A Model-Centric Solution to Link Content Uniformity Targets with API Particle Size Specifications and Process for a QbD Excercise

One of the contributing factors in determining targets for the particle size of an API can be the content uniformity of the dosage forms. This work presents a framework established with a model-based specification for particle size of the API that can be used in a bi-directional mode to: a) determine center point processing conditions for the API given a target in content-uniformity for the dosage form, and b) to propagate expected sources of variability in the API process onto the final quality of the product.

This work discusses the necessary considerations and advantages when a model-based specification is considered for the particle size distribution of the API and how this compares to common practices involving discrete points of the size distribution (such as D[10], D[50], D[90]).

Our discussion is centered on the need of a structural specification for the API particle size that can be effectively used to guide the design of the last stages of the drug substance manufacturing train. We also emphasize the need to standardize the descriptors of particle size in order to link the effects of the variability in the API process as it affects the drug product train and eventually the quality of the dosage form.