pharma / life science The OPTIMA Magazine Freeze Drying Interview with Managing Director Stephan Reuter Additional customer benefits

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1 pharma / life science The OPTIMA Magazine New modular machine The Multiuse Filler OPTIMA H4 Freeze Drying Interview with Managing Director Stephan Reuter Making the invisible visible Additional customer benefits

2 Editorial Content Editorial Welcome to the Third Millenium! in the words of an employee of Optima Pharma who recently expressed the commitment of the company in visualizing flow conditions. Of course, it is also an expression of company pride. The fact is that Optima Pharma has recognized future opportunities and is the pioneer in this field of pharmaceutical applications. Not only this but also further areas of virtual reality promise more insight Making the invisible visible Freeze Drying New modular machine Additional customer benefits Interview with Managing Director The Multiuse Filler OPTIMA H4 Stephan Reuter Access to this simulation technology is by means of supercomputing. On the surface, it is a field which would appear to be reserved for big science and major corporate entities with the necessary research budgets. In actual fact, supercomputing is undertaken in or in association with universitiesand state-financed research institutes. There is a need for specialists who are in a position to work with these supercomputers. Other specialists make the practical framework and create models which can then be calculated by supercomputers. The work of these specialists and the time spent on supercomputers must be paid for. Whether the calculation leads to usable results or not is only apparent after several hours or several days of computer operations. It is thus quite understandable The way to supercomputing for Optima pharma is leveled that medium-sized companies first shy away from approaching this technology. Access to these resources, however, is very important to mediumsized companies, since in many branches the technological requirements have increased rapidly. At the same time, today the universities of applied science also increasingly recognize their attractiveness (in other words: their potential in the economy) and are open to this market. In order to make the contacts easier and reduce the possible inhibitions (including those of a financial nature), the European Union has introduced the PRACE program which leveled the way to supercomputing for Optima Pharma. As one of eight companies in Europe, Optima Pharma has qualified for this project. (Further information on this project and a whitepaper can be accessed at The effect of these new competencies for customers can be found on page 16. Going beyond PRACE and supercomputing, our own contributions in this o-com show the will and the desire of Optima Life Science and Optima Pharma to conceive new technologies for their customers. Working on the details or major steps in development? The decisive criterion is What are the benefits to the customer and do the benefits outweigh the efforts involved? In principle, these developments show that the company is always open to new chances and new technology. Of course, this is always a gamble but without calculable risk, the long-term future existence of any company would be questionable. When the chances of success are weighed against the risks involved, then this is when true innovations come about. CompaCt 4 News 5 Production, latest state of art 5 Definition Virtual Reality Focus: Technology Valuable new insight Making the invisible visible. Additional customer benefits API-Dosing in Oral Films Focus: Company 6 9 Strong foundation, new goals Interview with Stephan Reuter At work High-tech in compact form A better way to test Good things come in small packages newly developed Flexibility and standardization combined 25 Are the gloves intact? Trend maximizing Product Yield Imprint o-com is the communication service of the OPTIMA packaging group GmbH Address OPTIMA packaging group GmbH Steinbeisweg Schwäbisch Hall Germany OPTIMA pharma GmbH Otto-Hahn-Straße Schwäbisch Hall Germany OPTIMA life science GmbH Steinbeisweg Schwäbisch Hall Germany Editor Felix Henning 2 o-com Magazine o-com Magazine 3

