Russell Sloboda presented on toxicological risk assessment for medical devices. He discussed how risk assessment plays an increasing role in preclinical safety evaluation under ISO 10993-1. Key points included how chemical characterization data forms the basis for risk assessment, and how tools like threshold of toxicological concern, quantitative structure-activity relationship analysis, and permissible exposure thresholds can be applied to evaluate risks. The goal of risk assessment is to identify hazards, evaluate exposure levels, and characterize overall risks to determine if biological testing is needed.
Integration of Risk Assessment and Chemical Characterization (MD&M Minn. 2017)Russell Sloboda
The Toxicological Risk Assessment (TRA) is an important tool in the safety assessment of biomedical devices, providing a chemical-based approach which complements a traditional animal-based testing program. The need for TRA is growing and in some cases, may be considered as a means of circumventing animal testing in the safety evaluation of devices.
Based on results of the chemical characterization, the TRA provides context to the chemistry data and the leachable compounds identified therein, which includes compounds expected to be found and compounds that are unexpected. The objective of the chemical characterization study is to identify and quantify substances that may be released from the test article during clinical use and in practical terms, is comprised of incubations of the test article in various media, e.g., water, ethanol, or hexane, at specific temperatures and durations.
By considering the end use of the characterization data in the TRA during the design of the chemical characterization study it can be assured that the study provides the most useful and informative data. Considering the needs of the TRA can also help in determining appropriate detection limits for the analysis, which in turn can help in determining the amount of test material needed for the study. Further, coordinating with the risk assessment team during the design of characterization study helps ensure that the data are usable and presented in the most suitable manner. By working together, the TRA and chemical characterization study provide an understanding of the impact of potential exposures on the overall safety of a device.
Material characterization per ISO 10993-18: When is it needed & how do I sati...UBMCanon
ISO 10993 provides guidance on biological evaluation of medical devices and consists of various parts covering topics like cytotoxicity, irritation, and systemic toxicity testing. Material characterization as outlined in Part 18 involves identifying all components that can migrate or leach out of a medical device under various conditions through extractable and leachable testing. Extractables are compounds that can migrate under aggressive extraction whereas leachables are those that migrate under normal exposure conditions. Understanding potential leachable sources from materials like polymers, metals, and residues is important for ensuring a comprehensive extractable/leachable profile.
ISO 10993 Series Part 1: Evaluation and Testing In The Risk Management ProcessNAMSA
ISO 10993 Series Part 1: Evaluation and Testing In The Risk Management Process discusses what ISO 10993-1 addresses, as well as the general principles governing the biological evaluation of medical devices within a risk management process.
Toxicological Risk Assessment for Breathing Gas Pathway Medical Devices - ISO...Russell Sloboda
The document discusses analytical methods for assessing the toxicological risk of breathing gas pathway medical devices according to ISO 10993 and ISO 18562. It provides details on the extraction and analytical requirements of each standard, including headspace gas analysis and particulate analysis. The document also presents case studies on a resuscitator delivery system and face mask to demonstrate how to conduct risk assessments for air pathway devices, including calculating exposure levels and margins of safety for identified chemicals.
ISO 10993 Biological Evaluation of Medical Devices UpdateNAMSA
The ISO 10993 Biological Evaluation of Medical Devices Update covers the revisions/updates that were discussed at the TC194 meeting in Mishima, Japan in April of 2014.
Chemical Characterization of Plastic Used in Medical ProductsSGS
Dr. Andreas Nixdorf presented on chemical characterization of plastics used in medical products according to ISO 10993 standards. He discussed the normative framework for chemical characterization and analytical methods for identifying extractables and leachables. Key points included sample preparation according to ISO 10993-12, using both exaggerated and accelerated extraction conditions. A variety of analytical techniques were outlined for separation and detection of extractable substances.
FDA Feedback Regarding Chemistry for Toxicological Risk Assessment – How to M...Greenlight Guru
One of the newest biocompatibility evaluation tools is extractable and leachable (E&L) testing. A correctly run E&L study, with an accompanying toxicological evaluation, can be used to replace traditional tests like systemic toxicity, genotoxicity, reproductive toxicity, and carcinogenicity. The data gained from these studies can help understand the total risk of your device to an intended population of users; but unlike the traditional animal tests, it comes with separate risks. These tests are not your typical “stamped” tests, where every lab gives a similar quality of results. Because of this, FDA has refined a strict, detailed, list of parameters that should be included in every test. This list is very dynamic and is changing rapidly; the best way to make sure you are performing the correct version of the test is to learn from the most recent FDA feedback on studies.
TAKEAWAY ITEMS:
• Understand recent FDA feedback and dissect what FDA is asking/looking for
• Learn how to address these concerns and develop a protocol to make sure you don’t receive similar questions
• Recognize how FDA is using the new ISO 10993-18 and where they deviate from that standard
This session took place live at the Greenlight Guru True Quality Virtual Summit, a three-day event for medical device professionals to learn to get their devices to market faster, stay ahead of regulatory changes, and use quality as their multiplier to grow their device business.
Pending (Potential) Updates to ISO 10993-17.pdfRussell Sloboda
The document summarizes potential updates to ISO 10993-17, which provides guidance on conducting toxicological risk assessments of medical device constituents. Key changes in the proposed updates include introducing a Toxicological Screening Limit to streamline assessments, providing more detailed methodology for estimating exposure doses and applying threshold of toxicological concern values, and deriving tolerable intake limits for both cancer and non-cancer endpoints. The updates are intended to add clarity and conservatism to the risk assessment process. The revised draft is expected to undergo additional balloting with the goal of final approval and publication in 2022.
Integration of Risk Assessment and Chemical Characterization (MD&M Minn. 2017)Russell Sloboda
The Toxicological Risk Assessment (TRA) is an important tool in the safety assessment of biomedical devices, providing a chemical-based approach which complements a traditional animal-based testing program. The need for TRA is growing and in some cases, may be considered as a means of circumventing animal testing in the safety evaluation of devices.
Based on results of the chemical characterization, the TRA provides context to the chemistry data and the leachable compounds identified therein, which includes compounds expected to be found and compounds that are unexpected. The objective of the chemical characterization study is to identify and quantify substances that may be released from the test article during clinical use and in practical terms, is comprised of incubations of the test article in various media, e.g., water, ethanol, or hexane, at specific temperatures and durations.
By considering the end use of the characterization data in the TRA during the design of the chemical characterization study it can be assured that the study provides the most useful and informative data. Considering the needs of the TRA can also help in determining appropriate detection limits for the analysis, which in turn can help in determining the amount of test material needed for the study. Further, coordinating with the risk assessment team during the design of characterization study helps ensure that the data are usable and presented in the most suitable manner. By working together, the TRA and chemical characterization study provide an understanding of the impact of potential exposures on the overall safety of a device.
Material characterization per ISO 10993-18: When is it needed & how do I sati...UBMCanon
ISO 10993 provides guidance on biological evaluation of medical devices and consists of various parts covering topics like cytotoxicity, irritation, and systemic toxicity testing. Material characterization as outlined in Part 18 involves identifying all components that can migrate or leach out of a medical device under various conditions through extractable and leachable testing. Extractables are compounds that can migrate under aggressive extraction whereas leachables are those that migrate under normal exposure conditions. Understanding potential leachable sources from materials like polymers, metals, and residues is important for ensuring a comprehensive extractable/leachable profile.
