ISO 10993-1:2025 Biological evaluation of medical devices — Part 1: Requirements and general principles for the evaluation of biological safety within a risk management process

Foreword

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This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical devices, in collaboration with the European Committee for Standardization (CEN) Technical Committee CEN/TC 206, Biological and clinical evaluation of medical devices, in accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).

This sixth edition cancels and replaces the fifth edition (ISO 10993-1:2018), which has been technically revised.

The main changes are as follows:

A list of all parts in the ISO 10993 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A complete listing of these bodies can be found at www.iso.org/members.html.

Introduction

The aim of this document is to provide guidance and requirements for the biological evaluation of a medical device within a risk management process to protect humans from biological risks arising from the use of medical devices and the materials from which they are made. Biological risk evaluation compares the estimated biological risk against given risk criteria to determine the acceptability of the biological risk as part of the overall risk management.

Biological evaluation is primarily concerned with medical device biological safety, through consideration of risks associated with biological hazards. Nonetheless, some activities undertaken in the course of biological evaluation in addition to assessments of long-term safety can also generate information on device performance. For example, functional implant models can be used to assess long-term responses such as tissue ingrowth. Biological evaluation, as described in this document, is synonymous with biocompatibility evaluation.

Biological evaluation is conducted on the finished medical device. The principles and methods described can also be useful in the evaluation of candidate materials or prototype devices during a medical device development process, and data obtained from such evaluations can be of value in the assessment of the finished medical device.

Medical device design is wide-ranging, and, at one extreme, a medical device consists only of a single material, which can exist in more than one physical form, while at the other extreme, is a complex article consisting of numerous components made from multiple materials. Biological safety cannot be considered in isolation from the overall medical device design and can require the balancing of conflicting requirements. For example, the choice of the best material with respect to its biological safety can result in a less functional medical device.

The evaluation of biological safety is conducted in the context of the intended use of a particular medical device. Materials can be safe in one medical device and not in another. It is impossible to make generalized conclusions about the safety of a particular material for all medical applications. Biological responses that are regarded as adverse, caused by a material in one application, are not necessarily regarded as adverse in a different situation.

Physical and chemical information supports the overall biological evaluation and can be used to inform testing needs, if any. When biological testing is required, such testing is based upon in vitro, ex vivo or in vivo models. The interpretation of the results of biological tests requires caution because the inherent variability in biological responses between species and individuals means that the biological response observed in animal or cell culture models can differ from those observed in clinical use. Differences in response to the same material among individuals means that some individuals can have adverse reactions, even to well-established materials. Thus, biological evaluation is an exercise in risk management. When applied to the evaluation of candidate materials or prototype devices during a medical device development process, biological evaluation allows the informed and timely consideration of risk control measures such as use of alternative materials, manufacturing processes or designs.

The biological evaluation process described in this document draw on all available sources of information relevant to biological safety of the medical device, including post-market information. This approach allows a comprehensive review of the medical device, the identification of biological hazards and the biological harms which can arise and estimation of the associated risks. This comprehensive approach allows for the identification of any gaps in the existing data set and the consequent need for supplementary assessments (e.g. chemical analysis and hazard identification, biological testing to refine a biological risk estimate) to be conducted.

This document is supported by a wide range of test methods and guidance published in other documents in the ISO 10993 series, as well as other standards. Those who use this document can also consider more specific guidance contained in device-specific standards, where available. For some complex or novel materials or technologies, it can be difficult to use the established methods described in the ISO 10993 series. This document allows for the use of alternative procedures where scientifically justified.

The welfare of animals is very important and the selection of test methods and evolution of testing within the ISO 10993 framework is directed to continue to reduce, refine and, where possible, replace the use of animals for biological testing.

1 Scope

This document specifies the requirements and general principles governing the biological evaluation of medical devices within a risk management process according to ISO 14971.

This document applies to the biological evaluation of medical devices that have direct contact or indirect contact with either:

Biological evaluation assesses the biological safety of the medical device by considering the biological risks associated with:

The biological evaluation specified in this document can address the biological safety of the medical device, considering the life cycle from design and development through initial use of the finished medical device to final decommissioning or withdrawal from use. The biological evaluation considers both the biological safety of the finished device in first use, and the significance of any changes to the medical device which can occur throughout the life cycle. However, the evaluation of risks related to environmental impacts of decommissioning of medical devices are not within the scope of this document. This document does not mandate re-testing of medical devices that are already on the market and have established and acceptable safety profiles (see 6.6.2).

This document can be useful to support clinical or usability evaluations of medical devices. For example, a biological evaluation is a pre-requisite for conducting a clinical trial. This means that principles outlined in this document can be applied to the evaluation of prototype or development stage devices, as well as to finished medical devices.

