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YY/T 1815-2022: Biological evaluation of medical devices - Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents
YY/T 1815-2022
Biological evaluation of medical devices - Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents
ICS 11.040.01
CCSC30
People's Republic of China Pharmaceutical Industry Standard
Applied Toxicology for Biological Evaluation of Medical Devices
Threshold of Concern (TTC) assessment
Biocompatibility of Medical Device Components
Published on 2022-05-18
2023-06-01 Implementation
Released by the State Drug Administration
directory
Preface I
Introduction II
1 Scope 1
2 Normative references 1
3 Terms and Definitions 1
4 Background 2
4.1 Overview 2
4.2 The protective effect of TTC value 2
5 Application of TTC to Medical Device Components 2
5.1 General 2
5.2 Selection of TTC value based on human contact period3
5.3 Coc3
5.3.1 General 3
5.3.2 Identification of Coc 4
5.4 Applicability of TTC values to mixtures 4
Reference 5
Applied Toxicology for Biological Evaluation of Medical Devices
Threshold of Concern (TTC) assessment
Biocompatibility of Medical Device Components
1 Scope
This document specifies a method for assessing the biocompatibility of components of a medical device using the Threshold of Toxicological Concern (TTC).
This document applies to.
--- Compare with the maximum concentration of known or unknown components in an extract (see GB/T 16886.18);
--- Toxicological equivalence studies;
--- Compare with the estimated maximum exposure dose of a known substance (see GB/T 16886.17).
This document does not apply to.
--- Obtain tolerable intake (TI) values for components with sufficient toxicity data (see GB/T 16886.17);
--- Other than carcinogenicity, systemic toxicity and reproductive toxicity in the biological evaluation of medical devices in accordance with GB/T 16886.1
Safety assessment of biological endpoints, such as. cytotoxicity, irritation, sensitization, hemocompatibility, material-mediated pyrogenicity and certain medical
Local reactions to tissues at the site of contact between the therapeutic device and the human body (e.g., observations in implantation studies);
--- Safety assessment of medical devices that have indirect contact with the human body through the air path;
NOTE. For the application of TTC of components present or released in such devices, see ISO 18562 series of standards.
2 Normative references
The contents of the following documents constitute essential provisions of this document through normative references in the text. Among them, dated citations
documents, only the version corresponding to that date applies to this document; for undated references, the latest edition (including all amendments) applies to
this document.
GB/T 16886.1 Biological Evaluation of Medical Devices Part 1.Evaluation and Testing in Risk Management Process
GB/T 16886.17 Biological Evaluation of Medical Devices Part 17.Establishment of Allowable Limits for Leachables
GB/T 16886.18 Biological Evaluation of Medical Devices Part 18.Chemical Characterization of Materials
3 Terms and Definitions
The following terms and definitions apply to this document.
3.1
component constituent
A chemical or compound present in or on an end product or constituent material of a medical device.
Note 1.Components may be expected (such as additives and antioxidants), or unexpected (such as impurities).
Note 2.When TTC is applied to leachables or leachables, the identified leachables/leachables represent medical devices that may be exposed to patients during use
components.
3.2
Leachable extractable
Components released when a medical device or constituent material is leached using laboratory extraction conditions and media.
Note. When TTC is applied to leachables, it is assumed that the amount of leachables is the amount of potential human exposure to the medical device during clinical use,
See GB/T 16886.17.
3.3
A component whose chemical structure is known.
3.4
leachable
A component released from a medical device during clinical use and potentially in contact with the human body.
Note. When TTC is applied to leachables, the amount of leachables is assumed to be the amount of potential human exposure to the medical device during clinical use,
See GB/T 16886.17.
3.5
Exposure levels of components below which there is no significant risk to human health.
4 Background
4.1 Overview
TTC was originally used to assess the toxicological risk of impurities present at lower levels when toxicity data on impurities were not available. The concept of TTC
It can be used to evaluate the presence or release of lower levels of components in medical devices.
4.2 Protective effect of TTC value
Different thresholds were developed based on the protective effects on both carcinogenic and non-carcinogenic aspects. Non-carcinogenicity thresholds by Cramer
Class 1), known objects can correspond to specific Cramer classes according to their chemical structures. Although some evaluation systems using the TTC also use
Non-carcinogenic and carcinogenic thresholds, but only one set of TTC values is described in Table 1 to simplify the application of TTC values for release groups in medical devices
Points of safety assessment.
1) In 1978, American scientists Cramer et al. classified the structures of non-carcinogenic chemicals from simple to complex based on the relationship between chemical structures and toxicity data.
The miscellaneous principles are divided into one, two and three categories, and the TTC values of different structural classes of chemicals are given.
The TTC values defined in this document are based on the International Conference on Harmonization (ICH) M7(R1) (2017) for single mutagenic heterogeneity in medicinal products
The daily acceptable limit value is derived from the quality. The ICH-derived mutagenic impurity threshold (1.5 μg/d) for the longest exposure classification is the most
In the Cramer classification of protective effects, the TTC value (90 μg/d) for protection against chronic exposure to non-carcinogens was even lower.
Carcinogens induce cancer through genotoxic or non-genotoxic mechanisms. The TTC values in Table 1 are expected to act by either mechanism
protection from exposure to carcinogens.
5 Application of TTC to Medical Device Components
5.1 General
ICH establishes thresholds for mutagenic impurities that are considered applicable to the occurrence of patient exposure to components released from a medical device.
Potential carcinogenic and non-carcinogenic effects are protective. ICH M7TTC values are established for oral or parenteral routes and are applicable to adult
people, children and pregnant women; therefore, the TTC values in this document are considered to be of general applicability to medical devices.
---α-Nitrofuran compounds;
--- Hydrazine, triazene, azide, azo compound;
--- Polycyclic amines;
---Steroid;
---Organophosphorus compounds.
In addition, TTC values do not apply to the safety of high molecular weight polymers, particles (including nanoparticles), ceramics, proteins and radioactive components
assessment, as these types of substances were not included in the data originally used to establish the TTC method.
Identify components (including Coc, see 5.3.2) through information collection, including but not limited to obtaining the medical device
Material processing, material composition, process/step or chemical composition (including possible impurities) of machinery, ingredients or materials.
5.3.2 Identification of Coc
When information collection indicates that Coc is contained in material processing or material composition, according to GB/T 16886.1, GB/T 16886.17 and
GB/T 16886.18 for further evaluation.
Examples of Cocs reported to be present in the material composition of medical devices include, but are not limited to.
The N-nitroso group is the product of the reaction between a specific organic precursor molecule, a secondary amine, and a "nitroso agent". In rubber compounds, secondary amines
Possibly formed by certain vulcanization accelerators such as thiurams and dithiocarbamates.
5.4 Applicability of TTC values to mixtures
Because multiple components are used in processing, handling, and sterilization of medical devices, medical devices and their constituent materials may contain and release complex mixed
compound components. The TTC values specified in this document apply to individual components, whether they are present in the extract alone or as many
One of the components is present in a complex mixture leached from medical devices. Due to the low exposure levels corresponding to TTC values are not expected to be
Toxicological interactions will occur, so no additional steps need to be taken to evaluate the cumulative effect of the various components in a mixture.
Note. Guidelines for toxicological risk assessment of mixtures are given in GB/T 16886.17.