HOF_kunden_en_170703_druckansicht_kor

HOF_kunden_en_170703_druckansicht_kor_einzel

HOF – editorial Dear Ladies and Gentlemen the freeze-drying principle is based on various physical basic principles which, by definition, are not subject to change. However, innovative and continual further developments of technologies around freeze-drying are necessary, in order to guarantee efficiency and safety in the manufacturing process of high-class products. Continual innovations and concepts are arising, particularly in the process technic area, plant safety and loading and unloading systems. As a machine manufacturer, we want to and have to react to these ever-increasing market re- quirements. “HOFinsight” – versatile and informative With the 1st issue of our new customer magazine HOFinsight, we would like to draw your attention to our innovations, solu- tions and developments. With regard to product and plant safety, we are further working on the detection of silicone oil and on the life-cycle optimization of flexible hoses, in order to avoid any case of average. At the same time, we are conducting studies about alternative refrig- erants to face the announcement of discontinuation of R404a. HOF also further optimizes SynchroFreeze, which was devel- oped as a controlled nucleation method. In our loading and unloading systems segment, a successful con- cept has been realized in direct collaboration with one of our cus- tomers, which consists of a flanging machine working along the unloading area. Thanks to this system, we can save floor space and precious process times. We are also pleased to announce that this year again, as in 2016, HOF ranks among the Top 100 most innovative compa- nies in Germany. We hope you are curious now and we look forward to an- swering your questions about the topics as listed above. We would like to invite you to our technical forum, which will now take place for the second time in November 2017. In this maga- zine, we will inform you about this event too. We wish you a lot of success for the future and hope you will enjoy reading the first issue of “HOFinsight”. Sincerely, the Hof family TOP 100-Innovator 2017 In 2017 HOF ranks once again among the innovation elite Following the award in 2016, in 2017 HOF again was awarded with the TOP 100 label and thus ranks among the top 100 most innovative companies in Germany. During a festive support program, all award winners were honored by Mr. Ranga Yogeshwar, the mentor of this competition, with certificate and trophy. This time again, HOF could particularly score with its innovation management and its accompanying innovation successes. The label itself was awarded for the 24th time in Essen and honores the German innovation elite in different categories. 2

HOF SynchroFreeze for optimized freeze drying processes HOF – innovation In the pharmaceutical area, the controlled nucleation is a frequently discussed topic. “SynchroFreeze” is a development, well-established by HOF over the last years. Its aim is to provide the user with an additional tool to increase the quality of the pharmaceu- tical product and simultaneously ensure an efficient operation of the freeze-drying sys- tems. SynchroFreeze is characterized by a conditioning phase, followed by cooling and vacuum-induced nucleation during the freezing process. In the conditioning phase, dissolved gases are withdrawn from the liquid product under partial vacuum, in order to prevent from strong gas bubble formation and swelling of the product in the sub- sequent freezing steps. The now largely degassed liquid is cooled and the nucleation is triggered by a further pressure drop at the desired freezing point in the lower millibar range (Figure 1). Product specifications matter Studies on SynchroFreeze are carried out by different development teams. Application related adjustments of the freezing phase are described within first publications [1]. Conditioning times are different, depending on the product, liquid level and temper- ature. Moreover, the selection of the freezing point and the subsequent pressure ad- justments offer further optimization potential even for difficult products. In many application cases, a required supercooling can be set by means of the shelf temperature, by reducing the pressure level in the freeze-drying chamber at the same time. After completion of these steps, the product is liquid and put at the required su- percooling level. Optimization of the product structure A further rapid pressure reduction enables a homogeneous freezing of the vials. The pressure reduction ensures the evaporation of the solvent contents on the liquid sur- face with local cooling, this triggers the freezing and crystallization process which prog- resses from the surface downward. Therefore, the adjustment of the chamber pressure enables a rapid and very efficient temperature change at the product surface. In many cases, the targeted application of SynchroFreeze allows the optimization of the pro- duct structure (Figure 2 and 3) as well as a significant reduction of the drying times. The larger structure of the lyophilisate simplifies the entry of the solvents and has a favorable effect for the reconstitution process. The high expectations put to the SynchroFreeze technology are confirmed by the pro- duct-specific test results. Furthermore, only limited plant modifications are necessary for the implementation. Figure 1: Crystal growth after vacuum-induced nucleation Figure 2: Lyophilisate structures of a 5% saccharose solution, for comparison: left SynchroFreeze – right standard Figure 3: Scanning electron micrograph; product structure after application of SynchroFreeze during freezing and following freeze-drying. Micrograph by courtesy of IDT Biologika. [1] Allmendinger, A., et al. (2016). Controlled nucleation during freeze drying using vacuum-induced surface freezing. Data base no. 633018, www.researchdisclosure.com HOF SynchroFreeze Synchronization of the the freezing process in the individual vials or product containers Conditioning of the product structure Improvement of the product homogeneity Reduction of required drying times Increase of the performance and reduction of the energy consumption 3

