Safety assessment of excipients (SAFE) for orally inhaled drug products.

The development of new orally inhaled drug products requires the demonstration of safety which must be proven in animal experiments. New in vitro methods may replace, or at least reduce, these animal experiments provided they are able to correctly predict the safety or eventual toxicity in humans. However, the challenge is to link human in vitro data to human in vivo data. We here present a new approach to the safety assessment of excipients (SAFE) for pulmonary drug delivery. The SAFE model is based on a dose response curve of 23 excipients tested on the human pulmonary epithelial cell lines A549 and Calu-3. The resulting in vitro IC50 values were correlated with the FDA-approved concentration in pharmaceutical products for either pulmonary (if available) or parenteral administration. Setting a threshold of 0.1% (1 mg/mL) for either value yielded four safety classes, allowed to link IC50 data as measured on human cell cultures in vitro with the concentrations of the same compounds in FDA-approved drug products. The necessary in vitro data for novel excipients can be easily generated while the SAFE approach allows putting them in the context for eventual use in human pulmonary drug products. Excipients, that are most likely not safe for use in humans, can be early excluded from further pharmaceutical development. The SAFE approach helps thus to avoid unnecessary animal experiments