related to 234 medicinal product batches listed with specific batch numbers. This also included two decisions concerning the withdrawal of all products but without statement of the number of these or of batch numbers (following closure of a factory due to lack of required permits). There were also several decisions which were amended or revoked.
Comparing this year with the previous one, in 2008 the number of medicinal product withdrawals was almost 50% lower than in 2007, which was a record-breaking year. More than half of all withdrawal decisions were taken by request of the responsible entity. This indicates that the manufacturers themselves have good understanding of the risks and are looking after patients’ interests. It cannot be ruled out, however, that some of these manufacturers’ own withdrawal decisions were made to pre-empt decisions by the Chief Pharmaceutical Inspector.
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reports, projects, plans
In our analysis we drew up statistics for withdrawals of medicinal products broken down by route of administration, grounds for withdrawal, and month. Analysis of route of administration among the medicinal products withdrawn by decision of the Chief Pharmaceutical Inspector shows that most were orally administered medicines, followed in second place by the relatively more critical parenteral products, behind which came products for external application on the skin and other types. As regards the reasons for withdrawal of medicinal products in 2008, we have only general information available, in view of the fact that the grounds for withdrawal as stated in the Chief Pharmaceutical Inspector’s decisions are often very unspecific. Nonetheless a certain amount of analysis was possible, showing that one of the chief reasons for withdrawals was the identification of defects in the printed packaging materials. Another category of grounds for withdrawal is generally defined quality defects, most often signifying non-compliance of product parameters with the specification, and excluding those which are detailed specifically in further categories, namely API content (including stability) and mechanical, physical and microbiological contamination. Some of the withdrawals were made for formal reasons, including withdrawals due to changes in licences, or the obtaining of new data etc. when the product was already on the market. Analysis of the number of withdrawals in the course of 2008 shows a marked rise in the number of withdrawals at the end of the year. The lowest numbers of withdrawals were recorded in the summer holiday season. We will conclude this brief summary by wishing all our medicines manufacturers zero statistics for numbers of suspensions and withdrawals in the coming years.
Source: www.e-gmp.pl
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reports, projects, plans
Dermocosmetics in Central and Eastern Europe an expanding niche market Monika Stefanczyk
Head Pharmaceutical Market Analyst, PMR Publications
In many Central and Eastern European countries such as Poland, governments have been adopting cost reduction measures in order to limit spending on drug reimbursement. Because of this, selling Rx drugs has became less profitable for pharmaceutical companies than selling OTC products1, including dermocosmetics, taking into account possible rates of growth and margins rather than total revenues. At the same time, consumers in the region have became better informed and educated with regard to care products of superior quality. As a result demand for dermocosmetics has been increasing steadily. The dermocosmetics business in the CEE countries still represents a new niche market, which is why it has significant growth potential. Polish dermocosmetics market expands at double figure growth rate Poland is an example of a country worthy of consideration in terms of its dermocosmetic market at present. In 2007, this market was worth approximately PLN 570m (€151m), having expanded by around 25% in comparison with 2006. This is double the size of its share as a proportion of the pharmacy market than that of Romania but is also not very substantial – some 2% of the overall pharmacy (retail) market. According to PMR estimates, in 2008 the market grew by more than 20% to approximately PLN 700m. Beyond dietary supplements, dermocosmetics2 represent one of the most rapidly developing health products sectors in Poland. The key drivers of market growth are: rising wages and greater interest in dermocosmetics among Polish consumers – as a consequence of greater social awareness and the assumption of western lifestyle patterns. Owing to the increasingly difficult situation on the pharmacy market caused by a growing number of pharmacies and ever stronger competition, pharmacies are more and more interested in diversifying their offerings through, for example, dermocosmetics, which yield higher sales margins than, for example, pharmaceuticals. Representatives of the management of companies active in the Polish dermocosmetics industry, who took part in the survey organised by PMR, also mentioned similar development factors. The vast majority of dermocosmetics sales in Poland are finalised at pharmacies. On the basis of answers pro-
vided by the companies surveyed by PMR, it is estimated that sales via non-pharmacy outlets, especially in cosmetic treatment rooms and SPA salons, represent close to 6% of the sector’s aggregate turnover. Online sales of dermocosmetics by both manufacturers and others make up the remaining 5%. Face-care cosmetics make up the largest category of the dermocosmetics market in Poland, mainly anti-ageing, cleansing and anti-acne preparations – which yield over half of the market value.
