Smithers

The 2024 FDA Draft Guidance for Industry and Food and Drug Administration Staff, Chemical Analysis for Biocompatibility Assessment of Medical Devices provides much needed regulatory guidance to the industry. The draft, however, includes several recommendations that would benefit from further discussion and eventual revision, clarification, or regulatory flexibility. These topics include the draft guidance recommendations on extractables study design, solvent selection, and approaches for exhaustive extractions among others. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium submitted a number of comments to the draft guidance public docket. ELSIE will present and discuss its comments related to these three important topics that many in industry believe require further scientific discussion and consideration. ELSIE will also present some common industry themes supporting some of the key comments to the guidance
Jeff Elich | Senior Research Scientist, Baxter Healthcare

The recent medical device chemical characterization guidance documents, including ISO 10993-18 and the related FDA draft regulatory guideline, provide more prescriptive requirements for study design, execution and interpretation of results. These updates provide a more defined road map for medical device manufacturers and testing laboratories. While the guidance documents help provide some standardization and increase the structure of studies, several critical industry decision points remain. This presentation will explore medical device chemical characterization case study examples, where the practical application of the guidance documents will be illustrated. These case studies will be used to highlight regulatory expectations and key challenges encountered during study design and data analysis
Sam Albeke | LC Manager, Element

This discussion will address any questions from the audience about the FDA guidance with speakers from the session and a few industry experts. 

Moderator: Ron Brown, Toxicologist, Risk Science Consortium, LLC (Retired US FDA) 


Panelists include:

• Sam Albeke, Chromatography Manager, Element Materials Technology
• Jeff Elich, Senior Research Scientist, Baxter Healthcare
• Dr. Piet Christiaens, Scientific Director, Nelson Labs Europe

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

Different manufacturing processes may require multiple single-use systems (SUS) to support product operations. These SUS’ may be integrated as sub-assemblies or complete assemblies to avoid duplicating required pre-processing and simplify the supply chain. Aseptic processes need integration of all process components end-to-end to avoid contamination from external environment. Due to such complexity and diversity in SUS, challenges are encountered during planning of extractable studies which would be discussed in the presentation. When to breakdown the assembly into individual components for study? How can material from alternate suppliers be accommodated in the assembly? One interesting challenge is selection of analytical evaluation threshold (AET). Different components of an assembly/subassembly would be having different individual AETs. However, while planning the study for assembly/subassembly, only one AET is needed. A simplest solution would be to select the lowest AET from the assembly/subassembly. However, additional consideration can include a margin while selecting AET to increase the scope of study for additional applications. Another challenge during planning of such study setups is to have the extraction conditions that meet regulatory expectations. USP <665> describes the extraction conditions only for individual components, and not much guidance is available for deciding on study setups for assemblies/subassemblies. Therefore, tailored conditions can be considered while planning the studies. Similar more challenges will be discussed in some detail. A case study would also be presented for a manifold and how the study setup was decided. At BioNTech SE, we have faced these challenges and worked through them to design solutions for our biopharmaceutical products. The presentation would be directed to share experience of different thought-process and principles that inspired us to develop such solutions.
Ikjot Sodhi | CMC Associate Director, BioNTech SE

Leachables risk management is a critical aspect of ensuring the safety of pharmaceutical products. In response to the industry's need for standardised approaches, a workflow that supports informed decisions in this area and is aligned with key use cases, guidelines and best practices is of great value to the scientific community. The proposal of this work is to demonstrate a Leachable Risk Management (LRM) tool that aims to guide users through the process steps of leachable risk management via a largely question-based knowledge gathering workflow where leachable risks are identified, assessed and evaluated against a predefined leachable risk matrix. An action plan for communicating and mitigating leachable risks is then derived. These leachable risks can come from a variety of sources including packaging systems, delivery devices or manufacturing materials. Appropriate action plans may include extractable or leachable studies derived from the identified leachable risk. Presentation to be confirmed.
Diego Zulkiewicz Gomes | Senior Global Alliances Manager, Lhasa Limited

