(33d) Islatravir Crude Isolation Development and Scale-up: Late-Stage Shift from Filter Dryer to Centrifuge to Mitigate Risks from Enzyme Filtration

Islatravir is a nucleoside reverse transcriptase inhibitor small molecule targeted for HIV. Islatravir is synthesized through a biocatalytic cascade using nine enzymes and has a single isolation. As such, the filtration was known to be challenging from the start of process development due to the presence of enzymes and proteins. Denatured enzymes can settle and clog the filter, resulting in elongated filtration times and limited rejection of residual proteins. Reducing enzyme loading levels and adding a filter aid were explored during early development to improve filtration efficiency in the filter dryer. These process modifications resulted in initial success as the process was scaled up from bench scale to the pilot plant. During further scaleup, the filtration progress became significantly slower, requiring days to complete the filtration. This highlighted both operational and quality risks long term for the process. This led to the decision to pursue a late-stage process change from a filter dryer to a centrifuge. This prompted the team to initiate rapid lab development to understand and mitigate concerns around differences between the two pieces of equipment pertaining to compressibility, washing, and temperature control. Centrifugation can be challenging to adequately evaluate at the lab scale due to the dependence on basket size and changing liquid height as the driving force. Dynochem modeling was leveraged to bridge the gap between bench and pilot scale to inform operating conditions for initial pilot scale batches. The pilot scale demonstration investigated a range of operating parameters and derisked the initial processing concerns, clearing the way for implementation of the process at commercial scale. The work culminated in the successful utilization of the centrifuge at manufacturing scale, achieving reproducible filtration performance across multiple batches, isolated product of desired quality, and additionally a significant reduction in drying cycle time. This talk will focus on the decision to change equipment, the risk assessment and considerations, as well as the modeling and implementation of the centrifuge across scales to enable a successful enzymatic filtration.