5.2.3. Prototyping and selection of formulation and process for ClaroSip ® taste masked pellets

Different formulations were investigated for the pellet formulation and the taste masking coating. The prototypes were then evaluated against the project target profile and the prioritised requirement of in-vitro dissolution in fluids simulating the contents of the small intestine where drug absorption takes place in-vivo only after the drug has been dissolved. The manufacturing processes of wet extrusion and spheronisation for pellet manufacturing and fluid bed coating for taste masking were selected based on prior knowledge.

The three most promising candidates differentiated by their in-vitro performance were tested in a small clinical pilot bioequivalence study versus the originator’s product. Thereby a correlation between the test measurement of in-vitro dissolution and the clinical performance in the patient (expressed as the bioequivalence to the originator’s product) was established and the candidate matching bioequivalence most closely could be selected for further development based on clinically relevant attributes.

The risk mapping was further detailed in FMECAs for the product composition, the manufacturing process, the scale up of the process and the packaging of the drug product, defining the specific risks, the potential causes for these risks, the probability of their occurrence, an evaluation of their criticality on product performance and the prioritised mitigations to investigate the extent, probability and potential for controls associated with each risk.

Critical material attributes and process parameters were investigated via DOE experimentation at a lab scale level, defining the edge of failure region and the region within which conditions can be varied without jeopardising the quality and the in-vivo performance of the product. A multivariate design space allows the definition of a safe process window or control space within which the defined product quality can always be achieved. The control space defined a robust manufacturing process and the validity of the established design space was conformed during scale up and process validation at pilot scale level (= scale needed to manufacture the drug product at the batch size required for primary stability studies and the primary bioequivalence study for marketing authorisation). At this stage process score cards were started to measure process capability for the manufacturing process in parallel to the product performance monitored in the product score cards.

When transferring the process to production and a production scale process capability had to be conformed and process score cards adjusted to the increased scale and batch size.