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3 more information on Programme Board: Grzegorz Cessak President of the Offi ce for Registration of Medicinal Products, Medical Devices and Biocidal Products Andrzej Szarmański President of ISPE Poland, Quality Director at Polpharma SA Pharmaceuticals. Irena Rej President of the Polish Pharmaceuticals Chamber of Commerce Daniel Gralak Director of GMP Inspection Department in Main Pharmaceutical Inspectorate dr Jarosław Jan Hołyński Polish Pharmaceutical Association prof. dr hab. Zbigniew E. Fijałek director of the National Medicines Institute Marcin Kołakowski Vice President for Medicinal Products of the Offi ce for Registration of Medicinal Products, Medical Devices and Biocidal Products Marek Gnyś chief technologist Polfa Warszawa dr n. farm. Leszek Borkowski EU expert of the matters of medicines, former President of the Offi ce for Registration of Medicinal Products, Medical Devices and Biocidal Products Quarterly, published by FARMACOM Wodzisław Śląski ul. 26 Marca 31/11 Editor-in-chief Robert Miller phone mobile Subscription and distribution FARMACOM Wodzisław Śląski ul. 26 Marca 31/11 phone Issue price ŚPF 16 PLN Annual subscription price 55 PLN Payments may be made to the account: ING Bank Śląski O/Wodzisław Śląski Editors Teresa Kubsz-Miller, Joanna Korzonek, Maria Kubsz-Łatas Tomasz Butyński, phone: DTP: PROGRAFIKA Printing: Bimart Number of copies printed: Partner: 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.

4 contents Projcts utilising Lean tools The largest biotechnology centre in Poland in the Gdańsk Science and Technology Park Facing the pharmaceutical future 48 6 Prescription for success. With passion 10 Product Safety and Development Strategies for Medical Devices 12 An innovative cleaning system for cleanroom type rooms, based on microfi bre technology 14 Projects utilising Lean tools 18 The largest biotechnology centre in Poland in the Gdańsk Science and Technology Park 20 Is microcrystalline cellulose rightly classified as a disintegrant? 24 Utilization of mass spectrometry in modern pharmaceutical analysis 28 Ventilation system Economic success through proper exploitation 30 Manager beware of boring lecturers! 32 Professionall system for sensors management at the click of a mouse 34 Antidote to chaos 38 Project in Brazil 40 Stability analysis of mostly-submicron dispersions 44 A Question of Use? 1/2013 download *.pdf version:

5 Antidote to chaos 34 A Safety Concept for Drug Packaging 54 Manager beware of boring lecturers! Facing the pharmaceutical future 61 The devil is not so black A Safety Concept for Drug Packaging 62 Shipping safety with dry ice 58 Why 2D? 64 Direct to pharmacy. New solutions download *.pdf version: 1/2013

6 6 interview Robert Miller talks with Maciej Wieczorek, President of the Board of Celon Pharma S.A. Prescription for success With passion A new therapeutic alternative for Polish patients suffering from asthma and COPD In March 2013 you introduced SALMEX into reimbursement lists. Where did the decision to extend your product portfolio by a pulmonary product come from? The mission of Celon Pharma is introducing into the market specialised products which address the most important clinical challenges and facilitate patients access to new therapies. SALMEX is undoubtedly such a product, and the combination of fluticasone propionate and salmeterol contained in the product constitutes currently a standard treatment of asthma and COPD worldwide. Decisions regarding the development of a particular drug are always taken based on the analysis of international trends and treatment regimens in conjunction with the capability of legal and patent nature. Global markets clearly show a tendency to use complex products in treatment of respiratory diseases. The expiry of the patent for an inhaler (on ) made it possible for us to commence development of a first such product SALMEX. Furthermore, in the future Celon Pharma S.A. envisages further development of the product portfolio dedicated to patients with asthma and COPD. SALMEX is the first step to achieving that aim. What is innovative about your product? How does it differ from the reference product of the competition? SALMEX is a generic product, a first equivalent of the reference drug SERETIDE Dysk in the world. All intellectual property rights of the reference drug expired in March 2011 and therefore the actions taken by Celon Pharma S.A. with the aim of introducing SALMEX into the market are carried out in compliance with the law and the highest ethical standards. The innovativeness of the drug lies in the technical production issues, the process taking place with the availability and use of newer technologies than in was the case during the development of SERETIDE Dysk several years ago. Among the innovative technologies used we may mention, among others: a precise blister filling process conditioning a very high dosing repeatability, allowing the patient to absorb the correct amount of drug at each application. In case of SALMEX it is also the case of a precise engineering technology, which hitherto has not been used on a national scale and probably also worldwide. The manufacturing process itself, due to the availability and use of new technologies should undoubtedly be considered innovative. 1/2013 download *.pdf version:

7 Maciej Wieczorek President of the Board of Celon Pharma S.A., doctor of medical science. He has many years of experience in the pharmaceutical industry. He held senior positions in pharmaceutical companies, where he was responsible, among other things, for the product strategy creation, as well as research and development of new products. Maciej Wieczorek is the author of several patents used in the pharmaceutical industry, as well as successful implementations of drugs. Furthermore he also performs managerial functions in other entities in the bio-pharmaceutical industry, such as Mabion SA, a Polish public company, developing the technology for the production of monoclonal antibodies. photo: Celon Pharma S.A. What studies have been conducted in order to confirm the efficacy of the product? Efficacy and safety of SALMEX has been confirmed by a very precise study of therapeutic equivalence on the basis of in vitro deposition profiles, with the use of the so-called artificial lung, a measurement technology. This was made possible by meeting criteria in compliance with the European guideline defining clinical documentation requirements for inhalation products containing known pharmaceutical substances (CPMP/EWP/4151/00 Rev.1 of 22 January 2009). We had decided to use deposition models in the form of the so-called artificial lung as in the case of inhalation drugs it is a far more precise test, characterised by a far more sensitive measurement, eliminating a whole range of variable and individual factors. It allows for a precise measurement of the available drug dose in different parts of the lungs. One should note the dose size of the drug, which is measured in micrograms of the particular active substances. How did the company obtain funds for the financing of the project? Did Celon Pharma S.A. afford to finance the project in full? We are a fully integrated pharmaceutical company which for many years has been successfully acquiring funds, both for research and for innovative manufacturing technologies from EU support programs. In addition, implementation of this project was made possible thanks to a unique, in the scale of our country, partnership of two companies of the pharmaceutical sector: Celon Pharma S.A. and Polfarmex S.A from Kutno. Are you planning to introduce further products? We invest in new research projects and simultaneously are searching for possibilities to develop generic specialist products. At the moment we are focusing primarily on the production of prescription drugs, in response to the unmet clinical needs of patients and these products can be found in our portfolio. We manufacture download *.pdf version: 1/2013

8 8 interview Celon Pharma S.A. drugs for patients with schizophrenia, hypertension, central nervous system diseases, breast cancer, as well as drugs for treatment of Human Immunodeficiency Virus (HIV). This year we are also planning to introduce a generic targeted therapy used in patients with leukaemia. This will be a yet another specialist product in the portfolio of Celon Pharma. What other plans does the company have regarding the year 2013? We continuously invest in new research projects and are searching for possibilities to develop new specialist products. Currently we finalised an investment worth over 25 mln PLN which allowed for successful introduction of SALMEX into the market. We are planning to introduce a targeted oncology drug. It is our intention to continue obtaining EU funds which allow us to faster execute the company s current business strategy. We will continue to participate in the debate, the aim of which is to create a favourable legal environment which will enable Polish pharmaceutical companies to invest in research and development and to introduce innovative therapies for patients. Polish pharmaceutical industry on the way to innovativeness From the point of view of a practitioner as well as owner and manager of a pharmaceutical company, please tell us: What are, to your mind, factors deciding about success in this industry? In order to achieve success in the pharmaceutical industry, which is one of the most regulated industries, certainly what is needed is interdisciplinary expertise, which is a combination of science and business, marketing intuition, as well as legal and financial issues. is an integrated pharmaceutical company conducting advanced research and producing modern drugs. It was founded in 2002 by a man with a vision, passion, interdisciplinary knowledge and experience in the industry Maciej Wieczorek. The primary goal of Celon Pharma is to produce specialised prescription drugs which improve the quality of life of patients and constitute an answer to the unmet clinical needs of patients. Celon Pharma S.A. has two fully equipped laboratories dedicated to research and development (R & D) of medicinal products, both generic and innovative ones. The two manufacturing plants of Celon Pharma S.A have appropriate Good Manufacturing Practice (GMP) permits. The headquarters and the laboratory parks are located within 30 km from the centre of Warsaw. The company currently employs 200 persons. The company employs 50 scientists in the fi eld of research and development, half of whom has, or is the process of obtaining, PhDs. An important competence in the case of this industry is the ability to assess the clinical value of products, anticipate changes on the market or behaviour of a selected therapeutic group at a given time. There is no single, proven and ready recipe for success. What is important is the ability to adapt to market conditions, but also to make use of the opportunities it creates and the possibilities it offers, such as additional funding for research projects. People are also a factor determining the possible success. Investing in employees development, establishing an appropriate system of values and a sense that the team is a part of something important significantly enhances the growth of their involvement and effectiveness in the workplace. Polish innovative drugs? Is it still possible? I am convinced that in the long run it is the only chance for development of Polish companies which currently manufacture mainly generic drugs. The search for innovation is a process determined by a number of variables - from successful co-operation with the Polish scientific environment, through the availability of adequate infrastructure and favourable, stable legal environment. That is how we understand innovativeness in Celon Pharma. Therefore our aim is the successful implementation of projects offering a chance for breakthrough drugs constituting an effective tool to fight diseases of civilization, and to increase availability of modern therapies to Polish patients. That is why since the year 2006 he have been significantly investing in the Innovative Drugs Research and Development Division. We employ 50 scientists, half of whom has PhDs, and many carry out research projects under the supervision of practitioners in Celon Pharma laboratories. Currently we are carrying out 9 innovative products, starting from the concept, through organic synthesis, in vitro studies, to preclinical tests on animals. The result of these works are currently three patent applications: in the field of oncology and central nervous system diseases. Do different types of clusters and associations contribute to increasing innovativeness in the pharmaceutical industry? The basic tool for the commercialization of scientific research results should be made small and medium enterprises. It is such organizations which are characterized by greatest cost efficiency with regard to innovation funds. Through various organisational forms, such as associations, they are able to promote their achievements and the chance for a better articulation of interests in dealings with representatives of the Polish science environment and government representatives. This is extremely important, e.g. from the point of view of effective fundraising for research activities. An example of such an institution is an association established in March 2013 in Łódz - Polish Biotech Association, of which one of the founding members is Celon Pharma. The statutory objectives, apart from presenting common interests of its members, include: influencing changes in legislation in the scope of creating favourable conditions for the running and developing small and medium-sized innovative companies in the biotechnology and life-science sector, coordinating various forms of co-operation of members of the association, including the creation of clusters as well as co-operating with universities and promoting Polish biotechnology and biopharmacy abroad. 1/2013 download *.pdf version:

9 New Pharma Pharma Technologies. Technologies. Future inspired. inspired. April 17-19, 2013 April Bologna, Italy 17-19, 2 BolognaFiere BolognaFiere Piazza Costituzione Piazza entrance Costituzione entrance opening opening times: am times: 5.30 pm am 5.30 pm Pre-register nowpre-register now Join our Group on Organizing Secratariat: Secratariat: Organized by: In conjunction with: Organized Supported by: by: With the patronage of: Ipack-Ima spa - Corso spa Sempione, - Corso 4 Sempione, Milano Milano - Italy - Italy tel tel fax fax In conjun

10 10 Product Safety and Development Strategies for Medical Devices Bill Treddenick Life Sciences Director at Lorien Engineering is a director of Lorien Engineering, and also of Coterie BioMed. He sits on the Industrial Board of the University of Leeds Biopharmaceutical Research Facility. Bill has been involved in pharmaceutical and life sciences manufacturing facility and process design for 20 years, and currently leads this activity for Lorien Engineering Solutions. Lorien Engineering are presently engaged on a range of pharmaceutical projects, as well as working on the commercial development of an implantable medical device with partners Neotherix and Smith & Nephew. Bill is leading this work, which is the technical basis of this article. The product development and manufacturing of Medical Devices poses some interesting problems, and for implantable devices even more so. As with any medical product, establishing a solid plan as to how the product will be tested and manufactured is the key. The commercialization process for all medical products is long and expensive. Reversals, omissions or big changes to the plan carries large commercial risks, and can effectively kill the product commercialization process. photo: fotolia.pl As with any project, the planning phase is vital so as to ensure a successful outcome. The second vital ingredient is knowledge; and this knowledge needs to come from a number of different sources: scientific, regulatory, product safety, programme management, technical/ engineering, commercial and clinical. This is a big team, and expensive of course. The most important first step on the journey is to define the Regulatory Pathway ; in which we should consider the territory into which the product will be launched in; the terms of reference that apply, and classification of the device; the approval route; longer term commercialization strategy (any other territories being considered, and when). It goes without saying, that if we proceed without this step being completed and agreed, the following work (which, depending on the nature of the device may last 1 to 4 years) can be put at risk. The formation of the Regulatory Pathway can be branched, but should not be iterative. An example of branching is that; if there is opportunity for the product development to meet a further clinical need or application, then the pathway would need to alter (by virtue of any new properties of the device such as being loaded with an active compound or cells). Branching can be planned to an extent, and costs allowed. This type of study may rule out such deviation from the central pathway, due to time and cost. On the other hand, iteration tends to be unplanned and the costs are not properly assessed. Unfortunately, scientific developments do tend to be iterative, which could explain why so many commercialization programmes fail. An example of the outputs from the Regulatory Pathway study would be to define how the medical device is regulated, validated and manufactured. Whilst ISO13485 (Medical devices Quality management system requirements for regulatory purposes) is an appropriate Quality Management System, whether the device is medically active or not will direct the developer (in Europe) to either using the Medical Device Directive 93/42/ EEC (MDD), or to apply EudraLex Volume 4 Annex 1 / Annex 2 for the Manufacture of Medicinal Products. The two pathways vary in approach considerably, and an early direction is important. 1/2013 download *.pdf version:

11 11 photo: sxc.hu The Risk Control Strategy is itself a pathway document, specifying and then recording (via the Risk Control Report) the steps taken to ensure that the device will not cause harm to the patient, the clinicians, or people exposed to the device during its manufacture. The standard followed is Medical devices - Application of risk management to medical devices EN ISO 14971:2009. Some of the key elements of a typical risk control strategy include: Synopsis of the product development so far; product classification, and approval / conformity assessment method Product safety testing method, standards to be employed and reporting (for example EN ISO various parts) Manufacturing process product safety risk assessment (for example an FMEA process, EN ISO 60812:2006) Personnel safety risk assessment (during the product s manufacture and clinical application). This should also include Environmental risks. The qualification process for the manufacturing system Product identification standards The Quality Management System under which the product is to be manufactured. The nature and contents of the risk control report. The risk control strategy standard ISO 14971:2009 will provide guidance on the following topics that also needs to be address in the strategy document, and risk control report: Risk/benefit analysis Risks arising from risk control measures Evaluation of overall residual risk acceptability The control of risk within the development pathway for a medical device is only one, but an essential, part of the development process. A key learning from medical device development is that there needs to be an overall management structure, with a number of parallel paths in operation at all times. At all stages the eventual compliance assessment must be kept in mind. Other important aspects to be considered at this time are: Assessment of the product s compliance with the MDD (through an MDD Essential Requirements Checklist) Procurement strategy for starting materials / parts and a GMP supply chain strategy Pre-clinical investigation, planning and execution (with engagement of pre- -clinical investigation partners, laboratory services, as needed) Clinical investigation, planning and execution (with engagement of a clinical advisory board, clinical partners, as needed) Patent search and patent application Health economics assessment Remuneration strategy / commercialization development Manufacturing equipment purchase and preparation (including qualification) Manufacturing for safety testing, and for pre-clinical and clinical investigations Design dossier compilation Working with a Notified Body towards CE Certification (as appropriate per the category of MD) This is a long list of work. As many of the activities are inter-dependant, coordination and effective communication is just as important as any individual task. Another consideration in planning the work is that much of the participation on these activities will be from specialists who will be working on a number of parallel programmes / projects. For some, such as the clinicians involved, the product commercialization programme will be a minor part of their normal working routine. The role of the Programme Manager should therefore not be underestimated, or under-resourced. Lorien Engineering Solutions is an engineering design and project management organisation, and is part of the Lorien Limited group of companies. With operations in the UK and Wrocław Poland, the company has a staff of more than 100 specialists who design and deliver manufacturing projects in the pharmaceutical, brewing, drinks, food and life sciences industries. Other areas of specialism are sustainable energy schemes, waste to wealth, manufacturing performance improvement, and health & safety consultancy. download *.pdf version: 1/2013