ISO 10993 Series Part 1: Evaluation and Testing In The Risk Management ProcessNAMSA
ISO 10993 Series Part 1: Evaluation and Testing In The Risk Management Process discusses what ISO 10993-1 addresses, as well as the general principles governing the biological evaluation of medical devices within a risk management process.
Toxicological Risk Assessment for Breathing Gas Pathway Medical Devices - ISO...Russell Sloboda
The document discusses analytical methods for assessing the toxicological risk of breathing gas pathway medical devices according to ISO 10993 and ISO 18562. It provides details on the extraction and analytical requirements of each standard, including headspace gas analysis and particulate analysis. The document also presents case studies on a resuscitator delivery system and face mask to demonstrate how to conduct risk assessments for air pathway devices, including calculating exposure levels and margins of safety for identified chemicals.
ISO 10993 Biological Evaluation of Medical Devices UpdateNAMSA
The ISO 10993 Biological Evaluation of Medical Devices Update covers the revisions/updates that were discussed at the TC194 meeting in Mishima, Japan in April of 2014.
Chemical Characterization of Plastic Used in Medical ProductsSGS
Dr. Andreas Nixdorf presented on chemical characterization of plastics used in medical products according to ISO 10993 standards. He discussed the normative framework for chemical characterization and analytical methods for identifying extractables and leachables. Key points included sample preparation according to ISO 10993-12, using both exaggerated and accelerated extraction conditions. A variety of analytical techniques were outlined for separation and detection of extractable substances.
FDA Feedback Regarding Chemistry for Toxicological Risk Assessment – How to M...Greenlight Guru
One of the newest biocompatibility evaluation tools is extractable and leachable (E&L) testing. A correctly run E&L study, with an accompanying toxicological evaluation, can be used to replace traditional tests like systemic toxicity, genotoxicity, reproductive toxicity, and carcinogenicity. The data gained from these studies can help understand the total risk of your device to an intended population of users; but unlike the traditional animal tests, it comes with separate risks. These tests are not your typical “stamped” tests, where every lab gives a similar quality of results. Because of this, FDA has refined a strict, detailed, list of parameters that should be included in every test. This list is very dynamic and is changing rapidly; the best way to make sure you are performing the correct version of the test is to learn from the most recent FDA feedback on studies.
TAKEAWAY ITEMS:
• Understand recent FDA feedback and dissect what FDA is asking/looking for
• Learn how to address these concerns and develop a protocol to make sure you don’t receive similar questions
• Recognize how FDA is using the new ISO 10993-18 and where they deviate from that standard
This session took place live at the Greenlight Guru True Quality Virtual Summit, a three-day event for medical device professionals to learn to get their devices to market faster, stay ahead of regulatory changes, and use quality as their multiplier to grow their device business.
Pending (Potential) Updates to ISO 10993-17.pdfRussell Sloboda
The document summarizes potential updates to ISO 10993-17, which provides guidance on conducting toxicological risk assessments of medical device constituents. Key changes in the proposed updates include introducing a Toxicological Screening Limit to streamline assessments, providing more detailed methodology for estimating exposure doses and applying threshold of toxicological concern values, and deriving tolerable intake limits for both cancer and non-cancer endpoints. The updates are intended to add clarity and conservatism to the risk assessment process. The revised draft is expected to undergo additional balloting with the goal of final approval and publication in 2022.
The document discusses extractables and leachables testing requirements for medical devices. It outlines two study designs: 1) For devices where leachables enter via a drug product, involving forced extraction of the device, validation of analytical methods to detect leachables in drugs, and assessment of drug compatibility and leachable levels. 2) For devices where direct tissue contact is the route of entry, involving exaggerated and simulated use extractions of the device to identify extractables/leachables. Both designs draw from ISO and FDA guidance to support 510(k) submissions for medical devices.
ISO 10993-6: Biological Evaluation of Medical Devices - Tests for local effec...NAMSA
ISO 10993-6 helps identify appropriate implantation sites, how long implants should remain in place during testing, implantation methods and biological responses at the macro- and microscopic level.
This document provides an introduction to extractables and leachables for pharmaceutical packaging. It defines extractables as compounds that can be extracted from packaging materials under aggressive extraction conditions, while leachables are those that migrate into drugs under normal conditions. The relationship between extractables, as the total potential pool of migrating compounds, and leachables, as the actual level that leaches into drugs, is explained. Key aspects of extractable and leachable screening covered include extraction/leaching conditions, regulatory guidelines, packaging material composition, and real examples of issues that have occurred.
This document discusses extractables and leachables (E&L) analysis for drug products. It defines leachables and extractables, provides examples, and outlines the risks. It describes forced extraction studies to identify potential extractables/leachables and determine safety thresholds. It discusses developing validated analytical methods, including leachables analysis in stability studies. The document emphasizes that careful E&L analysis is important to evaluate the safety of drug products.
Risk Based Classification of Medical Devices and groupingPaulyne Wairimu
The document discusses risk-based classification and grouping of medical devices in Kenya. It describes how medical devices will be classified into categories A, B, C, and D based on factors like invasiveness and risk level. It also discusses how devices can be grouped into single devices, device families that include variations of a device, and device systems which are groups of compatible devices that serve a common purpose. Proper classification and grouping is important for the registration of medical devices in Kenya.
Medical Devices Regulation (MDR) 2017/745 - Part I Purpose, Scope, DefinitionsArete-Zoe, LLC
This document provides an overview and summary of key changes and requirements in the new Medical Device Regulation (EU) 2017/745, which replaces previous directives. Some of the main changes include expanding the scope of regulated devices, implementing a Unique Device Identifier system for traceability, increasing requirements for clinical evidence and post-market surveillance, and removing grandfathering provisions. The purpose, scope, definitions and objectives are outlined to define the rules for placing medical devices on the EU market while ensuring a high level of safety and performance.
Occupational exposure limits (OEL) to chemical agents APIs - Quantitative Ris...Azierta
The Occupational Exposure Limit (OEL) is defined as the airborne concentration of a substance (expressed as a weighted average in time for a working day of 8 hours/day and 40 hours/working week) under which it is believed that nearly all workers may be repeatedly exposed (day after day, over a working lifetime) without adverse health effects (ACGIH, 2006; DFG, 2005).
Occupational exposure limits (OELs) are a useful tool to prevent adverse effects on health when managing chemical substances.
On a European scale…
• Employers are legally obliged to provide a work environment that does not threaten the health of the workers (Chemical Agent Directive 98/24/EC and Framework Directive 89/391/EEC).
• Under Directive 89/391/EEC, OELs can be developed nationally, Indicative Occupational Exposure Limit Values (IOELVs).
The document discusses the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH aims to harmonize technical guidelines for pharmaceutical drug development and registration among regulators in Europe, Japan, and the United States to ensure safety, efficacy, quality and reduce unnecessary testing. The ICH develops guidelines on clinical safety, good clinical practices, statistical principles for clinical trials, and other topics to increase efficiency and protect public health through international cooperation.
The regulation of medical devices in AustraliaTGA Australia
The regulation of medical devices in Australia involves classifying devices based on their intended use and risk level. Higher risk devices undergo more rigorous assessment procedures to ensure they meet essential safety and performance principles before being approved for market. Ongoing monitoring is also conducted after devices enter the market to protect public health. The TGA regulates medical devices to confirm they are suitable for their intended purpose and that their benefits outweigh any risks when used correctly.
