Nitrosamines: Evolving Regulatory Landscape and Its Potential Impact on Medical Devices and Combination Products
Date and Time:Tuesday, January 25, 2022, from 12:00pm to 1:00pm ET
Overview of US FDA guidance on “Control of Nitrosamine Impurities in Human Drugs”, Owen McMaster, US FDA
MDCPSS and CTSS Webinar: Practical Application of Computational Models to Predict Release Kinetics and Toxicity of Compounds Released from Medical Devices
Date and Time: Wednesday, June 2, 2021 from 12 Noon–1:30 PM ET
Use of Computational Models to Predict the Toxicity of Compounds Released from Medical Device Materials, Ron Brown, Risk Science Consortium, LLC
Toxicity data are not available for many compounds released from medical device materials. However, computational models can be used to help predict the toxicity of data-poor compounds. This webinar will show how computational toxicology models can be used for the biological safety assessment of medical devices and will provide some tips on the practical application of the models and interpretation of model-derived predictions. Some of the more recently developed tools to help with compound grouping and Read Across will be featured and promising models to provide quantitative toxicity threshold values (e.g. NOAEL, LOAEL) will be explored, along with models to predict biocompatibility endpoints such as skin sensitization.
Physics-based models to predict patient exposure to medical device leachables, David Saylor, US Food and Drug Administration
Medical device materials contain chemicals that may pose toxicological concern(s) if released in sufficient quantities. Toxicological risk assessment approaches are increasingly being used in lieu of animal testing to address these concerns. Currently, these approaches rely primarily on in vitro extraction testing to estimate the potential for patients to be exposed to chemicals that may possibly leach out of device materials, but the clinical relevance of the test results are often ambiguous. Recent developments suggest physics-based models can be used to provide more clinically relevant exposure estimates. However, the lack of data available to parameterize and validate these models presents a barrier to routine use. This presentation will provide an overview of these approaches, including considerations in developing and parameterizing exposure models, strategies that can be used to address the challenges associated with limited data, and potential future directions and improvements.
MDCPSS Webinar: Biostability and Product Life-Cycle Evaluation of Medical Devices
Date and Time: Friday, May 7, 2021 at 12:00 Noon–1:30 PM ET
In Vivo Long-Term Durability of Materials That Comprise Implanted Medical Devices, Dr. Kim Chaffin, Medtronic
In the 1980’s, Medtronic experienced one of the industry’s most consequential recalls, where the polymer insulation on implanted cardiac leads, the conduits through which energy is delivered to the heart, disintegrated in vivo. Amid this crisis, Medtronic scientists began a quest to better understand and screen for the factors that could impact a material’s long term biostability. After almost forty years of prioritizing research in this area, we lead the industry in our ability to screen and predict a material’s biostability in vivo. In this talk, Dr. Chaffin will review their scientific advancements, discuss how they continue to set the industry standard, and examine the scientific questions that are currently active areas of research for us. In demonstrating their leadership position in this area, she will review a manuscript (ACS Macro Lett. 2020, 9, 12 p. 1793–1798) that used strategically designed accelerated in vitro testing to provide important insights into the long-term biostability of materials; insights that could not be readily gleaned through the in vivo studies that dominate current regulatory guidelines.
Evaluation of Biological Safety over the Whole Life-Cycle of a Medical Device—Aspects to Be Considered, Dr. Katharina Weidmann, Tüv Süd Product Service GmbH
The ISO 10993 standard series presents a framework for risk management in order to reduce the biological risks of medical devices as far as possible. In August 2018, a new version of ISO 10993-1 was published, amongst other changes pointing out the importance of addressing the biological safety of medical devices over their complete life-cycle. While most of the available data from biological and chemical testing was generated with devices at a time point close to the production process in the past, now it is stressed that the potential impact of transport, shelf life, the clinical use and potential (re-)processing on the biocompatibility of the device under evaluation has to be discussed as well. The webinar aims to point out the different time points during life cycle to be looked at in the biological evaluation as well as to discuss potential approaches to address this requirement.
Webinar—Evolving Use of In Vitro Hemocompatibility for the Biological Evaluation of Blood Contacting Medical Devices
Date and Time: Tuesday, March 30, 2021 at 12:00 Noon–1:30 PM ET
Toxicology in the 21st Century has changed the way many Industries and Regulators evaluate the safety of chemicals, substances, and products, including medical devices. The evaluation of biocompatibility has begun to transition from in vivo methods to in vitro alternatives in an effort to improve the accuracy, increase the speed, and reduce the cost of testing without jeopardizing the quality of product safety assessments. Hemocompatibility testing, which is a biological endpoint of consideration for blood-contacting medical devices, exemplifies this transition as one area of medical device biocompatibility testing that has incorporated in vitro approaches. This webinar will review the available in vitro hemocompatibility tests as well as their limitations and advantages, study design considerations, and regulatory acceptance.
Overview of In Vitro Thrombogenicity Testing—US FDA/CDRH Research Update and Regulatory Considerations
Device related thrombosis and thromboembolic complications remain a major clinical concern and often impact patient morbidity and mortality. Thrombogenicity of medical devices is impacted by several device-related factors such as the blood-contacting materials, surface properties, and the geometry of the device. While the US FDA Biocompatibility Guidance Document and the international hemocompatibility standard ISO 10993-4 (Biological evaluation of medical devices—Part 4: Selection of tests for interactions with blood) provide general guidelines for thrombogenicity evaluations and serve as useful resources for selecting potential thrombogenicity tests, much work is still needed to develop specific test methods to help perform thrombogenicity assessments appropriately. In collaboration with US FDA reviewers and medical device industry partners, our research group in the US FDA/CDRH Office of Science and Engineering Laboratories has been working to develop, qualify, and standardize a panel of in vitro thrombogenicity test methods that can be used to effectively and efficiently characterize device thrombogenicity. Recently, two in vitro thrombogenicity testing standards, ASTM F2382-18 (partial thromboplastin time assay) and ASTM F2888-19 (platelet and leukocyte count assay), were updated and subsequently recognized by the US FDA for material-mediated thrombogenicity testing. Additionally, we are also working towards developing a dynamic in vitro blood flow loop thrombogenicity test system that may be used to characterize flow-mediated thrombogenicity relevant to device geometry and surface effects. This presentation will provide an overview of US FDA/CDRH research efforts on in vitro thrombogenicity test method development and regulatory considerations for the use of these methods in device thrombogenicity evaluations.
