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This thesis deals with different subjects in the scope of pharmaceuticals tablets manufacturing. 
The first part is a description of the tablets manufacturing processes and tablets products currently produced at Mithra CDMO in Flémalle. This section is important to explain the context of the project and give essential information to complete and support the understanding of the next two chapters. 
The second chapter deals with a granulation problem that occurred during the first Estelle (product name) active tablets technical batch. The following problem statement is defined and needs to be answered before the manufacturing beginning of the second technical batch: 
“During Estelle drug product first technical batch, problems occurred in the granulation step. Thus, powder with bad physical and flow characteristics and almost impossible to compress was obtained. The setting of the compression machine was indeed impossible due to irregular flow properties of the powder obtained during the granulation step. To solve this problem, different parameters will be investigated in this work. Amongst them, a particular attention will be given on the quantity of granulation liquid. Therefore the questions are: what is the influence of those parameters on the granules characteristics? What could be an optimal value for the amount of granulation liquid in order to produce granules with the right characteristics? What could be an efficient method to better monitor the granulation step? “.
In the second part, granulation process is studied deeply and the different mechanisms of granules growth are explained. After that, the produced granules are characterized and more than 35% of fine particles are found. The two possible hypotheses that are the most likely to explain the high quantity of fine particles are identified as the non-granulation and the potential explosion of the granules during the drying step. 
To evaluate the granules growth and the possible non-granulation, the theory of the impeller torque evolution during the granulation is chosen. First the torque evolution behavior for Estelle drug product powder has been identified on small scale R&D batches as being a stepwise growing behavior. This behavior looks like a sigmoid. As the same type of granulator and the exact same powder are used during the first technical batch, the torque stepwise behavior should be observed if the granules were produced. However, the torque does not show this pattern during the granulation of the technical batch, with an almost steady value around 60-70 Nm. This result supports the hypothesis that the granulation did not occur. Amongst the possible solution to answer this issue, the quantity of liquid is identified as the key parameter to form the granules. An investigation is dedicated to this variable. After studying different possibilities, the final chosen granulation liquid quantity to be used for the second technical batch has been estimated to 15.9 kg (instead of 13.8 kg) and the validity of this value is supported by a formula specifically designed to evaluate amount of granulation liquid (developed by Leuenberger). The level and peak detection method are proposed for the monitoring of the torque values during the second technical batch. Those methods will allow to determine the optimal quantity of granulating liquid and the granulation end point during the manufacture of this batch. 
The last part of this chapter is dedicated to the potential explosion of the granules during the drying step. It is found that the microwaves energy added in the first technical batch was greater that the energy necessary for the water evaporation. This could explain the possible explosion of the granules. A decrease of the microwaves energy is therefore advised for the next technical batch to exclude this possibility. 
Finally, the last part of this work deals with the compression step of Estelle placebo tablets. This step is statistically studied for Estelle Placebo last technical batch based on Haupt specifications. The following tablets attributes are studied: hardness, weight, thickness and diameter. After the statistical analysis performed on the last technical batch, new specifications that are more adapted to the non-coated tablets are given. Those new specifications are used for the statistical study of the tablets produced during the first validation batch. The advantage of the method is that the specifications are evaluated with and without a hold time on the compression powder. The hold time gives harder and smaller tablets due to a compaction effect in container before compression. As the hold time has an effect on the tablet attributes, the specifications are once again reviewed after the first validation batch. This statistical analysis is based on reference quality control documents which are the two following International Standards: ISO 2859-1 and ISO-22514-4.

Ingénierie, informatique & technologie > Ingénierie chimique