To comprehend the regulatory requirements to import medical Medical devices and authorization procedures in regulated markets of the United States and Australia
This document provides an overview of the regulatory process and classification rules for medical devices in the European Union according to the 2017 EU Medical Device Regulation. It discusses the classification of devices as Class I, IIa, IIb or III based on factors such as duration of use, invasiveness, and purpose. It also summarizes the key steps in the regulatory process, including appointing a Notified Body for review and certification, preparing a technical file, and designating an Authorized Representative in Europe.
The document defines medical devices and their classification according to various regulatory bodies. It begins by defining a medical device as any instrument intended for internal or external use in the diagnosis, treatment, or prevention of disease. It then discusses the classification of devices by the US FDA, CDSCO, and the European Union as Class I, II, or III based on increasing risk levels. The document provides examples of devices that fall into each class and outlines the regulatory processes, including premarket approval or clearance, that manufacturers must go through for devices in each class to be legally marketed.
CE marking and CE certification what is it why you need it who can apply
CE marking certification for medical devices. Medical Device Regulations. It Is Easy To Make Mistakes In The Regulatory Process That Can Delay.
Visit: http://www.meddevicecorp.com/
TSE/BSE is a type of disease affected to the animals which may transmit to the humans if any products obtained by the disease caused animal may affect to humans also
The many biologic products are expracted from the animal source so before the extraction the animal should be tested for TSE/BSE organism in their source/Body
Medical devices – Quality management
systems – Requirements for regulatory
Purposes. ISO is an organization that develops Standards for use
worldwide.
ISO 13485 helps companies do their share in protecting
consumers and users of medical devices.
ISO 13485 Outlines criteria for a good Quality
Management System (QMS).
QMS criteria are good business practices ...
for example:
• Set Quality goals
• Ensure that regulations and other requirements are
understood and met
• Train employees
• Control your production processes
• Purchase from suppliers that can provide products that
meet your requirements
• Correct problems and make sure they do not happen again
This document provides an overview of extractables and leachables (E&Ls) studies. It discusses that E&Ls studies are needed in industries like biomedical devices, food packaging, and pharmaceutical packaging to identify substances that can migrate from materials into products. Jordi Labs is introduced as a leader in E&Ls analysis with state-of-the-art facilities and over 80% of staff being chemists. The document outlines the basic process of an E&L study including sample selection, extractions, identification of E&Ls using techniques like mass spectrometry, quantitative analysis, and determining acceptable levels. Regulations for E&Ls from organizations like USP, FDA and ISO are also summarized.
The document discusses extractables and leachables testing requirements for medical devices. It outlines two study designs: 1) For devices where leachables enter via a drug product, involving forced extraction of the device, validation of analytical methods to detect leachables in drugs, and assessment of drug compatibility and leachable levels. 2) For devices where direct tissue contact is the route of entry, involving exaggerated and simulated use extractions of the device to identify extractables/leachables. Both designs draw from ISO and FDA guidance to support 510(k) submissions for medical devices.
ISO 10993-6: Biological Evaluation of Medical Devices - Tests for local effec...NAMSA
ISO 10993-6 helps identify appropriate implantation sites, how long implants should remain in place during testing, implantation methods and biological responses at the macro- and microscopic level.
This document provides an introduction to extractables and leachables for pharmaceutical packaging. It defines extractables as compounds that can be extracted from packaging materials under aggressive extraction conditions, while leachables are those that migrate into drugs under normal conditions. The relationship between extractables, as the total potential pool of migrating compounds, and leachables, as the actual level that leaches into drugs, is explained. Key aspects of extractable and leachable screening covered include extraction/leaching conditions, regulatory guidelines, packaging material composition, and real examples of issues that have occurred.
This document discusses extractables and leachables (E&L) analysis for drug products. It defines leachables and extractables, provides examples, and outlines the risks. It describes forced extraction studies to identify potential extractables/leachables and determine safety thresholds. It discusses developing validated analytical methods, including leachables analysis in stability studies. The document emphasizes that careful E&L analysis is important to evaluate the safety of drug products.
Risk Based Classification of Medical Devices and groupingPaulyne Wairimu
The document discusses risk-based classification and grouping of medical devices in Kenya. It describes how medical devices will be classified into categories A, B, C, and D based on factors like invasiveness and risk level. It also discusses how devices can be grouped into single devices, device families that include variations of a device, and device systems which are groups of compatible devices that serve a common purpose. Proper classification and grouping is important for the registration of medical devices in Kenya.
Medical Devices Regulation (MDR) 2017/745 - Part I Purpose, Scope, DefinitionsArete-Zoe, LLC
This document provides an overview and summary of key changes and requirements in the new Medical Device Regulation (EU) 2017/745, which replaces previous directives. Some of the main changes include expanding the scope of regulated devices, implementing a Unique Device Identifier system for traceability, increasing requirements for clinical evidence and post-market surveillance, and removing grandfathering provisions. The purpose, scope, definitions and objectives are outlined to define the rules for placing medical devices on the EU market while ensuring a high level of safety and performance.
Occupational exposure limits (OEL) to chemical agents APIs - Quantitative Ris...Azierta
The Occupational Exposure Limit (OEL) is defined as the airborne concentration of a substance (expressed as a weighted average in time for a working day of 8 hours/day and 40 hours/working week) under which it is believed that nearly all workers may be repeatedly exposed (day after day, over a working lifetime) without adverse health effects (ACGIH, 2006; DFG, 2005).
Occupational exposure limits (OELs) are a useful tool to prevent adverse effects on health when managing chemical substances.
On a European scale…
• Employers are legally obliged to provide a work environment that does not threaten the health of the workers (Chemical Agent Directive 98/24/EC and Framework Directive 89/391/EEC).
• Under Directive 89/391/EEC, OELs can be developed nationally, Indicative Occupational Exposure Limit Values (IOELVs).
The document discusses the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH aims to harmonize technical guidelines for pharmaceutical drug development and registration among regulators in Europe, Japan, and the United States to ensure safety, efficacy, quality and reduce unnecessary testing. The ICH develops guidelines on clinical safety, good clinical practices, statistical principles for clinical trials, and other topics to increase efficiency and protect public health through international cooperation.
The regulation of medical devices in AustraliaTGA Australia
The regulation of medical devices in Australia involves classifying devices based on their intended use and risk level. Higher risk devices undergo more rigorous assessment procedures to ensure they meet essential safety and performance principles before being approved for market. Ongoing monitoring is also conducted after devices enter the market to protect public health. The TGA regulates medical devices to confirm they are suitable for their intended purpose and that their benefits outweigh any risks when used correctly.
To comprehend the regulatory requirements to import medical Medical devices and authorization procedures in regulated markets of the United States and Australia
This document provides an overview of the regulatory process and classification rules for medical devices in the European Union according to the 2017 EU Medical Device Regulation. It discusses the classification of devices as Class I, IIa, IIb or III based on factors such as duration of use, invasiveness, and purpose. It also summarizes the key steps in the regulatory process, including appointing a Notified Body for review and certification, preparing a technical file, and designating an Authorized Representative in Europe.
The document defines medical devices and their classification according to various regulatory bodies. It begins by defining a medical device as any instrument intended for internal or external use in the diagnosis, treatment, or prevention of disease. It then discusses the classification of devices by the US FDA, CDSCO, and the European Union as Class I, II, or III based on increasing risk levels. The document provides examples of devices that fall into each class and outlines the regulatory processes, including premarket approval or clearance, that manufacturers must go through for devices in each class to be legally marketed.
