Substances from packaging systems that are leached into packaged medical products may have a safety impact on patients to whom such medical products are administered. The potential safety impact depends on the identity and concentration of the leached substances. The concentration above which a leachable must be identified in order to assess its safety impact is frequently estimated using an internal standard to "calibrate" the analytical response of a chromatographic system. Such an estimate is accurate to the extent that the responses of the internal standard and leachables are similar. To establish the accuracy of the internal standard approach, a database of gas chromatography-flame ionization detection (GC-FID) and gas chromatography-mass spectrometry (GC-MS) responses was generated for thirty-eight leachables and eight internal standard candidates. Although the FID and MS responses of many of the leachables and internal standards fell within a narrow band, acidic and basic compounds produced responses that were discernibly different from those of neutral analytes. While most of the internal standards were suited for concentration estimation, three of the candidates, dimethylphthalate, triphenylphosphate and 4,4-dibromobiphenyl, produced the smallest mean error in estimated concentration for the analytes examined. As the FID and MS responses were linear, internal standards could be used to estimate leachables concentrations even when the difference in leachable versus internal standard concentrations was as great as a factor of 25. A multiplier may be appropriate to adjust an estimated concentration to its greatest possible value, and it is this value that is used to convert an estimated Analytical Evaluation Threshold (AET) into a working or final AET.
Polymeric materials are commonly used in medical devices such as syringes. The plastic materials may interact with drug products contained within the device, potentially affecting the quality of the drug products. These interactions may include leaching, which is the migration of entities out of the material and into the drug product, and binding, which is the migration of substances out of the drug product and into the material. This paper examines the magnitude of leaching and binding for several materials that can be used in syringe parts such as the syringe barrel, plunger, and tip cap.
Triton X-100 (octoxynol 9) is a commercially available surfactant used as a solvent detergent in numerous pharmaceutical applications including virus inactivation. A byproduct formed during its synthesis is 1,4-dioxane, the cyclic dimer of ethylene oxide and a possible carcinogen to humans. The United States Pharmacopoeia (USP) contains a labor-intensive 1,4-dioxane test for Triton X-100. The method couples vacuum distillation to extract the 1,4-dioxane from the Triton X-100 matrix followed by gas chromatography (GC) using a packed column with flame-ionization detection. In order to provide a more automated and specific test methodology, a headspace GC-mass spectrometry (MS) method has been developed for this application. Analyte quantitation is accomplished by the method of standard additions. The automated sample preparation, coupled with the specificity inherent in high-efficiency capillary column separations together with single-ion MS detection, results in an assay that is more efficient, accurate, and precise than the USP procedure. Performance characteristics of the headspace GC-MS method are contrasted with those characteristics of the USP methodology.
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