(725e) Credibility Assessment of Mechanistic Roller Compaction Model Using ASME V&v 40 Risk Informed Framework

Roller compaction (RC) is a continuous dry granulation process in which the primary powder is compressed at high pressure by two counter rotating rollers to produce a ribbon. The ribbon is then crushed to produce granules. This prevents segregation of the constituents of the powder mixture and improves the flow properties and compaction characteristics. However, RC implementation for high drug load formulations can be challenging due to flow issues and a high consumption of active pharmaceutical ingredient (API). This has led to significant growth in the use of predictive mechanistic models in the design and scale-up of roller compaction processes over the past decade.

RC mechanistic model utilizes the analytical method developed by Johanson [Johanson, J. R. (1965)] for predicting compaction process performance. Their model predicts ribbon solid fraction as a function of roll gap, roll width and roll force parameters. The ribbon solid fraction is an important intermediate parameter that the process development team relies upon as an indicator of overall tablet quality. This provides guidance on the starting point of process operating conditions which will then be utilized during tech transfer activities, thus saving cost and time during drug product development.

It is important to establish that the model is credible for its intended use given the criticality of the RC model predictions for process development. Currently, there is no consensus on how to establish and assess model credibility, including the selection of appropriate verification and validation activities for pharmaceutical process models.

In this work, we summarize the application of the risk informed credibility framework outlined in the ASME Verification & Validation 40 (ASME V&V 40) standard for the roller compaction mechanistic model credibility evaluation (American Society of Mechanical Engineers, 2018). This standard provides a risk-informed credibility assessment framework for the development and assessment of computational models of medical devices, which was later adopted into model-informed drug development (Kuemmel et al., 2020; Viceconti et al., 2021). The key aspects of the framework include defining the Question of Interest that the model is going to address, the Context Of Use of the model, assessing model risk based on the impact of the model's influence in the decision as well as model’s impact on product quality and how this affects the patient, and establishing model credibility through various verification and validation methods described in ASME V&V 40 framework. This presentation will review the application of the ASME V&V 40 standard to establish the credibility of the RC to support scale-up activities.