CE marking and CE certification what is it why you need it who can apply
CE marking certification for medical devices. Medical Device Regulations. It Is Easy To Make Mistakes In The Regulatory Process That Can Delay.
Visit: http://www.meddevicecorp.com/
TSE/BSE is a type of disease affected to the animals which may transmit to the humans if any products obtained by the disease caused animal may affect to humans also
The many biologic products are expracted from the animal source so before the extraction the animal should be tested for TSE/BSE organism in their source/Body
Medical devices – Quality management
systems – Requirements for regulatory
Purposes. ISO is an organization that develops Standards for use
worldwide.
ISO 13485 helps companies do their share in protecting
consumers and users of medical devices.
ISO 13485 Outlines criteria for a good Quality
Management System (QMS).
QMS criteria are good business practices ...
for example:
• Set Quality goals
• Ensure that regulations and other requirements are
understood and met
• Train employees
• Control your production processes
• Purchase from suppliers that can provide products that
meet your requirements
• Correct problems and make sure they do not happen again
This document provides an overview of extractables and leachables (E&Ls) studies. It discusses that E&Ls studies are needed in industries like biomedical devices, food packaging, and pharmaceutical packaging to identify substances that can migrate from materials into products. Jordi Labs is introduced as a leader in E&Ls analysis with state-of-the-art facilities and over 80% of staff being chemists. The document outlines the basic process of an E&L study including sample selection, extractions, identification of E&Ls using techniques like mass spectrometry, quantitative analysis, and determining acceptable levels. Regulations for E&Ls from organizations like USP, FDA and ISO are also summarized.
Toxicology is the science of the adverse effects of chemicals on living organisms. It involves observing symptoms, mechanisms, detection, and treatments of toxic substances through various methods. Toxicology provides dose-response information through toxicity testing on animals and humans to evaluate chemical risks and ensure safety. The results of toxicity testing are used to regulate chemical exposure levels and approve safe product use.
Genotoxic impurities are potentially harmful compounds that must be strictly controlled in pharmaceuticals. They can cause mutations in DNA that may lead to cancer. Guidelines classify genotoxic impurities into five categories based on their mutagenic and carcinogenic potential to determine appropriate testing and control strategies. Analytical methods for detecting genotoxic impurities at the parts-per-million level or lower require sensitive techniques like mass spectrometry and NMR due to the stringent limits for these compounds.
Toxicological testing for medical devices focuses on biocompatibility rather than pharmacology. Devices are a diverse category ranging from bandages to pacemakers. Testing assesses the safety of device materials and potential leachables through established biocompatibility standards rather than traditional toxicology studies for drugs. For most Class II and III devices, testing relies on a predicate device through the 510(k) process rather than full premarket approval and clinical trials. The goal is to evaluate biological hazards while ensuring reasonable safety based on prior human exposure to similar materials.
Hans Steinkellner - Metabolites for dietary risk assessmentcropprotection
The document discusses tools for assessing the toxicological relevance of pesticide metabolites for dietary risk assessment. It summarizes several EFSA projects evaluating the applicability of thresholds of toxicological concern, quantitative structure-activity relationships, and the impact of metabolism on toxicity for this purpose. The projects concluded that thresholds of toxicological concern are appropriate for assessing metabolite risk and that combinations of models may help determine genotoxicity. A draft scientific opinion will apply these tools in case studies and address uncertainties to derive acute and chronic exposure thresholds for metabolites.
The document discusses various topics related to impurity profiling and stability testing of pharmaceutical drugs including definitions of impurities, classification of impurities, impurity profiling methods, factors affecting drug stability, types of stability testing, regulations for stability testing, and methods for accelerated stability testing and shelf life calculations. Impurities are classified as identified, unidentified, or according to USP and ICH guidelines. Various spectroscopic, separation, isolation, and characterization methods are described for identifying impurities.
Canadian Perspective on Problem Formulation for Biopesticides: Emma BabijOECD Environment
The seminar on Problem Formulation for the Risk Assessment of Biopesticides stemmed from a previous CRP-sponsored event on Innovating Microbial Pesticide Testing that identified the need for an overarching guidance document to determine when in vivo tests are necessary. Problem Formulation, a common practice in pesticide risk assessment, was highlighted as a useful approach for addressing uncertainties in data requirements for biopesticides.
The seminar featured presentations from various perspectives, including industry, regulatory bodies, and academia. Topics included the history and principles of Problem Formulation, industry perspectives on Problem Formulation and how it is applied internally for microbial pesticides, regulatory approaches, and specific case studies. The seminar provided an overview of the challenges, considerations, and potential solutions in harmonising Problem Formulation for biopesticide risk assessment. It emphasised the need for collaboration and discussion to develop Problem Formulation guidance for biopesticides.
Chemical Safety Guidelines with hazard and risk controlsDecentN
This course briefly covers chemical hazard and risk associated with appropriate safety controls. This presentation also cover chemical labeling and classification as per GHS system.
This document provides guidance on chemical safety practices, including hazard identification, labeling, storage, handling, and spill response. It summarizes the Globally Harmonized System for classifying chemicals and describes the new standardized label elements. The document outlines procedures for performing a chemical hazard assessment, applying proper controls, and responding to spills. Personnel are instructed to take various protective measures, such as using engineering controls, following administrative controls, and wearing personal protective equipment when working with chemicals.
Slides for the eLearning course Separation and purification processes in biorefineries (https://open-learn.xamk.fi) in IMPRESS project (https://www.spire2030.eu/impress).
Section: Mass transfer processes
Subject: 3.3 Safety issues
This document discusses the different types of toxicology. It begins with an introduction to toxicology, defining terms like toxin, toxicant, and toxicity. It then describes the major types of toxicology as mechanistic toxicology, regulatory toxicology, and descriptive toxicology. Mechanistic toxicology examines toxicity at the molecular level. Regulatory toxicology supports rulemaking and product approval. Descriptive toxicology focuses on toxicity testing in animals to evaluate hazards. The document provides examples and explanations of each type.
The document presents an overview of ICH guidelines. It discusses that ICH was created in 1990 to harmonize pharmaceutical regulations between Europe, Japan, and the US. ICH has developed over 45 guidelines divided into quality, safety, efficacy, and multidisciplinary categories. The quality guidelines address chemical and pharmaceutical quality assurance. The safety guidelines cover preclinical safety testing. The efficacy guidelines relate to clinical trial design, conduct, and reporting. The multidisciplinary guidelines cover topics that do not fit uniquely into the other categories. In summary, the document provides a high-level introduction to the structure and guidelines of the International Council for Harmonisation.
The document summarizes a study analyzing the toxicity classification of chemical reference standards according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and exposure limits set by NR-15 and ACGIH. The study found that 119 reference standards were highly toxic (class D or E). While ACGIH limits classified 12.6% of standards as highly toxic, NR-15 limits only classified 4.2% as such. The study concludes that both quantitative and qualitative analysis are needed for effective chemical risk management and worker protection.
Best practices on the interpretation of Toxicology Impact Categories in Life ...Leonardo ENERGY
The use of toxicology impact categories in life cycle assessment presents major challenges. Currently the use of toxicology impact categories is advised in some international fora. However, the potential benefits of including those categories in life cycle assessment are often missed due to an inaccurate interpretation of the results.
