CEN/TC 206 - Biocompatibility of medical and dental materials and devices

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 specifies the procedure for the assessment of medical devices and their constituent materials with regard to their potential to induce skin sensitization.
This document includes:
—    details of in vivo skin sensitization test procedures;
—    key factors for the interpretation of the results.
NOTE      Instructions for the preparation of materials specifically in relation to the above tests are given in Annex A.

This document specifies the minimum requirements to be satisfied to ensure and demonstrate that proper provision has been made for the welfare of animals used in animal tests to assess the biocompatibility of materials used in medical devices. It is aimed at those who commission, design and perform tests or evaluate data from animal tests undertaken to assess the biocompatibility of materials intended for use in medical devices, or that of the medical devices themselves.
This document makes recommendations and offers guidance intended to facilitate future further reductions in the overall number of animals used, refinement of test methods to reduce or eliminate pain or distress in animals, and the replacement of animal tests by other scientifically valid means not requiring animal tests.
This document applies to tests performed on living vertebrate animals, other than man, to establish the biocompatibility of materials or medical devices.
This document does not apply to tests performed on invertebrate animals and other lower forms; nor (other than with respect to provisions relating to species, source, health status, and care and accommodation) does it apply to testing performed on isolated tissues and organs taken from vertebrate animals that have been euthanized.

2021-12-09- JO-  the EN was submitted to FV wiith the link to the legislation (90/385/EEC, 93/42/EEC)
however since these legilsations have been repealed, the link has been removed and the EN is to proceed to publication

This document provides general principles for the systematic evaluation of the potential and observed degradation of medical devices through the design and performance of in vitro degradation studies. Information obtained from these studies can be used in the biological evaluation described in the ISO 10993 series.
This document is applicable to both materials designed to degrade in the body as well as materials that are not intended to degrade.
This document is not applicable to:
a)   the evaluation of degradation which occurs by purely mechanical processes; methodologies for the production of this type of degradation product are described in specific product standards, where available;
NOTE    Purely mechanical degradation causes mostly particulate matter. Although this is excluded from the scope of this document, such degradation products can evoke a biological response and can undergo biological evaluation as described in other parts of ISO 10993.
b)   leachable components which are not degradation products;
c)   medical devices or components that do not contact the patient's body directly or indirectly.

This document specifies requirements and gives guidance on the procedures in the preparation of samples and the selection of reference materials for medical device testing primarily in biological test systems primarily in accordance with one or more parts of the ISO 10993 series.
Specifically, this document addresses the following:
—     test sample selection;
—     selection of representative portions from a medical device;
—     test sample preparation;
—     experimental controls;
—     selection of, and requirements for, reference materials;
—     preparation of extracts.
This document is not applicable to live cells but can be relevant to the material or medical device components of combination products containing live cells.
Extractions for chemical characterization are covered in ISO 10993-18. Clause 7, 8, 9, 10 [with the exception of 10.3.5 and 10.3.11 b)], and 11 can apply to extractions for chemical characterization. Information given in C.1 to C.4 can also be relevant.

This document specifies the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation. The tests are designed to predict and classify the irritation potential of medical devices, materials or their extracts according to ISO 10993‑1 and ISO 10993‑2.
This document includes:
—     pre-test considerations for irritation, including in silico and in vitro methods for dermal exposure;
—     details of in vitro and in vivo irritation test procedures;
—     key factors for the interpretation of the results.

This document specifies:
—          the general principles governing the biological evaluation of medical devices within a risk management process;
—          the general categorization of medical devices based on the nature and duration of their contact with the body;
—          the evaluation of existing relevant data from all sources;
—          the identification of gaps in the available data set on the basis of a risk analysis;
—          the identification of additional data sets necessary to analyse the biological safety of the medical device;
—          the assessment of the biological safety of the medical device.
This document applies to evaluation of materials and medical devices that are expected to have direct or indirect contact with:
—          the patient's body during intended use;
—          the user's body, if the medical device is intended for protection (e.g., surgical gloves, masks and others).
This document is applicable to biological evaluation of all types of medical devices including active, non-active, implantable and non-implantable medical devices.
This document also gives guidelines for the assessment of biological hazards arising from:
—          risks, such as changes to the medical device over time, as a part of the overall biological safety assessment;
—          breakage of a medical device or medical device component which exposes body tissue to new or novel materials.
Other parts of ISO 10993 cover specific aspects of biological assessments and related tests. Device-specific or product standards address mechanical testing.
This document excludes hazards related to bacteria, moulds, yeasts, viruses, transmissible spongiform encephalopathy (TSE) agents and other pathogens.