HOF – products HOF’s loading and unloading systems: successful innovations Due to the long-term experience, HOF has become the suppliers of future-proof loading and unloading systems. Systems with all degrees of automation can be implemented in many ways, e.g. as an extension of existing freeze-dryers or integrated in new- ly developed production lines and be upgraded to be state-of- the-art. Through an intensive exchange between customers and HOF’s experts, it is possible to achieve a 100% solution meet- ing each application requirement. The demand for robot systems in the pharma sector shows a trend The application areas of the robotic technologies extend from extraction systems in the bulk freeze drying sector, up to the fully automatic frame handling for individualized storage. The design in matters of function and size for the respective application is variable, so that a suitable solution can be offered. HOF has already been implementing robot systems since 2006, amongst others for the extraction of bulk products. Furthermo- re it is possible to extend existing systems with robot systems or replace operator-assisted processes. Your advantages High flexibility Space saving systems Improved performance Combined HOF unloading system with superimposed sealing machine A new and innovative system has been developed in collabora- tion with a renowned pharmaceutical company. After the freeze-drying process, the vials are discharged via the HOF unloading system and are subsequently transported into the sealing machine along the unloading system. For this pur- pose, the system installed in the RABS (Restricted Access Barrier System) individually operates in front of the respective freeze- dryer. Your advantages Spatially reduced RABS area Simplified product handling High performance Shorter processing times Reduced running costs HOF SMART ACS – new developments currently under scrutiny HOF has found innovative solutions to meet the ever growing requirements in the pharmaceutical area. In the field of loading and unloading systems, new developments have been contin- ually strained in the past: in the sensor technology, hygienic designs, format parts, control system, visualization and system monitoring, in regard to “Industry 4.0”. HOF has designed a test plant, especially for this purpose, in order to put in practice all new developments in a target-oriented way. This test plant is installed in our facility in Mornshausen and can be used in the future to optimize further processes e.g. in regard of the control system technics. 6

HOF – innovation Optimization of the product safety by means of a relief of the corrugated hoses Among other components, stainless steel corrugated hoses also belong to the critical parts of a freeze-dryer. These flexible elements transport the silicone oil of the heat transfer system inside the chamber to and from the shelves and are subject to a very high stress level. Due to the fact that these flexible parts are under considerable strain and in combination with the long life time of a freeze-dryer, the corrugated hoses belong to the nat- ural parts subject to wear. It is very difficult to define change intervals and in case of dam- age, considerable breakdowns might happen. To counteract this, HOF has developed the so-called “relief shoe”. The repeatedly occurring rated break points at the shelf connecting bends are supported by these “relief shoes” and the pressure of the move- ment is then derived to further hose spirals. Bends in both directions can be supported by means of double shoes at the chamber connections. Because of the restricted space situation, the connecting points of the pipe elbows at the shelves are supported by a dynamic single shoe. Long-term tests have shown that the lifetime of the hoses could thereby be more than quadrupled. At the same time, the supporting elements are in conformity with the approved ma- terial classifications and are compatible with the common CIP systems. This could be verified in tests with elevated Riboflavin concentrations. In order to provide a benefit as big as possible concerning process safety, the elements were designed in a way, that the “relief shoes” can be generally retrofitted to ex- isting machines. without relief shoe using relief shoe (generation 1) using relief shoe (generation 2) durability [%] 100 200 300 400 500 Container Closure Integrity Because product protection and safety have an ever-growing priority, there are a lot of discussion topics about container clo- sure integrity. It is frequently reported that vial sealing plugs are not correctly or not fully pushed in and therefore the vial sealing is not satisfactory. In many cases, the resulting gap size can be neutralized by the downstream crimping machine, but some uncertainty remains for the time span between opening the freeze-dryer and the actual crimping of the vials with the alu- minum cap. These circumstances are usually directly associated with the freeze-drying machine. It must be admitted, that the handmade shelf area, as a welded construction, is certainly ad- justed and ground a number of times, nevertheless a 100% flat surface cannot be reached. The compliance with the specifications is confirmed by a corre- sponding certificate. However, major difficulties are met in this context due to variances in the used primary packaging material. Although these differences do range within the specified toler- ances, over-sized vials impede the sealing of under-sized vials. In order to offer a better understanding of safety in this context, HOF is conducting a study on vacuum tightness with different packaging combinations. An integrity check is carried out at dif- ferent time intervals on vials which are sealed under vacuum with defined gape-sizes. First tests showed that a gap size of up to 1,6 mm, even after a storing time under atmosphere, did not result in loss of vacuum. In order to cover a spectrum as wide as possible, we will go on with our checks, but we are confident that other packaging combinations will deliver similar results. ] g [ y t i c a p a c - l a v i 0,70 0,68 0,66 0,64 0,62 0,60 0,58 0,56 0,54 0,52 0,50 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 3,0 clearance [mm] We will be pleased to keep you in the loop of our results. 7

HOF – innovation HOF R&D Lyo – for continuous development With the objective of advancing and testing innovations and technical developments, HOF has established a freeze-dryer for development purposes in its own factory. The so-called R&D Lyo has 5+1 shelves, 1,64 m² shelf area and a 28 kg ice capacity. A special feature consists in 2 different refrigerating systems: on one side, the heat transfer system of the shelves is operated by conventional refrigeration, on the other side, the condenser is tempered by a technology of natural refrigerants. Besides many other issues, the further development of both systems is currently a top priority. More information regarding the R&D Lyo on page 10 … natural refrigerants 8

