Regardless of what type of extractable or leachable study is being conducted or what product is being tested (medical device, combination product, single-use system, container closure), one thing is consistent. The study should be designed with the risk assessment in mind.

• Importance of the Risk Assessment and overview of the process
• Key inputs for the Risk Assessment and how they relate to the E/L study
• Essential components of an E/L Study

Sandi Schaible | Senior Director, Analytical Chemistry and Regulatory Toxicology, WuXi AppTec Medical Device Testing

Moderator: 

• Lee M. Nagao, Ph.D., Senior Director, Science, Regulation & Policy, ELSIE

Speakers

• Cheryl Stults, PhD, Principal, C&M Technical consulting LLC
• Dennis Jenke, Chief Executive Scientist, Triad Scientific Solution
• Ron Brown, Toxicologist, Risk Science Consortium, LLC (Retired US FDA)

Flexible polymer formulations are instrumental for use as materials of construction in medical devices, single use components in manufacturer of drug substances and packaging of pharmaceuticals. However, performing extractable and leachable (E&L) studies on these flexible test articles can be challenging. E&L analysis of flexible plastics commonly leads to a higher number of extractables detected compared to rigid plastics due to the higher levels of additives and higher glass transition temperatures. There is an increased propensity for extractables to migrate from these softer plastics.
This presentation will focus on case studies which highlight some of these challenges from materials such as polyvinylchloride, polyurethane, ethylene-vinyl acetate, thermoplastic elastomers & fluorinated ethylene propylene with an emphasis on how the different plasticizers used can affect the extractable profile.
Sam Albeke | LC Manager, Element

At the US Smithers 2021 and 2022 conference, PPD explained the extractable profiles of LDPE, HDPE, polypropylene, ABS, butyl rubber, silicone rubber, PET, PBT and polycarbonate based on the polymerization reaction chemistry of these materials. In this presentation, we are going to explore the extractables profiles of other polymer materials commonly used in medical devices, including Polyoxymethylene (POM), Polyurethane, Polyamide and Cyclic olefin copolymer (COC). We will provide the typical extractable compounds from those materials and explain how they are formed from their polymerization chemistry
Eric Hansen | Sr. Scientist Extractables/Leachables, Development and Validation, PPD, Part of Thermo Fisher Scientific

The Extractables and Leachables Safety Information Exchange (ELSIE) is a consortium of bio/pharmaceutical and medical device companies with the aim of sharing knowledge and information on and advancing the science and regulation of leachables and materials quality. ELSIE recently launched its "Knowledge Base" (KB), a database designed in consultation with subject matter experts to share and store safety and extractable study data and assist experts and nonexperts in understanding key aspects of E&L evaluation. We will present the technical capabilities and design of the KB with an invitation to the community to include their extractable and safety data in the KB.
James M. Vergis, Ph.D. | Principal, ELSIE Secretariat

Physics-based mass transport models are tools that can provide more clinically relevant exposure estimates for leachable substances in polymeric medical device components.  However, there are inherent challenges with parameterization, validation, and implementation of these models and the level of regulatory acceptance can be uncertain.  Therefore, we have developed the CHemical RISk calculators (CHRIS), which are a collection of web-based applications intended to facilitate the widespread use of these models in regulatory submissions.  This presentation will cover the following topics:
* Types of regulatory tools and hierarchy of regulatory acceptance
* Mass transport models for exposure estimation
* Models for E&L testing
* CHemical RISk calculators (CHRIS) case study
David M. Saylor, Ph.D. | Research Materials Engineer, Division of Biology, Chemistry, and Materials Science, US Food and Drug Administration

With increasing chemical characterization requirements for identifying extractable compounds above analytical evaluation thresholds, read-across can be a powerful risk assessment tool to fill data gaps and evaluate safety. However, structural similarity is not enough to adequately justify a read across approach. In addition to documenting similarities between target and surrogate compounds related to chemical structure, reactive functional groups, and other relevant physicochemical properties, special consideration should be made for respective toxicokinetic and metabolic profiles. In silico methods can be useful for addressing data gaps related to physicochemical properties and hazard potential. Several predictive toxicology tools are available for such purposes, though should not be used as a "black box," and expert judgment may be required in evaluating the confidence and reliability of any predictions. This presentation will provide an overview of lessons learned from read across applied in other regulatory contexts, useful tools for filling data gaps and justifying read across approaches, as well best practices in accounting for uncertainty in such approaches. Lastly, a case study will be presented applying the concepts of good read across practice in identifying and justifying the suitability of proposed analogue compounds for the purposes of a read across risk assessment
Joel M. Cohen, Sc.D., DABT | Senior Toxicologist , Gradient

