1. Risk evaluation of impurities in topical excipients: The acetol case
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Jente Boonen, Lien Taevernier, Christian Burvenich, Bart De Spiegeleer, Nathalie Roche, Lieselotte Veryser, and Kathelijne Peremans
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Franz diffusion cell ,Pharmaceutical Science ,Pharmacy ,Pharmacology ,Dermal exposure ,Analytical Chemistry ,Km, Partitioning coefficient ,chemistry.chemical_compound ,QbD, Quality-by-Design ,Impurity ,Drug Discovery ,Electrochemistry ,Original Research Article ,ICH, International conference on harmonization ,GMP, Good manufacturing practice ,Spectroscopy ,Medicine(all) ,DP, Drug product ,API, Active pharmaceutical ingredient ,Transdermal penetration ,Permeation ,Dm, Diffusion coefficient ,Acetol ,TTC, Threshold of toxicological concern ,PG, Propylene glycol ,SCCS, Scientific committee on consumer safety ,EC, European commission ,PBS, Phosphate buffered saline ,EFCG, European fine chemical group ,FDC, Franz diffusion cells ,Excipients ,DD, Dermal drugs ,Glycerol ,Health risk ,PAH, Polycyclic aromatic hydrocarbon ,Chromatography ,SEdermal, Systemic exposure after dermal contact ,Biochemistry, Genetics and Molecular Biology(all) ,IPEC, International pharmaceutical excipient council ,lcsh:RM1-950 ,DS, Drug substances ,Risk evaluation ,lcsh:Therapeutics. Pharmacology ,Jss, Transdermal steady-state flux ,Specification limits ,chemistry ,Skin penetration ,Kp, permeability coefficient ,tlag, Lag time - Abstract
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 1.82Ã10â3 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/(dayâperson), 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: Acetol, Impurity, Excipients, Transdermal penetration, Specification limits
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