12 12 An innovative cleaning system for cleanroom type rooms, based on microfibre technology Łukasz Neumann Product Manager Piotr Żabowski-Żychowicz Sales Manager Central Europe We all agree that professional cleaning should be left to specialists, the same as for the management of operations in controlled environment. And even if the cleaning of controlled zones is critical for the functioning of cleanroom type rooms, reality proves that in many cases it is not the most cost-effective element of an operation. On the whole, procedures applicable to the cleaning of cleanroom type rooms are described in detail, including monitoring methods, and are subject to strictstandards. Thus, it is obvious that conventional cleaning materials will not work well here. On the one hand, the materials and products used should not increase contamination in cleanroom type rooms, and on the other hand they have to ensure the removal of any molecules and microbiological impurities and prevent bacteria proliferation after cleaning. Cleaning costs generated mainly by employees and connected with several cleaning process stages may constitute a considerable portion of operating costs for cleanroom type rooms. Finding, approval and the introduction of an appropriate and efficient cleaning system for rooms of this type consumes a lot of operating resources. In most cases the easiest way is to use disposable mops and cloths. A few years ago, two experts in the cleaning materials sector: Micronclean Holland as a supplier of textile products and Vileda Professional as a cleaning materials specialist, brought together their knowledge and experience in order to develop a reusable cleaning system for clients, who have cleanroom type rooms. The main goal motivating both companies was to find an ergonomic and economical high-quality solution. As a result, they managed to create MicronSwep. An ideal supplement for MicronSwep system was to combine it with an innovative mop service concept developed by a leading European service supplier for work clothes, entrance mats and sanitary equipment Berendsen Textile Service Company. The mop service offered for Cleanroom zones includes a comprehensive logistic solution, which covers the purchase of mops for the client s purposes, the delivery of clean ones and the removal of dirty ones, and a laundering service, which also includes sterilising, depending on the client s requirements. As a result, mops used in a controlled zone do not generate any extra contamination. Mops are laundered in specialised Cleanroom laundries, dedicated for industrial washing, which considerably reduces the risk of contamination. Modern Cleanroom laundries e.g. Berendsen laundry in Szamotuły near Poznan, are provided with technology and equipment that allows the restrictive standards, in compliance with ISO 5 class to be satisfied. How does MicronSwep system operate? The cleaning system is based on the following principle: dust removal with a mop, cleaning and drying in a 1-stage procedure. A mop has been engineered for this purpose, which consists of 100% polyester microfibres. This mop may be decontaminated or sterilised many times (either using radiation, or in autoclave). The use of microfibres allows not only the removal of molecules from the surface, but also trapping them in the mop. At the same time, the surface friction of the mop has been reduced to a minimum due to ergonomics, in no way affecting surface cleaning efficiency. photo: Berendsen 1/2013 download *.pdf version:

13 13 photo: Berendsen Finding an adequate solution Equipment selection Consulting regarding detergent selection and water proportioning Training in cleaning techniques Check and support Let s analyse consultancy process on the example of the MicronSwep system photo: Berendsen Before entering a cleanroom type room, an operator impregnates all the mops needed to clean a given area (up to 25m2 per 1 mop) using cleaning liquid. Thus, there is no need to carry buckets inside with cleaning liquid and/ or water for mop washing and wringing during cleaning. Mops are put onto a handle and are ready for surface cleaning. As soon as the process of cleaning with photo: Berendsen one mop is finished, simply put it into the bag, in which it will be taken to the decontamination plant. In this way, the risk of contamination transfer is eliminated. Due to the lightweight housing and low friction coefficient for mops, this system may be easily used for floor cleaning and also for walls and ceilings. Completed tests have confirmed that the ergonomics of this system constitutes one of its main advantages for operators. The use of a 1-stage system on the one hand reduces labour expenditure and the consumption of cleaning agents, and on the other hand contributes to the reduction of costs generated by cleaning operations. Professional mop decontamination guarantees that the operator receives a tool, which is ready to use and, depending on requirements, is either aseptic or sterile every time. Tests carried out by clients and by an independent laboratory have confirmed the effectiveness of the cleaning of the mop and their decontamination during laundering process, as regards the removal of impurities and the CFU number (colony-forming units). Individual marking using a barcode and microchip allows the mop to be tracked throughout its service life. Thus, mop laundering logistics is very much like the logistics employed in the case of clothes washing. In order to guarantee the efficiency of any cleaning system, independently of how simple it is in use, it is necessary to provide suitable personnel training on its correct usage. Therefore, a training program has been developed, which supplements the system, ensuring that all its advantages are used to the maximum possible extent. The increasing popularity of the MicronSwep system shows that it is possible to create an economical and ergonomic high-quality logistic solution in the field of cleaning surfaces in cleanroom type rooms, which will guarantee measurable benefits to its user. download *.pdf version: 1/2013

14 14 Projects utilising Lean tools Practical applications we like them best. Today s article will deal with the practical application of LeanSigma methodology. As an example, I have chosen a project which might have significance for all companies and trades, including the pharmaceutical industry. The packaging process is the last step in any production process. A greater number of markets, along with the orders they generate, are causing the processes in this area to become increasingly complex. The management of such processes is becoming more and more complicated; thus, successful cost and quality control presents a constant challenge. Andrzej Wróblewski Due to its complexity, custom packaging has the greatest potential for process improvement and optimisation. The Lean approach, together with the tools it proposes, works very well in such an environment, providing solutions to many problems. In accordance with information presented in the previous article on project methodology, a sample project will be presented in compliance with the DMAIC approach. Changeover optimisation on the custom packaging line Introduction As a result of implementing two new preparations into the blister line, it was necessary to increase line efficiency. Several products were packaged on the same line, each of them exported to several different markets over a dozen presentations in total, characterised by specific packaging materials. Because of the large diversity and small order volumes, the main product on this lines were changeovers. Initial analyses showed that changeovers took up ca. 50% of the available time and that the estimated mean reduction in changeover time should reach ca. 40%. SMED (Single Minute Exchange of Die) is a methodology used to optimise (i.e. shorten) changeover times. The main object of SMED is identifying activities which can be carried out before or after the setup, while the machine is running. Typical external operations which should be performed separately from the changeover itself are all sorts of preparatory activities, as well as material accounting and filling out documents. SMED also includes eliminating unnecessary steps and optimising the remaining ones. DEFINE The first step of the project consisted of defining responsibilities, goals and implementation times. Responsibilities: The foreman responsible for the line s operation was appointed as the project manager. The team consisted of two operators (one from each zone), a mechanic, a person responsible for supplying materials to the line, a planner and a worker possessing specialist knowledge of the techniques and tools for process optimisation. Time: 1 month, together with implementation Goal: Reducing changeover time by at least 40% MEASURE or COLLECT DATA The SMED technique was utilised in order to optimise the changeover procedure. The following data were collected: the number, times and kinds of changeovers. The data were collected on the basis of production documentation from the last quarter. order quantities and production line workload. The preparations exhibited no seasonal differences; thus, only 6 months were analysed the 3 months before implementing the project and the 3 months after its implementation. changeover stages. Several changeovers were subjected to observation. Various teams and various changeover types were monitored. Before observation commenced, the workers were informed about its goal. The project team prepared special sheets and standardised the designations used to note down data from the observation. 1/2013 download *.pdf version:

15 15 Andrzej Wróblewski Value Added and Non-Value Added Activities Born in Poznań, graduate of the Poznań University of Technology, Faculty of Chemical Technology, working in the pharmaceutical industry since 1994, initially as a Production Manager in Polfa Poznań, Surgical Suture Dept., subsequently in the Validation Dept. Following corporate restructuring, Andrzej Wróblewski now works for GlaxoSmithKline. Since LeanSigma implementation in 2001, he has been preoccupied with the streamlining of business processes. We can classify all the activities which make up our processes depending on their value, i.e. whether they add value to our product. Frequently, processing is considered a criterion for judging value. Evaluation can seem difficult until the moment when we, as clients, have to answer the question: what are we ready to pay for or not? If a suit s high price is justified by the high quality of the fabric, we will usually find such a justification acceptable, but an attempt to explain the price by transport and storage costs may meet with our resistance. The goal of distinguishing between VA and NVA activities is not simply their division into two groups. Various strategies of action are adopted depending on the classification. ANALYSE THE DATA The analysis was divided among two teams. The first team analysed the data regarding the number, times and types of changeovers which took place over 6 months. The results showed that the changeover time should be reduced by at least 35%. Around 80% of changeovers required neither a change of adjustments nor of format parts. Only the content of the packaging material changed. Changeovers requiring a change of adjustments or of format parts took up 50% of the total changeover time. It became clear that if the set goals are to be met, it is necessary to optimise both types of changeovers. The second team concentrated on the analysis of the conducted observations. They created logic, temporal and physical maps of the observed processes. On the basis of the process s logic map, they analysed the significance of each changeover step. The analysis was performed on the basis of the methodology of Value Added (VA) photo: chromastock and Non-Value Added (NVA) activities. It became possible to identify steps which can be performed while the machine is still running, i.e. before or after the changeover. On the basis of the results from these analyses, the following solutions were proposed: Elimination of ca. 20% of the activities, especially redundant ones, as well as eliminating unnecessary documentation and micro- -activities caused by a lack of precise planning of the changeover. Shifting ca. 30% of the activities outside the time of the changeover as such. Activities such as preparing the packaging materials, format parts and documentation were shifted to before the changeover. Cleaning of format parts, as well as the final material accounting and batch record were shifted to after the changeover. All activities were modified. The optimal sequence of steps was determined, the workload of operators and mechanics was equalised and all steps were standardised in order to create the optimal changeover procedure. A different approach to cleaning the line was adopted. Small technical modifications which speeded up the change of parts were also proposed. The entire line area was subjected to the 5S process. Unnecessary objects were eliminated from the area, and the remainder were arranged in an optimal fashion. download *.pdf version: 1/2013

16 16 5S a methodology of organising the workplace which guarantees that all necessary materials, i.e. semi-finished products, tools, parts, packaging, documents, etc stay within easy reach. This methodology was invented in Japan in the XX century. Its name comes from the first letters of the Japanese words which denote the consecutive steps of the process. 1S 2S 3S 4S 5S Seiri = Sorting remove all unnecessary objects Seiton = Storage set an optimal location for the remainder Seiso = Serviceability check the serviceability, repair or clean if necessary Seiketsu = Standardisation create standards for 1S/2S/3S Shitsuke = Self-discipline maintain and improve the system information regarding the achieved results. Regular meetings with the area management were an additional source of motivation for the workers. Ultimately, the changeover time was reduced by 38%. Thus, the initial goal of a 40% reduction was not achieved. One must remember, however, that the minimal necessary reduction determined by analyses amounted to 35%. It was conditionally decided to implement new preparations into the line. Analyses determined two further areas where the changeover time could be reduced. According to estimates, Optimisation of the Changeover Schedule and Standardisation of Packaging Materials should result in a reduction by another 15-20%. The last formal step in the project was its summarisation, or AAR (After Action Review). This review was carried out during the last meeting of the project team, ca. 2 months after the project s implementation. The following conclusions were drawn: the project significantly and sufficiently improved the efficiency of the production line the changeover optimisation should be carried out for the remaining lines as well further efforts should be dedicated to improving the mechanical training of machine operators during the subsequent implementations of the project, more time should be devoted to communication. All these solutions were evaluated with an emphasis on the procedure of monitoring the changes. The area management accepted all the proposed solutions. IMPROVE or IMPLEMENT After the solutions had been chosen, 2 weeks remained in which to implement them. The team prepared new procedures. Documentation was prepared with the aim of making it easy to understand. The same document served as training material and as the document confirming that all the required steps had been carried out. All the line operators were instructed in the new procedures. Small technical modifications of the line were also carried out. The change required a better organisation of work, especially an improvement in the communication between the line operators, mechanics, line suppliers and the planner and supervisors. A display board, accessible to all, showing the work schedule was set up and a simple chart for plotting the current results was placed on it. This chart was meant to show whether the set goals are being met. It made it possible to quickly pinpoint the most problematic areas where intervention was needed. The display boards were introduced as the new standard of work. The change was implemented at the beginning of the week. The first changeovers took longer to complete than before the implementation. After performing several changeovers, all the teams acquired skill and carried out the procedure in the former time with no problems. After another 2 weeks, the changeover times became closer to the goals which had been set. CONTROL Maintaining results is one of the more difficult tasks in project management. Their maintenance was to be guaranteed by a system of visualising results and by the involvement of the company s management. The system was created both for persons working in the area and for those working outside it. It provided cumulative Changeover shortening direct and indirect benefits. The direct benefits of changeover shortening include a more optimal use of equipment and of human resources. This can easily be translated into financial savings. However, many companies place a greater value on the increase in flexibility. Increased flexibility means easier and better planning, which makes it possible to maintain product flow, reduce stores and shorten the total production time. All these advantages elevate the standard of customer service, which represents a greater value in the long run than swift, direct financial gains. Summary The changes introduced during projects of this kind provide a large number of relatively minor improvements. Their strength lies in their combined effect, additionally fortified by the synergy phenomenon. In this case, the company was spared the necessity of investing in the purchase and launch of a new production line. The costs associated with the project s implementation were recovered in several weeks. The field of custom packaging is characterised by a high rate of change. Optimal solutions developed yesterday are today s standard, and tomorrow they will only constitute a breeding ground for new, better ideas. In the next issue, another project example will be presented this time from the field of semi-finished products: a handful of applications of Six Sigma statistical tools in batch processes. 1/2013 download *.pdf version:

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18 18 The largest biotechnology centre in Poland in the Gdańsk Science and Technology Park Polpharma SA has completed the first stage of construction of Polpharma Biologics, a state-of-the-art research and development centre in the Gdańsk Science and Technology Park. In the new centre, the company will work on biotech, biosimilar and biobetter drugs with a view to give more patients suffering from immune system diseases, nervous system diseases and cancer access to effective therapies. The newly opened part of the centre, with an area of 600 m 2, houses research laboratories where protein production processes can be developed and optimised, from the initial concept through the laboratory phase to pilot plant production. Analytical laboratories have also been established; they make it possible, among other things, to control product quality during the production process and to evaluate the quality of the final form of the drug. The centre is equipped with the latest technology, indispensable for effective work with complex high molecular weight proteins, such as monoclonal antibodies. The entire investment, when completed, will have a surface area of 2300 m 2 and will include installations for pilot plant production in the cgmp (current Good Manufacturing Practice) system. The centre is the largest facility of its kind in Poland. 12 specialists currently work here, with the target number of employees being 50 and possibly more. It offers the best young scientists a unique learning opportunity, giving them a chance to work hand in hand with experienced experts from the biotech industry. The team is led by Piotr Lassota, Ph.D., who pursued his scientific career in the United States, mainly in the field of oncology. He eventually decided to return to Poland in order to create Polpharma s biotech centre, unique on the national level. The company also emphasises cooperation with academic centres, both in the field of scientific activity (Medical University of Gdańsk) and in training future managers and experts for the biotechnology business sector in Poland (funding a new postgraduate course, Business in Biotechnology, at the Jagiellonian University). Polpharma is the largest Polish pharmaceutical company. Its headquarters are located in Starogard Gdański. Thanks to its activity on international markets, the Polpharma Group is among the 20 largest generic pharmaceutical companies in the world, with a turnover of 1 billion dollars per year. The company manufactures generic drugs based on small molecules, produced 1/2013 download *.pdf version:

19 19 Piotr Zień, Ph. D. Leader of scientific projects and manager of a project whose subject is the establishment of R&D, analytical and semi-technical production laboratories under the GMP Polpharma Biologics standard Piotr Lassota, Ph. D. Performs the functions of a member of the Board of Directors of Polphar ma Biuro Handlowe sp. z o.o., R&D Director of the Polpharma Biologics Business Unit at Zakłady Farmaceutyczne Polpharma SA and a member of the Board of the Polpharma Scientific Foundation. by chemical synthesis. Adding biotech (large molecule) drugs to Polpharma s portfolio will enable the company to develop further in accordance with the latest trends in modern medical sciences and pharmaceutical technologies. Initially, Polpharma intends to concentrate on developing biosimilar monoclonal antibodies in two therapeutic fields rheumatoid arthritis and oncology. Subsequently, the company will undertake work on medications for immunological disorders. In recent years, the dominant business model in the pharmaceutical industry has been changing. Up till now, the process of developing small molecule generic drugs took roughly 2 years to complete. Introducing a new product costs around 3-4 million zloty (PLN), with a low risk of failure. Currently, a new era of generics is dawning the era of biosimilar drugs, or biosimilars. For the last dozen years or so, the global market for biomolecular drugs has exhibited dynamic and constant growth. It is estimated that in this decade the value of this market will equal the value of the market for small molecule drugs, and then swiftly exceed it. Several years from now, 8 out of 10 of the largest molecules will be biotech products. However, developing them is much more difficult and costly. For biosimilar drugs the process takes, on average, 8 years and costs million zloty. The development of biosimilar molecules is less complicated, faster and cheaper than the development of innovative biotech drugs because the therapeutic target of biosimilars has already been confirmed in clinical trials by the original manufacturer. Thanks to the lower price of biosimilars, both the aging societies in developed countries and millions of patients in developing countries can gain access to cheaper and effective therapies. Taking these aspects into account, Polpharma has chosen biosimilar drugs as the first step in the development and production of biotech drugs, intending to gradually move on to more ambitious projects. download *.pdf version: 1/2013

