Extractables and leachables present a potential safety risk to patients receiving medical treatment.  Proper toxicological assessment of the safety risk requires that the concentrations of potentially relevant extractables and leachables be properly calculated and reported.  Unfortunately, specifying relevant compounds and properly estimating their concentrations is hindered as analytical response factors for these compounds vary significantly from compound to compound, creating uncertainty in the validity of reported results.

In this presentation the magnitude of response factor variation in the chromatographic methods typically used for organic extractables and leachables screening is established and the calculation of an uncertainty factor (UF) is described.  Possessing the UF, the presentation discusses the use of the UF in establishing what compounds require quantitation (use of the Analytical Evaluation Threshold (AET) and in calculating protective concentrations.

Presented by Dennis Jenke, Chief Executive Scientist at Triad Scientific Solutions

Dr. Dennis Jenke is the Chief Executive Scientist at Triad Scientific Solutions LLC, a consulting organization that provides integrated, science-based, and practical E&L solutions to the pharmaceutical, cosmetic, food industries. Dr. Jenke retired as a Distinguished Scientist from Baxter Healthcare Corporation where, for nearly 35 years, he was responsible for developing and defending E&L tactics and strategies. He is widely published on E&L and related topics and is an active member of national and international standard setting organizations.

The Impact of Physico-chemical Properties of Extractable Compounds on Their Analytical Responses: An Evaluation of GC/MS Response Data

In the last few years, the Analytical Chemistry approaches to characterize extracts of Medical Devices – In line with the new ISO 10993-18:2020 Standard – has grown considerably. Biocompatibility assessments, based on (experimental) Chemical Characterization of Medical Devices is now one of the standard approaches for a number of toxicological end points. However, one of the aspects that is under constant debate is how to make a non-targeted analysis – to detect and identify a broad set of compounds – sufficiently protective or quantitative allowing a subsequent reliable toxicological risk analysis.

While authorities indicate that a number of surrogate standards (eg 3 for GC/MS, 5 for LC/MS) should be used with varying retention times or functional groups to assist in the quantification of the detected extractables, no little or no guidance is given on the selection criteria on which surrogate to select to quantify a detected compound.

In a first step to address this issue, Nelson Labs has evaluated over 2700 compounds of which the analysis of authentic standards provided relative response values in GC/MS. GC/MS was selected as a first action as it is often a more standardized chromatographic and MS- method and it is considered as the “work horse” in E/L testing. Conclusions in GC/MS could also lead to guidance on how to optimize the orthogonal and complementary non-targeted analysis methodology (combining different techniques and detectors) it low responding GC/MS compounds could be well defined. 

The database of over 2700 compounds was evaluated against a number of physico-chemical properties, such as boiling point, molecular weight, retention time, LogKow… While a lot of these parameters show some impact on the response of a compound, there is one parameter that stands out and would allow either a differentiated approach in the use of responses for compounds detected in GC/MS or it would allow selecting surrogate standards in a more scientific way.

Presented by Dr. Jan Baeten, Scientific Advisor R&D, Nelson Labs Europe

Jan Baeten received his Ph.D. from the faculty of Bioscience Engineering at the University of Leuven (Belgium) in 2012. After his academic career as a post-doctoral researcher, he joined Nelson Labs in 2015 as R&D scientist, focusing on innovations in analytical services for the pharmaceutical and medical device industries. Driven by his technical expertise in chromatography and mass spectrometry, Jan works on the development of new analytical solutions, strategies and data processing flows. In his role of technical advisor, he also gives support to business development. Jan is also active in the structure elucidation team working on identification of unknowns.

Sponsored by Nelson Labs

Nelson Labs is a global leader in microbiological and analytical chemistry testing and advisory services for the medical device and pharmaceutical industries. Nelson Labs serves over 4,000 customers across 15 facilities in the United States, Mexico, Asia, and Europe.  We provide our customers with mission-critical testing services, which assess the quality, effectiveness, and end-to-end sterility of products and, ultimately, the impact of the products on patient safety. These services are necessary for our customers’ regulatory approvals, product releases, and ongoing product performance evaluations.  We have over 800 laboratory tests supporting our customers from initial product development and sterilization validation, through regulatory approval and ongoing product testing for sterility, safety, and quality assurance.  Pharmaceutical lab testing services include microbiology, biocompatibility and toxicology assessments, extractables and leachables evaluations of pharmaceutical containers, sterilization validation, sterility assurance, packaging validation and distribution simulation, and facility and process validation.  We also provide expert advisory services to help customers navigate the regulatory requirements applicable throughout their product’s lifecycle. We are regarded as a best-in-class partner with a strong track record of collaborating with customers to solve complex issues.