Evaluation of the NAVI Model for Thrombogenicity Assessments: Correlation between In Vitro Hemocompatibility TestResults and In Vivo Thrombus Scores
Common in vitro hemocompatibility tests such as partial thromboplastin time (PTT), platelet and leukocyte (P&L) counts, and complement (SC5b-9) activation are often used in evaluating hemocompatibility for changes in device materials. To evaluate if these in vitro test results correlate with in vivo thrombogenicity observations, an analysis of in vivo thrombus scores in non-anticoagulated venous implant (NAVI) studies on 15 devices was conducted. Our results suggest reduced PTT and increased SC5b-9 may be associated with in vivo thrombogenicity in the NAVI model. No association between platelet counts, assessed using citrated human blood, and elevated thrombus scores was observed. Platelet counts utilizing heparinized human blood per ASTM F2888:2019 may improve the correlation. There are many challenges in performing a NAVI study and factors such as implant technique, device placement, and individual animal differences in thrombotic potential lead to inconsistent thrombogenicity predictions. In vitro hemocompatibility tests, possibly combined with data from a dynamic in vitro flow loop may provide a feasible and appropriate alternative to using the in vivo NAVI model.
In Vitro Hemocompatibility Testing: Continuing Development
ISO 10993-4 thrombogenicity testing is widely used for meeting regulatory requirements for approval of blood-contacting medical devices. American Preclinical Services (APS) is continuing to optimize an in vitro thrombogenicity test using minimally heparinized ovine blood that has been successfully used in lieu of the non-anticoagulated venous implant (NAVI) assay in recent client submissions with the US FDA for catheter-like devices. APS also frequently performs the traditional NAVI model in canines. In both the in vitro Blood Loop and the in vivo NAVI assays, predicate devices that are used as controls are typically legally marketed comparator devices (LMCD). One rarely discussed observation is the frequent high thrombogenicity scores of LMCD’s in the NAVI assays. We have compared results from available and submitted NAVI studies and a similar number of in vitro Blood Loop studies for catheter-like devices. These compiled results show a frequent score a three or above for LMCD’s (>50% of the surface covered in thrombus) in the NAVI model while many fewer LMCDs perform this poorly in the Blood Loop assay. Overall, these results are supportive of the superiority of the alternative in vitro Blood Loop assay over the standard in vivo NAVI assay.
Design Considerations for Mechanical Hemolysis Testing
ISO 10993-4 describes the requirements for assessing the interactions of medical devices with blood and assigns a set of test categories and tests recommended for evaluation. The categories are based on intended use and duration of contact and include hemolysis and thrombosis. In 2017, ISO added a requirement for mechanically induced hemolysis as a subcategory and is required for devices that redirect flow or create blood turbulence within the circulatory system. Examples include hemodialysis/hemofiltration equipment, circulatory support devices, cell separators and mechanical heart valves. In addition, US FDA generally requires a mechanically induced hemolysis assessment for blood administration sets, blood warmers, and infusion pumps.
Mechanical hemolysis protocols should be designed to simulate the intended use of the device and adequately measure red blood cell lysis caused by fluid dynamic factors, such as blood flow rate, turbulence, and non-physiological shear force. Test methods that involve a single flow through of blood using gravity or by infusion pump are appropriate for a blood administration sets. Whereas, a protocol that involves circulating blood through a flow loop for an extended time period would be required for hemodialysis devices and equipment.
The focus of a full proposal would be on flowing loops and hopes to generate a good discussion about the topic and the general requirements which include:
Industry, CRO, and FDA Perspectives on Medical Device Chemical Characterization per ISO 10993-18:2020
Date and Time: Friday, September 25, 2020 at 12:00 Noon–2:00 PM, EDT
A Systematic Testing Strategy in Performing a Successful Chemical Characterization at Medtronic—How Industry May be Performing Chemical Characterization Differently than FDA Preferences and Why
This presentation will provide a general strategy overview in performing a successful chemical characterization to support biocompatibility evaluation of medical devices. A major focus is to examine critical issues in a chemical characterization to meet scientific and regulatory requirements. The topics of discussions include extraction solvent requirements and polarity scale, correlation of polarity scale with material swelling, fundamental principles in selecting multiple solvents for exhaustive and exaggerated extractions, difference between semipolar and nonpolar solvents for extraction, impact of material swelling on kinetics/thermodynamics of extractables release, and finally the technical considerations of NVR (nonvolatile residue) test and its relation to chromatographic measurement results. Medtronic general practices are outlined at the end.