This document specifies requirements for controls on the sourcing, collection, and handling (which includes storage and transport) of animals and tissues for the manufacture of medical devices utilizing materials of animal origin other than in vitro diagnostic medical devices. It applies where required by the risk management process as described in ISO 22442‑1.
NOTE       Selective sourcing is especially important for transmissible spongiform encephalopathy (TSE) risk management, i.e. when utilising animal tissue and/or their derivative originating from bovine, ovine and caprine species, deer, elk, mink or cats.
This document does not cover the utilization of human tissues in medical devices.
This document does not specify a quality management system for the control of all stages of production of medical devices.

This document applies to medical devices other than in vitro diagnostic medical devices manufactured utilizing materials of animal origin, which are non-viable or have been rendered non-viable. It specifies, in conjunction with ISO 14971, a procedure to identify the hazards and hazardous situations associated with such devices, to estimate and evaluate the resulting risks, to control these risks, and to monitor the effectiveness of that control. Furthermore, it outlines the decision process for the residual risk acceptability, taking into account the balance of residual risk, as defined in ISO 14971, and expected medical benefit as compared to available alternatives. This document is intended to provide requirements and guidance on risk management related to the hazards typical of medical devices manufactured utilizing animal tissues or derivatives such as:
a)   contamination by bacteria, moulds or yeasts;
b)   contamination by viruses;
c)   contamination by agents causing transmissible spongiform encephalopathies (TSE);
d)   material responsible for undesired pyrogenic, immunological or toxicological reactions.
For parasites and other unclassified pathogenic entities, similar principles can apply.
This document does not stipulate levels of acceptability which, because they are determined by a multiplicity of factors, cannot be set down in such an international standard except for some particular derivatives mentioned in Annex C. Annex C stipulates levels of TSE risk acceptability for tallow derivatives, animal charcoal, milk and milk derivatives, wool derivatives and amino acids.
This document does not specify a quality management system for the control of all stages of production of medical devices.
This document does not cover the utilization of human tissues in medical devices.
NOTE 1  It is not a requirement of this document to have a full quality management system during manufacture. However, attention is drawn to international standards for quality management systems (see ISO 13485) that control all stages of production or reprocessing of medical devices.
NOTE 2  For guidance on the application of this document, see Annex A.

This document addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the clinical performance or effectiveness and safety of medical devices.
For post-market clinical investigations, the principles set forth in this document are intended to be followed as far as relevant, considering the nature of the clinical investigation (see Annex I).
This document specifies general requirements intended to
—     protect the rights, safety and well-being of human subjects,
—     ensure the scientific conduct of the clinical investigation and the credibility of the clinical investigation results,
—     define the responsibilities of the sponsor and principal investigator, and
—     assist sponsors, investigators, ethics committees, regulatory authorities and other bodies involved in the conformity assessment of medical devices.
NOTE 1  Users of this document need to consider whether other standards and/or national requirements also apply to the investigational device(s) under consideration or the clinical investigation. If differences in requirements exist, the most stringent apply.
NOTE 2  For Software as a Medical Device (SaMD) demonstration of the analytical validity (the SaMD's output is accurate for a given input), and where appropriate, the scientific validity (the SaMD's output is associated to the intended clinical condition/physiological state), and clinical performance (the SaMD's output yields a clinically meaningful association to the target use) of the SaMD, the requirements of this document apply as far as relevant (see Reference [4]). Justifications for exemptions from this document can consider the uniqueness of indirect contact between subjects and the SaMD.
This document does not apply to in vitro diagnostic medical devices. However, there can be situations, dependent on the device and national or regional requirements, where users of this document might consider whether specific sections and/or requirements of this document could be applicable.

