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Five factors were identified affecting the development and validation of a TOC based analytical method to quantify trace detergents residues.These factors were the concentration and volume of the diluent, extraction method, location for TOC sample preparation, and oxidant flow rate.Key experimental parameters were optimized to minimize contamination and to improve the sensitivity, recovery, and reliability of the method.A Total Organic Carbon (TOC) based analytical method to quantitate trace residues of clean-in-place (CIP) detergents CIP100® and CIP200® on the surfaces of pharmaceutical manufacturing equipment was developed and validated. Five factors affecting the development and validation of the method were identified: diluent composition, diluent volume, extraction method, location for TOC sample preparation, and oxidant flow rate. Key experimental parameters were optimized to minimize contamination and to improve the sensitivity, recovery, and reliability of the method. The optimized concentration of the phosphoric acid in the swabbing solution was 0.05 M, and the optimal volume of the sample solution was 30 mL. The swab extraction method was 1 min sonication. The use of a clean room, as compared to an isolated lab environment, was not required for method validation. The method was demonstrated to be linear with a correlation coefficient (R) of 0.9999. The average recoveries from stainless steel surfaces at multiple spike levels were >90%. The repeatability and intermediate precision results were ≤5% across the 2.2–6.6 ppm range (50–150% of the target maximum carry over, MACO, limit). The method was also shown to be sensitive with a detection limit (DL) of 38 ppb and a quantitation limit (QL) of 114 ppb. The method validation demonstrated that the developed method is suitable for its intended use. The methodology developed in this study is generally applicable to the cleaning verification of any organic detergents used for the cleaning of pharmaceutical manufacturing equipment made of electropolished stainless steel material.