3 Compact Compact Retirement after 26 successful years Investments: OPTIMA Manufacturing GmbH OPTIMA expresses its thanks to Jürgen Schäfer Jürgen Schäfer (on the right) Celebration for Jürgen Schäfer, former CEO at Optima pharma: Recognition for his work and many thanks were the central message of Hans Bühler (CEO) in respect of the influence of Jürgen Schäfer, Seminar Lyophilization Compact Freeze-drying in theory and practice Regular seminars on freeze-drying take place at Optima Pharma (location Mornshausen, near Marburg) for employees of the departments Technology, Production and Quality Assurance in the pharmaceutical industry. The last one was in September 2014 when, in joint cooperation with Concept Heidelberg, the three-day event Lyophilization Compact was held. The aim of these events is to introduce the participants to the fundamental principles of freeze drying and examine the critical process steps in terms of validation, to better identify, evaluate and prepare for changes in the processes. At the end of two-days of theory which included talks by Optima employees, there then followed a practice day on site at Optima. During the factory tour and practical training all important components, functions and design possibilities could be viewed on site, everything to do with the latest freeze drying systems. In addition, the practical subjects included materials science and manufacturing. There were also more detailed aspects such as the use of a mass spectrometer for silicon oil detection, turnkey projects and mock-up studies. who retired from the company in summer On Jürgen Schäfer began his career at Optima in the then Paper Hygiene division. He took part in the subsequent expansion over the next 19 years. There were many highlights such as the take-over and integration of the company Amotek in Italy, the building up of overseas subsidiaries and important cooperations, all still very successful today. When he joined the executive management of OPTIMA pharma GmbH the industrial engineer and father of three faced the new challenges over the next seven years. His professional experience Up in the air and decisive action also brought him success in this phase of his career. Turnover doubled from 50 to 100 million Euro and Pharma personnel grew from 300 to the over 600 employees it is today. Jürgen Schäfer always emphasized: Nothing is possible without the right boss and there are many other people involved. It was and is always important for me to support and promote and to recognize where individuals can do their best and be allowed to run at the right time. Working together is important, just as in a big family. His successor is Sieghard Schuchmann, who has already been active at Optima Pharma for several months. D OITM follows D OPPG These abbreviations are recognizable; in aviator language as the numbers of two balloons. In 2006 Optima Balloon D OPPG first took off into lofty heights, mostly over the region around Schwäbisch Hall. The Balloon Team were often en route and look back on 450 hours in the air, with more than 300 starts and landings. Around 1,200 passengers experienced this adventure in the air at first hand. The balloon also took to the air in other countries, in USA, England, Switzerland, Austria, Netherlands, Belgium and Namibia. In 2015 however, this airship now goes into well-deserved retirement. The successor is now ready and waiting! With the new Optima Hot Air Balloon D OTIM (also fondly known as TIM), the Balloon Team of Optima employee Sven Grenzner will once again provide enjoyment for many people when they can look at the world from a perspective normally reserved for the birds. The balloon is also often used at customer events. With a little luck, employees of Optima can also take to the air. At Christmas celebrations for example, at each location people can win a voucher for a flight for two persons. Production, latest state of art Quality and cost benefits combined in production how to do this? In 2011 OPTIMA Manufacturing GmbH was set up as a subsidiary company of the Optima Group. Here production quality, deadlines and costs are directly controlled. At Optima Manufacturing there are ongoing investments and improvements. In 2011 the parts production department, at that time still a Profit Center became a subsidiary company of the Optima Group. Since then, Optima Manufacturing GmbH functions within the group as a service provider for the production of specified parts (and spare parts) and installation of complete assemblies. Customers include all four divisions of the OPTIMA group. Focus is on replacement parts and competence parts. Qualified, highly motivated employees meet requirements for component parts using the latest CNC machines. Definition Virtual Reality Virtual reality is defined as the representation and simultaneous perception of reality and its physical properties in an interactive, computer-generated virtual environment in real time. The term virtual reality is known from the author Damien Broderick in his science fiction novel "The Judas Mandala", published in The term first appeared as a theoretical concept in 1987 in the Oxford English Dictionary. Representation of virtual worlds requires special output devices. The best known are Head-Mounted Display e.g. Just in time for the fourth anniversary of this subsidiary company, on 18th November, a new milling center was commissioned. Highlights are automation with 20 pallets and the tool magazine for 273 tools. The plant can be operated unattended, with increased utilization rate. Permanent investments in tooling machines are an essential component of high production competence. Recently investments have also been made in a 5-axis CNC milling center (DMU65, 2011), in a cycle-controlled lathe (Weiler E40, Oculus Rift, large screens or CAVE. In order to create the impression of space, two images are produced from two different perspectives (stereoprojection). There are various technological systems to feed the respective image to the right eye and these are differentiated between active (e.g. shutter glasses) and passive systems (e.g. polarizing filters or Infitec). For interaction with the virtual world, special input devices 2012) and in two 3-axis CNC milling centers (DMC 1035V, 2013). Furthermore, in 2013 Optima Manufacturing also introduced a new CAM programming system (Computer Aided Manufacturing). This tool enables Optima Manufacturing economically viable compilation of NC programs and processing of parts. are needed. These include for example 3D-mouse, data glove and flystick as well as an omnidirectional treadmill with which movement in virtual space is controlled by real movements. To create virtual reality one needs special software designed specifically for this purpose. These programs must be able to calculate complex three-dimensional worlds in real time. i.e. with at least 25 images per second in stereo (separate for the left and the right eye). This value varies according to application a drive simulation for example needs at least 60 images per second in order to avoid nausea (simulator illness). Source: Wikipedia, German 4 o-com Magazine o-com Magazine 5

4 Focus: Company The Start Mr. Reuter, first a brief look back: What in particular did you notice when you started a year ago and has remained with you since? I immediately had a very positive impression of the highly motivated employees, who strongly identify with the company and are very willing to take on heavy workloads. The company can count on them even when unplanned service calls and business trips abroad are necessary. That is very positive. I also observed ideal conditions for developing and building highly specialized freeze drying systems. The production hall fulfills all the key requirements, with manufacturing on two floors and flexible ceiling openings. What skills and professional experience do you bring with you to Optima? I worked as a project planner and manager of plant construction for six years at the beginning of my career, followed by twelve years at a planning company operating exclusively in the pharmaceutical industry. Most recently, I coordinated global engineering processes and managed large projects at a pharmaceutical company. This experience has provided me with extensive knowledge of the pharma industry and the complete process chain. It is important to me that we are fully aware of the requirements of our customers. A profound understanding of the thought processes helps achieve the excellent quality our customers expect, in accordance with GMP. I intend to further anchor this philosophy in the company. What were your priorities at the beginning of your new job? One of the most important priorities for me was to meet everyone in the company personally. Employees and their qualifications are key resources for success. I tried to spend half an hour with every employee. At a company with a staff of almost 100? Yes, it took place over the course of about four months. Many are often out on service calls so it s not so easy to meet up with them all at the same time. It was also important to me to first understand current processes in order to make adjustments if necessary. I have high expectations of the responsible managers; they act as an extension of myself so to speak. Together we took steps to improve the organization. The truly lucrative work is project execution, which involves identifying potential for improvement and then actually capturing this potential, to allow us to carry out projects more quickly and efficiently. Klee: Interview with Managing Director Stephan Reuter Strong foundation, new goals Stephan Reuter took over responsibility for Technology and Sales at Klee one year ago. Who is the 45-year-old Managing Director, what is important to him, what things does he plan to change and what changes have already been carried out? 6 o-com Magazine o-com Magazine 7

