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

Authors: Heimbach T, Musuamba Tshinanu F, Raines K, Borges L, Kijima S, Malamatari M, Moody R, Veerasingham S, Seo P, Turner D, Fang L, Stillhart C, Bransford P, Ren X, Patel N, Sperry DC, Chen H, Rostami-Hodjegan A, Lukacova V, Sun D, Nguefack JF, Carducci T, Grimstein M, Pepin X, Jamei M, Stamatopoulos K, Li M, Sanghavi M, Tannergren C, Mandula H, Zhao Z, Ju TR, Wagner C, Arora S, Wang M, Rullo G, Mitra A, Kollipara S, Polli JE, Mackie C
Publication: Mol Pharm
Keywords: biopredictive dissolution, dissolution specifications, gastroplus, in vitro dissolution, PBPK modeling, physiologically based biopharmaceutics, safe space
Software: GastroPlus®
Division: PBPK

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.

By Tycho Heimbach, Flora Musuamba Tshinanu, Kimberly Raines, Luiza Borges, Shinichi Kijima, Maria Malamatari, Rebecca Moody, Shereeni Veerasingham, Paul Seo, David Turner, Lanyan Fang, Cordula Stillhart, Philip Bransford, Xiaojun Ren, Nikunjkumar Patel, David Sperry, Hansong Chen, Amin Rostami-Hodjegan, Viera Lukacova, Duxin Sun, Jean-Flaubert Nguefack, Tessa Carducci, Manuela Grimstein, Xavier Pepin, Masoud Jamei, Konstantinos Stamatopoulos, Min Li, Maitri Sanghavi, Christer Tannergren, Haritha Mandula, Zhuojun Zhao, Tzuchi Rob Ju, Christian Wagner. Sumit Arora, Michael Wang, Gregory Rullo, Amitava Mitra, Sivacharan Kollipara, Siri Kalyan Chirumamilla, James E. Polli, Claire Mackie