Standardization of Chromatographic Screening Methods for Organic Extractables and Leachables by Managing Outcomes

Abstract

Drug products and medical devices can contain impurities, termed leachables, which could produce an adverse patient health effect during clinical use. To establish patient exposure to leachables, drug products, packaging or manufacturing system extracts are analytically screened for extractables or leachables. Similarly, medical device contact media or extracts are also screened for extractables or leachables. Considering organic extractables/leachables, the screening process typically involves a chromatographic separation coupled with an information-rich detection method. Information contained in the detector response (e.g., the chromatographic peak) is processed to establish quantities and to elucidate identities. Organic extractables and leachables screening methods and procedures have proliferated with little, if any, attempt at standardization, creating the situation where virtually every testing laboratory has their own analytical testing and data processing methodology, raising the possibility that two different labs, screening the same extract or drug product, would report extractables or leachables profiles that differ in the number of compounds reported, the identities of the reported compounds and the extracted (or leached) amounts of the identified compounds. Although standardization of the screening methods and procedures themselves would reduce lab-to-lab variation, such an approach would be difficult to implement. Thus, standardization of the screening outputs by setting quality standards for the outputs is considered. For example, the method′s ability to detect a broad cross-section of potential extractables/leachables is established by testing of a test mixture of representative compounds. Additionally, this author proposes that reported compound identities should be confident to be used in safety risk assessment; use of lower quality identities requires use of an uncertainty factor in the safety risk assessment. Similarly, it is proposed that reported concentrations should be semi-quantitative to be used in safety risk assessment; use of lower quality concentrations requires use of an uncertainty factor in the safety risk assessment.