How do you match up the model solvents you use for testing with drug products?

Answer

The extraction studies conducted on single-use systems must try to account for as many extractable compounds as possible since the extraction efficiency of the fluids they are intended to contain will vary widely depending on a user’s specific formulations. In light of the many different classes of compounds that can have the potential to migrate from a material, an extraction study should include suitable solvents of differing polarities and pH values in order to achieve a thorough extraction. A range of solvent polarities is needed because the compounds that have the potential to extract from a material may have different polarities, in which case their solubility in one solvent may be better than in another. In addition, pharmaceutical formulations can vary widely in chemical composition, which can result in different extraction efficiencies. A simple, but useful guide to solubility is “like dissolves like”. For example, a nonpolar compound is more readily soluble in a nonpolar solvent, and therefore, more easily extracted from the matrix of a material. In some cases, the pH of the extraction solvent can have a significant impact on the removal of certain compounds. Thus, including both acidic and basic extraction solvents is important for the removal of such compounds.

Extraction studies with single-use bioprocess systems typically include the following solvents: neutral water (WFI or equivalent), pH 2 ± 0.2 (created with neutral water and HCl), pH 13 ± 0.2 (created with neutral water and NaOH or ammonium hydroxide), 50% ethanol in neutral water, 1% Polysorbate 80, and 5M NaCl. Neutral water is a polar solvent that readily solubilizes ionic compounds (i.e. salts, acids, bases etc.) and small polar organic compounds. The addition of both acidic and basic solutions provides a bracket approach to solution pH, which encourages the migration of both organic bases and acids, respectively. Mixtures of polar organic solvents such as ethanol with water allow for the extraction of a wider range of polar organic molecules. Ionic compounds and metals tend to be more readily soluble in high ionic strength solutions. The choice of a highly concentrated brine solution of 5M NaCl provides the type of ionic strength environment suitable for efficient extraction of such compounds. In order to extract non-polar molecules, surface active agents (surfactants) are used because they form aggregates in solution with hydrophobic cores (non-polar) that provide a more favorable environment for the solubilization of non-polar molecules. Polysorbate 80 is a surfactant typically used in pharmaceutical formulations to enhance the solubility of non-polar molecules; therefore, it is an effective solvent for extracting such compounds from the matrix of a material. The extraction study design implemented by GE Healthcare for single-use bioprocess systems is meant to simulate a wide variety of possible formulation compositions used in biopharmaceutical manufacturing, and therefore extract as many compounds as possible from a given material.