Microbial control during the biologics manufacturing process remains a key Health Authority focus area. In recent years, this expectation has expanded to include demonstration of acceptable levels of control pre-sterilizing grade filtration throughout the recovery and purification process. This is primarily due to the potential for harmful agents (e.g. endotoxins, exotoxins, proteases) resulting from the presence of bioburden in the manufacturing process to adversely impact product quality or patient safety. In this presentation, a case study will be shared based on efforts to validate microbial control at large-scale throughout the (centrifuge-based) harvest operation, the first recovery step following recombinant protein product formation. Study design included evaluation of microbial control during equipment setup, pre-use hold times (to support increased manufacturing flexibility), as well as throughout cell culture fluid (CCF) processing utilizing a worst-case conditions approach. A summary of findings as well as subsequent investigative efforts to more comprehensively understand the system will be provided. In addition, resulting best-practice GMP changes implemented as a result, along with evaluation and considerations for larger-scope continuous improvement initiatives will also be discussed. The key findings and lessons learned from this study highlight challenges for legacy products in which equipment capabilities and historical practices at an aging facility may need to be evaluated on an ongoing basis in order to align with present-day regulatory expectations. However, it also presents an opportunity and motivation to explore newer technologies (e.g. disposables) that enable closed-system processing for future product version upgrades as well as those currently under development within the clinical pipeline.

Case study: Commercial-scale microbial control validation during centrifuge harvest operations

255th National Meeting (2018)

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