Mitigating Response Variation and the need for Uncertainty Factors (UFs) in Extractables and Leachables Analysis
Chemical characterization of extractables and leachables from medical devices and combination products has become an important component of biocompatibility testing. Extractables and Leachables are those substances which leach out of a product under either the use condition or an exaggerated laboratory condition. The recently released ISO 10993-18: 2020 guidance has clarified many important aspects of how this testing should be conducted. This includes additional information on establishing an analytical evaluation threshold (AET) which aids in determining which chemicals are at a concentration which present a potential toxicological concern. A major problem in the application of the AET is quantitative error caused by response factor (RF) variation. This error occurs because most extractables do not give a consistent response using mass spectroscopy detectors. This problem is further exacerbated by the fact that many extractables and leachables cannot be readily obtained as commercial standards (oligomers, degradation products, catalyst residues, etc.) and are therefore quantitated using surrogate standards. Recent publications have highlighted the risks posed by RF variation for both LCMS (Jordi et al. Journal of Pharmaceutical and Biomedical Analysis 150 (2018) 368–376) and GCMS (Jenke and Odufu, Journal of Chromatographic Science 2012;50:206–212). The importance of this issue has been recognized by the FDA resulting in the addition of an uncertainty factor (UF) in the calculation of the analytical evaluation threshold (AET) designed to account for response variation. While this aids in mitigating the risks of under reporting of extractables, the resulting revised AET creates significant analytical challenges often exceeding the limit of detection (LOD) of current mass spectrometry instrumentation and requiring sample concentration. Degradation or loss of extractables during concentration can undo the perceived benefit gained by using the uncertainty factor. Response variation also creates questions as to the validity of risk assessments based on relative quantitation values and is one of the key issues at the root of poor reproducibility in recent high profile interlaboratory studies. It is therefore strongly desirable to define improved methods for quantitation with more universal RFs which mitigate the need for UFs. In this presentation, an alternative strategy for quantitation will be shown using triple detection liquid chromatography mass spectroscopy (LCMS) with ultraviolet (UV) and charged aerosol detection (CAD) as well as duel detection Gas Chromatography Mass Spectroscopy (GCMS) with simultaneous Flame Ionization Detection (FID). The response factor distributions for UV, LCMS, GCMS, FID and CAD will be described as obtained by analyzing a broadly constituted database of extractables. A method will be presented for reducing response variation through application of optimized detectors thus reducing the associated need for UFs and increasing confidence in the resulting risk assessments.
Chemical Analysis for Medical Devices: Strategies for Reducing Scientific Questions
Please note: slide 18 of the presentation has been updated for clarification since the webinar. This updated slide is included in the PDF slide presentation above.
Medical devices are unique in the diversity of materials of construction, extent/types of tissue contact, and duration of contact. When evaluating the safety of medical device extractables, it is these unique attributes that necessitate medical device specific analytical/toxicological considerations that will be discussed. Following publication of ISO10993-18:2020, and the CDRH partial recognition in July 2020 some scientific questions emerged in the field of chemical analysis of medical devices. Considerations of unique non-targeted analytical methods that generate data adequate for toxicological risk assessment will be discussed, including, but not limited to: extraction method design, analytical instrument/tool selection, system suitability, identification/semi-qualification, and data reporting. The selection and application of the analytical evaluation threshold (AET) will also be discussed.
OTSS/MDCPSS Virtual Career Panel—SOT Mentoring Event
The Ocular Toxicology Specialty Section (OTSS) and the Medical Device and Combination Product Specialty Section (MDCPSS) are holding a virtual career panel as a mentoring event for SOT members interested in career development within the ocular and medical device toxicology fields. The panel will consist of professionals at early, middle, and late stages of their career from Academia, Government, Industry, and Consulting. The panelists will introduce themselves, provide a brief overview of how they arrived at their current position, and address questions from the event moderators. Then the Q&A session will be opened to the audience to engage the panel on career advice, strategy, and goal setting. Please join MDCPSS for our upcoming virtual career panel.
2020 Annual Meeting—Medical Device Safety Assessments: Challenges & Approaches for Handling Chemical, Hazard & Regulatory Uncertainty
There are no recordings or slides from this event as it was an SOT Annual Meeting Workshop.
Date and Time: Thursday, April 16, 2020 at 1:00 PM–2:45 PM (EST)
Chemical Characterization Strategies for Medical Device Biocompatibility Assessment
Predictive Toxicology Approaches for Medical Device Biocompatibility Assessment
CDRH Scientific Perspective on Material Characterization and Toxicological Risk Assessment of Nontargeted Medical Device Extractables
The regulatory landscape for the safety evaluation, clinical testing, and commercial development of medical devices is undergoing considerable changes, including new requirements for material characterization and chemical risk assessment early on in the development process. In this dynamic environment, extractables/leachables (E/L) analysis is becoming a key tool in biocompatibility assessments to ensure patient safety and establish regulatory compliance. The first speaker will begin the discussion on medical device chemical characterization strategies, a necessary step for understanding potential chemical exposures from medical device components. The presentation will include examples of how information concerning material chemistry and the manufacturing process can reduce the cost and effort associated in resolving “unknown” extractable compounds. The next presentation will focus on predictive toxicology methods (e.g., computational toxicology programs, read-across, Threshold of Toxicological Concern) for evaluating potential risks from extractable compounds. Case studies will be presented to demonstrate the importance of expert judgment when interpreting in silico hazard predictions, as well as approaches for justifying a read-across approach for risk assessment of extractable compounds. The third speaker will then discuss the US Food and Drug Administration (US FDA) perspective on the issues raised in the preceeding talks. Agency experience with unique nontargeted analytical methods that generate data adequate for toxicological risk assessment will be presented, which include, but are not limited to, extraction method design, analytical instrument/tool selection, selecting an analytical evaluation threshold (AET), sample manipulation, system suitability, calibration, identification/semi-qualification, and data reporting. The final speaker will present a broader overview of the global regulatory landscape for medical device safety evaluation. Notable activity includes the revision of ISO 10993-1, implementation of the European Union’s revised Medical Devices Regulation, and amendments to California Proposition 65. This presentation will cover how new requirements for extractables/leachables analysis will affect the manufacturer’s ability to justify the safety of hazardous substances within devices, verify warning label exemption, evaluate biological equivalence of predicate/proposed devices, and support supply chain controls and ensure efficient change management
2020 MDCPSS Annual Meeting Reception
March 17, 2020 | Anaheim, CA
Impact of 2017/745 EU Medical Device Regulation (MDR) on Biological Evaluation of Medical Device
Date and Time: Thursday, January 16, 2020 at 11:00 AM–12:00 Noon (EST)
Speakers: Jeremy Tinkler, Director of Regulatory Consultancy and Quality Assurance, MedPass International SAS;
Brief Abstract: This webinar will focus on the impact of the 2017/745 EU Medical Device Regulation (MDR) on biological evaluation of medical devices. The webinar will compare relevant MDR General Safety and Performance Requirements (GSPR) with the Medical Devices Directive (MDD) Essential Requirements; compare MDR GSPR with ISO 10993 and ISO 14971; and discuss the impact of changes in ISO 10993-1:2018 and other ISO standards. A generous Q&A session is planned to accommodate conversation with the speaker—Chairman of ISO/TC 194 Biological Evaluation and Director of Regulatory Consultancy and Quality Assurance at an EU Authorized Representative, regulatory consultancy, and CRO.