This webinar will address the main challenges of using toxicology indicators in life cycle assessment. Critical points such as lack of data in Life Cycle Inventories and model characterisation, the factual errors in in the results, and the potentialities of the toxicology models will be explained.
With a focus on copper products and production, the webinar will include a list of practical and understandable questions the use of toxicity in life cycle assessment can answer, and will flag the most common mistakes when interpreting toxicology results life cycle assessment.
The document discusses changes to the Hazard Communication Standard to align it with the Global Harmonized System of Classification and Labeling of Chemicals. The revised standard requires consistent labeling with pictograms, signal words, and hazard and precautionary statements. It also mandates a standardized 16-section format for Safety Data Sheets to better communicate hazard information globally. The changes are intended to improve worker understanding of chemical hazards.
The document discusses changes to the Hazard Communication Standard to align it with the Global Harmonized System of Classification and Labeling of Chemicals. The revised standard requires consistent labeling with pictograms, signal words, and hazard and precautionary statements. It also mandates a standardized 16-section format for Safety Data Sheets to better communicate hazard information globally. The changes are intended to improve worker understanding of chemical hazards.
The ability to recreate computational results with minimal effort and actionable metrics provides a solid foundation for scientific research and software development. When people can replicate an analysis at the touch of a button using open-source software, open data, and methods to assess and compare proposals, it significantly eases verification of results, engagement with a diverse range of contributors, and progress. However, we have yet to fully achieve this; there are still many sociotechnical frictions.
Inspired by David Donoho's vision, this talk aims to revisit the three crucial pillars of frictionless reproducibility (data sharing, code sharing, and competitive challenges) with the perspective of deep software variability.
Our observation is that multiple layers — hardware, operating systems, third-party libraries, software versions, input data, compile-time options, and parameters — are subject to variability that exacerbates frictions but is also essential for achieving robust, generalizable results and fostering innovation. I will first review the literature, providing evidence of how the complex variability interactions across these layers affect qualitative and quantitative software properties, thereby complicating the reproduction and replication of scientific studies in various fields.
I will then present some software engineering and AI techniques that can support the strategic exploration of variability spaces. These include the use of abstractions and models (e.g., feature models), sampling strategies (e.g., uniform, random), cost-effective measurements (e.g., incremental build of software configurations), and dimensionality reduction methods (e.g., transfer learning, feature selection, software debloating).
I will finally argue that deep variability is both the problem and solution of frictionless reproducibility, calling the software science community to develop new methods and tools to manage variability and foster reproducibility in software systems.
Exposé invité Journées Nationales du GDR GPL 2024
BREEDING METHODS FOR DISEASE RESISTANCE.pptxRASHMI M G
Plant breeding for disease resistance is a strategy to reduce crop losses caused by disease. Plants have an innate immune system that allows them to recognize pathogens and provide resistance. However, breeding for long-lasting resistance often involves combining multiple resistance genes
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
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Toxicological Risk Assessment For Medical Devices - ISO 10993-1
1. Toxicological Risk Assessment For Medical Devices:
New Pathways to Success under ISO 10993-1
M edicalDeviceP reclinicalBootcamp– 02/13/2019
Russell Sloboda – S r.S cientist& R iskAssessmentS pecialist
2. Speaker Bio
•Analytical chemist and risk assessment specialist
•35 years’ experience
•Responsible for all aspects of toxicological risk
assessment as per ISO 10993-17 and ICH M7
guidelines, which includes:
•Exposure modeling
•QSAR models
•Toxicological profiles
•Calculation of tolerable intakes
•Study design and AET calculations
4. FDA On ISO 10993-1: Increased Role For Risk Assessment
•Evaluation and testing “within a risk management process”
•FDA Final Guidance (June 17, 2016) solidified role of Toxicological Risk Assessment
(TRA)
•TRA (and Chemical Characterization) is described as a prerequisiteto
biocompatibility testing
•GreaterDemandforChemicalCharacterizationandT oxicologicalR iskAssessment
•Update to ISO 10993-1:2018 emphasizes this expanded role, with a tiered
approach to testing beginning with physical and chemical characterization,
followed by assessment of toxicological risks, and use of results to focus/limit the
scope of biological testing
•Traditional Biocomp testing is NOT going away; however, rote biocompatibility
analysis (“check-box” exercise) is getting more difficult
M orethoughtneededinthedesignofaS tudyP lan
5. Roles of Risk Assessment in Medical Device Testing & Approval
•Development of a biocompatibility testing plan based on assessing the potential for
toxicological hazards and given the exposure category of a device and its intended use
•Gap analysis determines if additional biological tests are needed, based on review of
existing test results for compliance (proper/current methodology and passing results)
•Assessment of modifications to an existing, approved device to determine if
component and material changes require further testing (justification letter)
•Toxicological Risk Assessment (TRA) of chemical characterization data to evaluate if the
leachable levels of compounds exceed toxicological thresholds, given the quantity,
frequency, and duration of patient contact with the device
T R A isincreasinglyview edasaprerequisiteforbiocompatibilitytestingbecause,ifall
detectedlevelsarelessthantoxicitythresholds,severalbiologicaltestscanbeomitted
6. Risk Assessment: Regulatory Basis
•Regulatory Guidance:
•ISO 10993-17 (2002) – Toxicological Risk Assessment. Establishment of
Allowable Limits for Leachable Substances
• Toxicological effects of chemical leachates or impurities
• Provide direction (thresholds) to ensure adequate testing and appropriate evaluation of safety
• Currently undergoing revision – may change with upcoming ISO guidance on Thresholds of
Toxicological Concern
•FDA/ICH ‘M7’ Guidance. Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. 2018
•FDA/ICH ‘Q3D’ Guidance. Elemental Impurities. 2015
•ISO 18562. Biocompatibility evaluation of breathing gas pathways in healthcare
applications
•CAUTION: Several Similar Sounding Terms
•Risk Management: ISO 10993-1 - Evaluation and testing within a risk management process
•Risk Analysis under ISO 14971. Broader meaning, including all nature of hazards.
7. TRA per ISO 10993-1: Biological Safety Assessment
Evaluation Strategy ISO 10993–1:2018 BiologicalEvaluationofM edicalDevices: P art1:Evaluationandtesting w ithinariskmanagementprocess.
Test Methods
Part 5: Cytotoxicity
Part 10: Irritation & hypersensitivity
Part 11: Systemic toxicity
Part 3: Genotoxicity, carcinogenicity and reproductive toxicity
Part 6: Implantation and local effects
Part 4: Blood compatibility
Part 16: Toxicokinetic study design for leachables and degradation products
Part 20: Principles and methods for immunotoxicology testing
Reference Materials
Part 8: Selection of reference materials
Part 12: Sample preparation and reference materials
Animal Welfare
Part 2: Animal welfare requirements
Sterilization Residuals
Part 7: Ethylene oxide sterilization residuals
Degradation Products
Part 9: Framework for Identification and quantification of degradation
products
Part 13: Identification and quantification of polymeric degradation products
Part 14: Identification and quantification of ceramic degradation products
Part 15: Identification and quantification of metallic degradation products
Materials Characterization
Part 18: Chemical characterization of materials
Part 19: Physico-chemical, morphological and topographical characterization
Risk Assessment
Part 17: Establishment of allowable limits for leachables
8. Toxicological Risk Assessment - Objectives
•What is it?
