In recent years, the need to manufacture larger batch sizes to accommodate increased demand for biopharmaceutical drugs has grown significantly. This is particularly prevalent in the on-going effort to supply vaccinations to combat the current pandemic. An effect of this practice is the increased buffer consumption required to run downstream unit operations, which has in turn affected the labor requirement for buffer preparation and footprint for storage tanks. One solution, to overcome this growing issue is the use of in-line dilution systems to produce in specification process buffers on demand, from concentrated buffer stocks.<br/><br/>The successful implementation of an in-line dilution process is reliant upon the development of optimized concentrated buffers stocks from which the desired process buffers are produced. Buffer dilution must be proven to be repeatable and accurate due to the essential role that process buffers play in stabilizing the drug substance in downstream processing. Optimization of buffer concentrates involves firstly, evaluating process buffer salt solubility to determine a reasonable concentration factor, secondly, assessing the concentrate pH needed based on the buffer salt pKa shift upon water dilution and thirdly, determining the buffer concentrate conductivity. Work has been completed by Pall Corporation during the development of the Allegro™ Connect Buffer Management System (BMS) to optimize this process.<br/><br/>For this work, 6 buffer concentrates were optimized through theoretical predictions and at benchtop scale, to determine suitable dilution factors and target set points for conductivity and pH. Buffer concentrates were then scaled up to a manufacturing scale to assess the accuracy and repeatability of in-line dilution over multiple batches varying the run longevity, in-line dilution flow rate and downstream buffer draw rate. In-line dilution flow rates of 400 L/h to 1450 L/h at dilution factors between 5× to 20× were tested over 8 runs. The BMS was found to accurately and repeatably produce process buffers with average maxima deviations ± 0.12 and ± 1.35% from the pH and conductivity set-points, respectively. Buffer dilution was further assessed at an external Biopharmaceutical manufacturing site, where process buffer output lines were directly connected to a chromatography system. In-line chromatography measurements affirmed high process buffer accuracy within ± 0.05 and ± 3% of the pH and conductivity set-points, respectively.

Optimization of in-line, in specification buffer dilution with the Allegro™ connect buffer management system

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.