5 Focus: Company You ve brought up an excellent topic. When you look back at your first year, what has changed in the company? What still needs to change? We want to achieve a better integration of internal structures with the pharma headquarters in Schwäbisch Hall. There is potential for improvement there. At our site in Mornshausen, we ve modified some of the organizational structures and introduced the position of works management. In the service department, we ve appointed group heads. We ve also introduced the 5S process and have optimized work processes in production. Cleanliness has been further improved and we ve made a number of investments to improve this site. In process planning, we No equipment leaves the company before being 100 % tested. now have very clear rules for operational startup and FATs: no equipment leaves the company before being 100% tested. We ve improved the testability as well as the efficiency of our equipment tests and have passed all FATs. We ve also driven forward the standardization of our freeze dryer modules What do you see as the Klee brand s position today? When I started at Klee, its reputation was slightly tarnished, both in the market and within the group of companies. The main reason for this was that old orders were not completed before beginning new ones, which at times led to carelessness due to heavy workloads. This is now a thing of the past. Klee currently positions itself as an innovative brand with high quality. We ve learned from the mistakes of the past and have taken the necessary steps toward a strong future. What kind of feedback have you received from the market? We re pleased to have recently landed a major freeze dryer project here in Germany, an outstanding reference project at a renowned pharmaceutical company. We couldn t ask for better feedback. Currently, we re working on seven new projects and have a number of additional orders in the pipeline. And the most recently completed jobs were completed on time, on budget, with high quality. The technology... What technical improvements and innovations in freeze drying technology have you and your colleagues developed or implemented in your first year at the company? A number of development projects have been started with the aim of better standardization. We ve also refined the technological details of several assemblies. Controlled nucleation is one of our current development projects. Advances have also been made in alternative cooling, including the use of high-performance energy-saving coolants. Other new development projects will come to fruition in My goal is to build the best freeze dryer on the market within two years. Currently we are in the top 3. Ultimately our improvements help speed up process times in the freeze drying process. The formulations to be freeze dried are specified by the customers, and we hope to achieve considerably faster cycle times in the underlying processes. We will shorten the length of the process for a given formulation, for instance by making CIP/SIP cleaning and loading faster. This is the overarching goal of our development work: faster and less energy. What technical trends in freeze drying can you identify and what is your opinion of them? The focus in the future will increasingly be on format variability. The second key issue will be speed, the technical limits of which continue to be challenged. The most recent innovation is achieving faster and faster drying processes at increasingly lower pressures. We re also conducting a development project related to freezing. And the third trend is energy, specifically conserving energy in the future freeze drying process. In terms of formats, is it important to be able to process different types of containers? Yes. Plastic bags for instance cannot be freeze dried at the moment. Freeze-dried products are currently dried in the final containers. Alternatively, we can generate a granulate and store it in a plastic bag or other container, which is then filled as soon as it is needed. We ll increasingly be dealing with variations on the classic process, such as dynamic rotational freeze drying. We don t develop primary packaging itself but we work with customers who do. Optima Pharma focuses on the turnkey aspect in their advertising, the idea being to offer customers better integration of all functions, especially freeze drying, in turnkey projects. What do you think of this aspect today? Turnkey is the future. Complex projects and complex filling units are increasingly ordered on a turnkey basis. That is crystal clear. Customers want a single contact person; they want someone to centrally manage the risk of the various interfaces. Whoever can offer them this service will be awarded the contract. Our turnkey capabilities give us a considerable advantage, and this feature will continue to be of tremendous importance in the future. Does Optima Pharma continue to enjoy the same competitive edge in this area? Yes. Especially with Metall + Plastic as members of the group of companies, we re truly able to supply all processes from a single source. What do you see as the technological strengths of the Klee brand? Our process control and automation based on the current PCS7 from Siemens are certainly leading-edge. Moreover, our systems are highly compact and spacesaving in design. The same applies for our compact cooling equipment. Generally speaking, we re simply experts at what we do and supply excellent quality. What s also important is the overall package, from production capabilities to documentation and beyond. For example, we can supply systems around the globe and service them there as well. That doesn t necessarily go without saying. The future... What concrete goals have you defined for Klee? Our ambition is to produce highperformance freeze dryers with very short delivery times to ideally complement Optima Pharma s product portfolio. That is our goal. When it comes to the machinery business, we want to compete on price. And we intend to further expand our international service business and as well as expanding capacities at our site. Thank you very much for this interview, Mr. Reuter. 8 o-com Magazine o-com Magazine 9

6 Newly developed Trade Fair Première at Interphex 2015: OPTIMA H4 for three container types Flexibility and standardization combined A new type of filling and closing machine: The Multiuse Filler OPTIMA H4 covers a great number of diverse applications. At the same time OPTIMA H4 conforms fully to the customer wish for simple operation, ease of accessibility, reliability and low space requirement. High speed machine technology and design Modular and cost optimized Easy retrofit of: vacuum filling and stopper insertion IPC Syringes ml Vials up to 50 ml Containment: All systems orabs / crabs / Isolator can be economically mounted on the standardized machine table top plate. Output: Up to 36,000 objects/hr., extendable Cartridges 3 ml Optima H4 at Interphex (Stand No. 3103) and also at Achema (Hall 3, Stand No. A73) High-tech functions are used where these contribute to overall flexibility for the fundamental concept for the system. Extensive standardization in the development of OPTIMA H4 allow the premanufacture of modules, resulting in time and cost benefits. Nested vials, syringes and cartridges are all processed. OPTIMA H4 has its Interphex trade fair debut. Opening the tubs and removing the Tyvek papers can be done, if required, by a robot. The robot is already installed in the area of the filling machine, thus saving space. Semi-automated systems could also be integrated. There is also freedom of choice in respect of containment: Regardless whether orabs, crabs or isolators, all systems can be fitted to the standardized machine baseplate at low cost. For filling, a ten-position system is provided. For filling flexibility and simple format changes, rotary pistion pumps as well asperistaltic or time-pressure filling systems can be added and at any time. The transport system of OPTIMA H4 originates from high performance machinery. It has been simplified mechanically but nevertheless ensures even and particularly careful handling of the containers. A high output rate of up to 24,000 objects per hour is achieved. Retrofitting can also expand output up to 36,000 objects / hr. The same applies to upgrading of in-process controls (IPC) and for vacuum filling and vacuum stopper inserting. Both can be supplemented at a later date without requiring changes to the machine baseplate. The OPTIMA H4 is presented live at the fair. As a leading turnkey provider Optima Pharma also offers know-how in further technologies. In addition to filling and closing, finely adjusted interacting process technology systems are here at the foreground: for example washing machines, sterilizing tunnels, isolators and further containment systems. Pharmaceutical freeze drying and robotics for product handling complete the extensive Optima Pharma portfolio. 10 o-com Magazine o-com Magazine 11