When it comes to performing Extractable and Leachable studies, it is important to get it right: first and foremost for patient safety, as well as to ensure regulatory compliance. But what is “right”? If different results are observed for different approaches to extractables or leachables studies, which are correct? And what could explain this difference in results? 
There are various sources of variability: from study design, through different analytical instrumentation, to data processing software capabilities and MS libraries. Some of these factors, such as study design, can be controlled by implementing guidance documents and through regulation. However, the variability in the analytical equipment, software, and facilities utilised is less easy to control and can also have an impact on reported results of E&L studies.
This presentation will examine some of the sources of this analytical variability and will discuss the ways in which, and to what extent, they can impact E&L studies. It will also explore whether there is an opportunity to standardise analytical practices, and consider the challenges associated with implementing analytical standardisation, as well as the potential drawbacks of introducing analytical conformity.
 
Dr. Amy Johnson | Principal Scientist, Medical Device Testing, Smithers

The identity of an extractable or leachable is a critical foundation of toxicological risk assessment, as it is through the identity that the risk assessor obtains information about the compound’s toxicological profile and ultimately establishes a tolerable intake (TI). It is therefore of utmost importance to have identifications of compounds with the highest level of confidence achievable. The typical “generic” approach labs are taking to identify GC/MS-compounds is to perform library searches with commercial databases and suggest the identity of a compound, based upon the quality of the mass spectral match, based on different criteria (eg Match Factor, Reverse Match Factor, Probability, InLib Score). However, the identification of a compound only based on its mass spectrum may not offer a sufficient confidence that the mass spectral interpretation is correct. To increase the confidence, a second piece of independent information – which supports the compounds identity - is necessary. In addition to the mass spectral information, the NIST library also contains chromatographic information of most of the compounds. As chromatographic information (i.e. Retention Index) is completely independent from the compound’s mass spectral fingerprint, Retention Index information could be used in support of identification if the information is sufficiently accurate. In a first step, the presentation will evaluate how well the Retention Index information from NIST correlates with the retention time (converted to RI) over 3100 compounds – confirmed with analytical standards – that are in the Nelson Database. Based upon the statistics, we will evaluate if and how acceptance criteria can be derived for the RI-reconciliation (ΔRI). Once acceptance criteria for the ΔRI have been derived, the presentation will explain and evaluate how this criterion can be of value to augment mass spectral identifications, to reject false MS-identifications or how it could assist in structure elucidation performed by HRAMS GCMS.
Dr. Piet Christiaens | Scientific Director, Nelson Labs Europe

The concept of using an Internal (surrogate) Standard in E&L testing is proposed to be the best industry practice since the PQRI recommendation published in 2006. It has been widely accepted and highlights the practical use of Internal Standards (ISs) during extractables and leachables evaluation, for the following purposes: • Establishes relative response factors (RRF) for a wide range of analytes to support RRF databases • Establishes instrument / method performance at the Analytical Evaluation Threshold (AET) level in the samples via visualization • May compensates for injection associated variations • May compensate / establish recovery for sample preparation such as solvent exchange However, a detailed description was not provided regarding internal standard selection, appropriate concentration level needs to be used, number of internal standards appropriate for high quality testing data. As those criterions are not standardized the industry uses multiple “best practice” approaches. This presentation will provide some guidance regarding: • Selection of internal standards and appropriate concentration levels to be used • Impact on the IS to the RRF database • Limitations of RRF databases
Gyorgy Vas | Research Fellow, Intertek Pharmaceutical Services