•A complementary approach to traditional biocompatibility testing
•Often required by FDA
•It is built upon the chemical characterization
•For medical devices, it relies on extractability/leachability (E/L) data
•What are the questions it hopes to answer?
•What are constituents, additives, impurities of concern?
•What are the tolerable exposure levels for these impurities?
•Could there be an unacceptable risk to the patient?
For Medical Devices & Pharmaceuticals
9. What Are The Concerns Underpinning TRA?
•Constituent Materials
•Impurities/Contaminants
•Degradants
•Leachables/Extractables
•from constituent materials
•AND packaging
•Solvent residues
ACCORDINGLY, Analysis should be conducted on final, finished product.
…to capture chemical residues from processing, manufacturing, and packaging, as well as
leachable constituents
…totheextentthatthisispossible.
10. Toxicological Risk Assessment: Paradigm and Process
•HAZARD IDENTIFICATION
• C hemic alC harac terization
• Toxic ologic alC harac terization
•DOSE-RESPONSE EVALUATION
• D erive Tolerable Expos u re levels
•EXPOSURE ASSESSMENT
• N atu re ofd evic e/d ru gprod u c t
• Frequ enc y/D u ration ofUs e
•RISK CHARACTERIZATION
•Ford evic es , D A TA is typic ally from E/L A nalys is .
N O TE: O therforms ofd ata mays erve TRA !
•Toxic ityP rofile bas ed on literatu re s earc h
•Extrapolation ofanimald ata
•D ifferentrou tes ofad minis tration
•D ifferents tu d y d u rations (s u bac u te vs . c hronic )
•D es c ribe u s e ofd evic e/prod u c t, e. g. , natu re and
magnitu d e ofpatientc ontac t, patientpopu lation
•Explain u nc ertainties , margins ofs afety
•Therapeu tic benefits ofthe prod u c t?
11. TTC: Threshold Of Toxicological Concern
• TTCs are acceptable daily intakes intended to be protective of all toxicological
endpoints
• Not specific to any one chemical. A S afeDoseforAnyChemical!
• Chemical toxicity depends on how introduced into the body, so a TTC evaluation
can be specific to the route of exposure (e.g., oral, parenteral, or inhalation)
• Intended (originally) for daily exposureoveralifetime
• However, values have been established for less-than-lifetime exposures.
• S horterduration= HigherpermissibleDose
Duration of Exposure ≤1 month >1 – 12 months >1 – 10 years >10 years to
lifetime
Tolerable Intake
(µg/day)
120 20 10 1.5
13. TTC: Toxicological Threshold of Concern (cont.)
•May TTCs be used for SCREENING-LEVEL assessments?
•“T T C approachcanberecommendedasausefulscreeningtooleitherforprioritysettingor
fordecidingw hetherexposuretoasubstanceissolow thattheprobabilityofadversehealth
effectsislow andthatnofurtherdataarenecessary” (from EFSA Journal, 2012).
14. QSAR Analysis: Predicting Toxicity Of Unstudied Chemicals
•QSAR : Quantitative Structure-Activity Relationships
•Computational Models used to predict toxicology for chemicals
without any tox data (i.e., unstudied)
•Software packages:
•ICH M7 Guidance: For pharmaceutical impurities
•Focus is mutagenicity
•Must use dual model (Statistical-based + Knowledge based)
•Interpretation of model results is key part of the work
•ToxTree
•OECD Toolbox
•TOKAT
•Leadscope
•MultiCase
•DEREK/SARAH
15. QSAR: Additional Applications
ToxSmart Uses QSAR Models for Risk Assessment:
•Hazard Ranking / Chemical Categorization
• Cramer Classification: Grades 1 (low) , 2, and 3 (high)
•Surrogate Identification when No Data are Available for
Chemical of Interest
•Identify a chemical class
•Identify a very similar chemical (or analog) which has more
data
16. Risk Assessment: Turn-Around Time Is Important
Speeding up the process:
•Use screening evaluation in the face of many pages of data
•Make use of toxicity values from authoritative agencies
•EPA IRIS, EPA HEAST, ATSDR, ECHA, ESIS (EU), State Agencies, e.g., CAL-EPA, NJDEP,
Occupational Exposure Limits, TLVs, etc.
•ICH (Q3D), IOM (UL and RDA for elements)
•Library of Toxicity Profiles, Tolerable Exposures (TEs)
•The E/L Analyses for most medical devices identify similar constituents/additives.
•ToxSmart has toxicity profiles and route-specific toxicity values for >200 chemicals
18. Quantitative Risk Assessment Under ISO 10993-17
•TE = TI × mB × UTF; an adjusted tolerated exposure level of a chemical within a population subset
•where: mB = Body Weight and
UTF = Concomitant Exposure Factor ǂ (CEF) × Proportional Exposure Factor (PEF)
Uncertainty Factor Example Sources of Variation/Uncertainty
UF1 Intra-individual variation (in humans)
UF2 Inter-species variation (animal-to-human)
UF3
Overall study quality/relevance: Subchronic to chronic extrapolation, different experimental versus clinical
exposure routes, use of a LOAEL instead of a NOAEL, and other uncertainties
UF4 (optional) Toxicity data based on a surrogate compound
•Uses derived toxicity-based thresholds - Tolerable Intake level (TI, in µg/kg-day) and Tolerable
Exposure level (TE, in µg/day)
•Based on a toxicological “point of departure” (e.g. NOAEL) identified from a literature search
•TI = NOAEL / Modifying Factor (MF), which is made up of several Uncertainty Factors (UFs):
ǂ CEF applies if more than 1 device may be used concurrently
19. Risk Assessment At ToxSmart
• ToxSmart is embedded in one of the preeminent CROs in the U.S.:
• Surrounded by subject matter experts
• “In-house” chemistry lab
• We evaluate many, many devices and drug products
• A culture of QUALITY: Embedded in all operations at Toxikon.
• An SOP for Toxicological Risk Assessment
• Peer review and appropriate quality review is part of the system
21. Introduction
Extractables/Leachables (E/L) Analysis is the basis for most Toxicological Risk Assessments
for devices having direct patient contact
•Has a growing role in preclinical safety assessment, as per FDA (2016 “Use of ISO 10993-1” Guidance)
•Extractables analysis – incubation of a device in contact with a solvent, usually under elevated
temperature conditions – required by ISO 10993-17 for a TRA. Two subcategories:
•Exaggerated extraction – Fixed duration, designed to leach a greater amount versus simulated use
•Exhaustive extraction – Successive extractions repeated until virtually all leachable residue is removed
• Simulated use extraction – Extractions conducted under relatively mild conditions designed to closely
simulate clinical use of a device
• Leachables analysis - Analysis of a drug product solution after a prolonged storage period while in
contact with a container closure system, measured at intervals over a product’s shelf life
Gas flow simulation analysis measures the releasable amounts of volatile organic compounds and
particulates that may arise during use of a respiratory medical device, required by ISO 18562
22. Extraction Guidelines per ISO 10993-12: Biological vs. Chemical Tests
Biocompatibility Testing Chemical Characterization
T estarticlecondition Finished/sterilized/packaged device Same (Objective is the same)
Extractionratios ISO: 3 cm2/mL or 6 cm2/mL, based on
material thickness
Same (Objective is the same)
Extractionconditions ISO guidance: Several default
conditions, e.g., 50⁰C / 72 hrs or 70⁰C
/ 24 hrs; however, some biological
extractions (MEM) must be at 37⁰C
Exhaustive conditions should be used for permanent
contact devices, while exaggerated conditions are
intended for devices having a shorter clinical contact.
