Dermal Formulation Quality by Design Project Abstract The Office of Generic Drugs (OGD) is tasked, among other things, with reviewing sponsor applications for dermal dosage forms that purport to be bioequivalent to the approved formulations for the same drug. Sponsor companies want to have high confidence that applications they submit for dosage forms thought to be bioequivalent will receive favorable reviews. Software that embodies physiologically based pharmacokinetics (PBPK) and mechanistic absorption model (MAM) and accounts for formulation effects in predicting the local drug concentration in the skin as well as concentration in systemic circulation can be a useful tool to reduce the time and expense involved in designing new generic formulations and assessing their potential to be bioequivalent to approved dosage forms by industry and regulatory scientists. Developing a state-of-the-art capability for dermal MAM/PBPK software requires an extensive knowledge base to serve as the scientific foundation, talented scientists to apply the knowledge base in the development of useful equations and logic suitable for software, high-level computer programming skills to encode the equations and logic into user-friendly software, and experienced scientists to test, validate, document, and support the software for use by others not involved in its development. This proposed project will advance the state-of-the-art for dermal MAM/PBPK modeling to include the ability to identify and quantify drug-product-specific critical quality and performance attributes of transdermal dosage forms. This will be achieved through a combination of expanding the existing knowledge base and compiling a database of critical product quality and performance attributes for transdermal formulations, as well as enhancing the models in the Transdermal Compartmental Absorption and Transit? (TCAT?) MAM/PBPK model within the GastroPlus? software program to account for these formulation attributes in the assessment of virtual bioequivalence between brand and generic drug products. By basing the final software program on the well-established and validated TCAT model, which is in use at the FDA and within the pharmaceutical innovator and generic industries today, we will be able to focus project resources entirely on advancing the capabilities of the model rather than having to develop new code for the core program and its many support capabilities (e.g., integration, plotting, Parameter Sensitivity Analysis, Population Simulations). Throughout the effort, we will maintain close contact with the FDA program manager and the Consortium for Dermal Absorption Modeling (CDAM) that we will form with our collaboration partners and the FDA to ensure the project team focuses on model development and new experimental work. This will result in developing the optimum software capabilities to implement dermal product Quality by Design (QbD) and virtual bioequivalence assessment, within the scope of the project.
Dermal Formulation Quality by Design Project Narrative The proposed project will advance the state-of-the-art for dermal physiologically based pharmacokinetics (PBPK) and mechanistic absorption modeling (MAM) to include the ability to identify and quantify drug- product-specific critical quality and performance attributes of transdermal dosage forms. This will be achieved through a combination of expanding the existing knowledge base and compiling a database of critical product quality and performance attributes for transdermal drug products, as well as implementing enhanced models in the Transdermal Compartmental Absorption and Transit? (TCAT?) MAM/PBPK model within the GastroPlus? software program to account for these formulation attributes in the assessment of virtual bioequivalence between brand and generic drug products.
