be built with a few or several process units in the same manufacturing area. In the future, a more flexible and efficient approach could be even ´mobile´ CM lines built into a container (already available from GEA), which could be transferred between countries.
In our three studies, all the processes were performed in the same and small manufacturing area, which demonstrated that the process was adaptable to changes in the set-up operations. Another approach is the conversation from a batch mode manufactured product (already on the market) to a continuous mode i.e. requiring only a post-approval manufacturing change (ISCMP, 2014). This makes it possible to adopt more flexible variations in the operations. In our comparison studies, the bridging of these two methods was demonstrated with a granulated tablet product. Although there is a growing encouragement from regulatory bodies in the area of CM, there is a clear and evident need for a real harmonization of implementation procedures between different countries.
7.2 QUALITY BY DESIGN APPROACH
The guidelines issued by the regulatory authorities e.g. ICH Q8 (R2), ICH Q9 and ICH Q10 support the development approach called Quality by Design. This new option is the underpinning of the concept that there are quality aspects in the manufacturing of pharmaceuticals; the ´Control Strategy´ is the key factor of enhanced QbD -based manufacturing. This provides a better understanding of quality elements during the product’s lifecycle compared to the minimal approach as applied today in traditional manufacturing processes. Design Space follows the QbD principles; its target is to find the parameters which exert the greatest influence on the critical quality attributes of the product. Our results demonstrated that design space can be achieved in the whole CM process line producing a tablet that conforms to the quality requirements. Furthermore, we revealed the desired flexibility to operate in the CM process along with a scientific understanding of multiple combinations and the interactions between different parameters. The benefit of CM processes is that the DS does not need to be re-created in scaling-up processes as the equipment used is the same. In our results, the created DS covered the whole continuous process line. A similar kind of publication was not found in the literature in the context of continuous direct compressible tablet production.
7.3 THE MEANING OF THE MASS STREAM IN THE CONTINUOUS PROCESS
An understanding material transport operations between the steps and each unit process represents the basis of continuous manufacturing. Care must be taken with system 117
design, start-up and shut-down operations e.g. that there is a synchronized material transfer between the unit processes in order to avoid a control system runaway. It is clear that with a continuous process running 24/7, different kinds of interruptions (unintentional and intentional) during the runs will occur. One of the most important aspects of this dissertation was to investigate the factors influencing the mass stream; i.e.
lubrication, different set-up and disturbances. The study focused on the importance of achieving a constant mass stream during the runs on the process line with different unit process configurations. In our study, the CM process was subjected to stresses in every process step, in order to pinpoint the effect of interruptions during a long run on the quality of the final product. The study confirmed, in agreement with the results already published in the literature, that more studies using the whole CM line (not only a part of unit processes) should be performed. In addition to a carefully designed set-up, it is obvious that lubrication has an important role in the material transfer phenomena, as its function is to ease the contact between the particles and to enhance both flowability and tabletability. The effect of lubrication was examined in all our studies to demonstrate the influence of lubricant based parameters on a continuous manufacturing process.
Although the process parameters were shown to have a minor effect on the quality of the final product, they should be still evaluated, monitored and analysed. However, material properties had the most important influence on the final product. It was somewhat surprising that a high variation in the feed rates of lubricants did not exert a negative effect on the quality of the final product. This was mainly attributable to the flowing properties of the main components. Thus, the flow rate of main components and the mixing strategy need to be carefully planned and monitored.
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8 CONCLUSIONS
The present study demonstrated the feasibility and flexibility of the specific continuous manufacturing process line, allowing it to be modified into different configurations and formulations without encountering any significant quality issues. In addition, the effect of lubrication was systematically evaluated in all of these studies. On the basis of the results, it can be concluded more specifically that
I The continuous process line studied was found to be suitable for integration into a top-down model for direct compressible paracetamol tablets using QbD approach. The Design Space created showed the good feasibiliy and flexibility of the continuous line to produce tablets that conformed to the quality requirements.
II The continuous process line studied was suitable for being configurated into a horizontal model with several unit processes to produce direct compressible paracetamol tablets. Its flexibility was examined by exposing the process to both intentional and unintentional disturbances during long runs and determining which of these affected the quality of the product. In addition, the results highlighted the importance of connecting the unit processes together to maintain a constant mass flow throughout the whole process line.
III A feasible conversion from the HSWG batch to the DG continuous mode could be achieved with slight modifications of formulation and unit processes. Both manufacturing methods fulfilled the requirements, thus demonstrating more flexible and effective ways to allow the pharmaceutical industry to switch from batch manufacturing towards CM.
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