This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.

Conclusions

QbD tools made it possible to identify critical parameters, translate them to attributes that the drug product should possess, and establish how critical process parameters can be varied to consistently produce drugs with desired characteristics. QbD principles and tools presented in ICH Q8, ICH Q9, and ICH Q10 guidelines were considered in the current case study to explore relationships between formulation and manufacturing process variables and BCS Class II API DT to improve our fundamental knowledge of dis- solution testing (DT).

Risk analysis, identification of critical formulation/process varia- bles, understanding the effects of these critical variables and inter- actions on key product quality attributes are essential steps to achieve enhanced product and process awareness and offer opportunities to develop control strategies while ensuring final product quality. Indeed, as DT results at 60 min were all similar, it was not possible to model dissolution with operating conditions specified by USP. Preliminary results have shown that modeling at DT time of 10min can be performed allowing us to understand and predict DT. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate realtime quality control, leading to reduction of end-product release testing.

This case study exemplified the application of QbD principles and tools to drug product and process development. It demonstrated that DoE effects/response surface analysis represents a powerful tool to investigate the effects of selected factors (API PS, tablet hardness, and coating weight) on response–dissolution percentages, showing product and process robustness. The following points comprise the main new information brought forward by our study:

•  The two parameters impacting dissolution kinetics at 10 min are API PS and tablet hardness. They can easily be controlled during and after the manufacturing process with standard equipment such as an online laser granulometer and hardness tester, this information is highly useful for formulation improvement.
• Models can be used to predict DT if appropriate validation was to be performed.
• This QbD approach demonstrates product and process robustness.

The QbD concept can completely eliminate the need of dissolution testing or eventually either decreases required dissolution testing time as the finale dissolution percentage can be predicted knowing the first minute dissolution percentage the first minutes’ dissolution percentage. Thus, dissolution test can be reduced, or even eliminated, if confirmed by a validation procedure.

In conclusion, the methodology presented in this article (FMEA, DoE, and Design space definition) could be replicated and performed in other dosage forms like controlled release tablets, emulsions, suspensions, etc.

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