Optimization, scale-up, and validation ISSUES in FILTRATION of Biopharmaceuticals, Part II - - BioPharm International


Optimization, scale-up, and validation ISSUES in FILTRATION of Biopharmaceuticals, Part II

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
The characterization experiments should focus on the parameters that are most critical to process performance and most difficult to control to a precise setpoint at industrial scale. For parameters where it is determined that process characterization is required, the range of a particular parameter to investigate should be set based on the range expected during full-scale operations (bearing in mind manufacturing capability). It is also based on the range that is desirable to claim in a license application that will allow for any future process changes to be implemented.

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.

Cleaning Validation Cleaning validation is the third section of an overall validation plan and is the section that historically has received the most attention. The overall goals for cleaning validation are to demonstrate that 1) the membranes are returned to a state where the process will perform reproducibly each run, 2) contaminants are adequately removed to prevent run-to-run carryover, and 3) bioburden level is controlled. These goals must be met for the full-scale system, including membranes and all associated hardware. In addition, cleaning validation must establish the number of times the membranes can be cleaned and reused in a given process. While much of the cleaning validation is dependent on the specific equipment used for manufacturing and therefore must be carried out at full scale, anything related to membrane re-use is primarily dependent on the membranes and can be performed on a small-scale, representative system.

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