Development of a Physiologically Based Biopharmaceutics Model Report Template: Considerations for Improved Quality in View of Regulatory Submissions

Abstract

Pharmaceutical innovators and generic companies use Physiologically Based Biopharmaceutics Models (PBBMs) to guide drug product development and potentially waive clinical pharmacokinetic studies for both pre- and postapproval changes. This modeling approach can assist with biopharmaceutics risk assessment and the establishment of patient centric, clinically relevant drug product specifications. However, the variability of possible model strategies and the existence of gaps in scientific knowledge associated with the lack of standardized regulatory expectations for model parametrization, data requirements for model development, and criteria for fit-for-purpose model validation leads to varied acceptance rates and frequent requests for additional information and deficiencies in PBBM submissions across regulatory agencies. During the 2023 Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) PBBM Best Practices for Drug Product Quality: Regulatory and Industry Perspectives workshop, it was identified that a PBBM report template summarizing model considerations and proposing a structure for presenting question(s) of interest, model context, input data, a modeling plan, and validation would be beneficial for both industry and regulatory agencies. The present work is not a regulatory guideline but rather a summary of current best practices and considerations for PBBM submissions. The associated template can be downloaded directly from the Supporting Information to guide one in the preparation of PBBM reports. The current paper discusses the critical elements of the PBBM report template, which were identified during the industry-regulator scientific collaboration and interactions.

Keywords: Clinically Relevant Dissolution Specifications (CRDS); Context of Use; Model Risk Assessment; Model-Informed Drug Development (MIDD); Physiologically Based Biopharmaceutics Models (PBBMs); Question of Interest; Regulatory/Model Impact; Report Template.

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Model risk assessment matrix.