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22 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m ers, then analyzed for leachable silicone oil using the ICP–OES method described in Table II. Prior to ICP–OES analysis, the leachable silicone oil in the aqueous formulation solutions was extracted with an organic solvent, xylene, to avoid interference from inorganic silica. Inorganic silica was likely to be present in the aqueous formulations after the formu- lations were stored in the glass syringes for a month. Liquid-liquid extraction and solid-phase extraction were used to extract the leachable silicone oil from the aqueous formulation solutions. The liquid-liquid extraction procedures were used for all formulations with no surfactant. Equal volumes of formulation solution and xylene were used for the liquid/liquid extraction. The xylene solution was then used for ICP–OES analysis. For formulations with surfactant, liquid-liquid ex- traction with xylene caused excessive emulsion and made it difficult to separate the organic layer from the aqueous layer. Therefore, a solid-phase extraction method was used. A Bond Elut Plexa (Agilent, Part #12259506), with a styrene-divinyl benzene copolymer, was used for extraction. One milliliter of formulation solution was eluted through each column under ambi- ent conditions and dried for one hour under a vacuum of 15–20 mmHg. The columns were eluted with three separate 5-mL aliquots of dichloromethane (DCM) under ambient conditions, which were concentrated to near dryness under nitrogen flow. One milliliter of xylene was added into the residue and used for ICP– OES analysis. Evaluation of the ICP–OES method To evaluate the ICP–OES method as a means to ana- lyze leachable silicone oil in simulated biopharmaceu- tical formulations, this study looked at the following factors: the relative response factor of silicone oils with different molecular weights, method sensitivity, method non-interference, and linearity. Relative response factor. Usually, leachable silicone oil quantitation will need to use a silicone oil standard of different molecular weight and molecular-weight Analytics Table I: Simulated biopharmaceutical formulations for leachable silicone oil study. Formulation number Formulation Buffer 20 mM Bulking agent Stabilizer Tonicity modifier Chelating agent Surfactant Co-solvent (propylene glycol) 1 Phosphate buffer pH 6.8 Phosphate 2 Buffer with co-solvent pH 6.8 Phosphate 1% 3 2% 4 5% 5 10% 6 Chelating agent pH 6.8 Phosphate 7% Sucrose Sucrose 150 mM NaCl 0.1 mM EDTA 7 pH 6.8 Phosphate 7% Sucrose Sucrose 150 mM NaCl 0.5 mM EDTA 8 Surfactant pH 6.8 Phosphate 7% Sucrose Sucrose 150 mM NaCl 0.1 mM EDTA 0.05% Tween 80 9 pH 6.8 Phosphate 7% Sucrose Sucrose 150 mM NaCl 0.1 mM EDTA 0.1% Tween 80 10 pH 6.8 Phosphate 7% Sucrose Sucrose 150 mM NaCl 0.1 mM EDTA 0.5% Tween 80 11 pH 6.8 Phosphate 7% Sucrose Sucrose 150 mM NaCl 0.1 mM EDTA 1.0% Tween 80 12 pH pH 5.0 7% Sucrose Sucrose 150 mM NaCl 0.1mM EDTA 1.0% Tween 80 13 pH 8.2 7% Sucrose Sucrose 150 mM NaCl 0.1 mM EDTA 1.0% Tween 80 14 Bulking agent pH 6.8 Phosphate 7% Mannitol 150 mM NaCl 0.1 mM EDTA 15 pH 6.8 Phosphate 7% Trehalose Trehalose 150 mM NaCl 0.1 mM EDTA