Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure. An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82×10-3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 µg/(day∙person), the toxicity-qualified specification limits of acetol in topical excipients were calculated to be 90 µg/mL and 180 µg/mL for propylene glycol and glycerol, respectively. It is concluded that setting specification limits for impurities within a quality-by-design approach requires a case-by-case evaluation as demonstrated here with acetol.
Keywords: API, Active pharmaceutical ingredient; Acetol; DD, Dermal drugs; DP, Drug product; DS, Drug substances; Dm, Diffusion coefficient; EC, European commission; EFCG, European fine chemical group; Excipients; FDC, Franz diffusion cells; GMP, Good manufacturing practice; ICH, International conference on harmonization; IPEC, International pharmaceutical excipient council; Impurity; Jss, Transdermal steady-state flux; Km, Partitioning coefficient; Kp, permeability coefficient; PAH, Polycyclic aromatic hydrocarbon; PBS, Phosphate buffered saline; PG, Propylene glycol; QbD, Quality-by-Design; SCCS, Scientific committee on consumer safety; SEdermal, Systemic exposure after dermal contact; Specification limits; TTC, Threshold of toxicological concern; Transdermal penetration; tlag, Lag time.