Process Characterization and Performance Qualification of MCSGP

MCSGP (Multicolumn Countercurrent Solvent Gradient Purification) with AutoPeak control is increasingly used for production of synthetic peptides and oligonucleotides at scale, requiring guidance on how to perform regulatory-compliant Process Validation. This work, for the first time, presents a Process Characterization and Process Performance Qualification approach to support regulatory filings of therapeutics produced using MCSGP, based on the relevant Process Validation guidelines. The approach was demonstrated for the purification of synthetic Bivalirudin. During Process Characterization, MCSGP process parameter criticality was investigated, and the gradient slope was classified as a critical process parameter to be controlled within tighter limits. As a further outcome of Process Characterization, a supervision strategy was developed and verified in four Process Performance Qualification MCSGP runs. The strategy was backed by AutoPeak, a UV-based Process Analytical Technology. The Process Validation/Process Performance Qualification (PPQ) runs not only confirmed the selected control and supervision strategy but also the advantages of MCSGP/AutoPeak as a continuous manufacturing technology, including the fully automatic operation and the reduction in in-process control sampling and Process Mass Intensity (PMI). In the presented case, the PMI was reduced from around 5200 to 1400 kg/kg, the number of in-process controls (IPCs) was reduced from 81 IPCs (60 cm i.D. column batch) per kg to 3.2 IPCs per kg (2 × 30 cm i.D. column MCSGP), while yield (gross-to-gross) increased from 57% to 62%, comparing MCSGP/AutoPeak to a process with extensive side-cut recycling.