Determination of betamethasone residues on manufacturing equipment surfaces and PDE calculation in cleaning validation processes

Abstract

Determination of Permitted Daily Exposure (PDE) implies reviewing all relevant data available, identification of the pharmacological and toxicological effects and the therapeutic dose that can cause specific and serious adverse effect and understanding and applying several adjustment factors to account for various uncertainties (Bagade and Krishna, 2014; EMA, 2014; Geremia, 2019; LeBlanc, 2000). Topical formulations are generally considered to be safe and less potent than oral or parenteral formulations (Aung and Aung, 2021; FDA, 2008). The minimum and maximum daily dose of topical formulations can be calculated based on the criteria of finger-tip unit (FTU) set by Long and Finely (1991) (Ovais and Lian, 2008). The resorption of Betamethasone during topical administration is low and it is unreliable to result in toxicological systemic side effects (Aung and Aung, 2021; EMA, 1999; FDA, 2008; Mahalingam et al., 2008). There are no evident long-term studied to assess the potential carcinogenicity and mutagenicity of topical corticosteroids (FDA, 2008). However, the literature data proved some teratogenic effects in animal studies after systemic administration (EMA, 1999; FDA, 2008). According to data obtained from animal studies on rabbits the minimal obtained PDE value, extrapolated on topical administration, is 33 μg/day and the calculated MACO value is 0.82 ppm, or 80.67 mg carryover in subsequent product (EMA, 1999; FDA, 2008). Betamethasone dipropionate is the 17,21dipropionate ester of Betamethasone, a synthetic corticosteroid with dominant glucocorticoid effect (EMA, 1999; Manassra et al., 2010). Betamethasone is extensively used for topical application in the treatment of various skin disorders and is available in several semisolid pharmaceutical dosage forms with strength of 0.05% (Aung and Aung, 2021; Manassra et al., 2010; Sweetman, 2011). The aim of this study was to develop and validate sensitive reversed-phase high performance liquid chromatography (RP-HPLC) method for quantification of Betamethasone residues from manufacturing equipment surface in cleaning validation processes.