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Due to their relatively low production costs and their ease of administration, tablets for oral use are the most produced dosage forms. In addition to wet and dry granulation, tablets can also be produced by direct compression. Besides its numerous advantages, direct compression does introduce a wide spectrum of challenges, which makes this technique not suitable for every formulation. The FE55 tablet press of Fette Compacting, containing an additional, third compression roller leading to an extended dwell time, is able to produce up to 90% of all types of tablets. In this study, the added value of the third compression roller of Fette Compacting’s FE55 tablet press was investigated. A Design of Experiment approach was used to explore how powder X behaves when applying multiple levels of pre-, intermediate and main compression forces at different turret speeds. The quality of the tablets was evaluated based on eight responses, namely tablet weight, hardness, thickness, the variabilities of the three previous, ejection force and the variability of the main compression force. In addition the effect of a storage period on the tablet hardness and thickness was determined. Powder X has a mainly plastic deformational behaviour, combined with notable elastic properties, which is reflected by the significant direct elastic recovery and the additional elastic recovery over time. The hardness of the tablets is very dependent on the production rate. At lower turret speed, a higher tablet hardness can be obtained, especially when applying two high forces, combined with a lower pre-compression force. This can be explained by the over compression that occurs when exerting three high forces. At higher turret speed, the effect of the reduced dwell time becomes dominant, which will most probably result in less hard tablets. However, it is possible to acquire equally hard or slightly less hard tablets using a third compression roll. Further, it was discovered that a lower ejection force was observed when the first force applied to the powder bed is higher. Besides its effect on the ejection force, an increase in pre-compression force also leads to thinner tablets. Based on the analysis of four powders (an ibuprofen mixture, powder X, placebo S and Avicel®), a generic model was established, which took on the form of a decision tree. This decision tree serves as a tool to determine, in an efficient manner, the recommended tablet press settings for the production of tablets that meet the customer’s demand concerning tablet hardness.

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During this research project, a closer look was taken at the GMP advanced training, part of the training program at Pfizer Puurs. The aim of this training course is for white collar staff to develop a deeper insight into good manufacturing practice (GMP). Compliance to GMP guidelines is of utmost importance in order to guarantee the manufacture of safe, efficacious and quality drug products. The GMP advanced training constitutes of a classroom training which is followed by a self-study phase and is terminated when the participants pass a test. During this self-study phase, the participants have to study one of the departmental folders, which comprise of relevant GMP guidelines from the Food and Drug Administration (FDA), European Medicines Agency (EMA), International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Japanese pharmacopoeia. However, these folders appear outdated and are not practical to look up GMP guidelines. Therefore it was decided to update these folders to an electronic tool. In order for this tool to be relevant and user-friendly, inputs from different sources were used. First, a systematic literature review was performed in order to search for informative literature on selected, relevant topics. This literature review revealed some interesting information on GMP in general and on training for personnel in other GMP related instances. Moreover, some interesting literature on the development of supportive tools was found as well. Secondly, in order to select focus areas that would need to be highlighted in the tool, the databases of the FDA and EMA, as well as internal audit reports of the last two years were screened. The database screening revealed that GMP related documentation on data integrity and documentation practices would need to be highlighted in the new tool. The results of the screening of internal audit reports are confidential and are not displayed within this thesis. Then, in order to grasp the managers’ opinions on the current GMP training, GMP guidelines, audits, and for them to provide some inputs for the new tool, nine managers, responsible for varying departments at Pfizer Puurs were submitted to an exploratory questionnaire. This revealed that in general, the managers were satisfied with the current GMP training at Pfizer Puurs. They also indicated that the departmental folders are not up-to-date and impractical to look up GMP guidelines. Furthermore for the tool to be successful and helpful, they advised that it should contain an advanced search function and be relevant to Pfizer Puurs containing many practical examples. Finally, the content of the tool was determined after screening the available sources of the FDA, EMA, ICH, World Health Organisation (WHO), Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), and some national regulatory agencies (China, Japan, South-Korea, Turkey, Brazil and Russia) and an overlap analysis of the current departmental folders. This overlap analysis resulted in a reduction of complexity of the current departmental folders, which would also be included in the new tool. With these inputs, a potential concept for the tool was designed. The new tool should consist of three parts: one part containing general GMP requirements, the second part containing updated versions of the current departmental folders and the third part highlighting focus areas within the GMP guidelines.