Other parts of the ISO 10993 series cover specific aspects of biological evaluation, such as chemical characterization, biological testing, sample preparation, animal welfare and toxicological risk assessment.

For some types of medical devices, specific requirements from other standards (outside the ISO 10993 series) can be considered with a justification for the approach taken if there are differences between the requirements of the ISO 10993 series and those provided in other standards. For example, the ISO 18562 series provides specific requirements for biological evaluation of breathing gas pathway medical devices and ISO 7405 provides specific requirements for biological evaluation of dental devices.

The evaluation of risks related to infectious agents [e.g. bacteria, moulds, yeasts, viruses, transmissible spongiform encephalopathy (TSE) agents] is not within the scope of this document.

NOTE 1

The evaluation of bacterial endotoxins is addressed by ISO 11737-3.

NOTE 2

The evaluation of risks related to viruses, TSE agents and other pathogens originating from materials of animal origin is addressed by the ISO 22442 series.

2 Normative references

The following documents are referred to in the text in such a way that some or all of their content constitutes requirements of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies.

• ISO 10993-2 Biological evaluation of medical devices — Part 2: Animal welfare requirements
• ISO 10993-3 Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
• ISO 10993-4 Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood
• ISO 10993-5 Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
• ISO 10993-6 Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
• ISO 10993-7 Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals
• ISO 10993-9:2019 Biological evaluation of medical devices — Part 9: Framework for identification and quantification of potential degradation products
• ISO 10993-10 Biological evaluation of medical devices — Part 10: Tests for skin sensitization
• ISO 10993-11 Biological evaluation of medical devices — Part 11: Tests for systemic toxicity
• ISO 10993-12 Biological evaluation of medical devices — Part 12: Sample preparation and reference materials
• ISO 10993-13 Biological evaluation of medical devices — Part 13: Identification and quantification of degradation products from polymeric medical devices
• ISO 10993-14 Biological evaluation of medical devices — Part 14: Identification and quantification of degradation products from ceramics
• ISO 10993-15 Biological evaluation of medical devices — Part 15: Identification and quantification of degradation products from metals and alloys
• ISO 10993-16 Biological evaluation of medical devices — Part 16: Toxicokinetic study design for degradation products and leachables
• ISO 10993-17:2023 Biological evaluation of medical devices — Part 17: Toxicological risk assessment of medical device constituents
• ISO 10993-18:2020 Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process
• ISO/TS 10993-19 Biological evaluation of medical devices — Part 19: Physico-chemical, morphological and topographical characterization of materials
• ISO 10993-23 Biological evaluation of medical devices — Part 23: Tests for irritation
• ISO 14971:2019 Medical devices — Application of risk management to medical devices

3 Terms and definitions

For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminology databases for use in standardization at the following addresses:

3.1 biocompatibility

3.2 biological effect

3.3 biological equivalence

3.4 biological evaluation

3.5 biological risk evaluation

3.6 biological harm

3.7 biological hazard

3.8 biological risk

3.9 biological risk analysis

3.10 biological risk assessment

3.11 biological safety

3.12 biologically hazardous situation

3.13 chemical characterization

3.14 configuration

3.15 constituent

3.16 contact day

3.17 degradation

3.18 direct contact

3.19 extractable

3.20 finished medical device

3.21 implant

3.22 indirect contact

3.23 intended use

3.24 leachable

3.25 life cycle

3.26 manufacturer

3.27 material

3.28 medical device

3.29 medical device family

3.30 nanomaterial

3.31 non-contacting

3.32 novel material

3.33 physical and chemical information

3.34 reasonably foreseeable misuse

3.35 residual biological risk

3.36 risk estimation

3.37 risk management

3.38 sensitive population

3.39 substance

3.40 tissue

3.41 total exposure period

3.42 toxicity

3.43 user

4.1 Biological evaluation within the ISO 14971 risk management framework

The biological evaluation (biocompatibility evaluation) of a medical device shall be conducted within a risk management process in accordance with ISO 14971 (see Figure 1), which involves the identification of biological hazards, the estimation of the associated biological risks and the determination of their acceptability (see Clause 6 and Clause 7).

The biological evaluation shall be planned (see Clause 5), conducted and reported by competent personnel, capable of making informed decisions based upon scientific data and a knowledge of relevant medical devices. Competence shall be demonstrated and documented on the basis of education, training, skills and experience (see Clause 9).

NOTE 1

Biological evaluation tasks can be performed by representatives of several functions or organizations, each contributing their specialist knowledge and competence.

To understand the relationship between ISO 14971 and the ISO 10993 series, it is useful to apply the risk management terminology of ISO 14971 as follows:

The following summarizes the application of the ISO 14971 risk management principles to the evaluation of biological safety.

Figure 1

Biological risk analysis requires:

Biological risk estimation requires consideration of likely exposure to hazardous constituents or effects of physical characteristics of the medical device. If existing data are insufficient, further physical, chemical or biological testing (see 6.8) can be required to estimate biological risks (see 6.9).