Resorbable devices are fully dissolved but not denatured
Extractionmedia Polar and non-polar vehicles which do
not adversely affect the biological test;
usually Saline and Cottonseed Oil
(CSO) or Sesame Oil
Implanted device: Purified Water, Ethanol, or Hexane
Indirect contacting device: Medium that is most relevant
to drug formulation or communicating medium
Blood contact: Ethanol/Water mixture
Componentsurfaces In practice, err on the side of inclusion Test components that actually make contact (direct or
indirect) with patient; e.g, fluid path vs. immersion
23. Analytical Requirements: ISO 10993-18 Versus ISO 18562
•ISO 10993-18:
•General guidance: E/L testing is
conducted with polar, semi-polar,
and nonpolar solvents to
determine leaching of organic
compounds (10993-12)
•Volatile Organic Compounds (VOC)
can be determined either by:
1) Analysis of aqueous extracts, or
2) Direct analysis of test article by
heated headspace (90 – 115◦ C)
•ISO 18562:
•E/L is conducted by solvent
extraction using water to simulate
humidified vapor condensate
(18562-4)
•VOCs are analyzed by gas flow
through the device under
simulated clinical use conditions
(temperature, gas flow rate,
duration), with analysis by GC/MS
(18562-3)
•Particulates analyzed (<2.5 µm,
<10 µm) (18562-2)
24. Comparison of Methods: Extraction, Headspace, Gas Flow
Higher temperature in headspace analysis exaggerates the release of VOCs
Choice of extraction solvent significantly affects
polymer swelling and extraction of nonpolar
compounds. Purified water is the most realistic
solvent to simulate humidified vapor condensate.
25. Risk Assessment Is Built Upon Chemical Characterization Data
•Applicable to container closure systems, processing equipment,
packaging, as well as medical devices
•A complementary approach to biocompatibility testing in the
preclinical safety assessment
•Identify material constituents, additives, impurities, contaminants,
degradants, and residues of concern
•Establish tolerable exposure (TE) levels for the chemicals/elements
identified
•Must consider nature and magnitude of patient exposure:
•Classification of the device
•Duration of contact
•Route of exposure
26. The Ties that Bind: Chemistry and Risk Assessment (TRA)
GOOD CHEMISTRY DEPENDS ON…
Extractions:
•Conditions?
•Extraction media?
•Which components to include?
Targeting Analysis:
•AETs
Data Reduction:
•How to present data?
…CONSIDERATIONS FOR THE TRA
Understand the Device
Understand Device Use
Determine Data Needs
27. E/L Analysis: Think About Patient Contact
•DO test the Final, Finished Product (as packaged and delivered)
•DO send lab the device in the form that it would be sent to a user
•DO help lab understand the nature of patient contact
•DON’T forget to tell the lab to remove components that should not
be included, e.g., needle guards, hose clamps
Q: What is the harm of including non-contacting components?
A: You may dilute out smaller components that matter more
28. Categorize the Device: Exposure Duration
•Limited Exposure
•Less than 24 hours
•Prolonged Exposure
•24 hours to 30 days
•Permanent Exposure
•Greater than 30 days
29. Categorize the Device: Nature of Contact
•Surface Device
•Does it contact intact skin?
•Does it contact intact mucosal membranes?
•Does it contact breached or compromised
surfaces?
•External Communicating Device (conduit)
•Does it have indirect blood contact?
•Does it contact tissue/bone/dentin?
•Does it have contact with circulating blood?
•Implant Device
•Does it have contact with tissue/bone?
•Does it have contact with blood?
30. Risk Assessment Perspective On E/L Analysis
•E/L Analysis for risk assessment should emphasize the more relevant
conditions (e.g., leachables)
•Target normal (‘real-world’) conditions of exposure and migration from a
contact surface
•Where E/L analysis may go astray…
•Extraction to simulate aging/degradation of product may overshoot extent of
actual leaching
•Nonpolar extraction solvent swells and degrades polymer
•Non-patient contacting portions of a device may be included
•Although it is difficult to ignore data in hand, risks may be explained with a
caveat stating that these are ‘upper-bound’ estimates of risk, with little to no
relevance to clinical exposure
31. Risk Assessment Concerns With Combination Products
•Examples: pulmonary delivery device, drug-coated balloon catheter, prefilled syringe, transdermal
patch, wound dressing combined with drug product, or scaffold seed with cells
•Extractables testing is necessary to evaluate (1) leachables from device components, and
(2) leachables testing to assess stability/degradants in presence of drug product
•Study design involves input/review from multiple FDA agencies (CDRH, CDER, CBER, to be assigned
by the Office of Combination Products)
•Important to involve CRO’s toxicologists and chemists in study design and for consultation on any
FDA feedback, In particular,
•Customized extraction methods may be needed for gels, transdermal patches, etc.
•Time profile info on the in vivo absorption of resorbable products is important to risk
assessment
•FDA may have special concerns necessitating exhausting extraction
•FDA may want E/L even for transient drug-contacting components that provide drug delivery
32. Common Issues With Data Usability
•Exhaustive extraction not completed
•No information on time course of leachability
•Unidentified analytes (Chemical Unknowns)
•Components Included with Very Little or No Patient Contact
•Extraction Medium not Appropriate
•Detection Limits are Not Adequate (See AETs)
33. By Popular Demand… Is E/L Analysis Necessary?
•Is leachability the appropriate measure of exposure?
•Air pathway (respiratory) devices
•Resorbable materials?
•Predicate device assures safety
•No novel materials or chemicals
•Risks can be eliminated through a “worst-case” exposure
assessment
34. Analytical Evaluation Threshold (AET)
•Identifies analytes for further analysis or toxicological evaluation
•Defines a minimum threshold for adequate detectability for the lab
•Converts the µg/day (safety threshold) into a unit of concentration
(µg/unit) using information on the container volume, number of units
analyzed, the recommended (or maximum) dose
•May also be expressed in units of µg/mL of extract
“The threshold at or above which [the risk assessor] should
identify and quantify a particular extractable and/or leachable
and report it for potential toxicological assessment.”
– Prasad Peri, Ph.D., FDA, 2013
35. Analytical Evaluation Threshold
•AET concept is not new, but has undergone refinement over
last two decades
•AET requires an anchor in an appropriate Safety Concern
Threshold (SCT)
•SCTs are derived for different routes of exposure to toxicants
•SCTs are based on Toxicological Thresholds of Concern (TTCs)
and are distinct for genotoxicity (mutagenic carcinogens),
chemicals that are sensitizers, and general (noncancer) toxicity
36. Analytical Evaluation Threshold
•SCT for genotoxicity (ICH M7): ranges from 1.5 to 120 µg/day. SCT is
lowest for longer duration exposures, and is based on cumulative days
of exposure
•SCT for sensitization (PQRI, 2013): 5 µg/day. SCT does not necessarily
scale to a higher value for shorter duration exposures
•SCTs for noncancer effects (general toxicity) depend on Hazard Class I,
II, or III, as determined by chemical structure (Cramer, 1978)
•Thresholds for adverse noncancer effects depend on toxicokinetics
and toxicodynamics (absorption, distribution, metabolism, excretion).
•Is 3 mg once every 3 days as potent as 1 mg daily doses for 3 days?