Biological Risk Assessments for Ocular Medical Devices
Date and Time: Wednesday, August 28, 2019 at 12:30 PM–1:30 PM (EST)
Speaker: Simona Bancos, PhD, Center for Devices and Radiological Health, US Food and Drug Administration
Brief Abstract: This webinar will focus on reviewing the changes to the International Standard Organization (ISO) Fifth edition 10993-1:2018 and whether these changes have an impact on ophthalmic device biocompatibility assessments and on 2016 FDA Biocompatibility Guidance. The discussion will include an overview of relevant vertical standards and FDA guidance documents for ophthalmic devices including ISO 11979-5 Ophthalmic implants—Intraocular lenses- Part 5: Biocompatibility and Premarket notification (510(k)) FDA guidance document for daily wear contact lenses. The applicability of chemical characterization to the biological evaluation of ophthalmic medical devices will also be discussed.
CDRH Scientific Perspective on Analytical Testing and Toxicological Risk Assessment for Medical Devices
Date and Time: Wednesday, May 22, 2019 at 11:00 AM–12:30 PM (EST)
Speaker: Alan Hood, Berk Oktem, and Jennifer Goode, Center for Devices and Radiological Health, U.S. Food and Drug Administration
Brief Abstract: Analytical testing as part of chemical characterization is used to determine the extractable or leachable substances (E/L) including additives, degradants and impurities, present in patient contacting components of medical devices. Analytical testing generally involves one or more extractions followed by use of multiple analytical methods with sufficient sensitivity to identify and quantify E/L substances that could raise a toxicological concern. In this presentation, we will provide an overview of current regulatory review considerations for submissions to FDA/CDRH that contain analytical chemistry data and toxicological risk assessment information. Specific topics covered will include methodological approaches and reporting, including but not limited to, extraction design, analytical instrument/tool selection, sample manipulation, system suitability, calibration, identification/quantification, and data reporting. The selection and application of the analytical evaluation threshold (AET) will be discussed. There will also be discussion on when to conduct a toxicological risk assessment, the current state of reporting, and some considerations for assessing hazard, exposure, dose-response and risk characterization.
MDCPSS Sponsored Events at the 2019 SOT Annual Meeting and ToxExpo
ISO 18562 biocompatibility evaluation of breathing gas pathways in healthcare applications, what does it cover and how to put it to use
Date and Time: Wednesday, November 14, 2018 at 11:00 AM–Noon (EST)
Speaker: James Morrison, Senior Consultant at Brandwood Biomedical
Brief Abstract: The ISO 18562 series of standards Biocompatibility evaluation of breathing gas pathways in healthcare application was published by ISO in 2017. The series includes four parts, which cover the current thinking on gas pathway requirements. On June 7th 2018, US FDA added the ISO 18562 standards to their list of Recognized Consensus Standards, with partial recognition. ISO 18562 standards are now referenced in the newly released ISO 10993–1:2018, as international acceptance of these standards increases.
Unlike the ISO 10993 series of biocompatibility standards, which is a set of biological test methods, ISO 18562 evaluates biocompatibility using a set of toxicol ogical risk analyses. These toxicological methods are not novel, but their application in this way will greatly expand the knowledge and use of these concepts.
In this webinar, we discuss the four published standards, their applications, and add commentary about putting them into practice in real word situations.
The Application of Reconstructed Human Epidermis (RhE) Models as an In Vitro Skin Irritation Test for Detection of Irritant Activity in Medical Device Extracts.
Date and Time: Wednesday, May 9, 2018 at 11 AM (EST)
Speaker: Dr. Wim De Jong of RIVM
Brief Abstract: Assessment of dermal irritation is an essential component of the safety evaluation of medical devices. Testing the irritant capacity of medical device extracts is currently performed by either topical or intradermal injection in rabbits. Attendees will learn about an international validation study that evaluated living human tissues as potential replacements for the rabbit irritation test. In the chemical industry, the RhE model as described in OECD Test Guideline 439 is used to identify irritant chemicals. Although the basic principles remain the same, for application in other domains, adaptation of the assay may be necessary. Therefore, the OECD 439 protocol was modified for testing of medical device extracts. This modified protocol was first evaluated to demonstrate the presence of spiked irritant chemicals added to medical device extracts to show the capability of the modified RhE test protocol to detect irritants in a complex extract mixture. The real proof of the test would be to detect irritants in extracts of medical devices or materials used in the production of medical devices. Therefore, specific polymer materials were prepared containing irritant chemicals within the polymer matrix. With these materials two RhE models, EpiDerm™ (MatTek, Inc.) and SkinEthicTM RHE (EpiSkin, SA), were evaluated in an international round robin study. The read-out endpoint was the same as in OECD 439, that being tissue viability by the MTT method; in addition, Interleukin 1a release was also considered. In order to enhance the impact and future implementation of the RhE assay for medical device safety testing, a broad range of stakeholders were encouraged to join the round robin. Participants included medical device companies, contract research organizations, university and governmental laboratories. The results of the round robin study showed that RhE tissue models could detect the presence of strong skin irritants at low levels in dilute medical device polymer extracts. Consequently, the protocol will now be adapted and proposed as a new ISO 10993 standard for medical device irritation testing.
Assessing the Hazards of Fluoropolymers, a Class of Per- and Polyfluoroalkyl Substances (PFAS)
Date and Time: Tuesday, February 27, 2018, 11:00 am–12:00 noon Eastern Time
Speaker: Barbara Henry, PhD, Toxicologist, W.L. Gore and Associates
Brief Abstract: This webinar will be of interest to all toxicologists who perform toxicological risk assessments. The regulation of per- and poly-fluoroalkyl substances (PFAS) is a growing topic of interest, due in part to the widespread detection of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Some believe the most appropriate approach to PFAS regulation or consideration of their potential risks is to lump together both polymeric and non-polymeric categories, treating them as if they were a single class of substances. Fluoropolymers become aggregated into the highly broad PFAS classification without regard to distinct characteristics that qualify them as meeting the globally accepted criteria for Polymers of Low Concern (OECD, 2009; BIO by Deloitte, 2015).