7 At work Specific container for inhalers High-tech in compact form The aim of the project was to expand the production capacity at the pharmaceutical company by an ambitious 200%. The newly installed system boasts an output of 300 containers/min, while the currently installed line achieves 150 containers/ min. The two systems will operate in parallel in the future. Interestingly, the new system has a footprint of only 7m², New system has a footprint of only 7m² which is 80% less than the previous equipment. The inhaler system consists of a non-freestanding plastic container (similar to a vial) and a plastic housing. Within the processing line, the containers are first sorted in centrifuges and then transported onward on their sides Zero rejects A camera determines in what direction the horizontal containers are oriented. The vials are rotated via two wheels, which ensure that the containers are consistently inserted into the filling machine transport with the opening to the top, regardless of how they are fed horizontally. The system is equipped with in-process control including tare/gross weighing. During weighing, the empty containers are first removed by a swivel arm and placed on a freestanding load cell. A second arm removes the container from the load cell while the first swivel arm grabs another container. The second swivel arm uses this gap in the transport to return the weighed container to processing. The containers are filled 12 at a time by a time-pressure dosing system. The filling needles move horizontally in parallel with the direction of transport, as well as vertically for gentle yet fast filling. Filling below the meniscus prevents the product from foaming. Gross weight checking after the filling station takes place according to the same principle as the net weight checking. The check intervals can be individually specified in the recipe. When 2% of the containers are checked, the customer achieves excellent filling accuracy of 0.2% RSD (relative standard deviation) with a high output of 300 products/min or 18,000 products/hr. For even better accuracy, the filling time is adjusted according to product temperature. A special algorithm compensates temperature fluctuations. The purpose of inhalers is to provide a fine, long-lasting spray without the addition of propellants. Plastic containers containing pharmaceuticals are inserted into the inhalers. High aseptic quality is essential when processing these canisters; moreover, this project was characterized by very fast processing in a small space. output of 300 products/min. 12 o-com Magazine o-com Magazine 13

8 At work Reliable protection Specialized, fully automated ports facilitate the ingress of primary packaging materials which are delivered to the machine in tall bags weighing 8 kg. Due to the system s high output, the supply of containers into the isolator needs to be replenished every 15 minutes, and new caps about every 20 minutes. To make handling easier, the doors of the RTP ports automatically open after docking and a chute slides into position. A counterweight also makes it easier to lift the bag. It is essential to reliably protect operators against the concentrated but non-toxic pharmaceutical, which is why filling takes place under isolator conditions and the exhaust undergoes double filtration. A bag-in bag-out (BiBo) system is used for changing filters to prevent contact with potentially contaminated surfaces. The opening of the BiBo system to the filter is outfitted with a PVC filter bag. During replacement, the potentially contaminated filter is pulled into and sealed in the filter bag. A second filter bag containing a new filter is drawn over the contaminated residue still present. This residue is moved past the new filter into the filter bag and sealed there. The new filter is now ready for use. This procedure ensures that no individual is exposed to the concentrated pharmaceutical at any time. Sophisticated double filtration systems for the product feed combined with the isolator and its automated ports guarantee that the pharmaceutical remains aseptic. A CIP/SIP (clean-in-place/sterilizein-place) system has been installed for the filling system. CIP/SIP is a fully automatic process that doesn t require a glove port. During the cleaning program, the filling needles automatically move to the cleaning position. The complete filling system is first cleaned with warm water and then sterilized with steam. In the long term, it is planned to use the line for campaign production. Large quantities of microbiological monitoring material will then be needed inside the isolator. This monitoring material along with auxiliary equipment required in the isolator can first be decontaminated in a material transfer chamber (MTC) and then introduced to the isolator. The specific unloading area of this fast port has the advantage that the gloves never need to cross the product path to distribute the introduced materials, thereby preventing potential particle contamination of the pharmaceutical. Time-pressure dosing system Turnkey - State of the Art The closing process: The station consists of two transport wheels arranged on top of one another to which the containers or caps are fed. The caps are pressed on to the containers with a controlled force, which is delivered by pockets on spring-loaded mounts. Excessively high force indicates for instance that the plastic cap is deformed and could not be properly attached. A camera system monitors whether the caps are in the proper position. The discharge system features a separate reject outlet for in-process verification and sampling. Containers with any other kind of process defects are rejected via a second outlet. All containers passing inspection are actively transported to the good product discharge. The customer in this project benefitted from having a single contact person for all functional areas, including the filling and closing machine, CIP/SIP, the isolator and the fully automated feed systems for primary packaging. An INOVA VFVM filling and capping machine was combined with a Metall + Plastic isolator both products from the Optima Pharma group of companies. The system passed the SAT in July 2013 with an overall equipment effectiveness (OEE) of >98%. 14 o-com Magazine o-com Magazine 15

