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Best Practices for Integration of Dissolution Data into Physiologically Based Biopharmaceutics Models (PBBM): A Biopharmaceutics Modeling Scientist Perspective

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Abstract

Dissolution is considered as a critical input into physiologically based biopharmaceutics models (PBBM) as it governs in vivo exposure. Despite many workshops, initiatives by academia, industry, and regulatory, wider practices are followed for dissolution data input into PBBM models. Due to variety of options available for dissolution data input into PBBM models, it is important to understand pros, cons, and best practices while using specific dissolution model. This present article attempts to summarize current understanding of various dissolution models and data inputs in PBBM software’s and aims to discuss practical challenges and ways to overcome such scenarios. Different approaches to incorporate dissolution data for immediate, modified, and delayed release formulations are discussed in detail. Common challenges faced during fitting of z-factor are discussed along with novel approach of dissolution data incorporation using P-PSD model. Ways to incorporate dissolution data for MR formulations using Weibull and IVIVR approaches were portrayed with examples. Strategies to incorporate dissolution data for DR formulations was depicted along with practical aspects. Approaches to generate virtual dissolution profiles, using Weibull function, DDDPlus, and time scaling for defining dissolution safe space, and strategies to generate virtual dissolution profiles for justifying single and multiple dissolution specifications were discussed. Finally, novel ways to integrate dissolution data for complex products such as liposomes, data from complex dissolution systems, importance of precipitation, and bio-predictive ability of QC media for evaluation of CBA’s impact were discussed. Overall, this article aims to provide an easy guide for biopharmaceutics modeling scientist to integrate dissolution data effectively into PBBM models.

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Abbreviations

BE:

Bioequivalence

BCS:

Biopharmaceutics classification system

CRDS:

Clinically relevant dissolution specifications

CBA:

Critical bioavailability attribute

CFV:

Critical formulation variable

CMA:

Critical material attribute

CPP:

Critical process parameter

CQA:

Critical quality attribute

DLM:

Diffusion layer model

DDDPlus:

Dose disintegration and dissolution plus

EMA:

European Medicines Agency

GIT:

Gastrointestinal tract

IR:

Immediate release

IVIVC:

in vitro in vivo Correlation

IVIVR:

in vitro in vivo Relationship

MR:

Modified release

TNO TIM:

TNO (gastro-) intestinal models

PSA:

Parametric sensitivity analysis

PSD:

Particle size distribution

PBBM:

Physiologically based biopharmaceutics modeling

P-PSD:

Product particle size distribution

QC:

Quality control

SUPAC:

Scale up and post approval changes

SIVA:

Simcyp™ In vitro Data Analysis tool kit

USFDA:

United States Food and Drug Administration

USP:

United States Pharmacopoeia

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Acknowledgements

Authors would like to thank Dr. Reddy’s Laboratories Ltd. for providing an opportunity to publish this review article.

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  1. Biopharmaceutics Group, Global Clinical Management, Integrated Product Development Organization (IPDO), Dr. Reddy’s Laboratories Ltd, Bachupally, Medchal Malkajgiri District, Hyderabad, 500 090, Telangana, India

    Sivacharan Kollipara, Adithya Karthik Bhattiprolu, Rajkumar Boddu, Tausif Ahmed & Siddharth Chachad

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SK — concept and design, writing manuscript; AK — concept and design, writing manuscript; RB — concept and design, writing manuscript; TA — concept and design, manuscript review, approval for version to be published; SC — manuscript review, approval for version to be published.

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Correspondence to Tausif Ahmed.

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Kollipara, S., Bhattiprolu, A.K., Boddu, R. et al. Best Practices for Integration of Dissolution Data into Physiologically Based Biopharmaceutics Models (PBBM): A Biopharmaceutics Modeling Scientist Perspective. AAPS PharmSciTech 24, 59 (2023). https://doi.org/10.1208/s12249-023-02521-y

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