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

Drug products and medical devices can contain leachable impurities that could adversely affect patient health during their clinical use. To establish patient exposure to leachables, drug products and packaging, manufacturing system, or medical device extracts are analytically screened for leachables or extractables. For 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 for the detected compounds. Organic extractables and leachables screening methods and procedures have proliferated with little, if any, attempt at standardization, creating the situation in which virtually every testing laboratory has their own analytical testing and data processing methodology. This raises 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 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 that the lower quality be accounted for in the assessment, perhaps by use of an uncertainty factor. Similarly, it is proposed that reported concentrations should be semi-quantitative to be used in safety risk assessment; use of lower quality concentrations requires that the lower quality be accounted for in the safety risk assessment, perhaps by use of an uncertainty factor.