9 Focus: Technology Simulation of air currents in a turbulent isolator (Flow lines and pseudo particles made visible) in a capping machine. Flow visualization rapid prototyping Valuable new insight Flow visualization offers tremendous added value for the pharmaceutical industry. Optima Pharma has expanded its expertise in this area and is pleased to offer related engineering services to its customers. Initial projects, both internal and with customers, confirm the high expectations of this pioneering technology. Practice, projects and insights Typical questions that can be answered with the aid of flow visualization include: Is the space evenly filled with air? Are flows too fast, too slow or just right? Is exhaust equipment positioned effectively? Is there flow separation or turbulence? Gaining valuable insight but how? Through practical experience and trial and error? This method is simply too costly and risky in pharmaceutical projects. What is needed is scientific precision. Unfortunately, flow behavior in barrier-protected equipment and cleanrooms has not always been as predictable as desired by customers and system manufacturers. While smoke simulation studies are popular for learning about flows within barriers, the system must first be built before a smoke tube can be connected in the first place. What is thus needed is a procedure that can be used very early on in the design process to indicate necessary changes in a timely manner. This is in fact the purpose of simulations, since they can be carried out before the equipment is built. The ideal design and layout of system parts can be determined using simplified geometry (mock-up) and a few iterations in CAD, followed by simulations. Smoke tests also cost time and money and are very limited in terms of simulation. New and diverse ways of visualizing flow patterns 1. specific projects are evaluated in terms of flow behavior during the design phase, well before the system is built, whether as a mock-up or at full scale. 2. many findings from flow visualization are generally valid and can be re-applied to recurring situations. PRACE: paving the way for advanced simulations The mission of the EU-funded PRACE (Partnership for Advanced Computing in Europe) project is to provide SMEs with access to supercomputing know-how (supercomputing is also referred to as HPC - high performance computing). Depending on project, flow visualization may necessitate the use of supercomputers. Optima Pharma was selected as one of only eight European companies to be a partner in the project. Extensive interaction with these experts helped Optima Pharma broaden its own knowledge of flow visualization, which is very much in line with the declared objectives of PRACE. A close partnership has since been established with HLRS (High Performance Computing Center at the University of Stuttgart), where they speak the same language. The related knowledge and expertise obtained by Optima Pharma has two major advantages: 1. extensive preparation for and follow-up of complex customer projects can now take place at Optima Pharma, to minimize work at the computing center. This makes visualizing data for customers more technologically and economically feasible, and it can even take place over the course of several iterations if necessary. 2. optima Pharma can now carry out less complex analyses in-house. Investments have been made in internal hardware and software and projects that can be executed without a supercomputer are quick and cost-effective to carry out. Projects that Optima Pharma has carried out for customers or internally: - Various inlet stubs in the isolator section of a filling and closing machine were tested, with the objective of achieving as even a distribution of air flows as possible. One to three air inlets were simulated and tested. A range of flow directions were also investigated, including linear (tangential) in two main directions, radial linear and turbulent. The blade angles of the inlets were also experimented with virtually and their ideal basic positions and settings determined in advance. The customer confirmed that no major adjustments were necessary after installation. - examples of other customer projects: Laminar flow in an open RABS, flow visualization of the automatic loading and unloading unit of a freeze dryer and a capper assembly - How does nitrogen gas behave when introduced to a vial from above, at the mouth and the bottom of the container? What flow separation occurs? How quickly does gas exchange take place? Optima Pharma has since made good use of these valuable insights when designing its equipment. - exhaust equipment on a crimping unit for closing vials: The ideal position of the exhaust system and the rate of airflow were determined in a flow visualization, providing virtual insight into particle extraction. Summary and even more virtual and augmented reality Flow visualization is unsurpassed at depicting and analyzing flow patterns in pharmaceutical machines. It is ideal for cost-effectively testing machine prototypes during the design phase. The accuracy of flow visualization is in fact so good that optimizations in the design phase regularly lead to the desired results when the machines are actually constructed. The insights it provides are often useful in solving new issues. But the virtual depiction of flow patterns is by no means limited to virtual and augmented reality; other aspects include multiphysical effects, for example the integration of heat and flow. Mass transfer, vibration analysis and more can already be effectively visualized today. 16 o-com Magazine o-com Magazine 17

10 Trend Strategies to prevent underfilling and overfilling Maximizing Product Yield Since the advent of new biopharmaceutical products which are often expensive to produce, the focus of filling and closing processes has increasingly been on optimal product yield. The entire process chain is taken into consideration for the optimization. Further Strategies to Minimize Product Loss Under the presumption that a 100% IPC is being used, a re-dosing station can be installed to eliminate rejects due to underfilling. Units which have been underfilled by the primary dosing station are identified by the weigh cells, and the redosing station takes over, exactly topping up the fill to the required level. Another strategy to eliminate rejects is through redundant processing stations. In normal processing, a correctly filled container which would otherwise be sent to the reject for a missing or high stopper can likewise be re-stoppered, turning a reject into a saleable unit. This station only activates when needed. Modern filling and packaging machines can integrate numerous functions and technologies to glean the maximum number of saleable units from a limited amount of pharmaceutical product. Obviously, the number of rejected units due to underfills should be minimized. Overfilling is just as undesirable, since the sum of all overfills outside of normal tolerances could have been used to fill other saleable units. In either case, underfilling or undesired overfilling should be mitigated to maintain high product quality, patient safety and economic gain. Several strategies, new and old, are employed to this end. One of the strategic mainstays is the weighing scale. The capabilities of EMFR (Electro Magnetic Force Restoration) weighing technology are the key to accurate weight measurement in the shortest possible time. Signals generated by the electromagnetic force compensation when a load is put on the weigh cell are compared to movement in the weigh cell (photoelectric eye) and evaluated. Precise weight values can thus be made available within a hundred milliseconds. Such scales are so sensitive, though, that is important to minimize or systematically and reliably remove factors which could falsify any weighing results. In particular, vibration of the weigh cells must be eliminated. Mechanical design provides the solution, with an independent support base for the weigh scales. The weighing system is physically isolated from the machine(s) whilst remaining integrated within the functional processes of the line and the sequence of operation. Vibration from the floor as well as movement of liquid within the vial can also negatively affect the weighing accuracy of scales. To minimize movement of liquid in the vial, Optima Pharma uses a patented transport system which reduces oscillation of liquid, and thereby greatly improves the weighing accuracy. Other vibrations are compensated for via a software filter. Laminar air flow within the machine cabin can also falsify weighing results. Studies have shown that an air flow of 0.45m/s result in measured median weights 1-2 g higher than the control. The measured error in the signal (with software filter) was +/- 1mg. The same test carried out with an air flow of 0.6m/s resulted in a median value 10-12g higher than the control. The measured error was +/- 5mg. A constant laminar air flow speed and direction (vertically perpendicular to the weigh cell) must therefore also be ensured to obtain optimum measurement accuracy. A further negative influence on weigh cells is electrostatic charge on products. Studies with neutrally charged products show, as expected, that measured values remain constant over time. Products which have A constant laminar air flow speed must be ensured an electrostatic charge returned steadily decreasing weight measurements over time, thereby creating unreliable values. Technical solutions eliminate the offending static charge; ionization of the containers prior to tare weighing. Once the above possible sources of error have been dealt with, a 100 % inprocess control (IPC) using weigh scales significantly increases the dosing accuracy. The use of IPC halves the standard deviation (s rel ) versus periodic sampling. 100% IPC allows for the implementation of special priming and run-empty cycles. During the priming of the dosing system in conventional filling, vials are only partially filled or even overfilled while the dosing and weighing systems are being primed and calibrated. To counter this loss of product, priming of the dosing system takes place on the weigh cell; the first container which enters and leaves the line is properly filled. The same procedure can be used at the end of a batch, ensuring that all possible product from the batch tank is fully utilized. Without 100% IPC, filling would have to stop much earlier to prevent underfilled units from leaving the line. By using these strategies, product yield can be maximized. The additional cost of implementing these strategies is amortized in the shortest possible time, especially when the products are expensive. 18 o-com Magazine o-com Magazine 19

