Provoking an end-to-end continuous direct compression line with raw materials prone to segregation

Abstract

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.

The Comparison of Two Challenging Low Dose APIs in a Continuous Direct Compression Process

“…With respect to the feeder data, the variation was different with both APIs, but in all cases, variations were such that the mixer could smoothen out the variations as the tablets passed the final content uniformity test. This is in good accordance with the results already presented for mixer smoothing of brief variations in feeding [29,43,44,50]. One limitation in this study was the mixer used, as it is working basically all the time in the fluidized mixing mode (i.e., a high Fr number) limiting the possibility of comprehensively demonstrating the effect of mixing parameters on end product quality.…”

“…If one wishes to find a balance between sufficient flow properties for API and excipients and blend homogeneity, it is important to appreciate how different parameters affect the processability. Consequently, studies have been published describing the effect of raw material properties on mixing behavior [19][20][21]33,[38][39][40]; furthermore, the interaction between material properties and process parameters with different types of continuous manufacturing set-ups has been discussed [22,24,29,33,[40][41][42][43][44]. However, as far as we are aware, the number of studies where both a constant excipient formulation and excipient/API relation have been examined in a CDC process is very limited.…”

Comparison between integrated continuous direct compression line and batch processing – The effect of raw material properties

“…Previous studies investigating continuous mixing have noted that commonly used continuous mixers are very capable of handling mixtures with a segregation tendency (Oka et al, 2017;Pawar et al, 2016;Vanarase et al, 2013;Vanarase and Muzzio, 2011;Van Snick et al, 2017b). In addition, for more realistic industrial compositions, prone to segregation in batch manufacture, CDC was found notably advantageous (Lakio et al, 2017). However, it was also concluded that the quality of the end-product was largely dependent on the material properties.…”

“…A few continuously manufactured products have already received approval by the regulatory authorities, which further confirms the applicability of this technology and explains the desire of the companies to adopt this approach (Almaya et al, 2017;Brennan, 2016;DiProspero, 2018;PharmTech, 2018). The most straightforward manufacturing process for tablets is direct compression, and the ability to couple continuous mixing to tableting, which is inherently continuous in its nature, has already been demonstrated in several studies (Engisch and Muzzio, 2016;Ervasti et al, 2015;Lakio et al, 2017, 2016, Van Snick et al, 2017a, 2017b. With integrated continuous mixing followed by direct compression, one can avoid several unit operations, such as the steps related to granulation.…”

“…It has also been postulated that transitioning from batch to continuous direct compression could significantly reduce the risk for powder flow issues (Byrn et al, 2015). Continuous direct compression (CDC) has been shown to cope well with cohesive substances in several studies, such as (Lakio et al, 2017;Roth et al, 2017;Van Snick et al, 2017a).…”