20 20 Is microcrystalline cellulose rightly classified as a disintegrant? Jerzy Lasota, Farmaserwis According to numerous articles and handbooks, microcrystalline cellulose is a disintegrant, although it is known mostly as an excellent tablet binder. Could microcrystalline cellulose combine such opposite functions? Let us see how things are from the inside, i.e. from the loose materials mechanics lab. Let s start by recapitulating background information on the product by citing a fragment of a publication [1]. Cellulose (fibre) is a natural polymer (biopolymer), a polysaccharide consisting of the molecules of D-glucose, connected by β-1,4-glycoside bonds. Thanks to its β-configuration, cellulose may form very long, straight chains. Powdered cellulose and its microcrystalline varieties are made of the highest grade cellulose obtained from deciduous trees, produced in Scandinavia (Finland, Sweden) and in the U.S. Significant differences in applications of both types of cellulose are due to the differences in the technological processes [...]. Introduction Loose materials subjected to pressure forces may present different characteristics depending, e.g. on the magnitude of these forces and their mode of action, e.g. on their time profile. When attempting to convert powder into a monolith, appropriate cohesion is obviously the most desirable property. As drugs, tablets should meet certain special requirements, some of them conflicting with each other, such as high hardness combined with easy disintegration in water. A wide range of excipients are commercially available to pharmacists so as to facilitate conferring specific properties to the tablets. These excipients are classified according to their pharmaceutical functions, particularly to their functions in tablets. Quite frequently, the same excipient may be used for different purposes. Such is also the case of microcrystalline cellulose MCC), to which is attributed not only tablet-binding, but also disintegrant properties. These two properties are opposite, which makes the issue quite interesting. Let us examine when MCC acts as a binder and when it acts as a disintegrant, as intuition tells us it would be hard for it to act as both in the same conditions, although such situations occur occasionally. What conditions are these? The first is the quantity of MCC per tablet; the other is the magnitude of pressure forces. This, however, is not everything. One should also ask whether the properties we want to study would be present in all formulations. This makes the task somewhat more complex. However, it must be done, since every descriptive characteristics of the product usually lacks the most important element of the tableting process, i.e. the pressure force. A surprising trend, i.e. to generalize certain properties of excipients used in tablets may be observed, including unreflective extension of these properties to all cases, when in fact these properties are manifested only under specific conditions. This seems to be the case for MCC, and hence the idea for this study. Tablets were produced by continuous methods using substance-within-substance mixtures covering the entire range of contents. Also the pressure forces applied covered the entire range, from very weak forces, barely allowing tablets not to crumble between the fingers, to maximum forces obtainable without damaging tools. The use of this method was supported by earlier studies performed according to disintegrant-related standards [2], in which no disintegrant properties were observed for MCC when used at concentrations lower than 10%. This, however, has been studied in only one formulation: with aspirin. An assumption was made that if the results of any of the subsequent tests suggested that it would be purposeful to locally use any other concentration, it would be used in the next attempt. 1/2013 download *.pdf version:

21 Tests The objective of the tests was to study the behaviour of microcrystalline cellulose (MCC) in various conditions, with the changes pertaining to: the type of the base substance simulating the tableting formulation: not capable of spontaneous disintegration in water (aspirin), not capable of spontaneous disintegration, but moderately absorbing water (calcium phosphate), normally undergoing disintegration without any help from other substances (mannitol). MCC quantity per tablet from 0 to 100% in 10% increments. Pressure forces applied in the tableting process: 6 separate values in the range of 2-40kN. The above pressure forces were the maximum values of the respective tools, which means that the experiment was conducted in the full range of acceptable workloads, providing a full overview of the possible events as planned in the experiment. Eleven full tableting test runs were made for each of the 3 substances. A run consisted of two sets of 6 tablets, the first set subjected to crumbling tests and the others subjected to the disintegration time measurement test. The disintegration time was recorded at a resolution of 15 seconds (0.25 minute), although full-minute values only are listed in tables for less space and better clarity. Matrix push-out force was measured for each tablet. The second run was performed in a reverse order of pressure forces so as to make use of the highly sensitive method of tool seizure detection. For details of this and other methods used therein please see the Vademecum of Tableting, part I [4]. Although the study was prioritized on tablet disintegration time, other measurements were also made and are summarized and discussed below. Information on the use of magnesium stearate (MgSt), used in minimum quantities, pre-determined individually for each product, were obtained from the aforementioned reference. Precise observations of tablet disintegration were conducted until the time point of 0.5 h. Later on, a value of 55 or 99 was entered in the table, depending on the tablet s prognosis. The first value indicated probable disintegration over several hours, while the other suggested that no disintegration should be expected within 24 hours, or at all. Simultaneous to these measurements, information on three coefficients was also collected, namely tabletability, weight, and compactability. Although not presented here, the profiles of the respective functions were used to assess the correctness of tool operation and estimation of errors. Tabletability Tabletability, defined as measurable capability of a substance to be pressed into a tablet, is a ratio of cohesion (hardness) to adhesion (push-out) integrated over the entire range of acceptable pressures. In all cases, tabletability rose as MCC was added. A 4th order polynomial was the most appropriate for the approximation of this function. The increase in tabletability is associated with the characteristics of MCC, i.e. its very high cohesion and its apparent capability to bind (i.e. attract) other substances, allowing for easier push-out out of the matrix. Plots 34 through 36 illustrate the increasingly distinct reductions in the push-out force. MCC has no appreciable glidant properties, and it sometimes itself requires the addition of a lubricant (which was certainly required here, see below) but, under increasing pressures, it affords tablets an ever-lower, and in come cases virtually no, push-out force. Besides the high hardness of tablets, this confirms the unusual cohesion of this interesting substance. Tablet weights Tablet weights were always related to tablet thickness and separately calibrated in each of 33 runs due to great differences in density between MCC and the remaining substances. Being the lightest of the substances, MCC caused tablet masses to be reduced in each run along with the increase in MCC content; the process was precisely linear. A reminder: in these tests, every tablet pressed using a force of 10kN was 5mm thick, regardless of any differences in product density. All the remaining tablets, download *.pdf version: 1/2013

22 22 pressed with forces in the range of 2-40kN, had the same weight, as per process calibration, while the tablet thickness was a result of the pressure applied. This standard is independent of any differences in the density of tested products. Compactability Compactability is the percentage reduction in sample height (tablet thickness) after pressing with a particular force. The thickness of the tablet pressed under the force of 2kN is a convenient reference value. Compactability is an important parameter characterizing product involvement in the process of forming a monolith out of the powder. Since few substances can be compared to microcellulose in this respect, compactability increased with MCC content in mixtures with all the tested substances. The changes in compactability were a linear function of MCC content. Result plots A total of 42 plots were prepared, each labelled with an ordinal number. Thirty three plots were drawn directly from the results of tableting runs, while the others are the results of data processing. Substances used for tableting (and a plethora of those are available) should not be characterized in a descriptive and generalized manner, but instead by using detailed results that illustrate the substance s response to pressures applied. These results are the essence of the knowledge on substances produced with the aim of being processed into tablets. Special cases It is the special cases that make mechanical testing a little more adventure-like, interesting and crucial, particularly in the case of formulations for direct tableting. Plots present the profile of the push-out forces. As shown by the first plot, with both grey lines running alongside each other, the force distribution is favourable, with no risk of tool seizure. A somewhat different case is illustrated in plot 35, where distant grey lines may forecast problems with tablet push-out as deposits accumulate within the matrix. The formation of deposits may be inferred just by comparing the light grey line to the grey line, without the need to inspect the matrices. Yet another situation is observed for calcium phosphate (plot 36), where both grey lines overlap each other, allowing for potentially greater reduction in the quantity of glidant in the final formulation, if required. However, one exception applies. No MgSt was added to MCC in the phosphate tests as it was believed that such a small amount as that required by cellulose (as little as 0.05%) would be obtained from calcium phosphate. As shown, this was the case in all runs except the one where MCC was used as the only constituent. In this case it revealed its tendency to accumulate on matrix walls, as evidenced by a distinct separation of push-out forces at the end of plot 36. Another, much more serious case was observed for mannitol. It is worth special attention as it is associated with the quite common, albeit not always necessary, doubling of substances when designing drug formulations. Namely, the addition of MCC, being beneficial for the two other substances, (plots 37 and 39), is not so in the case of mannitol (plot 38 ). The paradox is evident, as marked by the red line. The addition of the product characterized by better cohesion not only does not lead to the expected increase in tablet hardness, but systematically lessens this hardness instead! This adverse effect, an explanation of which is beyond the scope of this article, strongly supports the purposefulness of studies such as the one presented herein. At the same time, it illustrates the scale of problems encountered when attempts are made to include formulation design in a computer-aided (CAD) form. What about disintegration? As seen in plots 40 and 42, actual shortening of disintegration time is possible with the addition of MCC, particularly when it is used at ca. 20%. This fully confirms information presented in some other sources. However, it should be noted that the disintegration effect is observed only in a narrow range of applications. This is best illustrated in plot 2, where the 10% addition of MCC significantly reduces the disintegration time, but only for low pressure forces, which are rarely applied in practice. Similar observations were made for the increasing content of MCC in ACA. Therefore, no generalizations are justified. On the contrary: limitations associated with pressure forces should be clearly mentioned. The type of substance to which MCC is added is an even greater limitation. This can be seen in plot 41, which completely contradicts the suggestion of microcrystalline cellulose being a disintegrant. Contrariwise, following the plot from the right to the left, one might say that the addition of mannitol 1/2013 download *.pdf version:

23 23 to MCC leads to a distinct and systematic shortening of cellulose tablet disintegration time. Should, therefore, mannitol be also unreflectively classified as a disintegrant? Summary Microcrystalline cellulose is not a disintegrant, although it may promote disintegration in certain conditions; these conditions were partially presented here. Therefore, microcrystalline cellulose should not be listed along with actual disintegrants such as gelatinized starch, sodium starch glycolate, crosspovidone or crosscarmellose. These substances are also subject to limitations with regard to their physical properties [2], but their mechanism of action is distinct from that of cellulose. Therefore, it seems that microcrystalline cellulose was rightly classified as a water carrier that accelerates disintegration while not being a disintegrant itself [1]. Bibliography 1. Mikołaj Marian Zgoda et al. Celuloza mikrokrystaliczna i jej granulometryczno morfologiczne modyfikacje, jako efektywne substancje pomocnicze w technologii tabletkowania środków leczniczych o ustalonej strukturze krystalograficznej, a także suchych mianowanych ekstraktów roślinnych [Microcrystalline cellulose and its granulometric/morphological modifications as efficient excipients in the tableting of medicinal products of precise crystallographic structures, as well as of dry titrated plant extracts]. Division of Drug Formulation Technology, Department of Applied Pharmacy, Medical University of Łódź. 2. Jerzy Lasota. Dezintegratory substancje rozsadzające stosowane w tabletkach. Badanie skuteczności [Disintegrants in tablets an efficacy study]. (3 parts). Świat Przemysłu Farmaceutycznego, issues 1-3/ farmacja.farmacom.com.pl/archiwum.php 3. only information pertaining to the last table. 4. Jerzy Lasota, Robert Miller. Vademecum Tabletkowania. Komentarz do edycji 1 [Vademecum of Tableting. A Note to the 1st Edition]. By courtesy of the editors, the author extends an open invitation to his class on the Operation of Tableting Machines, to be held in Warsaw on May 23 rd. Details: download *.pdf version: 1/2013

24 24 Utilization of mass spectrometry in modern pharmaceutical analysis Agnieszka Ulanowska, Grzegorz Strączyński LECO Polska Sp. z o.o. Introduction of high performance liquid chromatography combined with mass spectrometry (LC/MS) to analytical laboratories significantly changed a way of research performance, enabled obtaining more information from sample analysis in a much shorter time. Application of LC/MS systems in pharmaceutical analysis revolutionized this research direction allowing to detect and identify contaminations in medicine, check their authenticity and origin, and control the amount of active substances in pharmaceutical [1]. All methods used for determination of active compounds or medicine analysis and based on LC/MS technique have to be validated according to CPMP/ICH guidelines. The review articles on the use of mass spectrometry in pharmaceutical analysis usually considers the impact of the method of ionization of analytes in an LC / MS (ESI often, APCI, and MALDI) the final result of analysis are considered the possibilities and limitations [2]. In pharmaceutical research very important is not only ionization method but also a type of mass spectrometer. Therefore, this paper is a review through different mass spectrometers used in pharmacy, more precisely about a type of analyzers installed. Advantages and disadvantages of spectrometers hyphenated with liquid chromatography are presented, and analytical possibilities resulted in their construction and properties. Currently, on the analytical market, there are many different mass spectrometries with different type of mass analyzers and ionization methods. Analyzer is an inherent part of spectrometer responsible for separation of ions according to their mass-to-charge ratio (m/z). One of the most important parameter characterizing the mass analyzer is mass resolution. Mass resolution gives information about the ability of an instrument to distinguish two peaks of slightly different mas-to-charge ratios in mass spectrum. This parameter mainly depends on the type of mass analyzer. Generally, there are several different Due to simple construction, quadrupole is also the cheapest mass analyzer and often used in analytical laboratories for performing qualitative and quantitative analyzes. mass analyzers available and commonly used in analytical laboratories: quadrupole (Q), ion trap (IT), magnetic sector, time- -of-flight analyzer (TOF), orbitrap, Fourier transform ion cyclotron resonance (FT-ICR) and tandem mass spectrometers which are connections of two or three mass analyzers (MS/MS). From among mentioned systems, mainly TOFs, quadrupoles and tandem mass spectrometers like triple quads (connection of three quadrupoles, QQQ) or hyphenation of Q-TOF are widely used in pharmaceutical analysis. Therefore, their properties and analytical capabilities will be estimated in the article. Quadrupole is technically the simplest mass analyzer from others. It is built from four parallel bars to which direct current voltage and the potential of changing the radio frequency is applied. Under the influence of an electric current, ions oscillate between electrodes. In determined measuring parameters, only ions of a certain m/z ratio can move in stable wake and after leaving mass filter go to detector [3]. Due to simple construction, quadrupole is also the cheapest mass analyzer and often used in analytical laboratories for performing qualitative and quantitative analyzes. It belongs to the group of scanning analyzers which means that in particular moment signal from only one ion reached to the detector is record. This method of recording the signal affects the appearance of the mass spectra of analytes that vary depending 1/2013 download *.pdf version:

25 25 on the kind of ions at the time they reach the detector, causing distortion of the spectra (called spectral skew). In Figure 1 shows the look of mass spectra registered by scanning and non-scanning analyzer. In addition, scanning each individual ion, causes the amount of recorded spectra per second is comparatively small (up to 50 spectra) and is highly dependent on the measured range of masses. Both of these factors are crucial in identifying analytes and affect the efficiency and accuracy of spectral deconvolution Deconvolution is a mathematic algorithm enabling isolation of analytical peaks from the noise and overlapping signals from other disturbing substances. Thus, deconvolution allows to separate coeluting peaks based on spectral data. Selected ion monitoring mode (SIM) is very often used in case of quadrupole analyzers. SIM enables register only signals from defined ions (definied m/z ratio) with full omission of other ions. This approach decrease of limit of detection (LOD) for analytes ca. one order of magnitude (up to femtograms, fg) and increase method selectivity. SIM is perfect and often use solution for target analyzes, when you want to confirm or exclude presence of particular substance in the sample, e.g. for fast screening of trace level contaminations or during determination specified toxic compound in biological sample [4]. However, from last few years, the interest of pharmacists decrease in classical LC-QMS systems. A tandem mass spectrometry seems to give more analytical possibilities. With a simple construction and small size, quadrupoles are often combined together to form tandem system, characterized by a higher sensitivity and better resolution than a single quadrupole. Therefore, in pharmaceutical research triple quads (QQQ) are more often used. Two of three quadrupoles play role as analyzers, one of them (in the middle) is Figure 1. The look of mass spectra depends on type of applied mass analyzer scanning MS like quadrupole or non-scanning like TOFMS. In case of non-scanning mass analyzers, independently which ions are analyzed, registered spectra are always identical. Arrows show point when mass spectrum was registered. used as a collision cell. Figure 2 shows a tandem mass spectrometry system and functions of each element. All of the ions produced in ionization source enter to the first quadrupole (Q1). To choose among all the ions, ions of a certain m/z value, the first quadrupole (Q1) is used. Then selected ions go to the collision cell (Q2) and undergo further fragmentation. Fragmentation of precursor (parent) ions occurs by collision of ions with molecules of inert gas, usually nitrogen, helium or argon. This process is called collision- -induced dissociation (CID). Obtained fragment (daughter) ions are analyzed in the third quadrupole (Q3) according to their m/z value. The result of this stage is the registration of mass spectra for fragment ions produced from selected parent ion. Tandem mass spectrometry enables analyzes performance in many different ways [5]. The most popular and most commonly used method in MS/MS is the product-ion scan that relies on registering all of fragment ions produced during decomposition of parent ion previously determined by analyst. This technique is used for determination of the structure of molecule based on structure the most significant fragments. The idea of next method, called pecursor-ion scan, is recording a parent ion that undergo fragmentation on many product ions. It is used when it is known what the group of chemicals gives specific fragment ions. In constant neutral-loss scan, pairs of parent and daughter ions different by characteristic fragment, are monitored. It is used when you know that particular neutral loss mass Figure 2. Scheme of tandem mass spectrometry download *.pdf version: 1/2013

