Design of a vertical Loss-in-Weight feeder prototype with experimental proof of concept validation.

Loss-in-Weights (LiW) feeders are commonly oriented in a horizontal way. In this work, an experimental proof of concept, including mechanical and electrical design, construction, and operation, of a vertical LiW feeder prototype is performed. In a systematic design process, based on functional design specifications, the semi-automated vertical LiW feeder for dosing a wide range of powders, especially cohesive ones, is developed. The new dosing machine is assessed with regard to a number of key features such as high dosing accuracy, first-in-first-out powder discharge, easily interchange of the powder container, and flexibility in controlling the speed of the auger and stirrer motors independently. An experimental sensitivity analysis to study the functionality of the dosing machine and to investigate the weight variability of the weighing platform, i.e. mass flow rate, and quantity of dosed mass, is carried out. The results of the sensitivity analysis and the powder dosing tests of five diverse powders using different auger and stirrer geometries verified the proof of concept prototype.HighlightsA systematic design approach for validating a proof of concept of a vertical loss in weight feeder is appliedA full mechanical CAD design and implementation along with electric installation and software programming are executedSensitivity analysis approach is performed to validate the functionality of the semi-automated machine and successfully dispense dissimilar powders tested with different process parametersThe machine is characterized with a number of key features: first-in-first-out powder discharge, high dosing accuracy, flexible and modular concept design, flexibility in controlling the speed of the auger and the stirrer independently, lightweight and user-friendly design.

Deriving control parameter settings from process models to control capsule fillers integrated into continuous manufacturing.

The aim of this work was to investigate the mean fill weight control of a continuous capsule-filling process, whether it is possible to derive controller settings from an appendant process model. To that end, a system composed out of fully automated capsule filler and an online gravimetric scale was used to control the filled weight. This setup allows to examine challenges associated with continuous manufacturing processes, such as variations in the amount of active pharmaceutical ingredient (API) in the mixture due to fluctuations of the feeders or due to altered excipient batch qualities. Two types of controllers were investigated: a feedback control and a combination of feedback and feedforward control. Although both of those are common in the industry, determining the optimal parameter settings remains an issue. In this study, we developed a method to derive the control parameters based on process models in order to obtain optimal control for each filled product. Determined via rapid automated process development (RAPD), this method is an effective and fast way of determining control parameters. The method allowed us to optimize the weight control for three pharmaceutical excipients. By conducting experiments, we verified the feasibility of the proposed method and studied the dynamics of the controlled system. Our work provides important basic data on how capsule filler can be implemented into continuous manufacturing systems.

Using online content uniformity measurements for rapid automated process development exemplified via an X-ray system.

This paper addresses the relevance of automated content testing for the rapid automated process development (RAPD). Our previous work demonstrated that RAPD allowed a fast and efficient development of a continuous capsule-filling process. Target was the mean weight and the relative standard deviation of the weight. Likewise important are the content and the content uniformity. However, an implementation demands a certain level of automation. In general, technology is available that can detect active pharmaceutical ingredient (API) inside the capsules but the final application is linked to additional development and investment in machinery. To eliminate doubts regarding the benefits of an automated content check within the RAPD we present an application example. First, an X-ray system was used to detect barium sulfate accurately inside capsules. Second, a process was developed where barium sulfate was filled. The concentration of excipients was modified in the experiments, as well as the setting of the process parameter. The obtained model provided an explicit understanding of the process. Subsequently, the content uniformity model was compared to a model of the capsule weight relative standard deviation, confirming the benefits of an automated content check in the RAPD. Moreover, we presented another example illustrating the advantages of a connected continuous filling process, which permits evaluation of all process steps and their interactions (i.e. evaluation of the entire process).

Rapid automated process development of a continuous capsule-filling process.

This paper introduces a rapid automated process-development approach for a continuous capsule-filling process. In our proposed method, both the material attributes and the critical process parameters were varied to understand and to optimize the overall process. Using our approach a statistical process model can be generated with unprecedented speed (2 days), which is the prerequisite for effectively developing and operating continuous process platforms. In a first set of experiments a process model was developed using different mixture compositions of ascorbic acid, lactose and magnesium stearate while changing simultaneously the critical process parameters of the capsule filler (speed, pressure, immersion depth and powder bed height). Targets of the model were the mean fill weight and the relative standard deviation of the produced capsules. In a second experimental set the model was tested, i.e., the goal was to predict the behavior of the system at different set points in order to predict weight and relative standard deviation for predefined targets. Predictions were very good, thus validating our approach. The combination of the rapid automated process development approach and the continuous capsule-filling process resulted in a new strategy for the development and manufacture of pharmaceutical dosage forms.

Automation of a dosing-disc capsule filler from the perspective of reliability and safety.

The aim of this paper is to explore the possibility to develop an automatically adjustable, reliable, and safe capsule filling operation. Process parameters that are critical for the tamping pin process were reviewed based on the literature and via experiment. Dosing disc height, powder bed height, machine speed, pressure on the tamping pin, and immersion depth were reviewed. Two investigations were performed on a GKF 702. In the first one, the powder feed rate onto the dosing disc was examined and modified. A distance sensor with a PID controller enabled a constant powder bed level with an online changeable set point. For a bad flowing product an improvement of the fill weight variation could be achieved by automatically adjusting the feed rate to the correct speed and matching the actual process conditions of the capsule filler. The second part of the study concerned the safety of the filler operation. Introducing a force transducer on the transfer station is a promising option for running the capsule filler safely within its process specifications. The tamping pin pressure was used to provoke different transfer forces. A deviation from a defined process specification led to a safe stop of the machine. In summary, the automated adjustment of several critical process parameters appears to be feasible and supports the rational development of efficient production processes using a dosing disc capsule filler. This is especially relevant for continuous production of pharmaceuticals.

Preparation and measurement of combinatorial screen printed libraries for the electrochemical analysis of liquids.

A combinatorial approach to the development of new screen printing pastes is introduced. We used a novel technique for printing electrodes out of different binary mixtures of pastes. The pastes applied are based on the transition metals iridium and ruthenium in the form of their (IV) oxides. Using multielectrode arrays,these pastes were printed on the same substrate in one single step. In this work, pH sensors were printed based on a concept using solid state electrodes both with the measurement and the reference electrode.After the sintering process, the pastes were then evaluated using a robotic setup designed to handle the high impedances characteristic for pH sensors as well as to automatically manipulate the fluids in contact with the sensors.