The effects of unintentional and intentional process disturbances on tablet quality during long continuous manufacturing runs

Abstract

Several kinds of process disturbances can occur during (continuous) tablet manufacturing, i.e. unintentional or intentional disturbances. Long run-time continuous manufacturing studies are used to investigate the effects of intentional and unintentional deviations. In this study, the horizontal continuous manufacturing line included a double mixing - direct compression set up. The study consisted of two long duration test runs. In the first run, the API (paracetamol) was fed in during the first feeding and blending stage with lubricant (Mg.Stear.) added during the second feeding and blending stage. In the second run, the API and lubricant feeding stages were reversed. The run protocol included a long run with several feeder re-fills and an overnight hold-time, continuing with the same API concentration followed by a change to a higher API concentration on the fly (without cleaning). The objectives of this pilot study were to determine the intentional (e.g. overnight hold time, product concentration change) and unintentional (e.g. equipment or software failures) deviations, which could affect the critical quality attributes (CQA's) of the final product and to create a deviation document which would reveal the changes that had occurred in the product concentration during the runs. Another goal was to study the effect of feeding location of lubricant and API feeding. The CQA's were the assayed values of API, tablet strength, friability, tablet weight and its dissolution profile. The vacuum conveyors, which were needed to transfer materials in the horizontal set-up, were observed to introduce variation into the mass flow rates and feeding. Thus, there were significant challenges to ensuring a constant mass flow rate during the runs. One expected effect was that over-lubrication was evident when the lubricant was fed during the first feeding and mixing stage, resulting in a significantly reduced tablet strength and a slower dissolution of API. There were no observable trends over time in the process parameters or CQAs i.e. evidence of a stable process. The overnight hold-time did not affect the CQAs of tablets. Moreover, the variation in all CQAs was smaller after the overnight hold-time which was particularly unexpected. In conclusion, the results reveal that the process itself was able to produce a quality end product, but the set-up needs to be better designed and controlled to ensure a constant mass flow and prevent over-lubrication.

Keywords: Horizontal continuous manufacturing; Intentional and unintentional deviation; Long run; Mass flow; Over-lubrication; Overnight hold time.