26 26 is typical of a class of compounds and you want to identify mixture components that belong to that compound class. However, in order to obtain the highest possible sensitivity of the instrument a determination of a collision energy for precursor and fragment ions is necessary. The last technique used in MS/MS is a selected reaction monitoring (SRM) which is analogue method to SIM. In SRM fragmentation reactions of metastable ions are monitored. Reactions of normal ions are omitted. The abundance of metastable ions are usually very low in comparison to normal ions, so this technique reveals low sensitivity but high specificity. This solution is popular in research of medicine metabolites tested in vivo and in vitro [6]. Recording of mass spectra precursor and fragment ions enable exhaustive analysis of analyte structure. However, in case of appearance of unknown substance in measured sample, due to high sensitivity of instrument, this substance analyst could not be able to detect it. Because of applied method in tandem mass spectrometry signal from analyte could not be registered. QQQ systems are recommended only for target analysis [7]. Before purchasing modern analytical instrument, you should consider one more technical parameter mass resolution. In the case of single quadrupole and triple quadrupole system it is difficult to obtain high mass resolution. Usually, quadrupoles are characterized by the nominal mass resolution, it means that masses are measured as integers, for example, H=1, C=12, N=14. Therefore, in the case of substances containing different elements and complex chemical structure, there may be problems with the unique identification of the analytes. The difficulty of identifying analytes also affects the presence of different isotopes of the elements in the molecule of the analyte. In the pharmaceutical industry hybrid mass spectrometers are more often used. This hybrid mass spectrometers are a combination of two different analyzers, such as quadrupole and time of flight (Q-TOF). In such systems, the Q-TOF, quadrupole is used as a filter of ions and allows you to select the parent ions from the substances of interest to the analyst. Selected ions reach the collision cell, where they are ionized and then analyzed using TOF analyzer. Linear time of flight mass spectrometers have the form of a simple tube, where a beam of ionized analytes is introduced. Ions with different m/z ratio are separated according to their different speeds after the acceleration generated by the applied potential [3]. Heavier ions (with higher m/z), moving with a greater velocity than lighter ions on the ion path. If a beam of ions will be accelerated, and then passes The mass measurement is more accurate, the number of possible substance of the same molecular weight that exist in nature is less, and the lower the probability of errors during the identification of analytes through an area where the field is not working, the ions will reach the detector at different times, depending on their speed. The purpose of the electronic system is the conversion of the measured time of flight to the corresponding m/z ratio. By using reflectron (ion mirror), ions which have the same mass but different kinetic energy, and thus different speeds, they reach the detector at the same time improving the resolution [8]. A general principle of TOF analyzer is that the longer the flight path, the higher is instrument resolution. Some of the TOF analyzers are built from two reflectrons, in order to extend the flight path. However, this will significantly reduce the sensitivity of the system. TOF analyzers record a full mass spectrum of all ions reaching at a time to the detector, even for analytes covering a wide range of molecular weights. Using TOF, analyzes are always performed in the full scan mode (FS), and there is no need to use the SIM mode, as in the case of quadrupole, to increase the sensitivity of the determination. Application of TOF analyzer in Q-TOF systems, increase a speed of data acquisition and now it is possible to receive enough data points across the peak that is necessary for the proper performance of deconvolution. Using the system Q-TOF, it is possible to perform analyzes in the same manner as in the case QQQ, i.e. the experiment by scanning all fragment ions, registration of all parent ions, SRM, or by neutral-loss scanning. The advantage of Q-TOF, in contrary to QQQ, is possible to obtain high resolution (up to ) and the exact mass measurement, for example: H = , C = , N = (mass error is ca. 1 ppm). Figure 3 presents a comparison of the resolving power of the analyzer quadrupole and time of flight analyzer based on the measured mass ion. The mass measurement is more accurate, the number of possible substance of the same molecular weight that exist in nature is less, and the lower Figure 3. A comparison of the resolving power of the analyzer quadrupole (Q) and time of flight (TOF) analyzer based on the measured mass ion 1/2013 download *.pdf version:

27 27 the probability of errors during the identification of analytes. Some devices of this type also include the presence of different isotopes during the substance identification. Such a hybrid solution in combination with liquid chromatography are commonly used during analysis of metabolites present in the sample at a trace level [9, 10]. The newest and the most advanced technological solution in mass spectrometry, that only takes his first steps in the pharmaceutical industry, is high-resolution mass spectrometer, equipped with multi-reflectig time-of-flight analyzer (high resolution TOF, HRT) designed by Folded Flight Path. The scheme of FFP technology is presented in Figure 4. Its unique design enable very high resolution (R = ) by extending the ion flight path up to 40 m, without having to increase the size of the analyzer. Such extension of the flight path is possible by the use of a unique optical system provided by FFP technology, which allows multiple reflections of ions (up to 64 reflections), without noticeable loss of sensitivity of the system. This HRT instrument is able to maintain a very high resolution even during the analysis of the light ions, means less than 500 Da, which are the subject of research in pharmaceutical analysis [11]. High resolution time of flight mass spectrometers preform masses measuring with high accuracy (mass accuracy 10-5 Da). During the identification of analytes, HRT systems include an isotopic fine structure (IFS) and allow the separation and identification of peaks originating from isotopes [12]. In addition, HRT systems are characterized by a high speed data acquisition of 200 spectra/s, which makes full use of deconvolution and automatic peak find. The acquisition speed parameter also determines the mode of data collection (only FS is used), as well as there is no need to optimize collision energy in order to obtain the best instrument sensitivity, because at any second a full mass spectrum all of ions reaching the detector is recorded. HRT spectrometers can be equipped with a special two-channel system to record the spectral signals (comprehensive CID, MSc2), which allows simultaneous and independent spectra recording of generated parent ions and fragment ions. This solution is somewhat similar to MS/MS. However, in HRT the parent and daughter ions mass spectra may be recorded for all the substances introduced into the system. This solution is very useful in the case of non- -targeted analysis. Additionally, the overlapping of the signals from the precursor and fragment ions will increase the sensitivity of the system. Thanks to these properties, the high resolution time of flight mass spectrometers can be successfully employed in the metabolomic analyzes for detection trace contamination of samples [13]. They have an advantage over traditional tandem mass spectrometry, which is mainly focused on analyzing only the target analytes, which in the case of searching for new, unknown substances can be a serious problem. The challenges on a daily basis to meet analysts in pharmaceutical laboratories, they are motivated to find new analytical solutions. Very often it turns out that the only solution that will help overcome the problem is new analytical equipment, which allow to detect and identify of substances with even lower LOD than before, which in addition to qualitative analysis will enable efficient and rapid execution as quantitative analysis. All these aspects make the market analysis we have a huge variety of systems coupled with mass spectrometry, which, depending on your needs are able to meet expectations. You only need to specify the requirements for the type of research, a solution is at hand. Figure 4. A scheme of multi-reflecting time-of-flight mass spectrometer References: [1] I.D. Wilson, U.A.T. Brinkman, Hyphenation and hypernation the practice and prospects of multiple hyphenation, J. Chromatogr. A 1000 (2003) [2] C.-K. Lim, G. Lord, Current Developments in LC-MS for Pharmaceutical Analysis, Biol. Pharm. Bull. 25 (5) (2002) [3] R.A.W. Johnstone, M.E. Rose, Opis aparatury, in: K. Bar, M. Daniewski (Eds.), Spektrometria mas, Wydawnictwo Naukowe PWN, Warszawa, 2001, pp [4] P. Marquet, Is LC-MS suitable for a comprehensive screening of drugs and poisons in clinical toxicology?, Ther. Drug Monit. 24 (1) (2002) [5] N.J. Clarke, D. Rindgen, W.A. Korfmacher, K.A. Cox, Systematic LC/MS metabolite identification in drug discovery, Anal. Chem. 73 (15) (2001) A. [6] W.A. Korfmacher, Principles and applications of LC MS in new drug discovery, DDT 10 (20) (2005) [7] P. Susantakumar, A. Gaur, P. Sharma, Development and validation of LC-MS/MS method for the estimation of acylovir on pharmaceutical dosage form, Pharmacophore 2 (4) (2011) [8] H.J. Hubschmann, Mass Spectrometry, Handbook of GC/MS Fundamentals and Applications, WILEY-VCH Verlag GmbH &Co. KGaA, Bremen, 2009, pp [9] K. Cox, Special Requirements for Metabolite Characterization, in: W.A. Korfmacher (Ed.), Using Mass Spectrometry for Drug Metabolism Studies, CRC Press, 2005, pp [10] K.A. Cox, N.J. Clarke, D. Rindgen, W.A. Korfmacher, Higher throughput metabolite identification in drug discovery: Current capabilities and future trends, Am. Pharm. Rev. 4 (2001) [11] LECO Corporation, Increasing Confidence in Identifications of Pharmaceuticals by Employing the Comprehensive Collision- -Induced Dissociation Capabilities of MSc2 on the Citius LC-HRT, LECO Application note Form No /12 (2012). [12] LECO Corporation, Relative Isotope Abundance at Ultra High Resolving Power (100,000 (FWHM)) for Improved Formula Identification, LECO Application note No /12 (2012). [13] LECO Corporation, Analysis of Urinary Metabolites of Acetaminophen, Dextromethorphan, and Doxylamine by Liquid Chromatography/High Resolution Time-of-Flight Mass Spectrometry, LECO Application note No /11 (2011). download *.pdf version: 1/2013

28 28 Ventilation system Economic success through proper exploitation An important issue of maintain ventilation system is the costs estimation. Sometimes, it shows us that an annual costs estimation is greater than a replacement of the entire measurement system. Cezary Wronkowski Przemysław Siwek photo: B&L Calibration is a set of action, which aim is to determine the relationship between measured values indicated by a measurement instrument and the corresponding values of physical quantities carried out by the standard unit of measurement. In simple terms, it is determining a difference between an indication of a calibrated measurement instrument and a standard measurement instrument with an estimation of measurement uncertainty. The aim of calibration is an estimation of measuring properties of a calibrated measurement instrument. It shows us if instrument is useful for measurement. Unfortunately with the passage of time measurement instruments lose their accuracy and stability. In result, outcome of measurement may not meet the assumed accuracy of the measurement instrument. The lack of accuracy of measurement instrument can be a reason of high costs generated during desiccation/humidification and cooling/heating process. The accurate humidity measurement allows us to optimize a working time of machines and get big savings such as energy consumed by cooling systems and dehumidifiers in result. The simplest solution to a problem of a lack of accuracy of a measurement instrument is an adjustment. In simple terms, the adjustment is to adapt a measurement instrument to measurement results obtained by a standard. In practice, humidity and temperature instruments can be calibrated and adjusted with humidity standards in ampoules and climatic chamber. Temporary adjustment in climatic chamber is a good and easy solution to ensure adequate measurement accuracy of each thermo hygrometer. Sometimes, during exploitation of ventilation system there is a need for rapid estimation of costs incurred and determine the frequency calibration and maintenance of measuring devices and the replacement of an old and inaccurate one with some new high precision devices. For the purpose of estimating these costs we can use coefficient λ1%365, which can be used to determine the energy required to change the moisture content of 1% of one m3 of air in the period of 1 year. Coefficient is within the range: λ 1%365 = 0, ,277 [PLN h/m 3 year]* 1/2013 download *.pdf version:

29 29 Climate chamber HygroGen2 type (calibrator) by Rotronic On the basis of the coefficient, it is possible to quickly estimate the annual cost of electricity used to change the moisture content of 1% RH for industrial ventilation systems on the number of panels n: C 1%365 = λ 1 %365 * Σ Q n where: Q n costs of subsequent centrals C 1%365 - annual cost of energy to change a humidity of 1% [PLN/year] When selecting measurement devices should be paid on long term stability of sensor. This parameterhas a big influence on periodicity of calibration. During exploitation of transmitter for relative humidity and temperature with 1,5%RH accuracy it is possible, that lack of adjustment can generate additional about 1,5 x 30,00 PLN = PLN. This fast analysis shows, that in many cases costs of maintenance ventilation system are bigger than purchase of new measurement devices and confirm validity of calibration and adjustment. In simple terms for quick analysis we can use a coefficient: λ 1%365 =0,3 [PLN/year] Thus, the annual cost of electricity consumption to change the humidity of 1% for the ventilation systems of the central n is the number of: C 1%365 =0,3 * Σ Q n [PLN/year] Conducting a quick analysis proves that in many cases, annual usage costs exceed the expenditures that may be allocated to upgrading or replacing an obsolete measuring system, and should get one to perform periodical calibration and verification of measuring devices used. photo: B&L photo: B&L download *.pdf version: 1/2013

30 30 Manager beware of boring lecturers! Hints on making the GMP training a passionate event for your team. photo: fotolia If your Company belongs to the pharmaceutical production sector, it means that from time to time you have to delegate your team to the Good Manufacturing Practice training. Elżbieta Bętkowska ELPHARMA s CEO is a certifi ed trainer and consultant in the fi eld of pharmaceutical production and a TÜV Rheinland technical expert in the fi eld of: pharmaceutical manufacturing, healthcare, cosmetics manufacturing, manufacturing of packaging for medicinal products. Grzegorz Gustaw ELPHARMA is an organizational psychologist, a certifi ed business trainer, consultant, lecturer and journalist writing for the weekly Polityka and the weekly Wprost What I hear, I forget. What I hear and see, I remember a little. What I hear, see, and ask questions about or discuss with someone else, I begin to understand. What I hear, see, discuss, and do, I acquire knowledge and skill. Mel Sillberman 1/2013 download *.pdf version:

31 31 photo: chromastock If your Company belongs to the pharmaceutical production sector, it means that from time to time you have to delegate your team to the Good Manufacturing Practice training. Announcing it to your team could be difficult, because the idea of GMP training often doesn t raise enthusiasm. On the contrary, it rather invokes a nightmare of obscenely long days spent in the company of a tireless, sadistic teacher who tortures his audience with a Power Point supported monologue. Unfortunately, during such a training even those members of your team who have the most positive attitude towards lifelong learning will fall quickly into a slumber. Why does the Power Point assisted monologue kill participant s attention? Early in the twentieth century Norman Mackworth found out that the prolonged concentration on the same type of stimuli leads to a dramatic reduction in the efficiency of the reception of those stimuli. Thanks to the numerous experiments in the continuous performance paradigm, psychologists found out the following pattern: usually one is concentrated to the fullest during the first 45 minutes of the monotonous task. Afterwards, there is a major decline of attention. What does it mean for the GMP training? A well prepared lecture is still a very important part of the training in GMP. However, one should bare in mind that the method consisting of a teacher who is transferring knowledge from his head full of wisdom to those empty heads of the participants works only at an early stage of education of children. It isn t much efficient though in the area of teaching the adults. Why? Because we all have a specific knowledge on the topic and lots of professional experience. While the child absorbs new knowledge like a sponge absorbs water, every time an adult learns new things, he tries to link new information with his experience. A good lecture should contain though some elements of a dialogue with the participants. Furthermore, it shouldn t be too long. It is a good idea to mix lectures with various active learning techniques. In this way, the effectiveness of the training cycle is maximized. Modern GMP training how to marry the best content with the ultimate teaching experience? Choosing a training company that applies the latest findings of andragogy to prepare and implement GMP training in your company has several benefits. Andragogy is the science of understanding and supporting lifelong education of adults. In this framework it has been proved that adults are subject to different learning laws than children. Adults have a wealth of experience. They expect that during the training they would have an opportunity to share their experience and learn from the experiences of other professionals. They are also keen on gaining new experiences. Those can be provided by a range of methods such as: exercises, state of the art simulation games and role-play sessions. Adults often have a strong feeling that time is money. It is crucial though that the trainer helps them planning how they can practically apply the new knowledge and skills acquired during the training. Did you know that you have the right to the top quality GMP training. ISO 10015:1999 Quality management Guidelines For Training is an undiscovered gem in the ISO 9000 family of standards. It provides guidelines to assist organisations and their managers when addressing training issues. An ISO defines training as a four-stage process: (1) Defining training needs of your company, (2) Designing and planning adequate training, (3) Providing the training using correct methodology, (4) Evaluating the outcome of Training. Farewell boring lecturer! Each change brings fear. That s why we tend to prefer familiar situations, even though we clearly see their shortcomings. There is a proverb better is the enemy of the good. Thankfully it is not true for the modern GMP training. It s a high time to change the idea that your team has on Good Manufacturing Practice trainings from anything but that! to I can t wait. It s high time to retire boring lecturers! Maybe you would like to put us to the test? ELPHARMA training and consulting for the pharmaceutical business. Our website: download *.pdf version: 1/2013

