Material polarity determines compound migration patterns - semi-polar substances represent the middle ground between water-soluble and lipophilic extractables, requiring intermediate polarity solvents for comprehensive detection. Semi-polar non-volatile compound screening using isopropanol extraction followed by LC-MS provides comprehensive characterization of moderately polar, non-volatile substances occupying the intermediate polarity range between water-soluble and lipophilic extractables. This ISO 10993-12 and 10993-18 compliant analysis captures additives with intermediate polarity including plasticizers and stabilizers, oligomers from polymer processing, and degradation products formed through oxidation or hydrolysis reactions. The isopropanol extraction effectively solubilizes semi-polar compounds while maintaining compatibility with LC-MS analysis through appropriate dilution or solvent exchange, enabling direct injection without extensive sample preparation. Critical for devices containing polyurethanes where semi-polar additives enable processing and provide material properties, modified polymers with grafted functional groups creating intermediate polarity, and materials with complex additive packages requiring comprehensive characterization across polarity ranges. The LC-MS methodology accommodates compounds too polar for GC analysis yet not sufficiently ionic for standard reverse-phase LC, using gradient elution separating compounds across wide polarity range. Manufacturing validation confirms that processing removes semi-polar solvents used in fabrication, sterilization doesn't generate semi-polar degradation products, and aging doesn't produce oxidation products requiring safety assessment. For implantable devices, semi-polar extractables assessment characterizes chronic exposure to moderately polar compounds that accumulate at implant-tissue interfaces, while cardiovascular devices need screening ensuring blood contact doesn't extract harmful semi-polar additives.