Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

Modelling Based Approaches to Support Generic Drug Regulatory Submissions-Practical Considerations and Case Studies.

Model informed drug development (MiDD) is useful to predict in vivo exposure of drugs during various stages of the drug development process. This approach employs a variety of quantitative tools to assess the risks during the drug development process. One important tool in the MiDD tool kit is the Physiologically Based Pharmacokinetic Modelling (PBPK). This tool is extensively used to reduce the development cost and to accelerate the access of medicines to the patients. In this work, we provide an overview of PBPK modelling approaches in the generic drug development process, with a special emphasis on the bio-waiver applications. We describe herein approaches and common pitfalls while submitting model based justifications as a response to the regulatory deficiencies during the generic drug development process. With some in-house case studies, we have attempted to provide a clear path for PBPK model based justifications for bio-waivers. With this review, the gap between theoretical knowledge and practical application of modelling and simulation tools for generic drug product development could be potentially reduced.

A mechanistic physiologically based model to assess the effect of study design and modified physiology on formulation safe space for virtual bioequivalence of dermatological drug products.

Physiologically based pharmacokinetic (PBPK) models are widely accepted tools utilised to describe and predict drug pharmacokinetics (PK). This includes the use of dermal PBPK models at the regulatory level including virtual bioequivalence (VBE) studies. The current work considers the Topicort® Spray formulation, which contains 0.25% desoximetasone (DSM), as an example formulation. Quantitative formulation composition and in vitro permeation testing (IVPT) data were obtained from the public literature to develop a mechanistic model using the multi-phase, multi-layer (MPML) MechDermA IVPT module in the Simcyp Simulator. In vitro-in vivo extrapolation functionality was used to simulate in vivo PK for various scenarios and predict a 'safe space' for formulation bioequivalence using the VBE module. The potential effect of vasoconstriction, impaired barrier function, and various dosing scenarios on the formulation safe space was also assessed. The model predicted 'safe space' for formulation solubility suggesting that a 50% change in solubility may cause bio-in-equivalence, whereas viscosity could deviate by orders of magnitude and the formulation may still remain bioequivalent. Evaporation rate and fraction of volatile components showed some sensitivity, suggesting that large changes in the volume or composition of the volatile fraction could cause bio-in-equivalence. The tested dosing scenarios showed decreased sensitivity for all formulation parameters with a decreased dose. The relative formulation bioequivalence was insensitive to vasoconstriction, but the safe space became wider with decreased barrier function for all parameters, except viscosity that was unaffected.

Current State and Future Expectations of Translational Modeling Strategies to Support Drug Product Development, Manufacturing Changes and Controls: A Workshop Summary Report.

The implementation of clinically relevant drug product specifications (CRDPS) depends on establishing a link between in vitro performance and in vivo exposure. The scientific community, including regulatory agencies, relies on biopharmaceutics tools on the in vitro performance side, while to enable the link to in vivo exposure, physiologically based pharmacokinetic (PBPK) modeling offers much promise. However, when it comes to PBPK applications in support of CRDPS, otherwise called physiologically based biopharmaceutics models (PBBM), the tools are not yet at the desired level. Currently, it is not possible to integrate detailed variations in chemistry, manufacturing and controls (CMC) attributes and parameters into these models in a way that can consistently predict their effect on local and systemic drug exposure. Specifically, to achieve the desired level, there is a need to advance the science and policy of PBBM. This manuscript summarizes the proceedings of a three-day workshop where the following themes were discussed: 1) Challenges in the development and implementation of in vitro biopredictive tools needed for successful mechanistic modeling; 2) Best practices in model development, verification and validation; and 3) Appropriate terminology (e.g., PBBM vs. PBPK models for biopharmaceutics applications) and applications of PBBM in support of drug product quality.

Applications of Physiologically Based Biopharmaceutics Modeling (PBBM) to Support Drug Product Quality: A Workshop Summary Report.

This report summarizes the proceedings for Day 3 of the workshop titled "Current State and Future Expectations of Translational Modeling Strategies toSupportDrug Product Development, Manufacturing Changes and Controls". From a drug product quality perspective, patient-centric product development necessitates the development of clinically relevant drug product specifications (CRDPS). In this regard, Physiologically Based Biopharmaceutics modeling (PBBM) is a viable tool to establish links between in-vitro to in-vivo data, and support with establishing CRDPS. The theme of day 3 was practical applications of PBBM to support drug product quality. In this manuscript, case studies from US FDA, EMA and pharmaceutical industry on applications of PBBM in drug product quality are summarized which include 1) regulatory agency's perspectives on establishing the safe space and achieving study waivers, 2) model-informed risk assessment on the effects of acid reducing agents, bridging of dissolution methods, food effect, and formulation selection, and 3) understanding clinical formulation performance. Breakout session discussions focused on four topics - 1) terminologies related to physiologically based modeling in support of drug product quality, 2) regulatory harmonization on evidentiary standards, 3) CRDPS approaches and 4) bridging between biorelevant and quality control (QC) dissolution methods.

Prediction of fasted and fed bioequivalence for immediate release drug products using physiologically based biopharmaceutics modeling (PBBM).

Bioequivalence studies are an integral part of clinical pharmacology strategy for drug development. Physiologically based biopharmaceutics modeling (PBBM) can be a helpful tool to assess potential bioequivalence risks and predict the outcome of bioequivalence studies. In this study, GastroPlus™ was used for virtual bioequivalence (VBE) assessment of 6 case studies which includes four BCS 2, and one each of BCS 1 and 3 molecules. The purpose was to investigate if bioequivalence in fed state can be accurately predicted based on model developed on data from bioequivalence study in fasted state and known food effect from clinical studies. Our results show that we were able to successfully predict passing (5 cases) and failed (1 case) bioequivalence studies. Ultimately, if there is confidence in such models, a case can be made to waive fed bioequivalence study, on a case-by-case basis (e.g. for BCS class 1 and 2 molecules with known food effect mechanism, reliable estimate of human pharmacokinetic parameters, and available in vivo data in fasted state for model verification). This has the potential to reduce clinical burden in drug development, increase confidence in pivotal BE studies and support regulatory applications such as justify waiving of BE study for Scale-Up and Post Approval Changes (SUPAC). Hence VBE can significantly reduce time and cost of drug development, as well as minimize drug exposure to healthy volunteers.