37. Toxicology Focus
•AET must correlate E&L data to the actual Patient Exposure
•Adapt safety thresholds (TTCs) to the E&L study considering:
•Patient exposure type (location)
•Duration of use
•Device size
•Dosing frequency (cumulative exposure)
•For drug products, the underlying TTC is based on a daily dose
•To adapt concept to implants, consider AET in terms of a daily rate of leaching that
equates to exposure to a fraction of total leachables (fraction of a test article/day)
38. Threshold Approach For Medical Devices
AET in µg/mL, or µg/unit if Vext is omitted
SCT Safety Concern Threshold for the device/exposure type (µg/day)
UF Uncertainty Factor
(shouldbeconsideredw henutilizingS emi-quantitativemethods)
Dext Number of devices present in the extraction volume of Vext
Dc # of Devices clinically utilized in a day (Dc≥ 1 unlessstudyconditionsprovideadequate
resolutioninreleasekineticsofaprolongedorpermanentexposuredeviceandkinetics
demonstratelinearrelease)
Vext [Optional] Extraction Volume (in mL)
Note: BothVext & Dext mustberesolved accordingly to account for any extract modifications
such as concentrations and/or dilutions prior to analysis
UF
VD
D
S C TA ET
extc
ext
39. Example 1: AET Determination For A Syringe
AET expressed in µg/unit; Vext is omitted
SCT 1.5 µg/day, assumes long term (>10 yrs. to lifetime daily use), based on stringent SCT for
mutagenic chemicals
UF Uncertainty Factor (shouldbeconsideredw henutilizingS emi-quantitativemethods)
Dext # of Devices present in the extraction volume of Vext
Dc 4 devices can be used clinically per day
S C T
VD
D
UFA ET
extc
ext
AET expressed in µg/mL; Vext = 10 mL
g/u nit0 . 191. 5
4
1
0 . 5A ET
40. Example 2: AET Determination For An Artificial Disc Implant
AET in µg/mL
SCT 1.5 µg/day, assumes long term (>10 yrs. to lifetime), based on stringent SCT for mutagenic chemicals
UF Uncertainty Factor
Dext 2.47 Devices in extraction volume of Vext - Extract one 43 cm2 prototype; clinical device = 17.4 cm2
Dc 0.236 no. of devices used per day – equivalent fraction of total leached during first 24 hours of clinical use
(at 37◦ C). Model assumes 72-hour initial extraction NVR = 1.0 (nominal amount); 2nd extraction NVR = 0.3;
final extraction NVR = 0.1. Hence, total leached = 1.4; leachables in first 24 hours = 1/3 of 1.0 = 0.33, so
the fraction leached = 0.33/1.4 = 0.236.
Justified by ISO 10993-18: “Leachables can, in some cases, be determined by mathematical models as well
as tests.” Furthermore, draft ISO guidance for Application of the TTC states, “if sequential extractions
demonstrate that the amount of leachable chemicals change over time, then the 24-hour window with
peak exposure should be used.”
Vext 34.4 mL = 43 cm2 / 1.25* cm2/mL
*SA-Vol. ratio for an elastomer
S C T
VD
D
UFA ET
extc
ext
41. The Case for Worst-Case Risk Assessment:
W henExposureispredictablyT rivial
42. Screening TRA: A Worst-Case Exposure Assessment
•We don’t always need data …although a very conservative approach
•Conservative = Certain to overstate exposure and toxicity
•Useful for eliminating concern, where applicable
•Should have a sound basis for estimating an approximate release of
leachable chemicals, e.g., literature values?
•Utilizes the TTC (Toxicological Threshold of Concern): A safe dose for
any chemical
Concept: Small Device = Small Exposure
Sometimes TooS mallto be a Concern
43. Case Study: A Dental Cement Made From A Resin Composite
Background
•Cement applied in thin layers as a bonding agent for veneers, crowns, inlays, and onlays
•Device classification: Permanent implant
•Composition in mass percent: 13 ingredients, must assess each material for toxicity and history of safe use
Evaluation of a Worst-case Scenario
•Assume 150 mg of material is applied, which is comprised of 31% resin, or 47 mg.
•Cured resin - Literature studies report that ~2.5% of the total resin mass leaches over 30 days, or 1.2 mg
•Studies of resin toxicity report NOAEL of 100 mg/kg-day. Using BW = 70 kg & UF = 300, yield TE = 23 mg/day
•The calculated TE is 590X greater than estimated potential daily intake of 39 µg/day (1.2 mg resin/30 days)
•Non-resin ingredients – The highest non-resin ingredient is 1% of 150 mg, or 1.5 mg, 2.5% of which = 38 µg
•Dividing by 30 days exposure yields 1.3 µg/day exposure. This is less than the 1.5 µg/day most stringent TTC
Conclusion
•Risk from leachables released from any individual ingredient is unlikely to be of toxicological concern
•Leachability of 2.5% is based on previous studies with similar material
44. Case Study: An Optical Sensor On An Intravascular Pump
Background
•Device classification: External communicating device having direct contact with circulating blood
for a prolonged duration
•Total mass of a silicone coating: 3.1 µg
Evaluation of a Worst-case Scenario
•Part 1: Assume daily exposure to silicones as leachables is < 1% of the total mass (0.031 µg/day)
•Well below applicable TTC (150 µg/day)
•Part 2: Assume that the silicone contains a maximum plausible 10% level of a toxic leachable
•Assuming the same 1% leaching rate per day, this equates to 0.0031 µg/day; below the applicable
TTC of 5 µg/day
Conclusion
•Risk from leachables is unlikely to be of toxicological concern
•Leachability of 1% is based on NVR data, which was correlated with release of siloxanes
45. Resorbable Products: A Case For Bulk Material Analysis
•Test article: Polyglactin sutures
•Completely absorbed within 45 days
•Standard “extractables” study may not yield the right data
•Data will represent the initial (72-hour) release (X) from fresh material
•Will likely have to assume that a daily exposure of 1/3 of the measured
amount will continue for entire 45 days: Total exposure will be 15X ??
•Proposal: Exhaustive extraction, analyzing total content of target analytes
•Better measure of total patient exposure
•Total releasable amount is divided by 45 (days) to approximate
an average daily exposure. Exhaustive extraction will likely show
an asymptotic depletion curve, so this avoids over-estimating risks.
46. Case Study: Gas Flow Pathway - Volatiles Released vs. Time
Simulated use, 48-hr. gas flow analysis by GC/MS
ISO 18562 recommends
sampling at intervals
over the clinical
duration of use.
Results are used in the
Toxicological Risk
Assessment according
to ISO 18562-1.
47. Gap Analysis For Implanted Device
Sponsor wants to know if chronic toxicity and carcinogenicity studies
are necessary?
•Review biocompatibility data
•Are studies GLP compliant?
•Do they provide high-quality, relevant data?
•Evaluate device classification based on intended uses, nature of
patient exposure, and consult FDA biocompatibility test matrix
•E/L data: Consider toxicology of any known or identified constituents
•Make recommendations
48. ToxSmart: More Than Risk Assessment!
• Toxicological Risk Assessment
• Assistance with the design of E/L studies
• Toxicological Evaluations of Materials or Specific Additives/Impurities
• Literature search and review
• Biocompatibility Test Program Review
• Retrospective (Gap-Analysis)
• Forward-looking (Program design)
• Sponsor: “We have all this test data, but don’t know where we stand”
• Custom study design
• Third-party Review of E/L Data or Risk Assessments