Grouping Extractable and Leachable (E&L) Compounds with a Common Mechanism of Action for Toxicological Risk Assessment

The toxicological risk assessment of E&L compounds is typically conducted on a compound-by-compound basis; however, for compounds that lack toxicity data, it may be useful to group compounds together that have similar structural and physical-chemical properties, as well as a similar toxicological mechanism of action, to derive a class-specific Tolerable Intake (TI) or Permitted Daily Exposure (PDE) that is applicable for all compounds in that group. This talk explores ways to group compounds based on their structural and toxicological similarity and how to use computational models to identify a proposed toxicological mechanism of action for compounds in a group. The presentation will also review methods to conduct a cumulative risk assessment of the compounds in the assembled group.

This approach of first assembling a group of compounds with a common toxicological mechanism, then conducting a risk toxicological assessment of the compounds in the group, has the potential to streamline the toxicological risk assessment process when large numbers of extractable or leachable compounds are released from a polymeric material and provides a science-based method for setting TI/PDE values that is presumably less conservative than the use of Threshold of Toxicological Concern (TTC) values as default TI/PDE values for the individual compounds

Presented by Ron Brown, Toxicologist at Risk Science Consortium

Ron Brown is a toxicologist with 35 years of experience in regulatory toxicology and risk assessment. He recently retired from the US FDA and currently directs a small company, Risk Science Consortium, LLC, that provides consultation and training in toxicological risk assessment and computational toxicology. At the FDA, Ron was the senior toxicologist responsible for developing and reviewing toxicological risk assessments of extractable and leachable (E&L) compounds from medical devices. While at the FDA, he served in a number of leadership roles in standards development organizations. At the international level, he served for many years as convener of ISO TC194 WG11, which is responsible for the development and revision of the ISO 10993-17 standard, Biological evaluation of medical devices 17: Establishment of allowable limits for leachable substances. At the national level, he represented the United States as an expert on ISO TC194 WG11 and served as co-chair of the AAMI Biological Evaluation Committee. Prior to his position at the US FDA, Ron served as a Senior Associate at the ILSI Risk Science Institute. He is a founding member and former President of the Medical Device and Combination Products Specialty Section of the Society of Toxicology and former President of the Dose-Response Specialty Section of the Society for Risk.

Scientific quality improvement opportunities in extractable testing based on the “Chemical List of Analytical Performance” published by the FDA (CDRH)

The “Chemical List of Analytical Performance” (CLAP) published by the FDA (CDRH) could be a significant catalyst for improving and harmonizing chemical analyses for Biocompatibility assessment of medical devices.

Non-Target Analytical Methods (NTA-Methods) that are used for these types of analyses can exhibit a high level of variance and uncertainty and henceforth the CLAP can be considered a large step forward to address these inter- and intra-lab variability issues.

Nelson Labs has populated an extractable database with analytical information (MS, RT/RI, RRF) obtained through the analysis of 5000+ authentic reference standards and has evaluated the alignment of that chemical space with the chemical space of the CLAP compounds.  A comparative evaluation of the distribution of the physico-chemical properties shows that for most parameters, the CLAP-compounds are a generally good cross-section of the broader population of extractable compounds present in the Nelson database. However, when comparing the CLAP list compounds to Nelson’s most frequently reported extractable compounds, it was observed that the CLAP compounds are not consistently among the most frequently reported compounds. This exercise supports the relevancy of the selected compounds from both sides and allows us to present scientific quality improvement opportunities in extractable testing in terms of how a lab could use the CLAP list to set the basis for:

• Optimizing analytical methodologies to obtain the broadest coverage by minimizing gaps and addressing the uncertainty in detectability of a relevant set of compounds.
• Understanding variability of responses per technique
• Providing the basis to calculate Uncertainty Factors (UF) based on a reference set of compounds.
• Calculating the coverage for a methodology, using the derived UF.
• Providing the basis of a new way of generating Quantitative data: the RRF-approach.
• Minimizing inter-lab variability in Chemical Characterization results.

Presented by Philippe Verlinde, Ph.D. Senior Technical Advisor at Nelson Labs

Philippe Verlinde is a Senior Technical Advisor at Nelson Labs Europe.  With over 20 years of experience in trace analysis and pharmaceutical analytical research his current role is supporting Nelson Labs in providing best-in-class and innovative scientific services to the pharmaceutical and medical device industry with a focus on extractables and leachables (E&L) studies. Prior to joining the company (formerly Toxikon Europe) in 2013, Dr. Verlinde worked as a scientific support officer at the Institute for Reference Materials and Measurements (IRMM) of the European Commission’s Joint Research Centre contributing to metrological and standardization efforts in the context of regulatory related trace analysis. He holds a Ph.D. in Bioscience Engineering from the University of Leuven (Belgium) and has a vast interest in mass spectrometry of small molecules and non-targeted analysis / cheminformatics related topics.

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 3,000 customers across 13 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 900 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.