Substances that migrate (leachables) into a pharmaceutical product from the materials that comprise its manufacturing, packaging, and/or delivery system(s) have the potential to negatively impact its safety and/or quality. Mitigating the impact of this interaction typically includes the screening of substances that can be extracted (extractables) from these materials using appropriate solvents and exposure conditions. Because extractables can be predictive of product leachables, the data obtained from extractable screening studies are used to establish the safety and quality of the material(s) being assessed. Despite the importance of extractable screening studies in assuring product quality and patient safety, it has become apparent that inconsistencies in the execution of these studies between laboratories have resulted in the potential for significant differences in the qualitative and/or quantitative aspects of the extractable profiles obtained. Given that such differences can have a significant impact on the validity of the safety assessments performed, it is critical that they be understood and eliminated. Since this issue was discovered primarily through anecdotal accounts, the “lab practices” working group within the Extractable/Leachable Safety Information Exchange (ELSIE) conducted two industry surveys that inquired into critical aspects of extractable screening study design and execution. After completion of these surveys, it was concluded that there were numerous areas associated with the execution of extractable screening studies where labs were not well aligned that are likely having a significant impact on the data generated. To that end, this presentation will summarize the recommendations proposed by the ELSIE lab practices working group to address the discrepancies in extractable study design and ultimately produce more consistent and reliable extractable profiles between laboratories.
Steve Zdravkovic | Research Scientist II, Vantive

This presentation will offer a comprehensive framework for evaluating the potential risks associated with leachables from complex medical devices used in transfusion medicine. Drawing from extensive experience in reviewing submissions to the U.S. FDA, I will focus on medical devices that also function as container closure systems, often categorized as combination products. An example of these systems are devices designed to collect, process, and store blood components, as well as facilitate pathogen inactivation in closed systems. These devices typically consist of multiple interconnected bags and filters, with storage bags classified as Large Volume Parenterals (LVPs). The unique nature of such devices necessitates a multifaceted regulatory approach, addressing both pharmaceutical and medical device regulations. The discussion will cover the types of tests required for LVP devices/container closure systems, and applicable regulations and guidelines. I will emphasize FDA requirements and expectations for leachables assessment, particularly regarding the analytical study design. Special attention will be given to the unique challenges posed by LVPs, which necessitate carefully designed approaches for assessing leachables. These approaches often involve simulation studies, risk assessments, and a thorough understanding of regulatory expectations, all of which are key to developing an effective extractables and leachables (E&L) testing strategy for LVPs.By the end of the presentation, the audience will gain insights into the methods and approaches used in the evaluation of extractables and leachables testing for LVPs. These are crucial components in ensuring the biocompatibility and safety of these medical devices throughout their lifecycle, and to meet FDA regulatory expectations."
Silvia De Paoli, Ph.D | Biological Reviewer, Center for Biologics Evaluation and Review, FDA

    Chemical grouping is a vital technique in evaluating extractables and leachables (E&L), where quick and accurate predictions about potential toxicological risks are crucial for product safety. This method involves classifying chemicals based on structural, functional, or mechanistic similarities, facilitating efficient data use for regulatory and product development purposes. In E&L studies, grouping is essential for predicting toxicological endpoints for data-poor leachable compounds through read-across methodologies by using data from surrogates that are structurally or mechanistically similar to the data-poor E&L. Chemical grouping also provides a systematic approach to prioritize and rank extractables and leachables based on their potential risks. When combined with analytical data, grouping can consider the likelihood and concentration of a compound leaching from a material. Compounds that exhibit both structural concerns and higher exposure potential can be prioritized over those with comparable hazards but lower anticipated exposure levels. Grouping can reveal patterns in leachables associated with specific material classes (e.g., polyolefins or elastomers) or manufacturing processes. This insight supports proactive decision-making, such as choosing alternative materials with lower associated risks. This presentation will showcase the diverse applications of chemical grouping in the E&L field, highlighting its importance in enhancing safety assessments, supporting regulatory compliance, and fostering innovation in pharmaceutical and biocompatible material development. We will demonstrate the application of hierarchical agglomerative clustering for classifying and ranking clusters. We will also illustrate how functional grouping aids in evaluating the reactivity of leachables with biomolecules. By using grouping for prioritization and risk ranking, E&L assessments can concentrate resources on the most critical compounds, ensuring a thorough yet efficient evaluation process. This approach promotes proactive risk management, leading to safer product development and material selection.
Candice Johnson, Ph.D. | Senior Research Scientist, Instem