The ISO 10993 set entails a series of standards for evaluating the biocompatibility of medical devices to manage biological risk. These documents were preceded by the Tripartite agreement and is a part of the international harmonisation of the safe use evaluation of medical devices.[1]For the purpose of the ISO 10993 family of standards, biocompatibility is defined as the "ability of a medical device or material to perform with an appropriate host response in a specific application".
Iso 10993 1.pdf
The following table provides a framework for the development of a biocompatibility evaluation. Different biological endpoints may require evaluation for particular medical devices, including either additional or fewer endpoints than indicated. If it is unclear in which category a device falls, consulting device-specific guidances or contacting the appropriate US Food and Drug Administration (FDA) review division for more information is possible. The table "Endpoints to be addressed in a biological risk assessment" was revised by the 2018 edition of ISO 10993-1. The selection of endpoints for the biocompatibility evaluation is determined by the nature of body contact (e.g. implant device) and contact duration (e.g. long term contact of more than 30 days).
Specifically, FDA recognizes this standard and, in 2020, published a guidance document for recommended Use of International Standard ISO 10993-1 to help manufacturers understand biocompatibility testing considerations and apply risk-based biocompatibility evaluations, in accordance with the standard, in product submissions for entering the US market.
Conducting a biological risk assessment is an essential first step of demonstrating the biocompatibility of your medical device, in accordance with ISO 10993-1, and should be done within the framework of a risk management process.
Prior to the publication of ISO 10993-1, it was acceptable for manufacturers to run through a checklist of tests, but now, both ISO and the FDA expect clear justification that proves adequate biological testing has been done and all identified risks have been addressed. In order, biological testing must be conducted.
An underlying theme of ISO 10993-1 and the related FDA guidance document is being able to demonstrate the safety of a medical device through objective evidence from risk-based biological testing and evaluation methods.
Hemostasis plays a crucial role during every surgery allowing for a bloodless operating field. Fast and effective surgery leads to a reduced risk of postoperative complications. One of the latest methods for achieving homeostasis is using natural polysaccharide-based hemostatic powders. The study aimed to evaluate the biocompatibility according to the ISO 10993 standards of 4SEAL Hemostatic powder.
Chemical characterization (Headspace GC-MS, GC-MS, and ICP-MS), cytotoxicity, genotoxicity (MLA and AMES), endotoxin contamination, sensitization potential, intracutaneous reactivity, acute and subacute systemic toxicity with implantation, and pyrogenicity were evaluated to investigate the biocompatibility of the 4SEAL Hemostatic powder. Studies were conducted according to ISO 10993 standards.
The biocompatibility requirements according to ISO 10993-1 for 4SEAL Hemostatic powder were met. Based on the conducted in-vitro studies, 4SEAL Hemostatic powder shows a non-cytotoxicity and non-mutagenic potential. Also, the results of in vivo studies of 4SEAL Hemostatic powder shows no signs of toxicity, non-sensitizing, non-irritating, and no pyrogenicity potential. In the chemical characterization of 4Seal Hemostatic Powder, no compounds were identified above Analytical Evaluation Threshold (AET) and no elements with concentrations higher than element-specific PDE [μg/day] were detected.
Per ISO 10993-18, a semi-quantitative analysis of VOC (volatile organic compound) in product and SVOC (semi-volatile organic compound) in 4SEAL Hemostatic powder water extract was performed [8]. QP2010 Ultra gas chromatograph and QP-5000 mass spectrometer (Shimadzu) were used for analysis. In addition, quantitative analysis of elements concentration in 4SEAL Hemostatic powder water extract was performed using NexION 300D (Perkin Elmer). As per ICH Q3D (R1), the concentration of the following elements was examined: Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt, Li, Sb, Ba, Mo, Cu, Sn, Cr [9].
Genotoxicity of 4SEAL Hemostatic powder was evaluated using commercially available Bacterial Reverse Mutation Test AMES Penta 2 (Xenometrix) according to ISO 10993-3, ISO 10993-12, ISO 10993-33, and OECD Test No. 471 [7, 11, 12, 15].
Determination of extraction conditions for exhaustive extraction of 4SEAL Hemostatic powder has revealed that isopropanol and hexane cause product degradation and vehicle color change. Therefore, only water extract was analyzed as per ISO 10993-18.
MTT Cytotoxicity of 4SEAL Hemostatic Powder. No cytotoxic potential of cell culture medium extract and its dilutions to L-929 mouse fibroblasts was observed. Horizontal line at 70% represents a cut off below which the extract is considered cytotoxic as per ISO 10993-5
According to ISO 10993-11, instead of full histopathology, limited analysis was conducted [19]. From each group, control, and study group, two representative animals were chosen. Following organs were examined: lungs, heart, liver, kidneys, ovaries/testis, spleen, bone, bone marrow. No abnormalities were found during histopathology evaluation. The microscopic structure of the organs was normal, with no signs of apoptosis of structural cells of individual organs. No significant differences between control and test groups of animals were detected.
The FDA has not yet added ISO 10993-1-2018 to the recognized standards database. Still, the FDA guidance on the use of ISO 10993-1, released in February 2016, already addressed most of the changes contained in the new 5th edition.
The 5th edition includes a foreword that explains the changes from the 4th edition. The 5th edition replaces the 4th edition (i.e., ISO 10993-1-2009), and it incorporates the correction that was made in 2010. The most significant changes from the previous version are:
The 4th edition of the EN version has Table ZA.1 explaining the correlation between the standard and the European Directive. Specifically, Clauses 4, 5, 6 and 7 of the European Standard correspond to Annex I, Essential Requirements 7.1, 7.2 and 7.5 in the MDD. In the new Regulation (EU) 2017/745, these clauses correspond with Annex I, Essential Requirements 10.1, 10.2, and 10.4. Therefore, you should expect the European version of ISO 10993-1-2018 to include a table similar to Table ZA.1, but you should also anticipate that your evaluation of biological risks will need to be updated and additional testing may be required in order to remain compliant for any devices that are CE Marked.
However, the guidance provides details for each step, as well as general guidance on when changes may require a re-evaluation of biological safety, GLPs, and biocompatibility evaluation documentation. In general, the focus of ISO 10993-1-2018 is now on the evaluation of toxicological data in Annex B, rather than passing a few required tests that were previously identified in Table A.1. 2ff7e9595c
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