11 At work Short cycle times, simple maintenance A better way to test Unrivaled quality: what makes METALL+PLASTIC filling line isolators so special is also an advantage in the segment of sterility test isolators. This isolator model was recently installed at an international pharmaceutical company and features rapid cycle times with residual H 2 O 2 concentrations of less than 1 ppm. In order to verify the purity and sterility of filled batches and further improve product safety, even finished pharmaceuticals need to be checked for microbial load. A sterility test isolator from METALL+PLASTIC was recently put into operation for this purpose at the German location of an international pharmaceutical company. During the tests, the containers are opened in a sterile atmosphere and their contents are transferred via the glove ports to nutrient solutions. After a specified incubation period, it is apparent whether the pharmaceuticals are sterile or not. The tests are conducted in accordance with defined procedures, which means tested products are always positioned in the same arrangement in the test isolator. METALL+PLASTIC teamed with its customer to develop, validate and test with bioindicators a safe, time-saving H 2 O 2 decontamination cycle for exactly this scenario. It reliably reaches a defined sterility assurance level, which ensures that potential contaminants on the outside of the containers do not falsify the product test results. The difference is in more than the details What are the advantages of METALL+PLASTIC isolators for customers? Residue-free: flash vaporization Sterility test isolators from METALL+PLASTIC are designed to be operated from one side. Thanks to their compact design, the entire electronics can also be readily accessed from a drawer on the front side. Since the actual operation along with all maintenance work can be carried out from the front, these sterility test isolators are ideal for space-saving installation along a wall or even in a corner. This was of significant benefit for the customer in southern Germany. Exhaust is vented through a simple pipe hole in the ceiling, which means METALL+PLASTIC sterility test isolators can be permanently installed even in small, closed rooms. Glove test equipment and airlocks can nonetheless be individually positioned around the isolator. The advantages of the pneumatically inflatable seals on the doors are again apparent when introducing materials. Transport carts carrying materials simply roll through the transfer airlock into the handling area of the main isolator without having to pass over a threshold, as is present in other systems at zone transitions. Easy to install and remove from the door groove, the seals are simply inflated with compressed air and continuously checked for leaks. Compressed air is supplied to the door seals via special door hinges which were developed in-house. Leakage rates of max. 0.5% of the isolator volume is achieved at twice the normal operating pressure. To decontaminate the isolator, preconditioned carrier air is enriched with H 2 O 2 and blown in through the RGx vaporization system, which ensures a reliably reproducible process. After the decontamination process inside the isolator, the H 2 O 2 should be eliminated as quickly as possible. Thanks to catalytic ventilation, the METALL+PLASTIC system is up to two hours faster than comparable systems, based on the same anticipated residual concentration (ppm), which means less downtime before the system is available again for new tests. The arrangement of the catalysts ensures that even during sterility tests, the residual concentration does not increase from potential out-gassing from the packaging material, which eliminates the problem of materials that store H 2 O 2 and release it after a certain delay. The integrated glove test systems ensure reliable operation. Suitable test covers conveniently located in a drawer are quick to use and just as quick to put back away. In terms of ease of maintenance, METALL+PLASTIC has developed what is referred to as flash vaporization, a patented, nearly maintenance-free technique. During flash vaporization, a patented, nearly maintenance-free technique liquid H 2 O 2 is transformed into a gas without leaving behind a residue, a process that is only possible within a very narrow temperature range. The advantage is that the vaporizer requires practically no maintenance; no residues could be detected in the vaporizer even after the recommended maintenance interval of 6 months. Moreover, the system is central and easy to access. Other systems require inspection after 14 days, typically along with a cleaning process after every cycle of use. An added benefit of catalytic ventilation is that the HEPA filters are not overloaded with H 2 O 2. The catalysts at METALL+PLASTIC are upstream of the filters, which considerably extends their service lives. METALL+PLASTIC seals and their arrangement have another significant advantage should service be necessary: seals can be exchanged within just a few minutes without tools, since no adhesive is used. 20 o-com Magazine o-com Magazine 21

