Dokument: In-line monitoring of granule moisture in fluidized bed granulators using microwave resonance technology as novel PAT tool
| Titel: | In-line monitoring of granule moisture in fluidized bed granulators using microwave resonance technology as novel PAT tool | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=14290 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20100309-154913-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Buschmüller, Caroline [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Breitkreutz, Jörg [Gutachter] Prof. Dr. Kleinebudde, Peter [Gutachter] | |||||||
| Stichwörter: | PAT, moisture measurement, fluidized bed granulation | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | The United States` Food and Drug Administration (FDA) requires the implementation of process analytical technologies (PAT) in modern drug development and manufacturing processes. The desired aims of the PAT approach are to design, analyze and control manufacturing processes by monitoring, preferably in real-time, critical process parameters (CPP) which affect critical quality and performance attributes.
In wet granulation processes the granule water content has been identified as an eminently CPP. It significantly affects critical quality attributes, e.g. the stability of the active pharmaceutical ingredient (API) and particle size distribution. Furthermore, subsequent manufacturing steps, like compression to tablets, are influenced by granule moisture. To ensure product quality and to meet the FDA’s PAT approach, the real-time measurement of granule moisture throughout fluidized bed processes is required. The water determination by measuring the loss on drying, preferably by infrared light exposure (LOD/IR) or Karl Fischer titration (KF), are well established off-line measuring tools. However, it is not possible to obtain a real-time process control using these off line techniques. For the in-line determination of granule moisture only a few technologies are available. Several attempts to make use of infrared (IR) and near-infrared (NIR) spectroscopy for in-line moisture control in fluidized bed granulators have been reported. The main disadvantage of these techniques is the dependence on the total amount of measured particle layers and the product density. Consequently, a direct correlation with the water content of the tested material is not possible for moving bulk solids. In order to obtain reliable real-time moisture monitoring a density independent measuring technique is required. Within the present work the focus was on the two parameter microwave resonance technology (MRT), which is already applied in a few industries, e.g. timber and tobacco industry, as density independent in-line measuring tool. In order to use this technique in pharmaceutical production processes, the existing sensor setup was re-engineered in accordance to the requirements of the current guidelines of Good Manufacturing Practice (cGMP). The implementation of the novel sensor system into two different fluidized bed granulators was successfully performed. The chosen mounting positions ensured a reliable and representative moisture measurement throughout the entire processes. As MRT is an indirect measuring method, a calibration against a direct method for water determination was required. LOD/IR and KF were applied as reference methods. For both methods good correlations with the in-line results of MRT were obtained. The endpoint determination as well as the monitoring throughout the entire granulation process of crystal-water-free and crystal-water-containing products was proven to be reliable and reproducible. A considerable time saving of 75 % of the drying time was achieved. This results in a reduction of various quality detracting influences. Furthermore, a deviating process course caused by system failure could be identified at an early stage due to in-line monitoring. The prompt intervention in the defective process became possible. However, an impact of high moisture content on MRT results was observed. Above a product-specific threshold, MRT results were increasingly imprecise. The location of the threshold and the size of its impact on MRT moisture monitoring were found to depend on the granule composition. In further investigations an impact on MRT moisture monitoring by substances with swelling characteristics, such as crospovidone, was recorded. Due to the swelling and water absorbing properties of the excipient not all water molecules were detectable by MRT. Consequently, lower water contents were measured by MRT than by the reference methods. The size of the influence on the measuring results depends on the type of the swelling agent and as well as on its amount contained in the formulation. The simultaneous in-line monitoring of the product density and temperature, performed by the MRT sensor system, enhanced process understanding considerably. Consequently, the efficiency of process control has improved. The MRT sensor system was proven to be a valuable tool for real-time process control due to in line moisture monitoring. Essential requirements of the FDA’s PAT approach were met. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
| Dokument erstellt am: | 09.03.2010 | |||||||
| Dateien geändert am: | 04.03.2010 | |||||||
| Promotionsantrag am: | 13.05.2009 | |||||||
| Datum der Promotion: | 29.06.2009 |
