Identifying and Mitigating Errors in Screening for Organic Extractables and Leachables: Part 2: The Errors of Inexact Identification and Inaccurate Quantitation

Abstract

Patients can be exposed to leachables derived from pharmaceutical manufacturing systems, packages and /or medical devices during a clinical therapy. These leachables can adversely decrease the therapy′s effectiveness and/or adversely impact patient safety. Thus, extracts or drug products are chromatographically screened to discover, identify and quantify organic extractables or leachables. Although screening methods have achieved a high degree of technical and practical sophistication, they are not without issues in terms of accomplishing these three functions. In this Part 2 of our three-part series, errors of inexact identification and inaccurate quantitation are addressed. An error of inexact identification occurs when a screening method fails to produce an analyte response that can be used to secure the analyte′s identity. The error may be that the response contains insufficient information to interpret, in which case the analyte cannot be identified or that the interpretation of the response produces an incorrect identity. In either case, proper use of an internal extractables - leachables data database can decrease the frequency of encountering unidentifiable analytes and increase the confidence that identities that are secured are correct. Cases of identification errors are provided, illustrating the use of multi-dimensional analysis to increase confidence in procured identities. An error of inaccurate quantitation occurs when an analyte′s concentration is estimated by correlating the responses of the analyte and an internal standard and arises due to response differences between analytes and internal standards. The use of a database containing relative response factors or relative response functions to secure more accurate analyte quantities is discussed and demonstrated.