PBBM Considerations for Base Models, Model Validation, and Application Steps: Workshop Summary Report

Abstract

The proceedings from the 30th August 2023 (Day 2) of the workshop "Physiologically Based Biopharmaceutics Models (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives" are provided herein. Day 2 covered PBBM case studies from six regulatory authorities which provided considerations for model verification, validation, and application based on the context of use (COU) of the model. PBBM case studies to define critical material attribute (CMA) specification settings, such as active pharmaceutical ingredient (API) particle size distributions (PSDs) were shared. PBBM case studies to define critical quality attributes (CQAs) such as the dissolution specification setting or to define the bioequivalence safe space were also discussed. Examples of PBBM using the credibility assessment framework, COU and model risk assessment, as well as scientific learnings from PBBM case studies are provided. Breakout session discussions highlighted current trends and barriers to application of PBBMs including: (a) PBBM credibility assessment framework and level of validation, (b) use of disposition parameters in PBBM and points to consider when iv data are not available, (c) conducting virtual bioequivalence trials and dealing with variability, (d) model acceptance criteria, and (e) application of PBBMs for establishing safe space and failure edges.

Keywords: Bioequivalence; IVIVC; IVIVR; PBBM; bioequivalence safe space; context of use; dissolution; drug product quality; model credibility assessment framework; modeling.

Figure 1

Possible scheme for the model credibility assessment. This schematic includes concepts on model risk, the model risk grid, along with model influence and decision consequence.^−,

Figure 2

Presented decision tree for human iv data generation used in PBBM.⁻

Figure 3

Propagation of WSV in the physiological attributes of the GI tract through the interaction with attributes of the API and the formulation can be modeled with PBBM/PBPK. Figure is from Bego et al., https://creativecommons.org/licenses/by/4.0/.

Figure 4

Definition of safe spaces based on bioequivalence (top) or PK–PD (lower panel).

Figure 5

2-bin P-PSDs derived for 5 mg of zolpidem hemitartrate REF and TEST products using 900 mL of dissolution medium in USP 2, 50 rpm, phosphate buffer pH 6.8.