(389e) A Risk-Based Strategy for Intermediate Reprocessing in Filtration for Biomanufacturing

Downstream processing in the field of biomanufacturing usually refers to the recovery and purification of biotherapeutics starting from the harvest of bioreactor cell culture medium. A typical downstream process may contain multiple separation and purifications steps such as centrifugation, filtration, and chromatography. Among them, viral filtration and final filtration are critical as they are often used as the last guards to ensure the final biotherapeutic is safe from viral and impurity contamination. Atypical viral and final filtration events may occur occasionally during manufacturing operations. The action of repeating the filtration step following an atypical event is defined as reprocessing. Reprocessing of viral filtration and final filtration steps needs to be validated using small-scale and at-scale studies and approved by health authorities (e.g., U.S. Food and Drug Administration, European Medicines Evaluation Agency, etc.). A validated reprocessing step is a tool that biopharmaceutical manufacturers use to mitigate risks involved with compromised filter/container integrity or correct for certain facility-based excursions. Per health authority guidance, reprocessing can never be used to mitigate microbial contamination.

A validated viral filtration / final filtration reprocessing dataset usually contains small-scale and at-scale data from multiple manufacturing batches. The validity of a reprocessing dataset can be impacted by many operational and environmental factors. Therefore, the reprocessing plan must be deliberately designed to generate a succinct but powerful dataset to demonstrate process consistency, ensure product quality and show implementation feasibility.

In this study, a risk-based filtration reprocessing strategy was proposed to balance the likelihood of successful reprocessing validation with health authority with resources spent on the effort. A decision tree was proposed to recommend actions at each critical process step. A failure mode risk assessment was also conducted to identify potential risks and corresponding effect and mitigation. This risk-based strategy, if used properly, will significantly reduce the time and resources needed for biopharmaceutical manufacturers to validate reprocessing steps, thereby providing more flexibility to mitigate atypical filtration issues during routine biomanufacturing.