12 Focus: Technology Cutting techniques and their use API DOSING IN ORAL FILMS Modern orodispersible films are a new trend in drug delivery. The accuracy of ingredient dosing during manufacture of such films however is sensitive. Extremely specific conditions need to be taken into consideration in every production step to ensure accurate dosing. Film cutting is one of these key factors.* A variety of cutting methods are available when packaging modern orodispersible films: 1. Intermittent or rotary punching 2. two-stage cutting; longitudinal cutting followed by cross-cutting. There are a number of sub-categories for both techniques: Film pieces can be cut to length using the kiss cut method directly on the film substrate, whereby only the top-most layer is cut, not the underlying layer, or the film material can be cut after delamination from the substrate. When choosing a suitable cutting method, there are more factors to consider than just cutting accuracy and subsequent dosing accuracy. High-output production also brings with it issues of cost effectiveness: The accuracy of film cutting is critical for API dosing. Moreover, uneven edges and breakaway due to bad cutting quality lead to a loss of active ingredients. This article describes various cutting methods, application scenarios and potential disturbances. High cutting speed and parallel processing Optimum material utilization (to minimize active ingredient loss) Format variability (quick changeover to other film formats/sizes without having to use expensive format parts) 1. Intermittent kiss-cut punching on the film substrate This cutting method makes it possible to punch out film pieces in any shape with excellent precision. Standard deviations of % can be achieved for standard film sizes. The film substrate can withstand the dynamic stress of the feed equipment and absorbs any tension to keep the film itself tension-free. Proper humidity in the processing room is essential for accurate cutting to avoid edge fractures and prevent the film from separating from the substrate. A limiting factor for production capacity is the limited speed possible due to intermittent operation. Considerable amounts of active ingredients are lost due to punch waste, making material yield modest. As a result, this process is primarily used for laboratoryscale production. 2. rotary kiss-cut punching on the film substrate Rotary punching provides relatively good cutting results at high path speeds. The speeds of the line and the punching drum need to be closely coordinated to prevent distortion due to slippage. 3. Linear kiss crosscut on the film substrate following longitudinal cutting In a frequently used technique with excellent material utilization, wide films are first cut into multiple widths and then cut to length, typically by rotary cutting. The tension-resistant substrate prevents the film from stretching, which is essential if validation is to be carried out. Parallel processing of multiple strips combined with rotary cutters increases production speed by multiple factors. Controlled air humidity in the processing area is again essential here, to avoid 4. Linear free through-cut following longitudinal cutting As in the previous method, the film remains on the substrate for longitudinal cutting. The cut-to-width strips running in parallel are removed from the substrate by a delamination edge immediately before the rotary cutter. The now highly delicate film passes over a typically faster running transfer roller which stretches the film under negative pressure and keeps it under tension. Once the film has been cut by the rotary cutter, the transfer roller transfers it to the packaging line which runs synchronously. The highly accurate cutting and synchronous drive mean more accurate positioning and less dispersion. The critical issue in this process is the length of the strip between delamination and cutting, where the edge fractures and prevent the film from separating from the substrate. Films cut with this method are delaminated from the substrate in a manner similar to a label dispenser and directly applied to the packaging line, which typically runs faster. The film undergoes acceleration as it is transferred from the substrate to the packaging line. Where this speed transition takes place in the process is relatively random, which negatively affects positioning accuracy of the film on the packaging belt. film has been removed from the substrate and is subject to the tension of the transfer roller. Depending on the properties of the film (thickness, inhomogeneities, ingredients) and the ambient climatic conditions, elastic and plastic elongation may influence the precision of the crosscut. Tests have shown that longer films subject to greater adhesion to the transfer roller before being cut undergo greater stretching and yield greater dispersion in film length. The figure shows that films stretched from 16 to 32 mm in length have almost twice the range of dispersion of shorter films. 22 o-com Magazine Complete line for packing orodispersible film strips. The machine s flexibility makes it possible to use various cross-cutting methods to accommodate a broad range of product requirements. o-com Magazine 23

13 Newly developed In the cassette method, the film strips are combined on top of one another. Only a single cut is needed for all films in a blister, which is why all films in the same blister have very similar lengths (green dots in Figure 3). But if one compares the films of multiple blisters, the dispersion increases to 0.4 mm. The area dispersion of all measured film strips (blisters 1 4) is approximately 2.6%. Summary Mobile tests on the machine Are the gloves intact? Due to their material characteristics, gloves are one of the critical parts of an isolator. METALL+PLASTIC has developed a glove test system to test leak-tightness directly on the machine and document the results. The system is easy and convenient to use and provides reliable results. Example of how the length and width of modern orodispersible film strips vary: Blue, yellow and red dots represent pharmaceutical film strips from three different manufacturers produced with rotary cutting methods. The gray dots are from an experiment to investigate how length variation depends on film length (16 mm 32 mm) when cut without a substrate. The green dots represent a consumer product cut using a cassette technique. Because the dispersion does not have a normal distribution, the complete range of variation was used as the range of dispersion in each case (outliers ignored). The arithmetical standard deviation is therefore smaller than the range of dispersion depicted. It should be noted that the dispersion of the film strips is typically considerably higher in the length than in the width. Area dispersion with a relative standard deviation of approximately 1.1% was measured for two different film products available on the market with typical film sizes of 7-8 cm 2 (blue and red dots in the figure). Both cases involved pharmaceutical products manufactured in the US and Korea. For another product on considerably smaller film strips (0,7 cm 2 ) and with correspondingly higher concentrations of active ingredients, the same range of dispersion has a considerably more serious effect. This product (yellow dots in the figure) has approximately the same range of dispersion as the previously cited pharmaceutical products, but the relative area dispersion that is representative for fluctuations in ingredient dosing in this film increases to 4-5%. Dosing accuracy is of course less critical for consumer products such as breath fresheners. Sample analysis of two different batches of these products showed that the variation in widths is extremely large due to how they are produced: 24 parallel strips are cross-cut with an adjustable rotative cutter instead of a slitting roller. During packaging, one film strip from each line is inserted into a blister package. Every blister is thus characterized by approximately the same width distribution, which can lead to a width dispersion of roughly 0.5 mm. In terms of quality of the various cross-cutting methods, the kiss cut process on the substrate is better for achieving repeatedly accurate film lengths. Other considerations however may make free cross-cutting necessary. In many cases, the synchronization of the transfer roller speed with the packaging leads to more accurate positioning on the packaging material. Free cross-cutting of the strips without the substrate can be advantageous for sticky films, as they are immediately pulled apart by the higher speed of the transfer roller. In the kiss cut method, the film pieces remain on the substrate, where the edges may reconnect with one another (self-healing). It is better for fragile, instable films to be cut on the substrate. What method to use in individual cases must be carefully considered. The packaging machine from Optima Life Science shown above can carry out both cutting techniques without having to tediously retrofit the equipment. This flexibility provides manufacturers with greater freedom in product design. *Excerpt of a technical article. The complete article includes a description of the typical methods of quantity manufacturing and film production along with their advantages and disadvantages. Published in German in the trade journal TechnoPharm (Editio Cantor Verlag, Aulendorf), Issue 6 / 2014, pp The right test cover for every glove ring: Whether round or oval, the METALL+PLASTIC glove test system is suitable for nearly every shape of glove port. Up to six gloves can be tested at the same time in just 15 minutes. With two integrated compressors in the device, no external compressed air supply is required. The only thing needed is a power outlet. And thanks to RFID (Radio Frequency Identification), the test results can be unambiguously associated with the corresponding glove port to avoid confusion. A read head is installed on the test cover to recognize the glove port. Once a port s ID has been read, the system independently recognizes what glove is being tested to ensure unambiguous results in the test log. The process: The round or oval test covers are inserted into the glove ports. A special clamp secures the test cover in the port to prevent it from falling out when there is no air pressure. In the first step of the test, the seals to which the test cover is connected are inflated and checked for leak tightness. The main test sequence for the isolator gloves follows automatically and consists of three phases: 1. Distension phase 2. Stabilization phase 3. Leak test Leaks are detected by a drop in pressure. After conclusion of the test, a report can be generated on the 15 touchscreen and sent via secure WLAN module. All test logs are also saved as PDF files on the panel PC to be viewed by authorized operators. After the test, all covers and tubes can be conveniently returned to their storage hangers. 24 o-com Magazine o-com Magazine 25

