DEVELOPMENT OF A PAT MONITORED FLUID BED GRANULATION PROCESS USING THE EXAMPLE OF A LOW DOSE STEROID HORMONE

According to ICH Q8 process analytic technology (PAT) should be established to monitor critical quality attributes (CQAs) during manufacturing processes. Ethinylestradiol (EE) is a highly active and low dosed steroid hormone that is prone to oxidative degradation. The stability of this compound is therefore a critical quality attribute that has to be considered during drug formulation development. Beside the stability of EE, granule particle size and moisture are CQAs influencing the tableting ability of the resulting granules and the stability of EE. Both CQAs should be monitored during the production process. The investigations described in this thesis evaluate the implementation of in-line-sensors for monitoring of particle size (spatial filtering technology, SFT) and granule moisture (microwave resonance technology, MRT) during the fluid bed granulation process and the influence of process-variations on the stability of EE. The aim of these investigations was to develop an effective and mild fluid bed granulation process for a new model formulation based on microcrystalline cellulose as replacement for lactose as main filler excipient. The EE degradation products 6-alpha-hydroxy-EE, 6-beta-hydroxy-EE, 9(11)-dehydro-EE and 6-oxo-EE were quantified as an index for the stability of EE. It could be demonstrated that the surface of the filler substance influences the stability of EE due to the impact of water molecules. Hence, spraying sequence was determined to be a useful tool to improve the stability of EE. Correlations could be established for 6-oxo-EE with granule moisture and thermic parameters. The implementation of the SFT-sensor in the granulation process was successful. Measurement with the MRT-sensor for monitoring of granule moisture has to be improved.:Chapter I 1 1 Introduction Chapter II 41 2 Materials and Methods Chapter III 54 3 In-line Monitoring of Particle Size in a Fluid Bed Granulator: investigations concerning positioning and configuration of the sensor Chapter IV 72 4 Influence of in line monitored fluid bed granulation process parameters on the stability of Ethinylestradiol Chapter V 90 5 Influence of filler excipients on stability of EE Chapter VI 105 6 Discussion and Conclusion Chapter VII 131 7 Summary Chapter VIII 138 8 Zusammenfassung Reference List 146 Appendix 15

DEVELOPMENT OF A PAT MONITORED FLUID BED GRANULATION PROCESS USING THE EXAMPLE OF A LOW DOSE STEROID HORMONE

According to ICH Q8 process analytic technology (PAT) should be established to monitor critical quality attributes (CQAs) during manufacturing processes. Ethinylestradiol (EE) is a highly active and low dosed steroid hormone that is prone to oxidative degradation. The stability of this compound is therefore a critical quality attribute that has to be considered during drug formulation development. Beside the stability of EE, granule particle size and moisture are CQAs influencing the tableting ability of the resulting granules and the stability of EE. Both CQAs should be monitored during the production process. The investigations described in this thesis evaluate the implementation of in-line-sensors for monitoring of particle size (spatial filtering technology, SFT) and granule moisture (microwave resonance technology, MRT) during the fluid bed granulation process and the influence of process-variations on the stability of EE. The aim of these investigations was to develop an effective and mild fluid bed granulation process for a new model formulation based on microcrystalline cellulose as replacement for lactose as main filler excipient. The EE degradation products 6-alpha-hydroxy-EE, 6-beta-hydroxy-EE, 9(11)-dehydro-EE and 6-oxo-EE were quantified as an index for the stability of EE. It could be demonstrated that the surface of the filler substance influences the stability of EE due to the impact of water molecules. Hence, spraying sequence was determined to be a useful tool to improve the stability of EE. Correlations could be established for 6-oxo-EE with granule moisture and thermic parameters. The implementation of the SFT-sensor in the granulation process was successful. Measurement with the MRT-sensor for monitoring of granule moisture has to be improved.:Chapter I 1 1 Introduction Chapter II 41 2 Materials and Methods Chapter III 54 3 In-line Monitoring of Particle Size in a Fluid Bed Granulator: investigations concerning positioning and configuration of the sensor Chapter IV 72 4 Influence of in line monitored fluid bed granulation process parameters on the stability of Ethinylestradiol Chapter V 90 5 Influence of filler excipients on stability of EE Chapter VI 105 6 Discussion and Conclusion Chapter VII 131 7 Summary Chapter VIII 138 8 Zusammenfassung Reference List 146 Appendix 15

Background pathology of the ovary in a laboratory population of zebrafish Danio rerio