This document specifies a framework for the identification, and if necessary, quantification of constituents of a medical device, allowing the identification of biological hazards and the estimation and control of biological risks from material constituents, using a generally stepwise approach to the chemical characterization which can include one or more of the following:
—          the identification of its materials of construction (medical device configuration);
—          the characterization of the materials of construction via the identification and quantification of their chemical constituents (material composition);
—          the characterization of the medical device for chemical substances that were introduced during manufacturing (e.g. mould release agents, process contaminants, sterilization residues);
—          the estimation (using laboratory extraction conditions) of the potential of the medical device, or its materials of construction, to release chemical substances under clinical use conditions (extractables);
—          the measurement of chemical substances released from a medical device under its clinical conditions of use (leachables).
This document can also be used for chemical characterization (e.g. the identification and/or quantification) of degradation products. Information on other aspects of degradation assessment are covered in ISO 10993-9, ISO 10993-13, ISO 10993-14 and ISO 10993-15.
The ISO 10993 series is applicable when the material or medical device has direct or indirect body contact (see ISO 10993-1 for categorization by nature of body contact).
This document is intended for suppliers of materials and manufacturers of medical devices, to support a biological evaluation.

NEXT ACTION: TC ACTION BY 2022-10-26 : TC to send a revised annex ZA for assessment at PUB
2020-02-19- JO-CEN/TC 206 to take decision either to remove the link or send a revised annex ZA for assessment at PUB

ISO 10993-11:2017 specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions.

ISO 10993-16:2017 provides principles on designing and performing toxicokinetic studies relevant to medical devices. Annex A describes the considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices.

ISO 10993-4:2017 specifies general requirements for evaluating the interactions of medical devices with blood.
It describes
a)    a classification of medical devices that are intended for use in contact with blood, based on the intended use and duration of contact as defined in ISO 10993‑1,
b)    the fundamental principles governing the evaluation of the interaction of devices with blood,
c)    the rationale for structured selection of tests according to specific categories, together with the principles and scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests for evaluating interactions of devices with blood. This document describes biological evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a specific device.
The changes in this document do not indicate that testing conducted according to prior versions of this document is invalid. For marketed devices with a history of safe clinical use, additional testing according to this revision is not recommended.

ISO 10993-4:2017 specifies general requirements for evaluating the interactions of medical devices with blood.
It describes
a)    a classification of medical devices that are intended for use in contact with blood, based on the intended use and duration of contact as defined in ISO 10993‑1,
b)    the fundamental principles governing the evaluation of the interaction of devices with blood,
c)    the rationale for structured selection of tests according to specific categories, together with the principles and scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests for evaluating interactions of devices with blood. This document describes biological evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a specific device.
The changes in this document do not indicate that testing conducted according to prior versions of this document is invalid. For marketed devices with a history of safe clinical use, additional testing according to this revision is not recommended.

ISO 10993-6:2016 specifies test methods for the assessment of the local effects after implantation of biomaterials intended for use in medical devices.
ISO 10993-6:2016 applies to materials that are
-      solid and non-absorbable,
-      non-solid, such as porous materials, liquids, gels, pastes, and particulates, and
-      degradable and/or absorbable, which may be solid or non-solid.
The test sample is implanted into a site and animal species appropriate for the evaluation of the biological safety of the material. These implantation tests are not intended to evaluate or determine the performance of the test sample in terms of mechanical or functional loading. This part of ISO 10993 can also be applied to medical devices that are intended to be used topically in clinical indications where the surface or lining might have been breached, in order to evaluate local tissue responses.
The local effects are evaluated by a comparison of the tissue response caused by a test sample to that caused by control materials used in medical devices whose clinical acceptability and biocompatibility characteristics have been established. The objective of the test methods is to characterize the history and evolution of the tissue response after implantation of a medical device/biomaterial including final integration or absorption/degradation of the material. In particular for degradable/absorbable materials, the degradation characteristics of the material and the resulting tissue response should be determined.
ISO 10993-6:2016 does not deal with systemic toxicity, carcinogenicity, teratogenicity or mutagenicity. However, the long-term implantation studies intended for evaluation of local biological effects might provide insight into some of these properties. Systemic toxicity studies conducted by implantation might satisfy the requirements of this part of ISO 10993. When conducting combined studies for evaluating local effects and systemic effects, the requirements of both standards is to be fulfilled.

ISO 10993-3:2014 specifies strategies for risk estimation, selection of hazard identification tests and risk management, with respect to the possibility of the following potentially irreversible biological effects arising as a result of exposure to medical devices:
genotoxicity;
carcinogenicity;
reproductive and developmental toxicity.
ISO 10993-3:2014 is applicable when the need to evaluate a medical device for potential genotoxicity, carcinogenicity, or reproductive toxicity has been established.