14 At work Filling in the µl range for diagnostic products Good things come in small packages OP 75 for the larger formats. Filling of both containers takes place at a single filling position, after which the plastic caps are individually fed from a sorting bowl connected to a supply bin. A swivel arm with a grabber picks one screw closure, places it on the container, and closes it with a specified torque. completion of this procedure is confirmed by the operator, the machine processes the three to five containers that have been inserted. The containers are manually removed and their gross weight determined at the external weighing station in the immediate vicinity of the filling and closing unit. then includes both the number of samples and the measured weights, which are included in the batch documentation provided to the customer by the equipment operator. Labels are affixed to the containers at the next station, the information for which is entered on the central HMI of the KUGLER FLEXOFILL system. The only thing that varies from container to container is the product discharge: Sarstedt tubes that pass inspection are actively discharged via a chute for further processing. Tubes that do not pass inspection are rejected via a second outlet on the rotary filler and a chute. Freestanding plastic bottles are discharged using the same system, but are pushed to a conveyor and transported to a manual removal station. Format changeovers can be completed in 30 to 40 minutes. Sorting of Sarstedt collars Although the tasks of this machine solution are extremely small, a dosing volume starting in the microliter range and ending at 125 ml in fact represents an enormous range. This entry-level system boasts extremely high filling accuracy and comes ready to be upgraded to higher outputs and automation. The product range of this young, ambitious producer of diagnostics is rapidly expanding and also includes small batch sizes, depending on the segment. A broad range of plastic containers are processed, including non-freestanding Sarstedt tubes in formats of 0.5 and 2 ml as well as various shapes of plastic bottles with volumes of 20, 60 and 130 ml. The main challenge in this project was to achieve a long-term absolute filling accuracy of +/- 2% for small quantities starting at 50 µl. To clarify: a deviation of max. 1 µl is permissible for a target filling volume of 50 µl! The filling tubes and needles have an inside diameter of 0.2 mm. In this range, not only is precise dosing a technical challenge; weight checking is also at the limit of detection accuracy. Some 2,000 random measurements were carried out for the customer in advance to document the process stability of the peristaltic filling system and the reproducibility of the results. Filling, closing, labeling Precision at the limits of measurability The non-freestanding containers are transported from a bin into a sorting bowl. The tubes feature the typical Sarstedt collars, which allow them to be transferred from the sorting bowl to a linear suspended transporter. The freestanding bottles take another path: a disc sorting unit orients the containers for the linear transport system. All containers undergo processing on the same intermittent cycle rotary filling machine. The dosing station consists of two peristaltic pumps: an OPTIMA OP 45 peristaltic pump system for the smallest volumes of 50 µl to 10 ml, and an OPTIMA Optima Pharma has installed an external in-process weight control system to achieve the necessary filling accuracy, which in this case is especially challenging considering the tiny volumes. The equipment operator independently decides the frequency at which inspection needs to take place. This function is protected at a high level by a password. The control system automatically prompts the operator to perform in-process control. The machine first clears the machine transport, and informs the operator how to proceed. First, pre-weighed containers are placed in the system at a predefined position. After the Semi-automatic IPC Regular production mode cannot continue until the net weights are entered into the control system and confirmed by the operator. The recorded net weights are used to control the filling system and optimize filling accuracy. Another advantage of this system is that the process is documented. The measured and transferred sample information is logged in the batch record by the control system in the Optima machine. The documentation Prompt / Confirmation Entry-level system with superior quality The customer requested three expansion stages to allow it to flexibly react to growing demand. The output of the KUGLER FLEXOFILL in its current basic version is containers/h, depending on format. Higher outputs can be achieved at any time. Possible upgrades: The manual entry of the filling weights can be automated by connecting the scale to the Optima machine s control system. Furthermore, manual torque control can be replaced by a measuring unit in the capping head to measure the tightening value and document it. Both options are already available should they be needed. 26 o-com Magazine o-com Magazine 27

15 Flow line simulation of gaseous, sublimated solvents in a freeze dryer at low pressure (vacuum). Goal of the simulation is to investigate the optimal geometric arrangement for uniform loading of de-sublimated material (ice) onto condenser coils.