A new paper, in review for publication in Integrated Environmental Assessment and Management (IEAM), is intended to drive further clarity on the broad group of chemistry known as PFAS. The authors conducted a thorough review of the regulatory history of the hazard assessment of polymers and non-polymers, as well as the scientific foundation for the resulting paradigm ("polymers of low concern"), and they articulate a clear and compelling scientific basis for segregating fluoropolymers from other PFAS. Separation of fluoropolymers from the larger list of thousands of substances grouped into five different classes of PFAS is based upon the authors' demonstration that fluoropolymers constitute a distinct class within the PFAS group and, therefore, should be considered separately for hazard assessment or regulatory purposes. The paper further establishes that grouping fluoropolymers with all classes of PFASs for "read-across" or structure-activity relationship assessment is not scientifically appropriate, when a complete, good quality data set exists, as it does for fluoropolymers.
Quantitative Structure Activity Relationships: An Overview
Date and Time: Tuesday, November 14, 2017, 11:00 AM to 12:00 Noon EST
Speaker: Dr. Prachi Pradeep, US EPA/ORISE
Brief Abstract: Chemical risk assessment is often limited by the lack of experimental toxicity data for a large number of diverse chemicals. In the absence of experimental data, potential chemical hazard is often predicted using data gap filling techniques such as quantitative structure activity relationship (QSAR) models. QSARs are theoretical models that relate a quantitative measure of chemical structure to a physical property or a biological effect. QSAR tools are a widely utilized alternative to time-consuming clinical and animal testing methods, yet concerns over reliability and uncertainty limit application of QSAR models for regulatory chemical risk assessments. The reliability of a QSAR model depends on the quality and quantity of experimental training data and the applicability domain of the model. This talk will describe the basics concepts and best practices in QSAR modeling, principles associated with validation of QSAR models, summary of available QSAR tools, limitations and challenges in the acceptance of QSAR models within a regulatory framework, and the current status and prospects of QSAR modeling methods in the medical devices community.
Regulations, Standards and Practices for Biocompatibility & Toxicology Assessment in China
Date and Time: Friday, October 13, 2017 11:00 AM to 12:00 Noon EST
Speaker: Chenghu Liu, Director, Biological Evaluation Department, Shandong Quality Inspection Center for Medical Devices Jinan, China
Brief Abstract: The purpose of this webinar is to help participants learn about evaluating biocompatibility of medical devices in China. In recent years, the China Food and Drug Administration (CFDA) has released several important policies and regulations that impact local medical device submission and registration. At the same time, local biocompatibility evaluation standards have also evolved to align with advances in the global ISO 10993 standards. Technical Committee 248 of the Standardization Administration of the People’s Republic of China (SAC) is currently based at the Shandong Quality Inspection Center for Medical Devices and is chartered with establishing local biocompatibility standards. The current Chinese GB16886 standards were adopted from the ISO 10993 standards and are essential for biocompatibility evaluation in China. In addition, China has also developed specific test method standards to supplement the GB16886 standards. This webinar will provide an overview of the current status and future trends in biocompatibility evaluation, regulatory requirements, and best practices in China.
ISO 10993–1 Biological Evaluation—The Risk Management of Unstudied Extractables and Leachables (E&L) Impurities in Medical Devices and Combination Products
Date: April 10, 2017, 11:00 AM–12:30 PM EST
Use of In Silico Modelling in Preclinical Testing, Co-Sponsored with IVAMSS
Speaker: Kim Li, PhD, DABT, MPH, Amgen Inc. Thousand Oaks, CA
Abstract: In 2016, the FDA issued final guidance on the use of ISO 10993–1 “Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk management process.” The guidance describes a framework whereby chemical characterization of device materials and the toxicology assessment of the extractables and leachables (E&L) impurities may reduce certain biocompatibility testing requirements.
The chemical characterization of the device materials and components is often a comprehensive profile with known as well as tentatively identified structures (TIS). TIS may result from degradation and/or fragmentation of the chemical additives and processing aids used in the production of polymeric materials. The polymeric materials of construction in medical devices are also common materials of construction for bioporocess materials and primary containers that have direct contact with drug product. Therefore the widespread use of polymeric materials underscores the need for a holistic approach in the evaluation of leachables in combination products. Protein therapeutics are more susceptible than chemically synthesized drug products to the leachables that may impact product safety and quality.
While the risk assessment of known chemical compounds is well established based on the known toxicity endpoints (e.g. target organ toxicity, mutagenicity, carcinogenicity and reproductive/developmental toxicity), TIS are unstudied chemicals for which the current risk assessment practices and threshold concepts may not apply. However, it is neither practical nor technically feasible to conduct animal testing on TIS. On the other hand, biocompatibility tests using extracts as described in ISO 10993–12 do not have the specificity nor sensitivity offered by chemical characterization and toxicology assessment of the E&L profiles of the test materials.
This presentation will examine the science- and risk-based decision analysis to integrate the current threshold concepts with in silico tools for the screening of TIS impurities. The presentation will discuss the three different modules of Toxtree (IdeaConsult): in vitro mutagenicity (Ames test) prediction, Cramer classification for systemic toxicity and protein binding alerts. When integrated into a systematic analysis, these modules offer understanding of the chemical reactivity and toxicity for the TIS, which may form the basis to reduce certain unnecessary biocompatibility testing.
