Comprehensive Analysis of Free BDPE Content in Commercial Hyaluronic Acid Fillers: Implications for Safety Assessment and Regulatory Standards.

[BACKGROUND] Although manufacturers of 1,4-butanediol diglycidyl ether (BDDE)-cross-linked hyaluronic acid (HA) fillers assert effective removal of unreacted BDDE, the hydrolyzed derivative 3,3'-(butane-1,4-diyl)bis(oxy)bis(propane-1,2-diol) (BDPE) is routinely monitored, despite possessing structural features associated with sensitization potential.

[AIMS] To quantify free BDPE content across commercially available HA dermal fillers and assess potential safety implications.

[MATERIALS/METHODS] A validated liquid chromatography-tandem mass spectrometry method was developed to quantify BDPE levels in 38 commercial HA filler products from seven major manufacturers. In silico prediction models were used to evaluate the skin sensitization and irritation potential of BDPE.

[RESULTS] BDDE levels were non-detectable in all analyzed products. By contrast, free BDPE content varied markedly, with over 1000-fold differences observed between products, indicating substantial variability in purification efficiency across manufacturing processes. Considerable variability was also identified among Food and Drug Administration-approved products, with some containing BDPE concentrations exceeding 100 ppm. Conversely, several products exhibited low BDPE levels ranging from 0.1 to 2.5 ppm, further highlighting inconsistencies in manufacturing control.

[CONCLUSIONS] Industry claims regarding complete cross-linker removal may fail to account for the persistence of BDPE species. The substantial inter-product variability observed in this study suggests inadequate process control among manufacturers. Given the structural similarity of BDPE to known sensitizers and the direct dermal injection route that circumvents the skin barrier, free BDPE should be designated a critical quality attribute with defined acceptance limits. These findings suggest that BDPE can be reduced to concentrations below 2.5 ppm, supporting the need for stricter manufacturing standards.