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Recent onderzoek naar twin-screw hot melt granulation heeft geleid tot een beter inzicht in het onderliggende mechanisme. De voordelen maken deze techniek een waardevol alternatief voor de meer gangbare droge en natte granulatietechnieken. Er zijn inspanningen geleverd om een beter inzicht te krijgen in het granulatiemechanisme, de kritische procesparameters en de invloed van de binder op de uiteindelijke granule- en tableteigenschappen. Desondanks is er weinig bekend over het effect van andere formulerings- en procesparameters. Het doel van dit onderzoek was om het effect van de formulering- (graad van het actief bestanddeel, desintegrant) en procesparameters (configuratie) op de granule-eigenschappen en hun relatie tot andere formulering- (binderconcentratie) en procesparameters (schroefsnelheid, throughput) te onderzoeken. Daarnaast werd onderzocht of de tabletten die met deze granulaten werden gemaakt, in staat waren om in een redelijke tijd te desintegreren in de aanwezigheid van een extragranulair desintegrant en een oppervlakte-actieve stof. In deze studie werd vastgesteld dat de granulegrootte afhankelijk is van de aanvankelijke partikelgrootte van het actief bestanddeel en de aanwezigheid van een desintegrant. De schroefconfiguratie bleek een kritische rol te spelen. Een kleinere hoek tussen de kneedelementen veroorzaakte hogere afschuifkrachten, waardoor de granulegroei bevorderd werd. Bovendien werd vastgesteld dat de granule-opbrengst het grootst was in de aanwezigheid van een desintegrant, maar dit had tegelijkertijd een negatief effect op de deeltjesgroottedistributie. Uit de desintegratie-experimenten kon worden afgeleid dat desintegratie van het tablet alleen mogelijk was in aanwezigheid van het desintegrant. Dit onderzoek toont aan dat hot melt granulation potentieel als granulatietechniek binnen de farmaceutische industrie gebruikt kan worden. Daarnaast toont dit het belang aan van kennis over de formulatie en proceseigenschappen.

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Freeze drying of vaccines is important to ensure a stable product and longer shelf-life. Hence, the solid state of the freeze-dried vaccines must be characterised. The aim of this master thesis is to investigate the use of Modulated Differential Scanning Calorimetry for solid state analysis of freeze-dried vaccines at GSK Rixensart. In a first phase, glass transition temperature (Tg) and primary glass transition temperature (Tg’) of freeze-dried placebo vaccines containing sucrose are determined by both Conventional and Modulated DSC (MSDC) while varying the modulation parameters. Recommendations for the use of MSDC are made based on both literature review and experimental work. In a second phase, MDSC experiments are performed for diluted GSK product samples for which conventional DSC did not deliver an accurate thermogram. In a last phase, an annealing experiment is performed in which the relaxation behaviour of freeze-dried placebo vaccines is investigated. The influence of annealing time and temperature on relaxation enthalpy and glass transition temperature is determined. Modulated DSC can be considered as a good alternative for determining both the Tg and Tg’ of freeze-dried products. Especially when other endothermic events are observed in the same region of the glass transition temperature, MDSC is beneficial due to its ability to separate the heat flow into a reversing and non-reversing heat flow. Based on this research, the following recommendations for using MDSC are formulated: ensure four until six modulation cycles across the transition, keep samples masses low and flattened and use heat-cool cycles when determining the Tg. Optimal MDSC parameter setting combinations are determined for both Tg and Tg’ of the freeze-dried placebo vaccines and the diluted GSK product. Furthermore, an increase in modulation amplitude increases both Tg and Tg’ while increasing the modulation period solely increases the value of Tg. Finally, the relaxation behaviour of the freeze-dried placebo vaccines is assessed. When annealing temperatures closer to the glass transition temperature are used, the value of Tg will be higher and relaxation enthalpy will be larger as well. Moreover, the influence on relaxation enthalpy increases while using longer annealing times.

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The pharmaceutical industry shows a current shift towards continuous production due to several advantages like reduction of production costs and time. The major challenge of continuous direct compression of tablets lies in the varying powder properties like flowability and tabletability. Fette Compacting has introduced a new tablet press for continuous direct compression. The big advantage of this tablet press is the introduction of a third compression roller, next to the two compression rollers for traditional pre- and main compression. This extra compression roller extends the dwell-time so tablets can be produced at high tableting speeds without loss in tablet hardness or other increasing tablet defects. In this study the influence of the third compression roller will be investigated using a powder, placebo S, which undergoes mainly fragmentation. Using an experimental design, the experiments are set up where the effect of varying tabletting speed and varying forces of the different rollers on the properties of the tablets is investigated. Results of tablet weight, hardness, thickness and their respectively relative standard deviations are analysed to investigate the potential of this third compression roller. Additionally, the powder is characterized by parameters like moisture content, density and particle size distribution. Results of powder characterization indicate a good flowing powder. Evaluation of results of the experimental design show that increasing the tableting speed has a negative influence on both hardness and weight of the tablets. However, results show that the placebo S formulation benefits from the third compression roller. The values of the applied forces on the different rollers, which give rise to the optimal tablet properties, are dependent on the varying tableting speed. Finally, a generic method concerning tablet hardness is generated. For this purpose, three additional powders with varying deformation properties are analysed. These powders are compared among each other and a generic method for the use of the third compression roller is generated.