Animal-Specific Modelling for the 3R in Preclinical Assessment: A Bone Drugs Example
Speaker: Marco Viceconti, Executive Director, Insigneo Institute for In Silico Medicine, The University of Sheffield and Sheffield Teaching Hospital NHS Foundation Trust
Date: April 10, 2017, 11:00 AM–12:30 PM EST
Abstract: There is a growing societal pressure toward the Reduction, Refinement, and Replacement (3R) of animal experimentation in most developed countries, primarily motivated by ethical considerations. But there is also a growing concern that the approach used to test the safety and the efficacy of products potentially affecting human health needs some serious revision: a 2014 report of the Tufts Center for the Study of Drug Development suggests that the cost to take to the market a new drug today exceed US$2.5bn; most of these money is spent during the clinical assessment, but it is probably the preclinical assessment to be blamed most, if (according to Pharmaceutical Research and Manufacturers of America) out of five compounds cleared in the preclinical phase, only one will survive the clinical trials. This means that pre-clinical trials, which are mostly based on animal experimentation, are wrong four times out of five, and this is clearly unacceptable.
Under these combined pressures, the drive for the 3R is combining with the need for the development of Non-Animal Alternatives that not only help to solve this delicate ethical conundrum, but also improve our ability to predict safety and efficacy of a new product before it is tested on humans. There are other industrial sectors that develop products potentially hazardous for human health; if a large airliner crashes, or a nuclear power plant blows, hundreds if not thousands of lives can be at risk, and the environmental damage could eventually affect many more. But in none of these sectors it is conceivable to evaluate safety by trial and error, which is at the basis of the preclinical testing of products affecting human health. These products are most entirely tested through laboratory experiments, and the massive use of modelling and simulation. However, until recently no human health products regulator would even consider in a submission evidences obtained with modelling and simulation.
Here we present the results of a research funded by the UK National Centre for the Reduction, Refinement, and Replacement of animal experimentation (NC3R), where a well establish murine model widely used to test preclinically the efficacy of bone drugs was critically revised using animal-specific modelling based on longitudinal imaging. The methods developed were able to reduce of 63% the number of animals required to achieve statistical significance. But more important, the possibility of observing the effect of the drug being tested over large anatomical volumes, and over time in the same animal non-invasively, has put in serious question the need for a series of interventions that if removed would significantly refine this animal experiment. Last, we will present some preliminary results where animal-specific models are used to partially replace animal experimentation altogether, using an approach call in silico augmented study. We will conclude by suggesting that animal-specific modelling, when combined with human-specific model could produce conclusive evidences on non-animal alternatives are better suited than animal models in predicting the response in humans.
Effects of Nanoscale Particles in the Brain
Speaker: Alison Elder, PhD, Associate Professor of Toxicology in the Department of Environmental Medicine at the University of Rochester Medical Center.
Research Focus: Toxicology of Inhaled Ultrafine Particles and Engineered Nanomaterials
MDCPSS—ISO 10993-4 Biological Evaluation of Medical Devices: Selection of Tests for Interaction with Blood
Speaker: Michael Wolf, BS, MS, Medtronic Inc.
Abstract: For medical device companies with blood-contacting products, the ISO 10993-4 guidance document is important because it defines general requirements and considerations for evaluating interactions of concern between the devices and blood. The document describes: (1) classification of blood-contacting medical devices based upon intended use and duration of contact as defined in ISO 10993-1, (2) fundamental principles and scientific bases behind various methods of evaluating interactions of devices with blood, and (3) a structured selection of tests for consideration based upon intended use and blood contact duration. In short, this standard is a guide for start-up companies, established industry, and regulatory agencies to assess the apparent pre-clinical blood compatibility of candidate cardiovascular devices and materials intended for human blood contact applications.
The foundation of ISO 10993-4 has several sources. However, since its inception in 2002, the document has received only minor revision. Over the past several years the revision of this document has involved review of hundreds of comments from around the world, with the FDIS recommended for formal approval in 2016. Concisely, the new document provides a simplified process flow diagram for high level planning decisions, a reduced and simplified table of example devices vs. testing categories for consideration, and a streamlined table of actual tests for consideration in each test category.
Importantly, the standard suggests more opportunities for meaningful in vitro testing to supplement or replace certain animal testing. More emphasis is also placed on the importance of testing blood contacting devices for impact on thrombosis.
Evaluation of Medical Devices for Genetic Toxicity: A Global Perspective
Webinar Recording | Presentation Slides
The current presentation will discuss the topics below:
Use of International Standard ISO 10993-1, “Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing within a Risk Management Process”
Hosted by: US FDASpeakers: Jennifer Goode, Office of Device Evaluation, Center for Devices and Radiological Health
Date: Thursday, July 21, 2016, 1:00 PM–2:30 PM EST
Abbreviated Abstract: On July 21, 2016, the US FDA held a webinar for industry to review the Use of International Standard ISO 10993-1, “Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing within a Risk Management Process” final guidance document. The recommendations in this final guidance clarify and update how medical device developers may use ISO 10993-1 standard in their premarket submission to determine the potential for an unacceptable adverse biological response resulting from contact of a medical device with the body. This final guidance replaces the Office of Device Evaluation (ODE) Blue Book Memorandum #G95-1 (1995), entitled “Use of International Standard ISO-10993, ’Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing.”
Exploring Certifications in General Toxicology: An Introduction to ABT/ERT/ATS Certification
Hosted by: American College of Toxicology
Speakers: Bas Blaauboer, PhD, Emeritus Professor of Toxicology at the Division of Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Chair of the Registration Subcommittee of EUROTOX; Michael Holsapple, PhD, ATS, Director and Endowed Chair at the Center for Research on Ingredient Safety/Professor of Food Science & Human Nutrition at Michigan State University, President of ATS; and Christopher P. Weis, PhD, DABT, Toxicology Liaison/Senior Adviser, Office of the Director, National Institute of Environmental Health Sciences, Vice-President of ABT
Abbreviated Abstract: Professional toxicologists across the world pursue certifications to add value to their credentials as part of their career development. There are three primary professional certifications in toxicology.
I. The American Board of Toxicology (ABT) offers Diplomate status to qualified individuals who demonstrate relevant education, actively practice in toxicology, and pass a comprehensive examination.
II. The European Registry of Toxicologists (ERT) includes toxicologists, who demonstrate knowledge of the major areas of toxicology. This knowledge can be acquired by either following an appropriate academic program, e.g. by attending courses, or by practical experience and on the job training. At least 5 years of relevant toxicological experience is needed.