32 32 Professionall system for sensors management at the click of a mouse Measuring, calibrating and documenting at the production and lab side. Technical possibilities However, we all know that ambient conditions are not favorable for optimally calibrating sensors. Wouldn t it be better to calibrate all sensors from the process conveniently in the lab under constant conditions and retrieve all calibration values, measuring values and sensor information without any effort, simply by clicking a mouse? Thanks to management systems and digital sensors, this is possible. photo: Endress+Hauser Dariusz Figiel Endress+Hauser Polska Photo 1. Complete package for sensors management Digital sensors are based on non-contact data transmission between sensor and cable that makes the system absolutely robust against external influences such as moisture, corrosion and salt bridges. Correct calibration Unpleasant surprises from measuring point failures caused by these factors are a thing of the past and maintenance work such as calibration and sensor replacement can be planned in advance. Moreover, digital sensor technology are intelligent. In addition to calibration data, they save information such as operating hours under various conditions and the tag name. As a result, their use is not tied to a specific transmitter. This opens up possibilities for sensor management that you never had before. Sensors can be calibrated under constant conditions in the lab and all associated data is stored in a database. Reports are created simply by clicking a button. These options are unheard of for calibration on a process transmitter or would involve time-consuming and error-prone work by hand. For example, ph buffers must be manufactured in a buffer lab accredited by professionall staff. Just plug it in and start operate Sensors management system is based on the plug-and-play technology and identifies the digital sensors automatically and offers the right functions for the sensor. The program is simple and easy-to-understand, sorted by the work tasks of measurement, calibration, reports and sensor management. The intuitive operation and self-expla- 1/2013 download *.pdf version:

33 33 natory system, which also provides many helpful resources and instructions, allows every user to master the program after just a short time. This prevents operator errors from the beginning. Sensor management system operates up to four sensors simultaneously in any combination. This speeds up measurement and calibration of all digital sensors with an inductive plug-in head and ultimately saves time and money. Device which is sensor connection box determines the number of channels, which are available individually and can be retrofitted at any time. The system also saves work space in the calibration lab! You only need one interface for all types of sensors, no bulky transmitters and software for measuring, calibration and documentation. And finally, you have continuous savings on personnel costs in your operations, since analysis specialists only have to calibrate, while sensor replacement - which also had to be done by specialists - can now be done by non-specialist staff in a few minutes. Maximized availability of measuring points is a free extra. photo: Endress+Hauser Full reliability Sensors management system actively provides reliable and error-free work. Because the sensors are calibrated in a laboratory, calibration is always performed under optimal conditions - a critical factor for its accuracy and thus for the quality of measurements as well. The user administration also provides security and, with the configurable password specifications, adapts to the requirements of a company and pertinent standards and regulations. In addition, the lab environment is much safer for workers. In the process environment, where workers are often exposed to heat or cold, dirt and vapors, the required work steps have been minimized to replacing the sensor. Completely prepared for audits With complete automation, the sensors management system creates data records of operating conditions, measurements and calibrations and documents all of the associated information. This ensures seamless traceability and audits are prepared quickly and easily. Reports can be created in.pdf form at the click of a button. The data records can also be exported as.csv files and reused, without paperwork, for optimization and analysis in Excel. Of course, sensors Photo 2. Calibration in the laboratory is also possible.jpg management system enables you to work in conformity with FDA CFR 21 Part 11 thanks to the audit trail and 3-level user administration with electronic signature. Settings, serial numbers, software version, commissioning date and manufacturer, target value, batch and service life of reference solutions, user, time stamp (accurate to the second) and sensor history are part of each data record and thus have a fixed association with a calibration. This leaves no room for speculation. All of the information is stored in a local or central database which, thanks to a checksum, reveals any tampering and labels it in a manner that is impossible to overlook. The central database also enables multiple persons to have access at different locations, optimizing the flow of information and making work more efficient. Automated as found as left deviation monitoring How was the measurement quality of the sensor immediately before calibration and, in comparison, what was it like immediately after calibration? With the automated as found as left measurement, this can be carried out easily and documented as an optional part of all calibration procedures. Based on the identified delta values, differences in measured values before and after a calibration can be explained and the application-related sensor load can be better estimated and tracked. First-time reproducibility of laboratory and process values For the first time, the same calculation, the same cables and the same sensors as those in the process are used in the lab with sensors management system. This makes the measuring values genuinely comparable, since differences due to the measuring system are eliminated. Therefore, upscaling is also easier than ever: the sensors in the process are guaranteed to measure identically to those in the test system. With automatic temperature and medium compensation, the only explanation for different results can be the medium s reaction with air. The sensors can be validated at an early stage and accompany the product development process from the beginning with consistent results from start to finish. This allows sensors management system to enable production plant to centralize maintenance of all digital sensors, thus making it more efficient while giving you improved calibration quality and automated documentation that leaves nothing to be desired. download *.pdf version: 1/2013

34 34 Antidote to chaos photo: fotolia.com How can a software system help control the process of production and of logging the data which it generates? Zdzisława Drabent Director of Implementation I&B Consulting Sp. z o.o. Pharmaceutical companies are among the most complicated enterprises. They not only produce hundreds of drugs bearing their trademark, but frequently also carry out activities in other fields: research, production, packaging and custom packaging. All these operations must be conducted in accordance with the strictest regulations and norms and documented in detail. It is easy to get lost in all this, and every mistake proves very expensive. 1/2013 download *.pdf version:

35 35 Thus, pharmaceutical companies need comprehensive support in many areas of their everyday activity, as well as during its planning, monitoring and documenting. In short, they need ERP-class software with the Business Intelligence module, which acts as the company s nervous system. Norms, standards, regulations Norms exist in order to enforce standards. In theory, they should help regulate activities. However, on occasion they paradoxically only make things more complicated. Pharmaceutical companies are obligated by law to track products through the entire supply chain; this obligation is associated with additional duties and an extra workload. Compared to enterprises operating in other sectors, entities in the pharmaceutical industry are subject to the greatest amount of norms and regulations contained in pharmaceutical law. To this must be added a number of workplace standards In order to fulfil them all, it is necessary to control the company s activities literally at every turn. The first question consultants get asked by representatives of pharmaceutical companies interested in implementing a software system is its validation, or a confirmation that the system really does facilitate those processes, activities and procedures which it is supposed to facilitate, in such a way that the activities carried out with its help really produce the expected results, and that everything will take place in accordance with the standards which the company is subject to. Compliance with the GAMP5 standard guarantees that the system is capable of fulfilling these directives, especially as regards registration and documenting the process of manufacturing and storage in accordance with strict requirements. This standard is a set of instructions and good practices regarding software systems developed especially for organisations from the pharmaceutical sector. Orderly production management Although production in the pharmaceutical sector is characterised by exceptionally low employment, incomparable with other branches of industry, managing the manufacturing process is not simple at all. It is especially easy to lose orientation when several dozen different medications are to be produced in the factory on the same day. Automation proves the key to success; like low employment, in the pharmaceutical industry it has reached a level unparalleled in other branches of industry. The technical sophistication of production halls in pharmaceutical plants is usually in inverse proportion to the number of employees. Thus, the entire production process can be planned and executed flawlessly and with pharmaceutical precision. When planning production with the help of a system configured with MES systems, one can avoid many errors which occur when the so-called human factor plays a significant role in the process and when several workers are responsible for the different stages of manufacture. Under such conditions a small misunderstanding is enough to render an entire batch of medication useless. A software system makes it possible to plan production step by step, in several different variants. Because the formula is stored in the database, the software is capable of automatically dosing the correct amounts of different substrates. If the medication is produced in several versions, e.g. containing different doses of the active ingredient or in different variants containing various additives, as in the case of vitamin supplements for children, women or elderly people, it is also possible to plan production in such a way that a given amount of the different products will be manufactured during the same production cycle. The software is also capable of making sure that each of the products is properly labelled and packaged, and even of analysing samples to check whether the given medication is really the product indicated by the label. Furthermore, the entire production process can be optimised with the help of the right applications, limiting raw material losses and stoppages, as well as improving the scheduling of workers tasks. If the company carries out made-to-order production, the result is often chaos in the production hall. The more different products have to be manufactured both those produced under When planning production with the help of a system configured with MES systems, one can avoid many errors which occur when the so-called human factor plays a significant role in the process and when several workers are responsible for the different stages of manufacture the company s trademark and those ordered by other firms the greater the risk of decreased efficiency. A system that monitors literally each activity and every process taking place in the production hall points out the stage where the longest stoppages occur, e.g. because machines need to be cleaned after producing other substances, or for other reasons. When one knows the weak points in the process, it is possible to plan production in such a way that the time-consuming tasks are performed during shift changes or after the end of the workday. Automated quality control Quality control is absolutely crucial in drug manufacture. This issue is associated with the requirement of tracking each batch through every step of production from substrate delivery to the factory until the drugs are distributed to pharmacies. ERP-class software developed especially for pharmaceutical companies can be configured with external systems and measuring devices which control e.g. the temperature in the room where the given medications are produced or stored, or those which monitor the product contents. Data regarding the monitored parameters are sent directly to the analytical applications which facilitate the process of quality control. If a specific product batch becomes contaminated or damaged, the system will signal that an anomaly is present even before the medication leaves the plant. However, if a faulty batch of substrate is delivered to the plant and specific batches of medications need to be recalled, the system is capable of showing the wholesale firms, drugstores and hospitals where the ill-fated product was delivered, in just a few moments; thus, the medication can be swiftly withdrawn from the market. Furthermore, the application is able to very precisely indicate the products which need to be withdrawn. If only a specific batch is flawed, only that batch returns to the plant. It isn t necessary to withdraw a larger amount of the medication just in case. download *.pdf version: 1/2013

36 36 photo: sxc.hu If the appropriate software tools are used, raw material turnover improves and warehouse stocks can be reduced by as much as 50%. As a result, the company s expenses decrease significantly. Well-considered supply chain management When there is a lot going on, managing supplies can present a serious challenge. Storing substrates in the warehouse entails high costs. This is particularly true in regard to substances which require specific storage conditions (e.g. refrigeration) or have a high turnover rate not using them at the appropriate time causes financial losses. On the other hand, one cannot afford a situation where substrates run out, since this can not only halt production, but also ruin an unfinished batch of product if the given substance is not added to the mix in time. Production support systems constantly monitor the stock status of inventory items and analyse production plans well in advance. If the reserves of a given substance are approaching the minimal level, the application automatically signals that its delivery should be ordered. If the appropriate software tools are used, raw material turnover improves and warehouse stocks can be reduced by as much as 50%. As a result, the company s expenses decrease significantly. Orderly finances In large plants, calculating production costs also presents a problem. Substrate, energy and logistics costs change; occasionally a greater amount of a given ingredient is used up during production depending on the conditions within the production hall. Strict cost control and keeping track of expenses makes it possible to precisely determine the cost of producing a given batch of medication, broken down into individual components. The application presents all the data about production-related expenses in a clear, easily understandable form. The Business Intelligence module makes it possible to generate all sorts of reports, analyses and simulations on their basis. Thus, the system also makes it possible to instantly calculate the profitability of production orders. The value will, of course, be only an estimate based on archived data. However, if substrate prices and intermediate costs do not change drastically, it can be assumed that the costs will be estimated with high accuracy. Such knowledge protects the company against undertaking risky projects and possibly high financial losses, but can also give the incentive to take advantage of a situation where the competitors are afraid to pick up the gauntlet. A clear picture Highly complicated market conditions and the large scale on which pharmaceutical enterprises operate mean that successful management of such a company now requires more than just business intuition. Professional support is needed in the form of a software system. Applications developed especially for companies from the pharmaceutical sector make it possible to gather, browse, compare and analyse all the data pertaining to the company s activity, products and clients. Providing a clear picture of the company s situation: the number of employees, production costs, profit margins, the sales of individual drugs, etc. they enable us to base decisions on facts, and thus to reduce business risk. They not only significantly facilitate the work of individual departments and make it possible to optimise almost every process, but are also an important help in the management of the entire enterprise. Thanks to such applications, the company s managers gain detailed insight into all the numerous processes taking place within the enterprise. Thus, in the chaos, appropriately selected software tools serve as a compass which shows the right way. 1/2013 download *.pdf version:

37 bezwzględny i delikatny Poznaj unikalne technologie i produkty firmy Borer Chemie AG - wiodącego producenta środków do czyszczenia, konserwacji i dezynfekcji. W naszych procesach stosujemy sprawdzone technologie czyszczenia. Nasze produkty działają z prawdziwie szwajcarską precyzją: są bezwzględne dla zanieczyszczeń a delikatne dla mytych obiektów. "Trade & Consult Ltd. Sp. z o.o." Sp. k Stara Iwiczna, ul. Nowa 6 Tel , Fax

38 38 article sponsored Eric Marcellin head of Pharma/Biotech at Boccard Project in Brazil The unique character of the LFB project in Brazil lies in BOCCARD s capacity to offer a full solution When and in what manner did BOCCARD create its biotech division? The company took a decisive step towards biotechnologies in 2004, with the opening of its monoclonal antibodies production plant in Penang state, Malaysia. This Pharma and Biotech sector was immediately reattached to the Food/ Pharma division that had existed for about 20 years and specialised in delivering turnkey production facilities for liquids and semi-liquids, particularly for the export market. For its part, BOCCARD actually started its activities in 1918, specialising in industrial piping. Today, multiple sectors exist within the Food/Pharma division, in sectors such as oenology and beverages, brewing, food, cosmetics and of course Pharma/Biotech. But this year has seen the greatest growth in biotechnology. Due to the increasing role played by this sector in the development of new medication, the pharmacological industry has redirected its investment towards new production methods. BOC- CARD therefore took an interest in protein fermentation and purification techniques by developing a range of biofermenters, but also chromatography and ultrafiltration skids, enlarging the existing offer of water- -loop systems and CIP (cleaning-in-place) skids. However, during the last few years we have gained significant knowledge in the domain of plasma proteins thanks to the LFB group, which hired us in 2000 to install a production facility for coagulants at its Lille plant. Previously, we had been tasked by the Belgian Red Cross with building a Cohn process facility, which corresponds to a precise stage of the fractionation process. Today, we are proud to again accept LFB s offer to collaborate together in Brazil and deliver a turnkey fractionation process for its new plant. This is object of the deal signed between the French company and the Brazilian state-owned HEMOBRAS, which is active in fractionation. Plan of the Hemobras plant in Brazil and view of the building site. Boccard In what way is your know- -how specific to the domain of plasma fractionation? BOCCARD has in-depth knowledge of all the equipment used in the protein separation and purification process and shows extreme rigour with regard to quality assurance and conformity with regulations. From a technical point of view, plasma fractionation involves all the purification processes: centrifugation, precipitation, tangential flow filtration, frontal filtration, chromatography etc. For these two reasons at least, knowledge transfer requires the technology employed to be precisely adapted to the three types of proteins sought: albumin, coagulants and antibodies. There are not many laboratories in the world today that specialise in plasma fractioning and few suppliers have the necessary know-how to respond to their needs. Contrary to biotechnologies dealing with cell culture, here we have a process composed of many complex stages, sometimes as many as 10 successive chromatography, filtration and ultrafiltration stages before arriving at the final protein. Not many companies possess this expertise and that of LFB is renowned around the world. Taking the specific nature of this activity into account, for the same reason, BOCCARD is one of the few suppliers to master these particular technologies. Our collaboration in this domain also includes CAF in Belgium and other companies in Latin America, such as QuimBiotec in Venezuela, and in Asia. Boccard s presence around the world. Boccard What are the risks associated with transfers of technology? BOCCARD does not transfer technology but offers equipment to laboratories that already possess knowledge in a very specific domain. Of course, we have signed numerous confidentiality agreements with LFB concerning various aspects of the whole process, but it is LFB that is responsible with regard to the Brazilian state, because it owns and sells this technology. The unique character of the LFB project in Brazil lies in the capacity of a country such as France to offer a full solution with transfer of technology and a bioproduction tool. For its part, the Brazilian Health Ministry wanted to achieve self-sufficiency, modelled on that of France, by having a certain number of therapeutic specialities at its disposal. The state-owned HEMO- BRAS covered the construction costs for the plant on the basis of a public tender for offers for the civil engineering and engineering aspects. And the realisation of the whole process falls to LFB. BOCCARD, as LFB s partner, will deliver the equipment and provide its experience with managing projects abroad. 1/2013 download *.pdf version:

