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Continuous manufacturing of solid oral dosage forms is promising for increasing the efficiency and quality of pharmaceutical production and products. In this study a whole train continuous direct compression (CDC) line has been provoked using challenging formulations typically prone to segregation in batch powder processing. Industrial compositions including components with variable size, bulk density and cohesive nature were selected. An experimental design, including variables such as API/mannitol particle size, API amount, powder feed rate and mixer speed, enabled the output quality of the provoked process to be assessed. Contrary to previous studies, a broader range of finished tablet quality attributes were probed, including content, uniformity of content, tensile strength as well as release performance. Overall, the continuous direct compression line was found to be a capable and efficient manufacturing process for the challenging compositions studied and surprisingly tolerable to handle the materials susceptible to segregation in typical batch settings. As expected, and given the 'fixed' apparatus configuration used in this study, the particulate material properties were found to have the most significant impact on the finished tablet quality attributes. The results emphasize the importance for taking a holistic approach when developing the operational windows and the strategy for control, e.g. by integrating the appropriate material properties, the actual apparatus design, and the relevant formulation design. The CDC line's ability to handle cohesive materials also seem to be one of the key advantages, thus confirming the recent promising results from other continuous direct compression studies.

Roller compaction (RC) is a continuous process for solid dosage form manufacturing within the pharmaceutical industry achieving similar goals as wet granulation while avoiding liquid exposure. From a quality by design perspective, the aim of the present study was to demonstrate the applicability of statistical design of experiments (DoE) and multivariate modeling principles to identify the Design Space of a roller compaction process using a predictive risk-based approach. For this purpose, a reduced central composite face-centered (CCF) design was used to evaluate the influence of roll compaction process variables (roll force, roll speed, gap width, and screen size) on the different intermediate and final products (ribbons, granules, and tablets) obtained after roll compaction, milling, and tableting. After developing a regression model for each response, optimal settings were found which comply with the response criteria. Finally, a predictive risk based approach using Monte Carlo simulation of the factor variability and its influence on the responses was applied which fulfill the criteria for the responses in a space where there is a low risk for failure. Responses were as follows: granule throughput, ribbon porosity, granules particle size, and tablets tensile strength. The multivariate method orthogonal partial least-squares (OPLS) was used to model product dependencies between process steps e.g. granule properties with tablet properties. Those results confirmed that the tensile strength reduction, known to affect plastic materials when roll compacted, was not prominent when using brittle materials. While direct compression qualities are frequently used for roll compacted drug products because of their excellent flowability and good compaction properties, this study confirmed earlier findings that granules from these qualities were more poor flowing than the corresponding powder blend.

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