III. The Academy of Toxicological Sciences (ATS) awards Fellow status to individuals with demonstrated contributions to the discipline of toxicology over their career, as judged by peer review of relevant education, professional practice in toxicology, and professional recognition.
Each of these three certifications is complementary, professionally valuable, and has unique requirements for eligibility. This webinar will provide a primer on eligibility, value, and maintenance for each certification followed by a Q&A session.
Webinar: SCENIHR Opinion on the Determination of Potential Health Effects of Nanomaterials Used in Medical Devices
Speaker: Wim De Jong, DVM, PhD, Centre for Health Protection at the National Institute for Public Health and the Environment (RIVM)
Abbreviated Abstract: The use of nanomaterials in medical devices poses a challenge for the safety evaluation and risk assessment of these medical devices as the specific character of the nanomaterial used should be taken into consideration. The various aspects of safety evaluation and risk assessment of medical devices containing nanomaterials are addressed in this Guidance. The use of nanomaterials in medical devices can vary considerably. Examples are the use of free nanomaterials being a medical device and administered to the patient as such (e.g. iron oxide or gold nanomaterials for heat therapy against cancer), free nanomaterials in a paste-like formulation (e.g. dental filling composites), free nanomaterials added to a medical device (e.g. nanosilver as antibacterial agent in wound dressings), fixed nanomaterials forming a coating on implants to increase biocompatibility (e.g. nano-hydroxyapatite) or to prevent infection (e.g. nano-silver), or embedded nanomaterials to strengthen biomaterials (e.g. carbon nanotubes in a catheter wall). In all these cases the potential exposure to the nanomaterials should be considered. It is additionally recognised that wear-and-tear of medical devices may result in the generation of nanosized particles even when the medical device itself does not contain nanomaterials.
Guidance is provided on physico-chemical characterisation of nanomaterials, the determination of hazards associated with the use of nanomaterials, and risk assessment for the use of nanomaterials in medical devices. The safety evaluation of the nanomaterials used in medical devices is discussed in the context of the general framework for biological evaluation of medical devices as described in the ISO 10993-1:2009 standard. Therefore, the risk assessment should be performed taking into consideration the type of device, the type of tissue contact, and the contact duration, thus identifying the specific exposure scenario.
A phased approach is recommended for evaluating the risk of the use of nanomaterials in medical devices based on potential release and characteristics of the nanomaterials to avoid unnecessary testing. In phase 1 an evaluation of the potential for the device to release nanoparticles either directly or due to wear of the device during use should be carried out. In phase 2 the aim is to determine the distribution of the particles released and also their persistence potential. In phase 3 the hazard is assessed using appropriate toxicity tests taking account of the exposure characteristics and potential for persistence in specific organs. This will provide input for the final risk characterisation (phase 4). The estimated risk needs to be compared to the risk from the use of comparable devices not incorporating nanomaterials in judging the acceptability of the risk. In conclusion, the potential risk from the use of nanomaterials in medical devices is mainly associated with the possibility for release of free nanoparticles from the device and the duration of exposure.
Webinar: The Threshold of Toxicological Concern: Application to Medical Devices and Pharmaceuticals.
Speakers: Ron Brown, FDA, CDRH, and Douglas Ball, Pfizer
Abstract: Over the past 50 years, this question of assessing human health risk of unstudied or incompletely characterized chemicals has been the subject of many publications. The most widely accepted scientific approach to assess the risk of exposure to incompletely characterized chemicals is to consider a level of exposure for all chemicals below which there is no appreciable risk to human health; a threshold of toxicological concern (TTC). The concept of a TTC holds true across a wide spectrum of toxicity endpoints, such as genotoxicity, carcinogenicity, neurotoxicity, reproductive and developmental toxicity and acute and repeated dose systemic toxicity (Munro and Kroes [JECFA], 1998; Muller, 2006; Delaney et al., 2007; Bernauer et al., 2008; van Ravenzway, 2011). The literature provides evidence of the scientific community’s acceptance of the TTC concept, which many regulatory authorities around the world have also endorsed. The TTC concept has been applied to many applications including food packaging, food flavorings, pesticide metabolites in groundwater, pharmaceuticals, herbal substances and preparations and genotoxic drug impurities.
Application of the TTC to Pharmaceuticals: In 2013, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) published a draft consensus guideline on the Assessment and Control of DNA Reactive (Mutagenic) impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, M7. The ICH M7, which applies to products to the pharmaceutical market and to combination drug devices, was written “to provide a practical framework that can be applied for the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk.” The guideline also extends the TTC to less than lifetime patient exposures by allowing for higher thresholds for shorter exposure duration, such as during clinical drug trials. Douglas Ball (Pfizer) will provide background on the derivation of the TTC and how it is applied in pharmaceuticals and the pharmaceutical industry through case studies including a process-related mutagenic impurity and Leachable & Extractable qualification using a modified Cramer Classification strategy.
Application of the TTC to Medical Devices: Ron Brown will focus on how the proposed application of the TTC concept for Leachables & Extractables from medical device materials is similar to/different than the approach for impurities in drugs. The International Standards Organization (ISO) Technical Committee 121 has begun work on the development of a TTC approach for volatile compounds released from respiratory devices.