Romania: increasing investment in dermocosmetics In Romania, despite the fact that the OTC market is growing more slowly than its Rx counterpart3, interest in dermocosmetics on the part of pharmaceutical companies and pharmacy chains is growing. In 2008 companies such as Bayer and Actavis launched dermocosmetic products onto the market. In the case of the former this was the Dardia product line, and in the case of the latter – Decubal, a product which is expected to generate some €1m per annum on the Romanian market. In addition, Ivatherm, a local company which is one of the top five players on the Romanian dermocosmetics market, increased its portfolio from six products in 2005 to 24 in 2008. The dermocosmetics market has been the most rapidly growing area in terms of value. This applies to both cosmetics and OTC products in Romania. In 2007 the market grew by 30% to
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reports, projects, plans
more than €20m, and in 2008 was expected to grow by 20%, to €24m. Some local players predicted even more vigorous growth of 40%. Sales of dermocosmetics account at present for approximately 1% of the overall pharmaceutical retail market in Romania. In contrast, in other EU countries: e.g., France, Portugal and Greece, this percentage was close to 10% four years ago and we expect that it has increased further since that time. Many pharmacy chains owe a substantial proportion of their turnover to sales of dermocosmetics. For example Help Net expected to base some 19% of its €68m turnover in 2008 from dermocosmetic sales. Centrofarm expected to double the sales of dermocosmetics in 2008, from 15% of its total turnover in 2007. Other pharmacy chains are also interested in dermocosmetics: e.g. A&D Pharma, the owner of Sensiblu, has already launched its first dermocosmetics brand, Oxyance, manufactured in Italy, and expects sales growth of 40% in terms of value in the dermocosmetics arena in 2008. Some retailers, including Sensiblu, even have partnerships with producers in this field to develop their own dermocosmetics ranges. Others, such as Help Net, have been considering buying a player in the field. According to A&D pharma, the most sought after dermocosmetics in Romania are those for sensitive skin, cellulite, acne, hair loss and dandruff. The most important brands on the market in question are Avene, Vichy, Ivatherm, Roc, Galenica, Eucerin, Sebamed, Oxyance and Uriage.
Other CEE countries also attractive Poland and Romania are not exceptions in the CEE region. For example, in Ukraine, sales of dermocosmetics are also increasing very dynamically. Some companies still consider Eastern Europe to be an attractive location for expansion, despite the financial crisis. One of these is Nepentes, one of the leaders on the Polish dermocosmetics market, which will conclude a distribution agreement with a Russian partner on the marketing of its products in this country by the end of the first quarter. The company also dusted off plans to
start operations in Ukraine after putting the project on hold in mid-2008. Nepentes is banking on increased export sales to help it through the economic downturn. It may be also able to use the downturn to conclude bargain acquisitions in the latter country. The company is also pressing ahead with plans to open a subsidiary in Slovakia in the first half of 2009.
Effect of the global economic crisis On the one hand, we may assume that the financial crisis will carry the most serious consequences for pharmacy sales of non-reimbursed OTC products such as dermocosmetics, as these are primarily preparations which only assist or supplement treatment, thus, they will be the first not to be purchased by patients. Nevertheless, at present we have decided not to significantly downsize our development forecasts for the individual segments of the pharmacy market. We do not forecast a sales drop but only a slight decline in the fairly high pace of growth in sales of those products, as we expect demand for the products to continue to rise. In addition, the products from the abovementioned segment are from fairly high price shelves and their buyers are less sensitive to price fluctuations. The situation will certainly worsen in the case of typical medicaments and, indeed, the degree of dispensing prescriptions, mainly in the case of non-refunded or low-refunded drugs, can decrease considerably. More information on the dermocosmetics in Poland can be found in PMR Publications’ report, “Dermocosmetics market in Poland 2008. Development forecasts for 2008-2010”.
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OTC drugs and so-called non-drugs or parapharmaceuticals such as dermocosmetics or dietary supplements. Understood as pharmacy sales of all cosmetics in addition to sales of dermocosmetics via online shops and other non-pharmacy channels (SPA and beauty salons). For example, the OTC market grew by 9% y-o-y in terms of value, and that for Rx products – by 18.5% y-o-y in the 12 months between Q3 2008 and Q3 2007, according to Cegedim.
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INNOWACJE W OPAKOWANIACH
TARGI easyFairs® PACKAGING INNOVATIONS WARSZAWA 28-29 KWIETNIA 2009 R. Jedyne tego typu targi w Polsce!
www.easyfairs.com/piWarsaw Pierwsze w Polsce targi nowości w opakowanich, organizowane wg formatu europejskiej firmy wystawienniczej easyFairs® odbędą się 28 i 29 kwietnia w Hali EXPO XXI w Warszawie. Stawiamy na innowacyjność, toteż wśród wystawców znajdą się firmy oferujące niespotykane jeszcze na polskim rynku rozwiązania. Będzie można zobaczyć nowoczesne opakowania inteligentne czy ekologiczne. Nowości będą dotyczyły także materiałów, technologii, designu i logistyki. Wystawcami będą dostawcy opakowań szklanych, papierowych, plastikowych, metalowych; agencje kreatywne, studia projektowe, dostawcy technologii umożliwiających tworzenie innowacyjnych opakowań, dostawcy
rozwiązań z zakresu RFID, znakowania, kodowania i logistyki opakowań. Skorzystaj z okazji zwiększenia swojej sprzedaży i umocnienia pozycji na rynku. Zdobądź wiedzę o nowościach w branży podczas prezentacji learnShops. Wykorzystaj opakowanie swoich produktów, jako element brandingu firmy i sprzedawaj jeszcze więcej. Poznaj tańsze i bardziej przyjazne środowisku opakowania i zadbaj o oszczędności kosztów w Twojej firmie.
Zarejestruj swój udział już teraz!! www.easyfairs.com/piWarsaw
easyFairs® Poland Sp. z o.o. 31-564 Kraków, Al. Pokoju 82 tel.:+48 12 651 95 23, fax: +48 12 651 95 22 e-mail: angelika.matusik@easyfairs.com
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Gdyby wszystko było tak proste!
2009-02-23 16:43:20
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2009-02-23 16:43:23