Lipophilic non-volatile compounds represent the most challenging extractables - high molecular weight hydrophobic substances resist both aqueous extraction and GC analysis, requiring aggressive organic extraction and LC-MS for detection. Non-polar extraction using hexane followed by LC-MS analysis targets lipophilic, non-volatile compounds that complement GC-MS screening by capturing high molecular weight hydrophobic substances resistant to volatilization. Following ISO 10993-12 and 10993-18 requirements, this approach captures non-volatile plasticizers providing flexibility without vapor pressure, complex lipophilic additives including stabilizer packages and UV absorbers, and high molecular weight hydrophobic components that standard GC methods cannot analyze. Essential for devices with rubber components containing non-volatile additives including polymeric plasticizers and high molecular weight antioxidants, silicone devices with high molecular weight components like PDMS oligomers, and materials where comprehensive characterization requires both volatile and non-volatile analysis spanning full molecular weight range. The hexane extraction aggressively solubilizes lipophilic substances providing worst-case assessment, while LC-MS enables analysis of high molecular weight compounds through softer ionization preventing fragmentation. For implantable devices, non-volatile lipophilic extractables accumulate in fatty tissues surrounding implants creating chronic exposure scenarios requiring characterization, while blood-contacting devices need assessment ensuring lipophilic compounds don't partition into lipoproteins causing systemic distribution. The analysis proves particularly valuable when investigating cytotoxicity potentially caused by high molecular weight extractables that volatile screening misses, validating new polymers with unknown additive compositions, or qualifying alternative suppliers whose formulations differ from established materials.