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 10993‑13:2010 provides general requirements for the design of tests in a simulated environment for identifying and quantifying degradation products from finished polymeric medical devices ready for clinical use.
ISO 10993‑13:2010 describes two test methods to generate degradation products, an accelerated degradation test as a screening method and a real-time degradation test in a simulated environment. For materials that are intended to polymerize in situ, the set or cured polymer is used for testing. The data generated are used in the biological evaluation of the polymer. ISO 10993‑13:2010 considers only non-resorbable polymers. Similar, but appropriately modified procedures may be applicable for resorbable polymers.
ISO 10993‑13:2010 considers only those degradation products generated by a chemical alteration of the finished polymeric device. It is not applicable to degradation of the device induced during its intended use by mechanical stress, wear or electromagnetic radiation or biological factors such as enzymes, other proteins and cellular activity.

2010-01-06 SJ: Std cited under 98/79/EC through publication C293 on 2009-12-02, in error (should only be cited under 93/42). OJEU flag removed as well as OJEU publication data.

ISO 10993-5:2009 describes test methods to assess the in vitro cytotoxicity of medical devices.
These methods specify the incubation of cultured cells in contact with a device and/or extracts of a device either directly or through diffusion.
These methods are designed to determine the biological response of mammalian cells in vitro using appropriate biological parameters.

ISO 22442-3:2007 specifies requirements for the validation of the elimination and/or inactivation of viruses and TSE agents during the manufacture of medical devices (excluding in vitro diagnostic medical devices) utilizing animal tissue or products derived from animal tissue, which are non-viable or have been rendered non-viable. It applies where required by the risk management process as described in ISO 22442-1. It does not cover other transmissible and non-transmissible agents.

This document specifies the minimum requirements to be satisfied to ensure and demonstrate that proper provision has been made for the welfare of animals used in animal tests to assess the biocompatibility of materials used in medical devices. It is aimed at those who commission, design and perform tests or evaluate data from animal tests undertaken to assess the biocompatibility of materials intended for use in medical devices, or that of the medical devices themselves.
This document makes recommendations and offers guidance intended to facilitate future further reductions in the overall number of animals used, refinement of test methods to reduce or eliminate pain or distress in animals, and the replacement of animal tests by other scientifically valid means not requiring animal tests.
This document applies to tests performed on living vertebrate animals, other than man, to establish the biocompatibility of materials or medical devices.
This document does not apply to tests performed on invertebrate animals and other lower forms; nor (other than with respect to provisions relating to species, source, health status, and care and accommodation) does it apply to testing performed on isolated tissues and organs taken from vertebrate animals that have been euthanized.

This document specifies:
—          the general principles governing the biological evaluation of medical devices within a risk management process;
—          the general categorization of medical devices based on the nature and duration of their contact with the body;
—          the evaluation of existing relevant data from all sources;
—          the identification of gaps in the available data set on the basis of a risk analysis;
—          the identification of additional data sets necessary to analyse the biological safety of the medical device;
—          the assessment of the biological safety of the medical device.
This document applies to evaluation of materials and medical devices that are expected to have direct or indirect contact with:
—          the patient's body during intended use;
—          the user's body, if the medical device is intended for protection (e.g., surgical gloves, masks and others).
This document is applicable to biological evaluation of all types of medical devices including active, non-active, implantable and non-implantable medical devices.
This document also gives guidelines for the assessment of biological hazards arising from:
—          risks, such as changes to the medical device over time, as a part of the overall biological safety assessment;
—          breakage of a medical device or medical device component which exposes body tissue to new or novel materials.
Other parts of ISO 10993 cover specific aspects of biological assessments and related tests. Device-specific or product standards address mechanical testing.
This document excludes hazards related to bacteria, moulds, yeasts, viruses, transmissible spongiform encephalopathy (TSE) agents and other pathogens.

