ISO-10993 test

ISO 10993 testing is intended to evaluate materials such as metals and polymers that essentially do not interact directly with the human immune system. However, the presence of an antibody on the device surface introduces the potential for cross-species reactions that may not be indicative of performance in humans. These interactions may affect some or all ISO 10993 in vivo tests. For example, the duration of chronic toxicity testing may be limited based on induction of immune responses or carcinogenicity studies may not be appropriate based on the specific product attributes of the antibody. 

When the medical textile or part of it is considered as the medical device, then its toxicity performance testing requires validating under the ISO 10993 test standard. The fabric or parts of it are put in either direct or indirect contact with the cell culture system (eg, L929 cell Une), and then the cell viability resrrlts determine the release of toxic materials from the tested fabric or device. 

Good resistance to steam, pressurized hot water, ethylene oxide, and even gamma radiation makes SPS a good choice for applications that require sterilization. Favorable biocompatibility ratings (as measured by ISO 10993 testing) emphasize the capability to utilize SPS compounds for non-fluid/tissue contact medical devices. 

Biological evaluation of medical devices—Part 5 Tests for cytotoxicity in vitro methods. ISO 10993-5 1992(E). International Standards Organization, 1992. 

Medical grade plastics are discussed with reference to biocompatibility and the tests that the end-product manufacturer should perform in order to ensure the safety of the material. Regulatory requirements are described, and tabulated data is presented on mostly European suppliers of medical grade plastics. The data shows that most companies rely onUSP Class VI certificates to demonstrate the suitability of their materials for the medical industry. However, it is argued that most manufacturers of medical devices would benefit more from tests carried out according to ISO 10993. 6 refs. 

ISO 10993-3 (1993) sets forth clear guidance on testing requirements as summarized in Table 6.1. ICH (International Conference on Harmonization) guidance, shown in Table 6.2, has different but also clear requirements. They want to see an in vivo test conducted. While FDA has no clear guidelines, it expects that an appropriate adaptation of one of these two be performed. 

Genotoxic Effect to be Assessed for Conformance with ISO 10993-3 Significance of Test Tests Meeting Requirements... 

ISO (1993). Biological Evaluation of Medical Devices. Part 3 Tests for Genotoxicity, Carcinogenicity, and Reproductive Toxicity. ISO 10993-3. 

Some modifications to current in vivo testing methods both can and should be adopted. A current example of this would be in medical devices where a substantial portion of the requirements under the governing regulatory (ISO 10993) can be met with in vitro alternatives (cytogenicity, muscle cell implantation, the limulus test for pyrogens, and in vitro mutagenicity assays). 

Test of irritation and intra-cutaneous reactivity ISO 10993-10, OECD 404, 405... 

The cytotoxicity test described in ISO 10993-5 is a good example. It is a rapid, standardised test, very sensitive and can characterise materials and significant quantities of harmful extractables and their effect on cellular growth. Because of the high sensitivity, mouse fibroblasts L929 are used as the test cells routinely. 

Dosage-dependent test of the clear ( ) extracts and pure test samples according to ISO 10993... 

Evaluation of the cell growth by the growth inhibition test according to ISO 10993-5 using mouse fibroblasts L929 and crystal violet as staining substance... 

Before implantation several in vitro tests were performed. For evaluation of a possible toxic reaction, we investigated the material and the whole devices in vitro with cell culture methods. Direct contact and extraction tests with a mouse fibroblasts cell line (L 929) and a neuroblastoma cell line (neuro-2-a) were performed according to the international standard ISO 10993 ( Biological Evaluation of Medical Devices ). The materials and devices showed no toxicity, i.e. no significant differences in membrane integrity of the cell membranes, mitochondrial activity and DNA synthesis rate. The neuro-2-a cell line is so sensitive that even small changes in process technology are detectable. The flexible polyimide structures proved to be non toxic. 

As mentioned above, the types of animal species typically used to assess the toxicology profile of the mAb may not be the same species typically chosen for ISO 10993 device safety testing. 

The FDA has made several modifications to the tests required by Part 1 of the ISO 10993 standard for the category of surface devices that permanently contact mucosal membranes. The ISO does not require acute, subchronic, or chronic implantation tests as does FDA. FDA requires irritation, systemic toxicity, acute, subchronic, and chronic tests for external communicating devices, tissue/bone/ dentin with prolonged and permanent contact. Device manufacturers are advised to consider tests to detect chemical components of device materials that may be pyrogenic. This matrix is a framework and not a checklist and it is stressed by the FDA that necessary safety testing will be decided on a case-by-case basis. 

Standards ISO 10993 -5 1992 and EN 30993 -5 1994. Biological testing of medical and dental devices. Tests for cytotoxicity in vitro methods. 

The modified polymer beads [347] passed all of the standard battery of biocompatibility tests required by the International Organization for Standardization guidelines (ISO 10993). The tests included in vitro coagulation tests (plasma recalcification time), hemolysis study (extraction method), cytotoxicity study using the ISO elution method, etc. In in vivo experiments, extracts of the polymer beads did not elicit pyrogenic irritation or sensitization reactions in laboratory animals (acute systematic toxicity study in the mouse, acute intracutaneous reactivity study in the rabbit, rabbit pyrogen study). 

Methods of cytotoxicity testing are described in the literature, the ASTM Standards, the U.S. Pharmacopeia, and in ISO 10993-5 (Tests for Cytotoxicity In Vitro Methods). Selected tests are briefly outlined here and listed in Table 10.l. - ... 

Adhesives used in medical devices that are implanted or in contact with the body must be tested and shown to be non-toxic, biologically inert, and compatible with blood and body fluids. Compatibility with blood and other body fluids is especially critical. Surfaces in contact with blood must not serve as sites for coagulation and clotting of blood. Generally, qualification testing is performed to ISO-10993 or to U.S. Pharmacopoeia (USP) Class VI. The two standards specify slightly different tests. The USP Class VI standard specifies acute systemic (over the tissue), intracutaneous (under the skin), and muscle implantation tests. The lSO-10993 standard is a set of 12 documents that is more universal and more extensive than the USP standard. It specifies ... 

Some adhesives suppliers already have test data showing compliance of their adhesives to ISO-10993 and will provide a certificate of compliance for their products. However, passing the ISO or USP Class VI tests should be considered a starter in proving that an adhesive has a low level of toxicity it does not guarantee FDA approval. The FDA often requires more extensive testing. 

Guidance on Selection of Tests, ISO 10993, International Organization for Standardization. 

A world authority on standards for testing all types of materials that include plastics. Founded in the nineteenth century, its headquarters now are in West Consho-hocken, Pennsylvania. It publishes thousands of standards every year that are updated when required. See ISO ISO-10993 standard sterilization radiation, certification worldwide. 

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