A general procedure for the evaluation of the prediction fidelity of pharmaceutical systems models

Quantitative systems models have been increasingly used to accelerate the development of pharmaceutical processes that traditionally require time and resource-intensive experimental campaigns. However, despite the potential benefits of modelling in pharmaceutical process development, there is often a lack of confidence from stakeholders to adopt these approaches in a systematic way. This is particularly important in a highly regulated sector such as the pharmaceutical industry, where model uncertainty evaluation may have to be quantified and filed if model results are to be included as part of a regulatory submission. In this study, a systematic procedure is proposed, combining both standard techniques (e.g., global sensitivity analysis, model-based design of experiments) and new methods based on data analytics to assess model fidelity and to support practitioners in model usage for pharmaceutical development. A direct compression systems model for manufacturing oral solid dosage products is used as a case study. The systems model is comprised of the following sub-models: (1) Tablet press unit operation, (2) Tablet disintegration test unit, (3) In vitro dissolution test unit. The implementation of the methodology is critically discussed, showing the effectiveness of the approach and the benefits of the proposed techniques in (i) evaluating model fidelity as a result of uncertainty in parameter estimation, (ii) assessing whether it is necessary to estimate all systems model parameters in a statistically satisfactory way, and (iii) analyzing whether model calibration should be carried out on a unit basis or considering the overall system.