Ronald Brown | Toxicologist, Risk Science Consortium, LLC & US FDA(Retired)

ELSIE has developed a series of publicly available papers that propose and describe a framework for conducting risk management for leachables evaluation.  These papers are relevant for drug products as well as manufacturing processes.  ELSIE developed these papers because a risk management process is fundamental to rationalized control of leachables.  This presentation will address:

• Why it is important to have a framework for leachables risk management
• The rationale for and scope of the ELSIE risk management papers 
• Description of key aspects of the risk management framework, such as materials screening and selection, risk assessment, chemical and safety risk control and lifecycle 
• Update on development of the ELSIE Knowledge Base (data sharing platform)

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

The biocompatibility evaluation of medical device involves a series of activities, including understanding the chemical composition of medical device (through the qualitative or semiqualitative E&L study when necessary), in vitro and in vivo test, and historical clinical use data analysis etc. With the progress of biocompatibility evaluation principals, test technologies, and standard requirements, the E&L study plus toxicology risk assessment of medical device has received more attention and challenges as well. For example, the chemical composition of medical devices’ leachables & extractables could be very complex. Some chemicals in very low content are lack of available toxicological data. Thus, a reliable tolerable intake can’t be determined, and the toxicological risk assessment can’t be completed. Threshold of Toxicological Concern (TTC) is one of the approaches to solve such problems. TTC is a pragmatic risk assessment tool based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health.  This presentation will briefly introduce the basic concepts of TTC, the role of TTC in the biocompatibility evaluation of medical devices, and related standard requirements. There will also some case sharing of TTC application.
Wei Zhang | Principal Scientist , Medtronic

With the publication and implementation of the new version of ISO10993-18:2020 on the chemical characterization of medical device materials in the risk management process, and the CMDE public soliciting opinion in June 2020 regarding to the "Guidelines for Technical Review of the Establishment of Evaluation Methods for Unknown Leachables of Medical Devices and chemical characterization (Draft for comments)”, medical device chemical characterization and toxicological risk assessment combined with biocompatibility test results for biological evaluation has become a new trend in the development of medical device biological evaluation. How to treat the role of extractable study in the overall biological evaluation? How to establish a method for extractables? And how to identify unknown compounds? These are issues that medical device companies are major concerned before registration and after product launches. This presentation will share the cases of extractable screening methods applied in the chemical characterization of medical devices according to the latest guidelines, to enable medical device R&D to better apply extractable screening method to obtain the necessary data in biological evaluation for the medical device registration and product safety.
Dongdi Sun | Director of Chemistry Laboratory, Medical Device Testing Center, WuXi AppTec (Suzhou) Co., Ltd

Feimei Cai | Chief Engineer, Mindray

Extractable and Leachable studies can be challenging and time consuming. A careful consideration should be therefore given when designing a study, not only to fulfil the regulatory requirements but to do so in the most cost and time efficient, albeit justified approach. 
In this webinar, Ewa will discuss the importance of creating a robust study design and how utilising project management tools can aid in a successful product delivery. This includes methods ranging from detailed planning, determining the project constraints, undertaking risk assessments, establishing the project’s lifecycle, creating control & monitoring measures and continuous learning.
Ewa Miaskiewicz | Project Manager, Smithers

The E&L responsibility of the analytical chemist to is to supply accurate, true and complete data to the toxicologist for safety risk assessment.  Critical activities performed by the analytical chemist include discovering all the relevant compounds above a defined safety-driven threshold, establishing the true identity of the discovered compounds and accurately quantifying the discovered and identified compounds.  In the ideal world, these activities are achieved effectively and reproducibly.  In the real world of challenging thresholds, low concentration analytes, and difficult analytical matrices, uncertainty in the analytical outcome is the rule (rather than the exception) and E&L profiles are imprecise and can vary within labs and across labs.
In this presentation, sources of analytical variation are considered and the presenter provides practical insights into the management and control of the various sources of the variation, including the proper use of uncertainty factors. 
 
Dennis Jenke | Chief Executive Scientist, Triad Scientific Solutions, UK

Extractables and leachables (E&L) are defined as compounds that can be extracted or leach from elastomeric, plastic components or coatings of the container and closure system when in the presence of an appropriate solvent(s), or as a result of direct contact with the formulation. Structure elucidation and quantitation of E&L in pharmaceutical and medical products, cosmetics, food packaging and contact materials are crucial because unidentified and potentially toxic leachable impurities can pose health hazards to people. Therefore, extractables and leachables investigations have received significantly increased emphasis from regulatory agencies in recent years. Owing to the diverse chemical structures and properties of E&L compounds, various analytical challenges are encountered during their identification and quantification process. Today’s report provides an overview of analytical challenges encountered during E&L analysis by UPLC-MS, APGC-MS. Some of these challenges including complex identification processes, and quantitation are discussed. High resolution mass spectrometry (HRMS) and related techniques have played a significant role in the analysis of E&L. In addition, the E&L workflow solution from Waters including experimental design, sample preparation and software functions will be introduced by sharing use cases. A simple workflow demonstration, that includes scientific library creation, multivariate statistical analysis, elucidation and reporting, using a single platform informatics solution which can facilitating the decision making process, by aiding analysts in the evaluation of complex data in a more efficient way through simplifying data review.
Kejun Qian | Application Manager, East & Central China, Waters

The delivery route of transdermal patches is becoming more and more popular, and the effect of the delivered drugs can be localized, reducing or even eliminating systemic side effects. Transdermal patches are composed of various types of polymers, which are bonded together by an adhesive layer or adhesive. The leachables from the transdermal backing membrane, release liner, storage bag may
cause potential risk to patient safety.
"Transdermal and Topical Delivery Systems-Product Development and Quality Considerations Guidance for Industry" formulated by FDA (2019), "Technical Guidelines for Pharmaceutical Research on Transdermal Patches of Chemical Generic Drugs (Trial)" formulated by the Center for Drug Evaluation of China National Medical Products Administration (2020), both require an evaluation of extractables and
leachables. The extraction test should be carried out under severe conditions with a variety of solvents in a variety of polar ranges to maximize the content of extractables and determine as many potential extracts as possible. The conditions of the leachable study should be as close as possible to the "worst case" skin clinical conditions (for example, sweating during strenuous exercise), choosing the appropriate solvent/solution selection (for example, salt concentration), temperature, degree of
agitation, and exposure to solvents The duration and so on.
This speech will formulate strategies for transdermal patches and their packaging systems, focusing on choosing different extraction conditions, using different test methods to determine potential extractables in transdermal patches, and introducing methods for evaluating actual extractables, monitoring the leachables by using validated analytical method.
Yi Zhang | Laboratory Director, Guangzhou Brunslab Co., Ltd