Webinar: Medical Device Color Additives: Legislative History and Regulatory Perspective
Presenter: Brenda Seidman, MS, PhD, RAC
MDCPSS 2015 Annual Reception
Date: Tuesday, March 24, 2015, 6:00 PM–7:30 PM
Continuing Education Courses
Date: Sunday, March 22, 2015
MDCPSS Fall Webinar: Quantitative Risk Assessment of the Genotoxicity and Tumorigenicity of CoCr-Containing Hip Implants
Date: September 24, 2014, 12:00 Noon
Description: Cobalt-chromium (CoCr) alloys have long been used in metal-containing hip implants because of their biocompatibility. Like all implant materials, CoCr alloys undergo some degree of wear and corrosion in vivo, and as a result implant patients experience blood and tissue Co and Cr(III) concentrations that are higher than background levels associated with dietary intake. Although to date epidemiology studies do not indicate an increased incidence of cancer in patients with hip implants, questions continue to be raised about the potential cancer risk posed by CoCr-containing implants. To address these concerns, the scientific literature investigating the genotoxic and tumorigenic effects of Co particles and ions, Cr particles and ions, CoCr alloy particles, as well as CoCr alloy implants was gathered, and NOAEL/LOAEL values were compared with body burdens of Co/Cr particles and ions that were calculated to exist in systemic tissues of hip implant patients under normal and excessive wear conditions. This presentation will illustrate the quantitative methods that were used to evaluate the weight-of-evidence regarding a causative relationship between CoCr-containing hip implants and increased cancer risk to determine whether the existing toxicology data support epidemiological findings.
Supporting Information: Toxicology-based cancer causation analysis of CoCr-containing hip implants: a quantitative assessment of genotoxicity and tumorigenicity studies. Christian WV, Oliver LD, Paustenbach DJ, Kreider ML, Finley BL. J Appl Toxicol. 2014 Sep;34(9):939–67.
Speaker Bio: Whitney V. Christian, PhD
Dr. Whitney V. Christian is a Health Scientist II with Cardno ChemRisk. He received a PhD in Molecular Toxicology from the Department of Environmental Medicine at the University of Rochester and a BA in Biology from Davidson College. Prior to attending graduate school he conducted cancer research in the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. Combining his experience with genetics and toxicology, Dr. Christian possesses a unique understanding of gene-environment interactions and their contribution to the development of human disease. Dr. Christian’s areas of expertise include applied toxicology involving the use of exposure assessment methods, such as physiologically-based pharmacokinetic (PBPK) models, for quantitative risk assessment as well as specific areas of toxicology, including toxicokinetics, endocrine-disruption, metal toxicology, nanotoxicology, neurotoxicology, and genotoxicology/carcinogenesis.
Webinar: Use of Computational Toxicology for the Biological Evaluation of Medical Devices
Presenter: Ron Brown, FDA CDRH OSEL
Recording Date: Monday, June 23, 2014, 12:00 Noon
Description: The biological safety of medical devices is typically assessed by conducting biocompatibility testing of an extract of the device or the device itself; however, there is growing interest in an alternate approach that involves characterizing the chemical composition of the device extract and conducting a risk assessment on the compounds identified in the extract. One limitation to the practical implementation of this chemical characterization/risk assessment approach is the lack of toxicity data for many compounds released from device materials. To address this need, computational toxicology models, such as Quantitative Structure-Activity Relationship (QSAR) models, are being increasingly used to predict the toxicity or carcinogenicity of compounds based on their chemical structure. Efforts are underway to validate the predictive ability of QSAR models for compounds that are known to be released from device materials. This webinar will describe the computational modeling approaches available to predict the toxicity, mutagenicity, and carcinogenicity of compounds released from device materials and will explore ways to use model-derived predictions as part of the biological evaluation of a device, notably, to determine when certain types of testing may not be necessary.
MDCPSS 2014 Annual Reception
Date: Monday, March 24, 2014, 6:00 PM–7:30 PM
Location: Sheraton Paradise Valley Room
Symposium: In Vitro Medical Device Testing
Date: December 10–11, 2013
Location: Johns Hopkins University, Mt. Washington Conference Center, Baltimore, Maryland
This symposium, hosted by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), will examine how the National Academy of Sciences, Toxicity Testing in the 21st Century can be applied to Medical Devices. The program will examine current requirements and testing approaches, followed by an examination of in vitro assays useful in medical device testing. The agenda includes speakers from industry, academia, and government.
Webinar: Medical Device Testing In Vitro—Pyrogenicity Testing and Beyond
Date: Friday, May 24, 2013, 11:59 AM
Speaker: Dr. Thomas Hartung
Description: In vitro methodologies are only slowly embraced by the field of medical device safety testing. The Limulus amebocyte lysate assay might be considered a forerunner for non-animal tests here as it is applied to eluates from medical devices in order to determine microbiological contaminations. However, this test is limited to Gram-negative bacterial endotoxin. More recently, assays based on the human fever reaction were developed. They make use of human white blood cells, which respond to many further stimuli. Especially the whole blood pyrogen assay allows to measure directly on the surface of the medical devices avoiding pyrogen eluation. Its adaptation to medical devices showed, that both eluation and depyrogenation by standard methodologies are not adequate to determine and remove pyrogen burden of medical devices. This test case is used to discuss opportunities and limitations for in vitro medical device testing in general. The webinar will benefit toxicologists involved with the safety assessment of medical devices, drugs, and combination devices.
Webinar: Current Testing and Alternative Methods for Assessment of Medical Device Blood-Material Interactions
Presenter: Michael Wolf, BS, MS, Medtronic Inc.
Date: Friday, February 8, 2013, 12:00 Noon
Description: One of the most complex organs in the body is blood. There is a rich diversity of cells, proteins, small signaling molecules, electrolytes, etc., in the blood, and maintaining equilibrium in the interconnected systems is critical for health. Materials utilized in medical devices can interact directly or indirectly with blood and related systems, and ensuring and verifying hemocompatibility is a primary concern in interventional health care products. Technologies and strategies for assessing hemocomaptibility have appreciably advanced over the last several years, and the webinar will address emerging approaches. Any toxicologist with particular interest in hemocompatibility, or working on projects or programs where the blood or blood components are potential targets or effectors will benefit from the discussion. It should be noted that the speaker, Dr. Michael Wolf is a recognized expert in hemocompatibility, and is the chairperson for the ISO 10993 committee responsible for the ISO 10993 standard on hemocompatibility.
Webinar: Polyphenol-Eluting Stent reduces Restenosis and Promotes Vascular Healing in a Rat Model of Arterial Angioplasty and Stenting
Date: November 2, 2011, 11:00 AM
Presenter: Jim Kleinedler, LSU Health Science Center