Adult zebrafish Danio rerio originating from one stock used as control animals in a toxicological study were examined histopathologically for the occurrence of spontaneous lesions in the gonads. While no histopathological changes were seen in the testes, the ovaries showed lesions consisting mainly of acute granulomatous inflammation with increased atresia and the presence of egg debris in the ovarian parenchyma and in the oviduct. Since infectious agents could not be detected and the fish were not exposed to toxicants, we consider these lesions as spontaneous alterations of the ovaries

Kutanes Osteosarkom bei 2 Hunden: Fallberichte und Literaturübersicht

Das kutane Osteosarkom ist ein seltener Weichteiltumor beim Hund. Patienten mit Weichteilosteosarkomen haben, wie in der Literatur beschrieben, eine kurze Überlebenszeit. In den beiden hier beschriebenen Fällen wurde eine Exzision des Knotens vorgenommen und eine Therapie mit einem Chemotherapeutikum begonnen. Aufgrund der stark verlängerten Überlebenszeit der beiden Hunde mit kutanem Osteosarkom sollte die Zugehörigkeit der kutanen Form zu anderen Formen von Weichteilosteosarkomen in Frage gestellt werden

Evaluating the surveillance for swine dysentery and progressive atrophic Rhinitis in closed multiplier herds using Scenario tree modelling

Background: The Swiss pig population enjoys a favourable health situation. To further promote this, the Pig Health Service (PHS) conducts a surveillance program in affiliated herds: closed multiplier herds with the highest PHS-health and hygiene status have to be free from swine dysentery and progressive atrophic rhinitis and are clinically examined four times a year, including laboratory testing. Besides, four batches of pigs per year are fattened together with pigs from other herds and checked for typical symptoms (monitored fattening groups (MF)). While costly and laborious, little was known about the effectiveness of the surveillance to detect an infection in a herd. Therefore, the sensitivity of the surveillance for progressive atrophic rhinitis and swine dysentery at herd level was assessed using scenario tree modelling, a method well established at national level. Furthermore, its costs and the time until an infection would be detected were estimated, with the final aim of yielding suggestions how to optimize surveillance. Results: For swine dysentery, the median annual surveillance sensitivity was 96.7 %, mean time to detection 4.4 months, and total annual costs 1022.20 Euro/herd. The median component sensitivity of active sampling was between 62.5 and 77.0 %, that of a MF between 7.2 and 12.7 %. For progressive atrophic rhinitis, the median surveillance sensitivity was 99.4 %, mean time to detection 3.1 months and total annual costs 842.20 Euro. The median component sensitivity of active sampling was 81.7 %, that of a MF between 19.4 and 38.6 %. Conclusions: Results indicate that total sensitivity for both diseases is high, while time to detection could be a risk in herds with frequent pig trade. From all components, active sampling had the highest contribution to the surveillance sensitivity, whereas that of MF was very low. To increase efficiency, active sampling should be intensified (more animals sampled) and MF abandoned. This would significantly improve sensitivity and time to detection at comparable or lower costs. The method of scenario tree modelling proved useful to assess the efficiency of surveillance at herd level. Its versatility allows adjustment to all kinds of surveillance scenarios to optimize sensitivity, time to detection and/or costs

Gay Community Periodic Survey: Canberra 2013

The Canberra Gay Community Periodic Survey is a cross-sectional survey of gay and homosexually active men. Participants are recruited from gay venues and community events. The major aim of the survey is to provide data on sexual, drug use and testing practices related to the transmission of HIV and other sexually transmissible infections (STIs) among gay men. From its start in 2000, the project has been funded by ACT Health and coordinated by the AIDS Action Council of the ACT. In the 2013 survey, the sixth conducted in Canberra, 173 men were recruited from the Canberra springOUT Festival Fair Day, gay social venues and a sex-on-premises venue

Gay Community Periodic Survey: Canberra 2015

The Canberra Gay Community Periodic Survey is a cross-sectional survey of gay and homosexually active men. Participants are recruited from gay venues and community events. The major aim of the survey is toprovide data on sexual, drug use and testing practices related to the transmission of HIV and other sexually transmissible infections (STIs) among gay men. From its start in 2000, the project has been funded by ACT Health and coordinated by the AIDS Action Council of the ACT. In the 2015 survey, the sixth conducted in Canberra, 303 men were recruited from the Canberra springOUT Festival Fair Day, gay social venues, a sex-on-premises venue, a sexual health clinic and, for the first time, through online recruitment. Online recruitment was conducted through the social networking site Facebook. Men were directed to a website with an online version of the GCPS questionnaire (http://gcpsonline.net). The advertisements were targeted to all men aged16 and above who were located in the Australian Capital Territory and indicated in their Facebook profile that they were ‘interested’ in men