ISO/TC 194/WG 11 - Allowable limits for leachable substances

This document specifies the process and requirements for the toxicological risk assessment of medical device constituents. The methods and criteria used to assess whether exposure to a constituent is without appreciable harm are also specified. The toxicological risk assessment can be part of the biological evaluation of the final product, as described in ISO 10993-1. The process described in this document applies to chemical characterization information obtained in line with ISO 10993-18. When a toxicological risk assessment of either the compositional information or analytical chemistry data (e.g. extractable data or leachable data) are required to determine whether the toxicological risks related to the constituents are negligible or tolerable. The process described in this document is not intended to apply to circumstances where the toxicological risk has been estimated by other means, such as: — constituents, excluding cohort of concern or excluded chemicals, that are present in or extracted from a medical device at an amount representative of patient exposure below a relevant, toxicologically-based reporting threshold (see applicable requirements in ISO 10993-18:2020, Annex E and ISO/TS 21726); — a new or changed medical device for which chemical or biological equivalence has been established with an existing biocompatible or clinically established medical device (see applicable requirements in ISO 10993-18:2020, Annex C). The process described in this document is also not applicable to: — medical device constituents that do not contact the body (e.g. in vitro diagnostics); — biological risks associated with physical interactions of the medical device with the body (i.e. application of mechanical forces, energy or surface morphology, etc.), provided that the chemical exposure is not changed; — active pharmaceutical ingredients of device-drug combination products or biologic components of device-biologic combination products as additional regulatory considerations can apply; — exposure to a particular constituent that arises from sources other than the device, such as food, water or air.

This document describes the basis for, selection of, and general applicability of a threshold of toxicological concern (TTC) value for a constituent present in/on a medical device or released from a medical device. The TTC values in this document can be used for: — comparing to a maximum concentration of an identified or unidentified constituent in an extract (see ISO 10993-18); — supporting toxicological equivalence; — comparing to a maximum exposure dose estimate of an identified constituent (see ISO 10993-17). NOTE Constituent is defined in 3.1. ISO 10993-18 specifies how to convert TTC (µg/d) into a concentration (µg/ml). TTC is not applicable to constituents with adequate toxicity data for deriving a tolerable intake (TI) value (see ISO 10993-17). The TTC values established in this document are protective for carcinogens, systemic toxicants, and reproductive toxicants (see Clause 5). This document does not include TTC values for other biological endpoints assessed as part of the biological evaluation of a medical device, per ISO 10993-1, for example: — cytotoxicity; — irritation; — sensitization; — hemocompatibility; — material mediated pyrogenicity; — local effects that occur in tissues at the site of contact between a medical device and the body (e.g. the observations from implantation studies). The TTC values in this document do not apply to potential exposure via gas pathways of medical devices. For application of TTC for constituents present/released from these devices, see the ISO 18562 series. The TTC values presented in this document are not applicable for the safety assessment of cohort of concern (see 5.3).

ISO 10993-7:2008 specifies allowable limits for residual ethylene oxide (EO) and ethylene chlorohydrin (ECH) in individual EO-sterilized medical devices, procedures for the measurement of EO and ECH, and methods for determining compliance so that devices may be released. Additional background, including guidance and a flowchart showing how the standard is applied are also included in informative annexes. EO-sterilized devices that have no patient contact (e.g., in vitro diagnostic devices) are not covered by ISO 10993-7:2008.

ISO 10993-17:2002 specifies the determination of allowable limits for substances leachable from medical devices. It is intended for use in deriving standards and estimating appropriate limits where standards do not exist. It describes a systematic process through which identified risks arising from toxicologically hazardous substances present in medical devices can be quantified. ISO 10993-17:2002 is not applicable to devices that have no patient contact (e.g. in vitro diagnostic devices). Exposure to a particular chemical substance may arise from sources other than the device, such as food, water or air. ISO 10993-17:2002 does not address the potential for exposure from such sources.

Specifies allowable limits for residual ethylene oxide (EO) and ethylene chlorohydrin (ECH) in individual EO-sterilized medical devices and procedures for the measurement of EO and ECH. Does not apply for EO-sterilized devices that have no patient contact such as in vitro diagnostic devices.