Process Characterization Process characterization work is typically carried out at small scale in order for the labor and feedstock requirements to be reasonable. This requires that a small-scale system that is scaleable to the full-scale process system is available and gives reliably representative results. These experiments are done to establish a window of acceptable operation for each critical process control setpoint. During process development, setpoints are determined for certain parameters that give acceptable process results. For a TFF process, these can include, but are not limited to, crossflow rate or pressure drop, transmembrane pressure or retentate pressure, process temperature, filtrate flux (more common in microfiltration than ultrafiltration), total volume of feedstock processed per area of membrane, number of diavolumes, and diafiltration buffer composition. In full-scale manufacturing, it is unlikely that all parameters will remain precisely at their setpoint value throughout the course of a process run or from one run to the next. Therefore, in order to create a manufacturing procedure that is both feasible to operate in a plant environment and one that results in good product, an appropriate range for the process parameters must be determined.

Calculation of Product Volume Required for Scale-Down TFF Experiments

Process Validation Process validation, a second segment of the validation strategy, demonstrates that the process that was developed and defined at small scale operates successfully and reproducibly at manufacturing scale. Typically, process validation is achieved by performing several (often three) qualification lots, using feedstock that runs sequentially through all steps of the process and, ideally, using the equipment intended for manufacturing. Product material and process data from the runs are analyzed to demonstrate that all critical process parameters are consistently controlled to their setpoint, that processing times are consistent and within specification, that bioburden is consistently low and controlled at all sampling points, and that the final material is consistent from run to run and meets all yield, quality, and purity specifications. In addition to the actual intended process, there are other factors associated with a TFF step that are important in a manufacturing environment, such as allowable hold times and temperatures for the feedstock and product pools and any allowable re-work steps. Although it adds extra work to a validation strategy, validating a range of hold times or rework possibilities allows additional processing freedom at large scale.