39 39 Boccard production process. Boccard So the Brazilian plant will be like the existing plant in France? The process will be rigorously the same, with the exception of certain modifications due to the specific characteristics of the composition of Brazilian plasma and the scale of the production. For instance, the size of the vats will be changed, since LFB decided that a litre of Brazilian plasma contains higher concentrations of some proteins compared to European plasma. This specificity has repercussions on the sizing of the vats for instance, as well as that of peripheral equipment. The total fractioning capacity of the HEMOBRAS plant should reach litres of plasma per year. At what stage is the work and how will the installation of the equipment take place? HEMOBRAS has finished the earth works and the construction of a refrigerated storage facility for keeping the plasma at temperature of -35C. The foundations for the other buildings are being laid and the civil engineering works should be completed in Afterwards, the mechanical and electrical installation will take place. Followed by commissioning, pharmaceutical qualification and verification. The project has been subdivided into several successive stages, the last of which will be in What are the greatest challenges facing BOCCARD? The project has a specific dimension, because apart from the contract with LFB, the Brazilian government has instigated a policy of industrialisation in less developed areas in the north-east of the country. The plant is located in a rural region, 60 km from Recife on the eastern point of Brazil. Apart from the installation of the equipment, which can only be performed on site, there is also the significant investment in time required by the commissioning and the qualification of the equipment. Concerning oversight and management, we have planned several expatriations of personnel, but we are obliged to try and find local suppliers whenever it is possible, with the inherent difficulties that this creates due to the size of the country. But BOCCARD is used to this type of constraints as we have already built several pharmaceutical laboratories in Brazil and had the same types of experiences on the site in Penang, Malaysia. How are your biotechnology activities currently spread out around the world? What is the turnover from this sector and what are your new export projects? The joint turnover for the Pharma/ Biotech sector is 90% achieved by biotechnology. The spread between France and export markets varies each year as it mostly depends on large projects. Essentially, we are focusing on the emerging markets in Latin America, but also Eastern countries, such as Poland, Russia and Kazakhstan. China is not a priority for us. Despite the Chinese being fond of biotech technology, their market is still quite complicated and for the time being not very profitable. On the other hand, the HEMOBRAS project is an good contract for BOCCARD. However, due to our confidentiality agreement, I am unable to provide you with precise figures. But the public tender for the entire validated process, including training for Wi-Fi input/output for mobile skids. This technology allows the installation of mobile skids that do not need to be physically attached by cables to each workstation. Boccard the operational teams and coordination, amounts to 150 million euros. Contrary to what some may think, Brazil is not a cheap country. And by comparing equipment costs with Europe, HEMOBRAS decided that in France we were competitive in most cases. Chromatography skid Boccard How do you respond to the requirements of laboratories with regard to the level of cost/productivity demanded of equipment? As an equipment manufacturer, BOC- CARD strives to optimise the laboratory production facilities. We design and machine parts that allow to limit product losses during the manufacturing process or we try to limit the use of water and detergents during cleaning-in-place operations. For example, at the LFB Les Ulis site, we are working on two new pieces of equipment that allow to increase the yield of the purification equipment. For each new concentration stage, the added value of the product increases by unit of volume. So we are forced to innovate in order to recover every last millilitre. We mostly concentrate on these aspects, but also work on a number of innovations relating to controlling equipment. Since computer keyboards are unwelcome in clean rooms, with a partner, we are developing interfaces designed to allow an operator to control equipment without touching, through a simple movement of the hand. Although it isn t always easy to propose the newest bleeding-edge technologies in an industry that is very regimented and where well-tested solutions are preferred, our innovations could lead to multiple gains in terms of: operational comfort with a bridging manifold with RFID technology, which allows automatic systems to know at any given moment which pipes are connected, without the need for accessories that are hard to clean; ergonomics with the Wifi-enabled I/O automata; mobility with touch HCI (Human computer Interaction) or finally profitability thanks to various solutions for reducing wastage... download *.pdf version: 1/2013

40 40 Stability analysis of mostly-submicron dispersions by simultaneous combination of DLS and SPOS Improved quantitative characterization of particle size distributions (PSDs) of mostly-submicron colloidal dispersions, such as polymers, latex and resin dispersions, can be achieved by combining dynamic light scattering (DLS) and single particle optical sensing (SPOS). These two radically different techniques are naturally complementary. David Nico Particle Sizing Systems The hybrid method of DLS+SPOS produces PSD results of significantly higher accuracy and resolution for mostly-submicron dispersions, compared to those obtained from a combination of two popular ensemble techniques, classical Mie scattering (MS) and Fraunhofer diffraction (FD). For colloidal systems composed of predominantly submicron particles, especially where the refractive index is close to that of the solvent, DLS results are often superior to those produced by Colloidal dispersions which contain particles predominantly in the submicron size range are ideal candidates for particle size analysis using the combined techniques of dynamic light scattering (DLS) and single particle optical sensing (SPOS). Our new Accusizer 388 hybrid instrument system combines results from both of these systems simultaneously, yielding particle size distribution (PSD) results over a wide size range with unprecedented resolution. The DLS subsystem provides a broad-brush description of the overall PSD, often using a simple Gaussian or log-normal shape, where the resolution is limited by the ensemble nature of DLS, requiring data inversion techniques. The resulting mean diameter and standard deviation can be used to identify the end point of the particle manufacturing process (e.g. grinding, homogenization, emulsion polymerization, etc.). The complementary SPOS subsystem provides a precise picture of the outlying, large-diameter tail of the primary particles/aggregates, which often can severely compromise the quality of the final product associated with the dispersion. Proprietary Autodilution (Pat.) and specialized data analysis techniques permit the PSD results from the two subsytems to be coupled quantitatively. MS, because the diffusivity of particles in suspension is unaffected by their composition and, for sufficiently dilute suspensions, concentration. However, even when DLS can provide a good 2-parameter representation of the PSD of an emulsion using simple cumulants (Gaussian) analysis, its absolute accuracy and resolution are inherently limited, owing to the ill-conditioned nature of the mathematical process required to invert the raw data of the intensity autocorrelation function. A specific limitation of the DLS technique is that it cannot reliably yield the small volume fraction of the tail of largest particles in the PSD. Unfortunately, these outlying particles are typically very important. First, they often significantly influence the physical characteristics (e.g. viscosity and gloss) and overall quality of a final product. Secondly, they can provide an early indication of the onset of instability in a colloidal system, e.g. a latex dispersion. By contrast, the SPOS technique possesses exceptional resolution. By definition, it is able to size particles individually, one at a time. Its accuracy is also quite good. Hence, SPOS can provide quantitative characterization of the small fraction of outlying particles which cannot be reliably inferred from analysis by DLS alone. The underlying principles of SPOS are very simple. Liquid containing suspended particles flows though a small view volume, a thin (typ pm), slab-like zone of illumination, typically produced by a laser diode. The suspension is diluted sufficiently (e.g. by continuous, exponential dilution) so that the particles pass one at a time through the view volume, thereby avoiding coincidences. Particles are detected and sized individually, using one of two physical techniques. For particles larger than about 1.3 pm, the method of light extinction (LE) is effective. In this case, a detector is located across the flow channel, opposite the light source. In the absence of a particle, the detector receives the maximum illumination. When a particle enters the photozone, a small amount of the illuminated 1/2013 download *.pdf version:

41 41 of ensemble techniques, DLS in the time domain or Fraunhofer diffraction in the spatial domain. In these methods, particles of all sizes contribute simultaneously to the signal, requiring inversion algorithms to extract what is, at best, only an approximate PSD. Because they are ill-conditioned, these inversion techniques cannot reliably reveal subtle features of the true PSD which relate to only a small fraction of the overall particle population. The combined DLS-SPOS approach to the characterization of mostly-submicron colloidal systems, such as polymer dispersions, is very powerful. For a wide variety of such systems, DLS provides a good broad-brush picture of the true PSD, yielding reproducible results for distributions that can be approximated by a Gaussian-like shape or a bimodal of sufficient separation. This provides an effective means of monitoring a wide variety of manufacturing processes, including the homogenization of oil/ water emulsions and emulsion polymerization of latex. The DLS technique provides a fast, reproducible means for identifying the end point for such processes. The only significant disadvantage of DLS, of course, is that it cannot provide quantitatively reliable information about the details of the PSD. By contrast, SPOS is ideal for measuring subtle features of the PSD, notably the population of oversized primary particles and/or aggregates. The absolute particle volume contained within a given size range, and therefore its fraction of the total volume of the dispersed phase (emulsion droplets, latex beads, etc.), can be determined easily, quickly and accurately. Hence, the SPOS part of the combined DLS-SPOS system is suitable for evaluating the quality of a colloidal system, given that the desired process end point has been reached. photo: sxc.hu area is effectively blocked, owing principally to the ability of the particle to act as a tiny lens, refracting light away from the forward detector. (Additional, secondary effects include light scattering and absorbance). A small, negative-going pulse occurs in the detector output, with a height proportional to the square of the particle diameter for particles smaller than the width of the view volume. The PSD is constructed rapidly (typ. 7,500-10,000 particles/sec.) by interpolation from a standard calibration curve. For particles smaller than about 2 pm, the method of light scattering (LS) provides the high sensitivity needed to detect individual particles. Scattered light is collected from the photozone over a range of solid angles chosen to optimize the response curve of the sensor, resulting in a pulse height which increases smoothly and monotonically with particle diameter over a wide range of refractive indices. We have designed a hybrid sensor, which combines the response of light scattering and that of light extinction: LS + LE. This results in the desirable characteristics of high sensitivity, provided by the LS response (min. diameter 0.5 pm), and wide dynamic size range, provided by the LE response (max. diameter pm). The allowable concentration limit, which avoids coincidences, is approximately 10,000 particles/ml. The SPOS technique yields real PSDs, constructed one particle at a time, which have exceptional resolution, good accuracy and excellent reproducibility (given adequate sampling statistics). The raw PSD data require no significant mathematical manipulation. This attribute contrasts sharply with the requirements Representative Results Figure 1. DLS result for a latex made with emulsifier Figure 1 shows the Volume-weighted PSD which was obtained by DLS for a dilute suspension of latex emulsion (vinyl-acetate), produced by using a particular amount of emulsifier. This simple, 2-parameter PSD was calculated from the original Intensity-weighted result, which was obtained using cumulants analysis. The Volumeweighted mean diameter is nm, and the standard deviation is 36.9 nm (11.4% of the mean diameter). The low value of chi-squared (0.287) indicates that this simple Gaussian fit should be reliable. download *.pdf version: 1/2013

42 42 Figure 2 shows the population PSD obtained for this same emulsion (1 ml injected into 100 ml water) using the SPOS technique with an LE-type sensor (AccuSizer 780, Particle Sizing instrument. The decaying histogram in Figure 2 represents actual particle counts; it appears to be smooth because the number of particles counted in each channel is large compared to the statistical fluctuation. Figure 2. SPOS result for the latex made with emulsifier Figure 3 shows the Volume-weighted PSD which was obtained by DLS for Systems). This shows the tail of the distribution of latex droplets, which define the uppermost edge of the PSD. The 58,226 droplets which are larger than 1 pm represent 0.024% of the entire volume of latex which was injected into the Autodilution (Pat.) system of the this same emulsion, only this time from a batch produced without emulsifier. As expected, the mean diameter increased because of the lack of emulsifier. Hence, there is an obvious difference compared with the batch prepared with emulsifier (Figure 1). Also, the standard deviation indicates that the particles have agglomerated or coagulated to some extent, therefore forming a population of bigger particles. Figure 4 shows the population PSD obtained for the emulsion produced without emulsifier (also 1 ml of the latex sample (Figure 2). The tail represents 0.634% of the entire volume of latex injected. This is a much larger fraction than that found for the other sample, due to the fact that the tail of outlyers extended out to much larger diameters. Indeed, its shape differs markedly from that of the tail seen in Figure 2. was introduced into 100 ml of water). In this case the number of particles found to be larger than 1 pm is 90,075, nearly twice the number found for the other Figure 3. DLS result for a latex made without emulsifier Conclusion These results are consistent with the well-known observation that inadequate addition of emulsifier can result in destabilization of polymer emulsions, leading often to dramatic growth of outlyer particles. There is very substantial growth in the number, as well as the average diameter, of the over sized particles. Consequently, there can be a dramatic increase in the volume fraction of these outlyers. However, despite this increase, the fraction is typically small enough in absolute value to remain undetected by ensemble sizing techniques, notably Fraunhofer (laser) diffraction. Figure 4. SPOS result for the latex made without emulsifier The combined DLS+SPOS technique is compatible with the demanding needs of both the research lab and the QC/production environment. SPOS is a powerful tool for extending the reach of the DLS method for particle size analysis. It provides a fast, simple and reproducible method for quantitatively characterizing the quality of a final polymer emulsion product. SPOS yields precise, quantitative measurements of the actual number, as well as size, of particles which populate the uppermost region of mostly-submicron PSDs. Clearly, it is a very attractive alternative to optical microscopy, a tedious, time consuming and subjective technique with limited statistics. The absolute volume fraction of particle outlyers which can be determined by SPOS offers an invaluable window on both the quality and stability of a wide variety of colloidal suspensions and dispersions. 1/2013 download *.pdf version:

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44 44 A Question? Use? of Multilayer plastic parenteral vials with improved barrier properties and increased impact resistance are providing manufacturers with a welcome tool for the delivery of biopharmaceutical formulations Wolfgang Dirk Gerresheimer AG Figure 1. Multilayer parenteral vials 1/2013 download *.pdf version:

45 45 The major challenges in protein and peptide production include reproducibility, easy scale-up and process robustness. In addition to being safe and efficient, the drug has to be applied in the right way for the patient to experience its therapeutic effect. Delivering a protein as a parenteral therapeutic is a complex challenge and involves investigations on stability, pharmacokinetics and bioavailability, all of which are potential sources of failure. Although peptide and protein drugs have a limited shelf-life in solution, most biopharmaceutical drugs are launched as injectables because they cannot survive the oral administration route.therefore, parenteral packaging components for biopharmaceuticals play a major role in the phase of developing the drug delivery concept, as they can have a significant influence on the stability of the respective drug product formulation. In a nutshell, the specific properties of biopharmaceuticals mean that they require more sophisticated container closure systems and glass, as the conventional material for syringes sometimes reaches the limits of its capabilities. Plastic polymers such as polyethylene and polypropylene as an alternative material to glass for packaging components are well established in various areas of application, such as solid and ophthalmic preparations, as well as infusions. These polymers are not ideal candidates for injectables due to their lack of transparency after sterilisation and their limited gas barrier properties. Polymer Usage There are two examples of plastic polymers in the class of polyolefin compounds, which can be used for primary packaging components and permit the long-term storage of a liquid drug product. One is cyclic olefin copolymer (COC),a copolymer of a six- member cyclic carbon hydride with polyethylene.the other is cyclic olefin polymer (COP), a polymer based on a five-member cyclic carbon hydride polymerised by metathesis reaction. Superior properties compared to polyethylene or polypropylene are high transparency, low level of organic extractables - being typical for plastics - and no extractable metal ions. The question is why these plastic compounds have not yet conquered the sector of primary packaging for parenterals? The reasons for this lack of universal use include limited experience in the environment of the regulated pharmaceutical industry and long drug development times. In contrast, the Japanese pharma market has already been using parenteral plastic vials and syringes produced from COP for many years now. Another is cost pressure because high quality polymers like COC and COP are rather expensive compared to glass. Finally, there is a difference in the processing of plastic vials on standard glass vial filling lines because they cannot be introduced using the conventional method via the traditional depyrogenisation oven. The complexity and sensitivity of biopharmaceuticals has changed the picture and makes the use of high- end plastic polymers for parenteral containers an interesting solution for primary package of injectables. Stability and Adsorption There are various degradation mechanisms which affect the stability and availability of biopharmaceutical drugs, such as Figure 2: Two 5ml glass vials (tubular glass type 1) are first rinsed with acetone and then twice with WFI. The test vial (left) is filled with 5ml of 20 per cent BSA solution in WFI. After a storage time of 24 hours at ambient temperature the solution is retracted by Pasteur pipette. Then the test vial and the blank vial are treated with 5ml of dye solution (0.1 per cent Coomassie Violet R200, 10 per cent acetic acid, 20 per cent methanol in WFI) and emptied by Pasteur pipette after a storage time of 24 hours. The colouration of the test vial displays the significant adhesion of protein on the vial surface. The blank vials were not treated with BSA solution and subsequently show no colouration of the inner side walls. Figure 3: One 5ml multilayer plastic vial (COP/PA/COP; left) and one 5ml glass vial (tubular glass type 1; right) are first rinsed with acetone and then twice with WFI. Both vials are filled with 5ml of 20 per cent BSA solution in WFI. After storage time of 24 hours at ambient temperature the solution is retracted by Pasteur pipette. The vials are treated with 5ml of dye solution (0.1 per cent Coomassie Violet R200, 10 per cent acetic acid, 20 per cent methanol in WFI) and emptied by Pasteur pipette after a storage time of 24 hours. The most intense colouring and therefore the strongest protein adhesion is found in the glass vial. peptides or proteins, during storage in the final container. Several investigations have been performed to ascertain the level of adsorption of protein-like molecules on the surface of different materials used for primary packaging. It has been observed that adsorption is proportional to surface area and depends on the type of protein and formulation. Other publications claim that absorption is a very dynamic process of protein resorption occurring within 24 hours until equilibrium is reached. As a result, low concentrated protein-based drug formulations sustain degradation up to 50 per cent of the original concentrations. Bovine serum albumin (BSA) as a model protein showed moderate absorption of nine per cent (3). Even this moderate loss requires a significant overfill as compensation with adverse effect on the efficiency of the manufacturing costs. Figure 2 (page 105) shows the product loss of BSA onto glass surface. Figure 4. Multilayer vial: COP = cyclic olefine polymer, PA = polyamide download *.pdf version: 1/2013