This document addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the clinical performance or effectiveness and safety of medical devices.
For post-market clinical investigations, the principles set forth in this document are intended to be followed as far as relevant, considering the nature of the clinical investigation (see Annex I).
This document specifies general requirements intended to
— protect the rights, safety and well-being of human subjects,
— ensure the scientific conduct of the clinical investigation and the credibility of the clinical investigation results,
— define the responsibilities of the sponsor and principal investigator, and
— assist sponsors, investigators, ethics committees, regulatory authorities and other bodies involved in the conformity assessment of medical devices.
NOTE 1 Users of this document need to consider whether other standards and/or national requirements also apply to the investigational device(s) under consideration or the clinical investigation. If differences in requirements exist, the most stringent apply.
NOTE 2 For Software as a Medical Device (SaMD) demonstration of the analytical validity (the SaMD's output is accurate for a given input), and where appropriate, the scientific validity (the SaMD's output is associated to the intended clinical condition/physiological state), and clinical performance (the SaMD's output yields a clinically meaningful association to the target use) of the SaMD, the requirements of this document apply as far as relevant (see Reference [4]). Justifications for exemptions from this document can consider the uniqueness of indirect contact between subjects and the SaMD.
This document does not apply to in vitro diagnostic medical devices. However, there can be situations, dependent on the device and national or regional requirements, where users of this document might consider whether specific sections and/or requirements of this document could be applicable.

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.

20090130 - WI abandoned due to duplication under WI 00206035

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.

2010-01-06 SJ: Std cited under 98/79/EC through publication C293 on 2009-12-02, in error (should only be cited under 93/42). OJEU flag removed as well as OJEU publication data.

ISO 10993-10:2010 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and skin sensitization.
ISO 10993-10:2010 includes:
pretest considerations for irritation, including in silico and in vitro methods for dermal exposure;
details of in vivo (irritation and sensitization) test procedures;
key factors for the interpretation of the results.
Instructions are given for the preparation of materials specifically in relation to the above tests and several special irritation tests are described for application of medical devices in areas other than skin.

ISO 10993-2:2006 is aimed at those who commission, design and perform tests or evaluate data from animal tests undertaken to assess the biocompatibility of materials intended for use in medical devices, or of the medical devices themselves. It specifies the minimum requirements to be satisfied to ensure and demonstrate that proper provision has been made for the welfare of animals used in animal tests to assess the biocompatibility of materials used in medical devices.
ISO 10993-2:2006 also makes recommendations and offers guidance intended to facilitate future further reductions in the overall number of animals used, refinement of test methods to reduce or eliminate pain or distress in animals, and the replacement of animal tests by other scientifically valid means not requiring animal tests.
It applies to tests performed on living vertebrate animals, other than man, to establish the biocompatibility of materials or medical devices.

ISO 10993-12:2012 specifies requirements and gives guidance on the procedures to be followed in the preparation of samples and the selection of reference materials for medical device testing in biological systems in accordance with one or more parts of ISO 10993. Specifically, ISO 10993-12:2012 addresses the following:
test sample selection;
selection of representative portions from a device;
test sample preparation;
experimental controls;
selection of, and requirements for, reference materials;
preparation of extracts.
ISO 10993-12:2012 is not applicable to live cells, but can be relevant to the material or device components of combination products containing live cells.

2010-05-19 EMA: Consultant added following e-mail from PM sent to dataservice on 2010-05-17.

ISO 22442-2:2015 specifies requirements for controls on the sourcing, collection, and handling (which includes storage and transport) of animals and tissues for the manufacture of medical devices utilizing materials of animal origin other than in vitro diagnostic medical devices. It applies where required by the risk management process as described in ISO 22442‑1.
NOTE 1 Selective sourcing is considered to be especially important for transmissible spongiform encephalopathy (TSE) risk management.
The manufacturers should refer to ISO 22442‑3 for information on the validation of the elimination and/or inactivation of viruses and TSE agents.
ISO 22442-2:2015 does not cover the utilization of human tissues in medical devices.
ISO 22442-2:2015 does not specify a quality management system for the control of all stages of production of medical devices.
It is not a requirement of this part of ISO 22442 to have a full quality management system during manufacture, but it does specify requirements for some of the elements of a quality management system. Attention is drawn to the standards for quality management systems (see ISO 13485) that control all stages of production or reprocessing of medical devices. The quality management system elements that are required by this part of ISO 22442 can form a part of a quality management system conforming to ISO 13485.
NOTE 2 A general principle for the application of this International Standard is that it is advisable to give due consideration to the requirements and recommendations contained in all three parts of the standard.

