Downstream late-stage development involves various activities aimed at demonstrating process robustness to ensure consistent delivering of intended products at large-scale commercial production. It typically begins after the process is preliminarily locked for pivotal production. A detailed risk assessment is conducted based on potential CQAs and historical process knowledge to identify high-risk parameters and develop mitigation plan. Activities include scale-down model qualification, process characterization, intermediate hold time study, resin lifetime studies, etc.
Qualification of the scale-down model involves qualitative and quantitative comparisons to determine if there are significant differences in column performance between different scales.
UV280nm curves of chromatography A from scale-down model and GMP:
Conductivity and pH curves of chromatography A from scale-down model and GMP production scale:
Results of scale down model qualification:
In process characterization studies, high-risk process parameters are identified and evaluated using OFAT or DOE to determine their effect on product quality attributes and process performance. The % Tolerance is calculated to classify critical process parameters (CPP), key process parameters (KPP) and non-KPP. Acceptance criteria are defined based on contour plots or Monte Carlo simulations.
1. PDATR 60-3 Process Validation: A Lifecycle Approach Annex 2: Biopharmaceutical Drug Substances Manufacturing