This research focuses on the implementation of Operational Excellence (OE) in the pharmaceutical industry, especially in companies that transformed from PT Askes (Persero) to the Health Insurance Organizing Agency (BPJS). One approach adopted is Lean Six Sigma (LSS) which is supported by the Manufacturing Execution System (MES) to improve the efficiency and quality of the production process. This research takes a case study on product A with a focus on improvements to hardness issues. Through the Define, Measure, Analyze, Improve, and Control (DMAIC) stages, traditional methods and advanced analysis based on Machine Learning (ML) algorithms are used to improve production processes. The results showed success in achieving significant improvements in the productivity index and quality of product A production processes, making a valuable contribution in the context of Operational Excellence research in the pharmaceutical industry. The LSS method, which has been modified by integrating with ML algorithms and MES, provides productivity aspects consisting of LT, PCE and TD, as well as quality aspects consisting of better Pp, Ppk and sigma levels. The modified LSS method also provides the potential for COGM savings of 2,66 billion Rupiah and reduces the risk of production process failure to less than 200 batches for every 1 million production batches. Based on this, it can be concluded that the development of the Lean Six Sigma method which has been integrated with ML and MES algorithms has the positive potential to increase OE at ABC Farma.