ISO 22442-1:2015 applies to medical devices other than in vitro diagnostic medical devices manufactured utilizing materials of animal origin, which are non-viable or have been rendered non-viable. It specifies, in conjunction with ISO 14971, a procedure to identify the hazards and hazardous situations associated with such devices, to estimate and evaluate the resulting risks, to control these risks, and to monitor the effectiveness of that control. Furthermore, it outlines the decision process for the residual risk acceptability, taking into account the balance of residual risk, as defined in ISO 14971, and expected medical benefit as compared to available alternatives. This part of ISO 22442 is intended to provide requirements and guidance on risk management related to the hazards typical of medical devices manufactured utilizing animal tissues or derivatives such as
a) contamination by bacteria, moulds or yeasts;
b) contamination by viruses;
c) contamination by agents causing Transmissible Spongiform Encephalopathies (TSE);
d) material responsible for undesired pyrogenic, immunological or toxicological reactions.
For parasites and other unclassified pathogenic entities, similar principles can apply.
ISO 22442-1:2015 does not stipulate levels of acceptability which, because they are determined by a multiplicity of factors, cannot be set down in such an International Standard except for some particular derivatives mentioned in Annex C. Annex C stipulates levels of TSE risk acceptability for tallow derivatives, animal charcoal, milk and milk derivatives, wool derivatives and amino acids.
ISO 22442-1:2015 does not specify a quality management system for the control of all stages of production of medical devices.
ISO 22442-1:2015 does not cover the utilization of human tissues in medical devices.
NOTE 1 It is not a requirement of this part of ISO 22442 to have a full quality management system during manufacture. However, attention is drawn to International Standards for quality management systems (see ISO 13485) that control all stages of production or reprocessing of medical devices.
NOTE 2 For guidance on the application of this part of ISO 22442, see Annex A.

ISO 14155:2011 addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out in human subjects to assess the safety or performance of medical devices for regulatory purposes.
The principles set forth in ISO 14155:2011 also apply to all other clinical investigations and should be followed as far as possible, depending on the nature of the clinical investigation and the requirements of national regulations.
ISO 14155:2011 specifies general requirements intended to protect the rights, safety and well-being of human subjects, ensure the scientific conduct of the clinical investigation and the credibility of the results, define the responsibilities of the sponsor and principal investigator, and assist sponsors, investigators, ethics committees, regulatory authorities and other bodies involved in the conformity assessment of medical devices.
ISO 14155:2011 does not apply to in vitro diagnostic medical devices.

ISO 10993-18:2005 describes a framework for the identification of a material and the identification and quantification of its chemical constituents. The chemical characterization information generated can be used for a range of important applications, for example, as part of an assessment of the overall biological safety of a medical device (ISO 10993-1 and 14971), as a measurement of the level of a leachable substance in a medical device in order to allow the assessment of compliance with the allowable limit derived for that substance from health based risk assessment (ISO 10993-17), for judging equivalence of a proposed material to a clinically established material, for judging equivalence of a final device to a prototype device to check the relevance of data on the latter to be used to support the assessment of the former, or for screening of potential new materials for suitability in a medical device for a proposed clinical application.
ISO 10993-18:2005 does not address the identification or quantification of degradation products, which is covered in ISO 10993-9, ISO 10993-13, ISO 10993-14 and ISO 10993-15.
The ISO 10993 series of standards is applicable when the material or device comes into contact with the body directly or indirectly (see 4.2.1 of ISO 10993-1).
ISO 10993-18:2005 is intended for suppliers of materials and manufacturers of medical devices, when carrying out a biological safety assessment.

ISO 10993-11:2006 specifies requirements and gives guidance on procedures to be followed in the evaluation of the potential for medical device materials to cause adverse systemic reactions.

ISO 10993-16:2010 gives principles on how toxicokinetic studies relevant to medical devices should be designed and performed. Annex A describes the considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices.

ISO 10993-4:2002 provides general requirements for evaluating the interactions of medical devices with blood.
It describes
a classification of medical and dental devices that are intended for use in contact with blood, based on the intended use and duration of contact as defined in ISO 10993-1,
the fundamental principles governing the evaluation of the interaction of devices with blood,
the rationale for structured selection of tests according to specific categories, together with the principles and scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests for interactions of devices with blood. ISO 10993-4:2002 describes biological evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a specific device.