HOF – innovation HOF R&D Lyo – for continuous development Sustainability by means of natural refrigerants According to the European F-gas regulation, the use of hydro- fl uorocarbons (HFCs) must be signifi cantly reduced. Conse- quently, there are some restrictions in the use of conventional refrigerants. Alternatively, natural refrigerant can be used. Nevertheless, one natural refrigerant alone cannot reach the re- quired temperatures in the condenser. That is the reason why HOF already launched a cascade system in 2007, in which eth- ane (R-170) and propene (R-1270) are used. This cascade system consisting of 2 separate circuits, forms an individual module, which can be combined with further modules, for redundancy purposes or to improve the performance. Because ethane and propene are combustible hydrocarbons (group A3), the cooling devices are designed according to the ATEX guidelines. Depend- ing on the building concept it is also possible to waive the ATEX requirement if gas detection systems are used. Product safety by means of silicone oil detection Any leak of silicone oil in the drying chamber means product losses and production losses. In case a leakage is visually assess- ed, it is in many cases no longer possible to trace back when the silicone oil leak occurred for the fi rst time and we must cast doubt on the quality of many product batches. Mass spectrometry enables to detect the smallest quantities of silicone oil in the drying chamber, so that any contamination can be immediately identifi ed. Depending on the production concept and on the process requirements, cyclical or continual measurements are made. Currently, we are testing different de- tection systems at our R&D Lyo, while the limits of the actual method are also checked. At the same time, we are testing the Alternatives in the fi eld of conventional refrigeration technology To achieve the objectives of the F-gas regulation, there is a step- wise reduction of the HFC quantities which are allowed in the EU. A scarcity of available conventional refrigerants is arising. The limit value for the scarcity is fi xed at a GWP100*-value of ≥ 2.500. Among those also R-404A (GWP100= 3.922) and R-507 (GWP100= 3.985) are listed. Sure, up to the 1st of January 2030, these refrigerants can be implemented in low-temperature areas but already now, there are shortages in the availability and the prices are considerably rising. Consequently, HOF is using the R&D Lyo to check the readiness for use and effi ciency of diverse alternative refriger- ants in order to enable the offering and usage of alternatives in * The GWP100-value describes the global warming potential of a refrigerant over a period of 100 years. 10 implementation of this technology in existing automatization concepts. By means of a defi ned additional metering of differ- ent types of silicone oil, it is possible to clearly identify the cor- responding masses. In parallel, optimal test conditions can be observed. the fi eld of conventional refrigerating technology. Basic con- dition for this is a technically fl awless application, without any elaborate system modifi cations. Up to now, two alternative re- frigerants could meet all criteria, they are now standing in the fi nal testing phase.

HOF – news HOF‘s technical forum 2017: “Always think ahead” Our 2nd technical forum will take place on the 16th of November 2017. We will welcome our guests with varied lectures, current de- velopments and interesting guest speakers from the freeze-drying sector, as well as presentations of our company departments. This time again, you will get the opportunity to exchange information with HOF experts and other users. 16th of November 2017 Welcome Hotel Marburg The event will take place at the Welcome Hotel in Marburg. Further information and details about lecture contents will be published on time. Retrospective of the 1st HOF‘s technical forum of 2014 “Gained in praxis, for the praxis” On the occasion of the 25th anniversary, HOF Sonderanlagenbau held its 1st technical forum. During the symposium, notable experts from fi elds of research and industries reported on their recent research results and innovative fi elds of application in the manufacturing process. More than 100 attendees came to our site in order to exchange experiences. Here, you can watch the video about the event: www.hof-sonderanlagen.de/en/the-1st-hof-technical-forum.html 11

HOF – company Head offi ce HOF Sonderanlagenbau GmbH Ludwig-Rinn-Str. 1–3 | 35102 Lohra | Germany phone + 49 6462 9169-0 | fax + 49 6462 9169-199 info@hof-sonderanlagen.com | www.hof-sonderanlagen.com Mornshausen facility HOF Sonderanlagenbau GmbH Vor dem Langen Loh 2 | 35075 Gladenbach-Mornshausen | Germany phone + 49 6462 9169-0 | fax + 49 6462 9169-199 info@hof-sonderanlagen.com | www.hof-sonderanlagen.com company information publisher: HOF Sonderanlagenbau GmbH Ludwig-Rinn-Str. 1–3 | 35102 Lohra | Germany phone + 49 6462 9169-0 | fax + 49 6462 9169-199 | www.hof-sonderanlagen.com responsible according to the press law: Alexander Hof, Stefan Becker conception, design, editorial assistance: exposé Marketing & Werbung, Marburg, Michael Grebe, contact: + 49 6421 484880 print and handling: L&W Druck GbR, Bad Endbach, contact: + 49 2776 922990 picture credits: fotolia.com and HOF Sonderanlagenbau GmbH