A health-based toxicological risk assessment is the overall goal of conducting extractables and leachables studies. This assessment must be performed on all compounds found in the final drug product at concentrations above the analytical evaluation threshold (AET) by a qualified toxicologist. As there are no specific guidance documents on toxicological assessments, we will present a scientifically defensible stepwise approach of how to assess these compounds. Additionally, a case-study toxicological assessment will be presented.
Mac Taylor D.V.M., DABT | Managing Toxicologist, SafeBridge Regulatory Life Sciences Group

Extractables and leachables need to be assessed for their toxicological safety, whether they are found in pharmaceutical products or medical devices, with the major toxicity endpoints of concern being mutagenicity, sensitisation, and systemic toxicity. This study sought to investigate the role that in silico models, including expert systems and various statistical models, could play in predicting the mutagenicity and sensitisation potential of E&Ls as part of a wider risk assessment. Nearly 800 E&L chemical structures were collected from the published ELSIE and PQRI datasets, and publicly available mutagenicity and sensitisation data was located for these wherever possible. This reference data was used to assess the performance of various expert knowledge-based and statistical in silico models, and combinations thereof, for these endpoints. Two existing in silico models (expert knowledge in the form of structural alerts in Derek Nexus and a statistical self-organising hypothesis network model in Sarah Nexus) were applied to predict the bacterial mutagenicity of E&Ls. These models, when used in combination but before any expert review were applied, showed excellent performance with a sensitivity of 75% and specificity of 94% . This approach is already recommended within the ICH M7 guideline for the assessment of potentially mutagenic impurities, and this study shows that the same approach can be applied to accurately predict the mutagenicity of E&Ls. For the sensitisation endpoint , expert knowledge (in the form of skin sensitisation structural alerts in Derek Nexus) was used to predict hazard with a sensitivity of 73% and a specificity of 85%. A novel workflow has been designed which combines this expert knowledge with a statistical model (a k-nearest neighbours model in Derek Nexus) and threshold-based default predictions to predict dermal sensitisation potency. This approach was able to predict whether E&Ls were strong/extreme sensitisers, weak/moderate sensitisers, or non-sensitisers with an overall accuracy of 71%. As the science involved in the toxicological risk assessment of extractables and leachables advances, in silico approaches are expected to play an increasingly important role. This is especially pertinent in the context of the upcoming ICH Q3E guideline, which is hoped will bring much-needed clarity and international harmonisation to this area. This study analysed various expert knowledge-based and statistical in silico models and has shown that different combinations of models are well placed to help assess the mutagenicity and sensitisation potential of E&Ls moving forwards.
Charles Modlin | Principal Scientist, Lhasa Limited

In silico tools play an increasingly important role in the toxicological evaluation of extractables and leachables (E&L). It is useful to understand the chemical space defined by E&L chemicals in order to identify procedures and principles governing the use of these tools. The Extractables and Leachable Safety Information Exchange (ELSIE) Consortium and the Product Quality Research Institute (PQRI) have published datasets of E&L chemicals. The combination of the datasets resulted in 783 structures which were used to perform chemical structure-based clustering that allowed a description of the E&L chemical space. 74% of the chemical classes identified in the combined dataset included examples from both ELSIE and PQRI and the most populated classes included linear and branched alkanes, carboxylic acid derivatives (esters and carboxylic acids) and aliphatic alcohols. In silico models that predict bacterial mutagenicity and potent dermal sensitizers were used to assess potential hazards associated with E&L. Approximately 9% (69 out of 783) of chemicals were flagged as potential mutagens and around 3% (25 out of 783) were flagged as potent dermal sensitizers. These observations support previous findings that there is a low prevalence of potent dermal sensitizers in the E&L chemical space. Additionally, this presentation will describe a collaborative effort to determine the feasibility of setting class-based limits for E&L chemicals.
Candice Johnson, Ph.D. | Senior Research Scientist, Instem

Speakers:

• James M. Vergis, ELSIE Secretariat - Faegre Drinker Biddle and Reath, LLP, Director Science, Research, & Innovation
• David M. Saylor, Ph.D., CDRH, FDA
• Dr. Joel Cohen, Principal, Gradient
• Mac Taylor D.V.M., DABT, Managing Toxicologist for SafeBridge Regulatory Life Sciences Group
• Charles Modlin, Principal Scientist, Lhasa Limited
• Candice Johnson Senior Research Scientist Instem 

Advisory Board