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ABSTRACT The implementation of site‐specific integration (SSI) systems in Chinese hamster ovary (CHO) cells for the production of monoclonal antibodies (mAbs) can alleviate concerns associated with production instability and reduce cell line development timelines. SSI cell line performance is driven by the interaction between genomic integration location, clonal background, and the transgene expression cassette, requiring optimization of all three parameters to maximize productivity. Systematic comparison of these parameters has been hindered by SSI platforms involving low‐throughput enrichment strategies, such as cell sorting. This study presents a recombinase‐mediated cassette exchange (RMCE)‐capable SSI system that uses only chemical selection to enrich for transgene‐expressing RMCE pools in less than one month. The system was used to compare eight mAb expression cassettes containing two novel genetic regulatory elements, theAzin1CpG island and the Piggybac transposase 5’ terminal repeat, in various orientations to improve the expression of two therapeutic mAbs from two genomic loci. Similar patterns of productivity and mRNA expression were observed across sites and mAbs, and the best performing cassette universally increased mAb productivity by 7‐ to 11‐fold. This flexible system allows for higher‐throughput comparison of expression cassettes from a consistent clonal and transcriptional background to optimize RMCE‐derived cell lines for industrial production of mAbs.