46 46 Proposals to reduce protein adsorption include the following measures: The inclusion of high concentrations of an inert protein in the drug formulation to saturate the glass surface The addition of carbohydrates, surfactants or amino acids to reduce interaction between container surface and protein Silicone oil treatment of the glass vial surface to reduce the adsorption At the same time it is reported that silicone oil droplets can cause aggregation of proteins (4). Last but not least, the correct selection of the container material also influences the stability of protein solutions. CJ Burke et al evaluated the protein adsorption properties of different materials such as glass, polyester, polypropylene and polyamide in an empirical study (5).The result of this study demonstrated that the correct selection of container material for each protein is essential to achieve minimisation of product loss by adsorption. Figure 3 (page 105) shows an extract of a study where a comparative test of protein adsorption on type 1 glass vial and a multilayer COP vial was performed utilising BSA as a model protein. The figure clearly shows the reduced adsorption level of BSA on the inner surface of the COP multilayer vial compared to the glass vial. Based on this, it seems important to include COP vials in drug container compatibility screening tests for novel protein-based biopharmaceuticals parallel to the glass vials - a notion supported by the work of Hoffmann-La Roche (6). As shown above, it is obvious that the use of COP-based plastic vials can improve drug potency by reduced adsorption on the container surface and could save overfill of typically expensive biopharmaceuticals which should more than compensate for the higher costs for the COP plastic vial. Metal Ion Release at High ph Values Glass is composed of a set of inorganic oxides that forms a three- dimensional structure during the manufacturing process. Parenteral drug solutions with with a ph value above seven attack the surface. Under such conditions the glass releases metal ions with potential adverse effect on the stability of sensitive biopharmaceuticals. In severe cases the attack on the glass surface can even cause flaking, which has led to an increased rate of recalls (7). One can easily imagine that a ph shift or released metal ions would be sufficient to cause an adverse effect on the drug, in that it would denature a protein in a biopharmaceutical formulation. COP-based vials are an ideal solution to problems experienced in connection with parenteral drug solutions with high ph-value. Despite the superior compatibility properties commonly available, COP vials suffer from weak gas barriers, which can impact the shelf-life of oxygen-sensitive biopharmaceuticals. This weak barrier has forced the industry to add additional barrier bags as separate packaging components or freeze-dry in glass vials, which creates additional process costs and related investments for freeze-drying equipment. Very recently, multilayer plastic vials have been introduced with improved barrier properties (see Figure 4). Thus, the main characteristics of the high-end cyclic olefine polymer are enhanced by high gas barrier properties without the loss of any advantages such as low adsorption tendency, no metal Figure 5: Vials are filled, stoppered and crimped. The integrity test has been performed according to the defect evaluation list for blow-moulded plastic containers. The left vial is intentionally treated with a tool to destroy the vial. No leakage was observed. ion release, high transparency and high drainability.the drug contact surface area remains COP, which is known to be a very inert and clean material. The advantage of the multilayer design is the increased show five to 10 times higher impact resistance compared to glass vials. Figure 5 shows the impressive impact resistance of the multilayer plastic vial, which remains intact even when the outer shell is broken. The puncture- resistant polyamide layer of the multilayer structure prevents the liquid leaking and predestines multilayer vials for usage of cytotoxic drug solutions, for example for anticancer treatments. Higher break-resistance gives the biopharmaceutical production the opportunity to reduce production costs generated by breakage during filling and transportation. This aspect could be also a significant contribution to cost saving. We expect that combined considerations, such as stability, throughout the shelf-life, safety during filling, transportation and handling will change the niche role of multilayer plastic vials as parenteral containers with superior properties addressing the specific functional requirements of sensitive biopharmaceuticals and will make drugs more efficient and safe in the long run. oxygen barrier and improved integrity when the container suffers from external impact or incidental drop due to the extremely high puncture resistance of polyamide which strengthens the structure. Regarding the gas barrier properties, measurements of the oxygen barrier of the new multilayer plastic vials demonstrated a barrier level which is superior to any available plastic material in use for parenteral pharmaceutical packaging. Conclusion The enhanced barrier properties of the multilayer plastic vial based on COP offer a new alternative to glass vials for sensitive biopharmaceuticals without the typical limitations of existing monolayer plastic vials made from PE, PP or the COC and COP. The increased impact resistance of the multilayer design addresses concerns such as secure sterility of the filled injection solution during transport or storage or protection of hospital staff and patients against contamination of toxic drug solutions through accidental breakage. Comparing the impact resistance of glass and plastic vials, the result depends on the selected method and the plastic grade. Multilayer plastic vials based on COP. 1/2013 download *.pdf version:

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48 48 Pharma Industry Outlook 2013 Facing the pharmaceutical future In 2013, the pharmaceutical industry will continue to witness major changes and challenges. Considering global economic uncertainties, increasing healthcare costs, and expiring patents, the industry appears to be in a state of turmoil. At the same time, markets are diversifying and new fields of growth are opening up. Rapid development of the emerging markets, progress in drug research, the rise in generics production, the availability of high-potency drugs and innovations in manufacturing processes will sustainably modify the global pharmaceutical landscape. Dr Jérôme Freissmuth Bosch Packaging Technology, NIEMCY Analyzes upcoming trends in the pharmaceutical manufacturing process and their impact on processing and packaging equipment According to a recent survey, global annual spending on pharmaceuticals is set to reach almost 1.2 trillion US dollars in The so-called pharmerging markets account for more than two thirds of the world population. Doubling their spending on pharmaceuticals over the next five years, these markets will reach 30 percent of global expenses by 2016, as population growth and rising incomes contribute to dramatically higher use of medicines. Improved access to drugs is supported by a broad range of governmental healthcare policies and programs. Due to increasing cost pressure and increased local demand, production is being relocated to the emerging markets. In many cases, this also applies to the production of generics. While the share of the industrialized nations in global pharmaceutical expenditure will continue to decline, spending on generics will increase due to expiring patents accompanied by higher generic use for off-patent molecules. Biologics will also contribute to higher spending, as research brings clinical advances for the treatment of patients all over the world. Cutting-edge developments in personalized medicine have led to sophisticated solutions tailored to stratified groups. We observe a global trend towards combining pharmaceuticals with medical technology applications. The development of new drug delivery devices increasingly focuses on pa- Studied technical chemistry at the Technical University of Vienna, Austria. He holds a doctorate in technical science and has worked as a management consultant focusing on strategy and organizational projects for the pharmaceutical machinery industry and process industry for several years. In 2010, Jérôme Freissmuth joined Robert Bosch GmbH as Director of Business Development, Product Management and Marketing in the Packaging Technology division, Business Unit Pharma. From June 2013, he will take over the position as Plant Manager Pharma in Hangzhou/China. He can be reached at Jerome. The Static Division (SD) technology, developed by Eisai Machinery, detects moving particles in pharmaceutical liquids by us of an optical sensor 1/2013 download *.pdf version:

49 Manufacturers increasingly rely on the use of barrier technology such as isolators tients individual needs. Some of the devices such as inhalers are necessary applications to transport the active substance to where it is needed. Tools such as insulin pens have been optimized, in particular with respect to convenience and ease of use, while the equipment generally tends to be smaller and much safer to handle. In this sense, medical technology applications improve the quality of patients lives. At the same time, drug delivery devices are used as a targeted measure for product differentiation. The availability of high-potency treatments has also exploded in the past decade. High-potency active pharmaceutical ingredients (HPAPIs), for example, is a fast growing segment, and is projected to grow at a compound annual growth rate (CAGR) of 9.9 percent through To keep pace with these advances, engineering expertise is required to design equipment that can handle, package and secure such substances. Pharmaceuticals, biopharmaceuticals, vaccines and anti-virals must be manufactured and packaged with the utmost caution and attention-to-detail. It is with these requirements in mind that we see five particular trends emerging in the field of pharmaceutical processing and packaging equipment, namely: a rising demand for pharmaceutical quality and safety through inspection technology; the ability to handle potent substances; adapting lines for small batch sizes and research purposes; an increasing use of single-use components; and the need to improve productivity by optimizing manufacturing processes with respect to Overall Equipment Effectiveness (OEE). Ensuring pharmaceutical quality and safety Strict pharmaceutical quality and safety standards such as the American Food and Drug Administration s (FDA) Process Analytical Technology (PAT) guidance, as well as Good Manufacturing Practice (GMP) set the framework for pharmaceutical manufacturing processes. They aim at reducing the risk of product recalls and, most importantly, are designed to safeguard consumers welfare. In order to comply with these regulations, the industry requires reliable and high-end inspection technology equipment to be integrated in their production lines. Since 100 percent control has become obligatory, manufacturers are continuously challenged to increase output and improve efficiency, as well as inspection accuracy, the main focus will be on fully automated solutions. Manual and semi-automated devices remain in use for research purposes, customized smaller batch applications and the re-inspection of rejects from fully automated machines. Physical inspection via spectroscopic methods, pressure decay or high-voltage can be used to detect leakages and fissures of containers. Quality control is essential for liquid and solid pharmaceuticals such as syringes, ampoules, vials, as well as tablets and capsules. One of the most common and reliable methods for particle inspection is the static division (SD) technology. It derives its name from the ability to differentiate static from moving objects, using light transmission to detect moving particles by measuring dynamic light fluctuation. Projecting light through the liquid onto an optical SD sensor enables the differentiation between particles contained in the liquid and immobile objects. The SD technology is also suited for inspecting filling levels. Ultramodern high-speed cameras in turn allow for the reliable detection of particles and cosmetic container defects. The combination of these two inspection methods provide for best inspection results. Machines based on x-ray technology serve as systems for comprehensive quality and weight control of capsules. These technologies are advancing rapidly due to software development and new imaging capabilities. Most recently developed download *.pdf version: 1/2013

50 50 inspection units are able to simultaneously check all quality features like weight, foreign particles, deformation of capsule top and bottom, as well as length in real-time and at high throughput rates. The exact process control adopts several functions of visual systems for error identification and provides significant benefits such as reduced reject rates and the prevention of packaging errors. Managing high-potency substances The use of high-potency pharmaceuticals Bosch Packaging Technology Business Unit Pharma Bosch Packaging Technology Business Unit Pharma is one of the leading providers of process technology and packaging solutions for the pharmaceutical industry. The portfolio includes single units, systems and complete solutions for process technology of sterile liquids and powder processing. It also comprises primary packaging for sterile fill&finish and solid dosage forms, secondary packaging as well as inspection technology, qualification, validation and services. The following product brands are part of Bosch s pharma portfolio: Eisai Machinery, Hüttlin, Manesty, Moeller&Devicon, Pharmatec, SBM Schoeller- -Bleckmann Medizintechnik, Sigpack and Valicare. For more information, please visit has grown extensively, causing manufacturers to pay more heed to protecting all elements of the supply chain from their potentially harmful effects. Particularly in the past ten years, containment has steadily moved up the agenda for drug manufacturers and will continue to do so. Advances in oncology and immunology have led to increased use of highly potent and cytotoxic substances in the treatment of cancer, and hence new challenges in the containment of these substances. In the supply chain, both workers and the drugs themselves are at risk if containment technologies are not applied effectively. Also, for high potency drugs such as hormones, Good Manufacturing Practice (GMP) guidelines require dedicated facilities to minimize the risk of cross contamination. The handling of highly potent drugs is therefore built around the principle of protecting drugs and employees from contact with each other, with as little manual intervention as possible. The latest equipment solutions favor the use of automation and robotics technology to reduce human contact with any substances that are being manufactured. As a result of the increasingly strict guidelines from regulators, manufacturers increasingly rely on the use of barrier technology such as isolators. Barrier Technology allows fully enclosed, sealed and pressurized units completely separated from operators. They offer far greater sterility assurance than conventional cleanrooms, and can significantly lower costs associated with more traditional filling and finishing methods. The most advanced, closed restricted access barrier systems (crabs) contain toxic compounds, usually in their use of positive pressure and air filtration systems within the chamber. Technological advances in air suits, gloves and sleeves further diminish the risk of cross-contamination. Automated cleaning features allow for machine parts to be cleaned without manual disassembly, and give employees greater protection from potentially harmful substances. Producing small batch sizes Although personalized medicine still is at an early stage of development, targeted drugs that take account of genetic variations will allow large numbers of patients to receive highly individualized treatment in the near future. Personalized medicine will continue to demand ever more flexible and versatile processing and packaging solutions. Smaller batch sizes shift the emphasis from speed and mass production of standard dosage products to more individualized products packaged in high-quality materials. Short start-up times, easy changeovers and a high degree of automation are key considerations. Before being introduced to the market, personalized medicine requires a great deal of research and development (R&D) effort. Devised on very small laboratory equipment, the recipes need to finally be transferred to production-scale machinery. However, manufacturing lab equipment is highly complex and costly. New machinery developments demonstrate the possibility of covering almost the entire manufacturing process in one single machine, thereby dramatically reducing investment costs. From research and development via scale-up to industrial production scale, manufacturers strive to reduce time to market. Laboratory processes can be optimized by implementing small and flexible machinery. Key production parameters are clearly defined and allow for an easier transfer from lab to production scale. Recently developed software is now able to calculate the required process conditions and, hence, to considerably save time. Numerous trials provide scientists with the required information to transfer small batch trial results to large production machinery. In the fast-paced pharmaceutical market, it is difficult for manufacturers to anticipate which products will be required next. Therefore new machinery must be future-proof, have scalable and flexible platforms, and be adaptable to new products, characteristics and formulations. These solutions are supported by the enhanced use of pre-sterilized packaging styles like syringes, vials and cartridges. With their flexible platforms, state-of-the-future machinery is capable of processing many different containers. Moreover, equipment providers will be well- -advised to increase their services in terms of formulation and development support. This service can range from operator training sessions for a trouble-free usage to the rental of entire laboratories including personnel and equipment for the development of galenic formulations. The data generated in these 1/2013 download *.pdf version:

51 51 The laboratory device Solidlab 1 from Bosch Packaging Technology combines three process modules in one single machine: powder mixing, granulating and coating of pharmaceutical pellets and tablets test runs must be suited for an easy scale-up to the customer s own production equipment. Utilizing single-use components The demands for greater flexibility and the elimination of possible contaminants will find another effective ally in the form of single-use components. This trend is a consequence of industry safety regulations, growing use of highly potent substances, and a shift towards smaller batch sizes. The time-consuming process of cleaning, sterilization and validation of product contact parts, particularly during changeovers has long been a hindrance in achieving operational efficiency. Single-use, pre-validated, pre-assembled and pre-sterilized parts including hoses, product bags, filling needles and tubing remove this inefficiency and can eliminate the loss of capacity resulting from lengthy cleaning validation as well as the risk of contamination between batch runs. In 2013, pharmaceutical manufacturers will be increasingly drawn to the simplicity and speed of single-use systems, which easily meet industry standards. Assembled in DIN ISO class 7 cleanrooms, the latest single-use components are connected to the product stream via sterile plug-and-play connections and are easily removed, bagged and disposed of without breaking connections and exposing the environment to the product. Market-leading experts offer ready-to-install-solutions that can easily be validated. Flow behavior, interfaces, tubing layout, distribution and connection aspects are pursued using a holistic approach. This makes new single-use filling systems easy to connect and operate. They are precise and safe, and allow significant time savings on product changeovers. Improving productivity In general, rising cost pressure in production will press manufacturers to further improve productivity with respect to Overall Equipment Effectiveness (OEE) over the next few years. Large-scale production of generics will increasingly be re-located to the emerging markets, calling for durable and highly productive machines. To maintain and improve a plant s OEE, aftermarket services are becoming more and more important. A processing and packaging specialist who wants to keep pace with the industry needs to offer download *.pdf version: 1/2013

52 52 With the new product line PreVAS (Pre-Validated, Pre-Assembled, Pre-Sterilized), Bosch offers cost-effective plug and play tools which provide additional flexibility for aseptic filling operations. Bosch Packaging Technology Based in Waiblingen near Stuttgart, Germany, and employing 500 associates, the Bosch Packaging Technology division is one of the leading suppliers of process and packaging technology. At over 30 locations in more than 15 countries worldwide, a highly-qualifi ed workforce develops and produces complete solutions for the pharmaceuticals, food, and confectionery industries. These solutions are complemented by a comprehensive after-sales service portfolio. A global service and sales network provides customers with local points of contact. Additional information is available online at www. boschpackaging.com. comprehensive consulting services all over the globe. OEE is equally important when it comes to the development and market introduction of new pharmaceuticals. So far, the production of small batches has been quite an expensive venture. But with the optimization of machines in terms of flexibility, automation, easy changeover and scale-up, the situation has changed significantly and will continue to do so in the future. These improvements enable manufacturers to develop new drugs with short time to market, while complying with strict regulations. Pharmaceutical companies that offer machinery and services along the pharmaceutical value chain clearly lead the way into an exciting future of changes and opportunities. References mvc/bosch-presents-enhanced-inspectiontechnology-portfolio asp IMS Institute for Healthcare Informatics (2012): The Global Use of Medicines: Outlook Through DevelopmentApprovalProcess/SmallBusinessAssistance/ucm pdf global-high-potency-active-pharmaceuticalingredients-hpapis-market-expecte 1/2013 download *.pdf version:

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54 54 A Safety Concept In the pharmaceutical industry, blister packaging has become the most widespread solution for packaging drugs. It provides effective protection to unit doses such as tablets or pills extends shelf life and offers a degree of tamper resistance at the same time. photo: Faubel Blister packaging being child-resistant, young children cannot easily access the packaged product or, ideally, cannot manage at all. Designing blister packaging that complies with EN standard for pharmaceutical products in Europe or with US 16 CFR in the USA is a technical challenge for which many factors have to considered. Thanks to the Child-Resistant and Senior-Friendly Blister Label (CRSF), it is now possible for the first time to simplify this process, to achieve child safety in pharmaceutical packaging while complementing it with various possible applications. Young children s health Young children begin to explore their environment at a very early age. They tend to do so by using all their senses and putting almost everything they find in their mouths. And pills can be so easily confused with sweets! This is why young children under four are unfortunately the most prone to accidental poisoning with over 80% of cases concerning this age group. In Germany alone there are some 100,000 cases of child poisoning per year, more than 50% of which are caused by drugs. photo: Faubel Fig. 1: Medicine is the most common cause of poisoning in young children Dr Rolf Abelmann ivm Institut VerpackungsMarktforschungs GmbH, Brunswick, Niemcy Reinhard Kuge Faubel Melsungen, Niemcy Higher Safety with Child-Resistant Packaging Child-resistant packaging can remedy this by preventing young children from accessing the contents of drug packs, should they manage to lay their hands on them despite all precautions. Blisters are a suitable type of drug packaging as they comply with EN 1/2013 download *.pdf version:

55 55 for Drug Packaging Child-Resistant and Senior-Friendly Blister Labels or US 16 CFR stipulating the use of non-reclosable child-resistant packaging for pharmaceutical products. It has been achieved by combining adequate packaging materials with an ingenious opening mechanism. While in Europe push-through packaging is still used with multi-layer laminated films - hence reinforced to meet these requirements - more sophisticated systems are currently gaining momentum in the United States. Besides requiring more strength from the user, they feature various barrier levels involving cognitive and motor skills (e.g. peel/push blister packaging). Fig. 2: How to open peel/push blister packs Legal requirements for the protection of young children With its Poison Prevention Packaging Act (PPPA), the United States were, historically speaking, the first country to enforce the use of child-resistant packaging for prescription medicine and for a number of over-the-counter drugs in the 1970s (see 15 USC Sections , US 16 CFR 1700). Today, there are similar regulations and standards in use in Germany as in the rest of the world (see D Stipulations, section 28 of the German Medicine Ac, Section 12 Narcotics Prescription Act, AUS - Therapeutic Goods Act, UK - Medicines (Child Safety) Regulations, EN 14375, and ISO 8317). After passing the tests, the conformity of the packaging with current regulations (see will be evidenced by certificates. Child-resistant packaging for drugs is ruled by an ever-increasing array of national regulations. The need for worldwide harmonization as well as growing awareness of child safety in medicines are likely to boost the use of child-resistant packaging and make higher demands on child safety in the future. Functional reliability Packaging designed to prevent access to drugs by small children must be tested for reliability. Sophisticated opening mechanisms relying on tricks or the use of certain materials are no guarantee that young children will not able to open the pack if they try hard enough. Time and again, supposedly child-resistant packaging happens to fails in practice because young children manage to open it fairly quickly. How effective a type of child-resistant packaging truly is depends on a great variety of factors. Safety requirements for pharmaceutical blisters The tests required to establish how safe blister packaging is for young children are described in the EN standard as well as in the procedure set forth by US 16 CFR (U.S.) for non-reclosable packages containing pharmaceutical products. The suitability of packaging for senior adults is investigated, too. In two test periods of five minutes each, about 200 children aged between 42 and 51 months are asked to open blister packs filled with placebos. Before the second trial, opening is demonstrated to them without any further explanation. Within the first 5-minute time period, the percentage of children able to extract more than eight unit doses from the pack shall not exceed 15%. (For testing according to US 16 CFR , the number of units to open can be adjusted to the toxicity and the dose of the individual packaged product and therefore be lower.) Not more than 20% der children shall have managed to open the packs within 10 minutes. In tests involving senior citizens, at least 90 out of 100 participants between 50 and 70 years of age shall be able to extract a unit dose from a blister card in less than one minute. To be certified, the packaging concerned must have passed both tests, the one involving young children and the other one, senior adults. Testing and certification is carried out by institutes whose accreditation must comply with to be acknowledged by market participants and institutions (see download *.pdf version: 1/2013

56 56 CRSF-Label: an innovative safety concept The CRSF label has been developed to take into account the principle of child resistance and senior friendliness in packaging as well as the safety issue. Thanks to its special safety features, the CRSF label can enhance a finished pharmaceutical blister card with no child protection. So far unique, this concept has a wide range of applications. In addition, it can accom modate detailed client and product information which, normally, would not fit on an ordinary blister card. By enhancing blister packaging with a CRSF label, one obtains a child-resistant packaging that fulfills the safety requirements set forth by various standards. It contains four barrier levels that make it difficult for young children to open blister cards whereas senior adults can access their medication without effort. Besides, it can be affixed to either side of a blister card like a label. Not only does this solution meet high expectations in terms of safety but it is also very cost-effective. Blister packaging protected by this label has already been certified according to EN and US 16 CFR First barrier level: A labeling layer which can be custom-designed is pulled up. Second barrier level: To open the peelable seal of a single unit dose, you need to understand the corresponding pictogram. If you press the blister pack from both sides, it will bend in the middle, raising the opening grips of the cavities. Third barrier level: Once the opening grip is up, it can only be fully removed by pulling it straight up, thus requiring more effort. Fourth barrier level: as explained by the pictogram, applying the motion trick, a slight twist to the right, helps to open the peelable seal. photo: Faubel Fourth barrier level: Once the peelable seal has come off, the push-through layer becomes visible. Simply pressing it through is virtually impossible, even with considerable force. Fig.: Child-resistant and senior-friendly: Multiple barriers for enhanced child protection and effective senior adult use The six-barrier principle To design packaging which is safer for children, it is important to integrate obstacles which can only be overcome with difficulty by children but easily by senior adults (between 50 and 70). To solve this dilemma, the opening of a Child-Resistant and Senior-Friendly Solution relies on the following user abilities: strength, fine motor skills, logical thinking, experience, patience and intuition. These labels are made of three layers: A layer covering the entire blister card which is to be peeled off first (peelable layer). An additional peelable layer covering each unit dose which only comes off if a motion trick is applied. A push-through layer which can only be pressed through by applying force along marked break points. These three layers are designed to form six safety barrier levels: three mechanical and three logical ones. Fifth barrier level: A text and a pictogram explain how to open the push-through layer easily by pressing along marked break points. By pressing out the tablet, it is relatively easy to break through this barrier layer but only in the Open here area. Sixth barrier level: The lidding aluminum foil can only be broken now to remove the tablet from its cavity. Mechanical barriers made of three layers tend to reduce the likelihood of young children accessing the contents of the blister card by using skill, effort or by scratching off the lidding foil. But Fig. 4: How to open a blister pack protected by a CRSF label 1/2013 download *.pdf version:

57 Mechanical barriers and logical an umbrella safety photo: sxc.hu overcoming logical obstacles deciphering pictograms, understanding the mechanism and as a result, find out the way to proceed through experience and intuition - is very difficult for children aged between 42 and 51 months. Opening by trying is complicated by the fact that children do not have the patience and the ability needed to concentrate for a longer time. The six-barrier principle is, however, no challenge to the cognitive or motor skills of senior adults. Opening packs of this kind quickly becomes an automatism. The materials used to produce child-proof labels are saliva-, bite- and tear-proof; the adhesives used are certified food safe. Produced separately, the Child-Resistant and Senior-Friendly Label can be affixed to blister packs with different contents. It is available in many standard packaging sizes and it can be adapted to the particular nature of the cavities. Such a state-of-the art, child-resistant and senior-friendly solution can be realized in cooperation with the drug manufacturer and tailored to meet the level of efficiency and cost-effectiveness required in the production process. A common path for protecting children In pharmaceutical packaging, the proportion of child-resistant packaging is expected to increase worldwide. This is spurred by harmonized regulations and their being more effectively enforced. As a result, companies feel the need to address the resulting challenges at the right time. The key question that forward-looking businesses are asking themselves is: What actions and changes are needed to promote child-resistant packaging? In many cases it has become obvious that the widespread use of child-resistant packaging requires considerably less effort and expense than originally expected. Often, the appropriate measures merely involve catering for the ongoing replacement of materials such as foils or packaging components like seals once at the beginning. The CRSF-Label is a versatile element of the system. Until the packaging is finally certified, this process is a particular challenge to the cooperation and communication between the partners involved, i.e. pharmaceutical companies, packaging manufacturers, service providers and testing institutes but the our children s health of is well worth the effort. download *.pdf version: 1/2013

58 58 2D Why A significant increase in the number of attempts to bring counterfeit products onto the pharmaceutical marketis being observed worldwide since the beginning of the new century. In 2000, 240 thousand forged medicine boxes and 2 tons of materials were found in Italy. Jacek Rządca I.E.S. International According to statistics, in China 100 thousand people fell victim to counterfeit drugs in In 2003, 200 thousandbottles of the anti-cholesterol drug Lipitor were withdrawn from the market in the USA. This year, the Food and Drug Administration (FDA) has mustered a special team in order to develop a strategy of fighting the distribution of counterfeit medications. A bit of history In the years , marking and identifying medical products intended for human use with a special code was made mandatory in USA (FDA), France (AFSSAPS) and Turkey (the Ministry of Health).So-called online-coding in the form of the 2D Data Matrix took the place of the classic barcode. Previously, the barcode was printed on the container by, e.g., the packaging supplier. The new type of code is printed on each individual container in an online mode, during custom packaging of the drug. The code contains, among others, information about the lot number, expiration date and Global Trade Item Number (GTIN), an identifier for trade items a series of numbers which identify the country of origin, the producer and the product type. This new solution forms the basis of a current hot topic in the Polish pharmaceutical industry, namely Track&Trace. Why has the 2D Data Matrix code superseded the classic barcode? First of all, it allows the inclusion of much more information on a smaller surface area. In a square measuring... by, containing 32 rows and 32 columns (ECC200 mode),it is possible to encode 60 8-bit ASCII characters or a sequence of 91 alphanumeric symbols. Second, the 2D code contains redundant (superfluous) data. The algorithm makes it possible to decode the character even when the code is damaged or the image quality is low. How should 2D codes be printed? The new technology compelled manufacturers to use printing technologies which exceeded the capacity of one-dimensional code technologies. At the outset, the printing of individual labels was ruled out because of the possibility of fraud through their unsticking and sticking on another container. It was necessary to utilise a technology of printing directly on the carton. Two printing technologies are currently in use: laser marking and inkjet marking. In the first case, the background needs to be coated with dye. A laser heats microdots on the surface, causing the outer layer of dye to melt and evaporate. In this way we can obtain, for example, a white inscription on a dark background. The quality of the inscription depends on the interactions between the laser beam and the surface. The advantages of this technique are: a high repeatability, speed and precision. The disadvantages are a high energy consumption and the large size of the apparatus. 1/2013 download *.pdf version:

59 photo: prografi ka.com.pl 59 kod 2D Inkjet is a technique used earlier in PC printers. The printing quality depends on numerous factors, such as e.g. interactions between the ink and the material on which we are printing or the positioning of the container against the print head. The print head must be very close to the surface (up to 20 mm). The advantages of this technique include a lower price, a high efficiency and good contrast. In the microscale, the edges of the inscription have an irregular shape because of the degree of absorbency of the material and the irregular shape of ink drops. The printing quality affects the time, correctness and repeatability of code reading. The ISO/IEC norm specifies a number of parameters which influence the final evaluation of the marking. A comparison of the results of printout qualification on a device, depending on the printing method CellContrast scale from 0 to 4. The value of this parameter can worsen if the background is too dark, too shiny or insufficiently coated with dye. Modulation this parameter reflects the distribution of dark and light pixels. A good quality of modulation means that the light and dark areas are of uniform value. The value of this parameter depends on whether the carton is transported smoothly during marking. AxialNon-Uniformity scale from 0 to 4. Depends on the smoothness of transport. Refers to the amount of deviation along the symbol s X and Y axes. GridNon-Uniformity scale from 0 to 4. This parameter refers to the greatest deviation of vector values of the symbol s sections as compared to a reference value. The value of this parameter depends on the velocity and stability of the carton during marking. Fixed PatternDamage scale from 0 to 4. Describes any abnormalities in the symbol s control area. The value of this parameter depends on whether the carton is transported smoothly during marking. Unused Error Correction scale from 0 to 4. Indicates the safety margin provided by the algorithm of error correction (Reed/Solomon algorithm). Its value depends on the visual condition of the symbol (damage, readability). Decode this parameter has two values: NOK / OK. It checks the correctness of the algorithm of the data encoded within the symbol. The most frequent cause of problems are printer software errors. Code quality verification can be performed using scanners with software developed in accordance with the requirements of the ISO/IEC norm. The final grade, expressed on a scale from A to F, is derived from the sum of all the parameters. According to ISO norms, a C grade is the minimum for 2D Data Matrix codes. Current machine capacities make it possible to fulfil this criterion at speeds of up to 400 cycles per minute. A comparison of the results of printout qualification on a device, depending on the printing method. How should 2D codes be read? In the Track & Trace system, the printed code should be read repeatedly while the container is still on the production line, e.g. in order to transmit the data to the system s database, where they will be stored. The 2D code requires the use of a device capable of reading in two dimensions. This rules out the laser scanners used to read one-dimensional download *.pdf version: 1/2013

60 60 barcodes. Thus, a vision system is the typical solution. The scanning process takes place in two stages: image acquisition by the camera, then image processing anddecoding by the vision system software. Many suppliers of vision system components are present on the market. Cooperation with producers who specialise in solutions for the pharmaceutical industry is particularly worth considering. They have an advantage over competitors functioning in many other branches of industry not only because of their greater expertise and familiarity with conditions characteristic for packaging medications, but Positive carton transport also because they offer complex solutions in terms of hardware and software developed especially for the pharmaceutical industry. How should the 2D code system be implemented? Clients frequently ask about the possibility of integrating a 2D code printer into the existing equipment. Machines not adapted to such modifications (cartoner, balance etc.) significantly limit the available options. First of all, the location of the code frequently changes depending on the carton format. Cartons may differ in size, colour or the type of surface. Second, the labelling-verifying module would have to utilise an existing rejection system; as a result, it becomes impossible to determine the flaw which was the cause of rejection in any given case. Third, old machines will never permit a high printing qualityand full control over the process. Fourth, the costs of the mechanical modification, integration with the existing steering system, the launch itself and subsequent problems and stoppages make such a procedure uneconomical. When choosing a dedicated device for printing and verifying 2D codes, it is a good idea to take advantage of the offer of a company which has a lot of experience in the construction of labelling machines. In order to maintain control over the process, renowned producers use positive carton transport, in which each container is indexed and tracked by the system. The inputs must equal outputs + rejected products. Maintaining a constant distance between cartons, regulated guide rails along the X, Y and Z axes make it possible to print the code under identical conditions, and thus maintain a high repeatability and quality. Furthermore, labellers dedicated for this purpose can also perform additional functions, e.g. apply vignettes or tamper evident (TE) seals which protect the container against opening. A printer and camera are not everything Rising market requirements and the amended legal regulations of national health protection services will soon force all drug manufacturers to begin using 2D codes on a mass scale. It should be remembered that Track&Trace is the process of tracking the current and previous location of an individual object. The 2D Data Matrix code is only a medium used to store this information, together with many other data. Purchasing a printer and camera is not enough to fulfil the demands of the new law, since a system for gathering and managing data is also needed. The best solution is taking advantage of the offer of companies which propose complex hardware and software solutions: the T&T application, the Manufacturing Execution System (MES), as well as applications for gathering data and passing them on to the distribution chain, etc. The companies which prepare for this operation in advance will save time and money. We encourage you to take interest in this issue, since the topic is hot. 1/2013 download *.pdf version:

l dustry.p a-in harm w.p w l w dustry.p www.farmacom.com.pl o-in w.cosm w w MAGAZINES PORTAL CONGRESSES

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