Converting a batch based high-shear granulation process to a continuous dry granulation process; a demonstration with ketoprofen tablets.

When one wishes to convert a batch based manufacturing process of an existing tablet product to a continuous process, there are several available strategies which can be adopted. Theoretically, the most straightforward way would be to proceed with the corresponding processing principles, for example to change a wet granulation (WG) batch process into its continuous WG counterpart. However, in some cases, the choice of roller compaction (RC) could be very attractive due to the notably simpler and inherently continuous nature of the RC manufacturing principle. The aim of this study was to examine a process conversion from batch based high-shear wet granulation (HSWG) to continuous RC manufacturing, without any significant formulation changes. An optimization of the formulation is often needed during the process conversion. However, our primary goal was to demonstrate the possibilities to perform this kind of process adaptation with minimal formulation changes. Furthermore, the effect of three different locations of lubrication feeding with two production rate levels was studied. An additional target was to identify possible over-lubrication with these manufacturing configurations, and to clarify which of these three possibilities steps produced a final product that conformed to the same quality requirements as HSWG tablets. Previously, the effects of lubrication only on compacted ribbons (Miguelez-Moran A.M, 2008) and final product with CDC (continuous direct compression) (Taipale-Kovalainen, et al., 2017; 2019) have been investigated. Here, the effect of lubrication on both ribbon and on final product was examined. No signs of over-lubrication were observed, but there was a clear effect of the feeding location of lubricant on the final product. On the basis of these results, it is concluded that in the future, if a good product/process understanding of the alternative manufacturing process with different techniques can be obtained, it will be possible to devise more flexible and effective ways to allow the pharmaceutical industry to switch from batch manufacturing towards CM.

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

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.

Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets.

The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental design was used to generate a structured study plan which involved 19 runs. The formulation variables studied were the type of lubricant (magnesium stearate or stearic acid) and its concentration (0.5, 1.0 and 1.5%). Process variables were total production feed rate (5, 10.5 and 16kg/h), mixer speed rpm (500, 850 and 1200rpm), and mixer inlet port for lubricant (A or B). The continuous direct compression tableting line consisted of loss-in-weight feeders, a continuous mixer and a tablet press. The Quality Target Product Profile (QTPP) was defined for the final product, as the flowability of powder blends (2.5s), tablet strength (147N), dissolution in 2.5min (90%) and ejection force (425N). A design space was identified which fulfilled all the requirements of QTPP. The type and concentration of lubricant exerted the greatest influence on the design space. For example, stearic acid increased the tablet strength. Interestingly, the studied process parameters had only a very minor effect on the quality of the final product and the design space. It is concluded that the continuous direct compression tableting process itself is insensitive and can cope with changes in lubrication, whereas formulation parameters exert a major influence on the end product quality.