(605d) Challenges in Transfer of a Shear Sensitive Lubricated Formulation from a Dosator-Type to a Dosing Disk-Type Capsule Filling Machine

According to current SUPAC Guidance, changes in equipment from the same class but different subclasses should be considered carefully and supported with appropriate scientific data to justify that the quality attribute(s) of the drug product are not adversely impacted. During transfer of a lubricated formulation from a dosator-type to a dosing disk-type encapsulation machine (same class but different subclasses), a significant decrease in both the rate and extent of dissolution, a critical quality attribute (CQA), was observed at the end of the encapsulation run, based on testing of samples pulled in a stratified fashion. Additionally, a reduction in plug hardness was observed towards the end of the encapsulation run. It is well known from the literature that the amount of shear energy (as a function of rate and time) induced on the blend can be much greater when a dosing disk-type encapsulation machine is used compared to a dosator-type encapsulation machine. This excess shear occurs within the feed hopper itself (via the rotating agitator) and in the powder bowl (via the rotating tamping pins and/or level scraper) and can reduce the hardness (tensile strength) of the plugs.

The lubrication sensitivity of the blend in the feed hopper of a dosing disk-type encapsulation machine and associated dissolution slowdown was first mimicked using a lab-scale Turbula blender, where the excess dispersion of the hydrophobic lubricant, magnesium stearate, was assessed. Next, a qualitative/semi-quantitative disintegration-based Process Analytical Technology (PAT) was developed and enabled prediction of the dissolution performance of capsules in parallel with the encapsulation unit operation. Subsequently, the feed hopper was re-designed by complete removal of agitator (main source of shear), and finally granule characterization (from a prior roller compaction step and via factorial DoE) was optimized to ensure proper flow and compactability of the blend. These approaches led to a successful transfer of the new process and ensured continuity of drug product CQAs to meet or exceed all regulatory commitments, specifically those around the Quality Target Product Profile (QTPP).