Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of product registration and for subsequent process maintenance, we review practices to explore RM variations. The relatively miniscule data sets accessible in product development – used to predict response to hypothetical risks – become less relevant as real-world experience of actual variability in the commercial landscape grows. Based on observations of development and manufacturing, we propose a holistic framework exploiting a hierarchy of RM variability, and challenge this with common failure modes. By explicitly incorporating higher-ranking RM variations as perturbations, material-conserving experiments are shown to provide powerful and enduring robustness data. We illustrate how contextualizing such data in development is valuable for evaluation of changes occurring later in the drug product lifecycle.
Learning Objectives:
Implement a holistic raw material (excipients and API) framework for drug product development and manufacturing, exploiting a hierarchy of raw material variability and challenging this apporach with common failure modes.
Gain better understanding of attribute-performance relationships at the time of new product registration and for
subsequent process maintenance.
Contextualize better development data in formulation and process development to avoid traps of historical QbD approaches and changes which may occur later in the drug product lifecycle.