The characterization of extractables and leachables (E&L) is an integral part of ensuring biocompatibility for many medical devices and pharmaceutical products. Guidance for E&L has been provided in USP <1663> and <1664> for pharmaceutical products and in ISO 10993-18 for medical devices. The first step in the E&L process involves detection of those compounds which are suspected to be at or above the level of toxicological concern. This process is accomplished through the use of the Analytical Evaluation Threshold (AET) which links the toxicologically relevant concentration to the observed analytical signals. A significant problem in AET evaluation is caused by response factor (RF) variation. It is an unfortunate reality that compounds which are at equivalent concentration do not always or even often give equivalent signal response on various detector systems including mass spectrometers. Recent publications have highlighted these risks for both LCMS (Jordi, et al. J. Pharm. Biomed. Anal. 2018, 150, 368–376) and GCMS (Jenke and Odufu, Journal of Chromatographic Science 2012;50:206–212). The prominent and necessary use of surrogate standards for AET evaluation introduces error into the precise estimation of the signal strength which corresponds to the toxicologically relevant concentration. To overcome this problem, an uncertainty factor has been introduced into the AET equation and regulatory agencies have provided recommendations as to values for the UF (GC/MS with UF =4, LC/MS with UF =10). While this approach does account for response variation, it also introduces other difficulties including lower AET values which can be difficult or impractical to achieve which then require additional sample concentration due to limited instrument sensitivity. This has the potential to counteract the perceived benefit resulting in compound loss or degradation and additional regulatory scrutiny of the sample preparation process. This approach also results in a significant potential for false positives (I.e., compounds that are below the AET concentration are determined to have a peak area above the threshold associated with the AET). An alternative approach is therefore desirable.
In this webinar, a new case study will be presented using the multidetector approach to AET evaluation contrasted with the use of the recommended UF of 4 and 10 for a model polymer system. The multidetector approach leverages the independence of the response factors for a given compound obtained on different detectors and chromatographic systems to overcome potential weak signals on any one detector and thus reduces the reliance of the method on UF to overcome response variation. The multidetector approach was summarized in two recent publications (Jordi, et al. J. Pharm. Biomed. Anal. 2020, 186, 1-14 and Jordi, et al. PDA Journal, vol. 75, No. 2 2021, pg. 289-301). The effectiveness of using a combination of triple detection Liquid Chromatography Mass Spectrometry (LCMS) with Ultraviolet (UV) and Charged aerosol detection (CAD) as well as Gas Chromatography Mass Spectrometry (GCMS) will be presented. Quantitation for a series of reference compounds characteristic of the polymer systems will be used to gauge the potential for false positives using the different AET approaches. Finally, the benefits of this approach for detection of compounds with little to no mass spectrometry response will be highlighted.
Key Learning Objectives:
- Objective 1: What is the Analytical Evaluation Threshold and how should it be applied?
- Objective 2: Review a Case study comparing the use of regulatory agency recommended approaches to AET evaluation and a multidetector approach.
- Objective 3: How can using a multidetector approach reduce the need for large UF and by extension the need for additional sample preparation steps?
Who Should Attend:
- Laboratory managers
- New product developers