Biological risk evaluation is the determination of the acceptability of the estimated biological risks (see Clause 7).

Biological risk control (see Clause 8) consists of any actions taken to reduce identified biological risks. Risk control measures shall be applied in the following priority order:

1. a) inherently safe design and manufacturing;
2. b) protective measures in the medical device itself or in the manufacturing process;
3. c) information for safety and, where appropriate, training to users.

Re-analysis of biological risks (which can include additional testing) is necessary to confirm that the identified biological risk was reduced, and no unacceptable new risks have been introduced by implementation of biological risk control measures (see Clause 8).

The evaluation of overall residual risk is conducted following the implementation of all risk controls (see ISO 14971:2019).

NOTE 2

Biological safety is determined based on a biological evaluation of all of the available data rather than the findings for any individual biological effect.

A biological evaluation report shall document the biological evaluation process, including the outcome and conclusions on the biological safety of the finished medical device (see Clause 8).

Production and post-production activities include monitoring of post-market feedback from users or patients and evaluation of any adverse biological effects observed. This information can be used to update and revise the biological evaluation (see 6.9) and, if required, provide input to biological risk control e.g. design changes (see Clause 8).

4.2 Biological evaluation process

The overall process for the conduct of a biological evaluation is depicted in Figure 2. The biological evaluation process shall be established, implemented, documented and maintained over the life cycle of a medical device (see 4.3 and Clause 10).

NOTE

The flowchart in Figure 2 is provided as a visual aid but does not capture all necessary considerations. Refer to the identified clauses and subclauses of this document when using this flowchart.

Figure 2

4.3 Medical device life cycle

The biological evaluation of a medical device shall consider its life cycle.

In the selection of materials to be used in the manufacture of a medical device, the first consideration shall be fitness for purpose with regard to characteristics and properties of the material, which include chemical, toxicological, physical, electrical, morphological and mechanical properties. Further guidance on material selection can be found in Clause A.2.

The potential for change in the characteristics of the medical device during transport, storage or use (e.g. where there is anticipated degradation or potential for physical failures causing exposure to previously unevaluated materials or constituents) shall be considered.

For reusable devices, evaluation of biological safety shall take into consideration the number of processing cycles based on the expected use life of the device. If the maximum number of processing cycles is not specified by the manufacturer, the biological risk control measures shall be justified and documented.

Post-market data can show that the biological safety of the finished medical device can be different from that anticipated during its development. Therefore, biological evaluations shall be reviewed and updated as required by post-market information or where new or changed biological risks are identified. This is part of the overall risk management process.

4.4 Animal welfare

Any in vivo testing shall be conducted in accordance with ISO 10993-2. The conduct of any in vivo biological testing shall be minimized to that which is strictly necessary to complete the biological evaluation. In the following order, where possible, the biological evaluation shall:

The approach taken shall be justified and documented.

In vivo testing shall not be carried out where:

1. a) valid results are available from relevant non-clinical studies that have been carried out previously on the medical device or on a medical device where biological equivalence has been established (see 6.7);
2. b) valid results relevant to the specific biological effects under evaluation are available from the existing clinical data on the medical device or on a medical device where biological equivalence has been established (see 6.7); in assessing the data, both the quality of the data and the type of available clinical information should be taken into account; or
3. c) risk evaluation indicates an unacceptable risk to the animal based on the existing information (e.g. expected skin corrosion based on pH).

NOTE

Additional information on validity of testing is included in ISO 10993-2, ISO 10993-11 and ISO 14155.

5 Biological evaluation plan

The biological evaluation shall be planned and the plan documented (see also ISO 14971). The biological evaluation plan should include or refer to:

1. a) a description of the finished medical device or medical device family under evaluation, including materials of construction, configuration, manufacturing processes and other processes to which the medical device is exposed throughout its life cycle (e.g. sterilization, reprocessing);
2. b) intended use;
3. c) reasonably foreseeable misuse;
4. d) medical device categorization (including frequency, duration, and type of body contact) (see 6.4);
5. e) identification of characteristics related to biological safety (see 6.2);
6. f) identification of biological hazards, biologically hazardous situations and potential biological harms (see 6.3 and 6.5);
7. g) criteria for acceptability of specific biological risks associated with the medical device;

   NOTE 1

   See ISO 14971 and ISO/TR 24971 for general guidance on the development of criteria for risk acceptability considering relevant parts of the ISO 10993 series.

   EXAMPLE

   Acceptability criteria can be expressed in terms of:

   — the absence of specific biological hazards;

   — the combination of maximum tolerable severity and probability of occurrence of relevant biological harms;

   — the expected outcome from a conducted test.

8. h) gap analysis of relevant existing data (see 6.6);
9. i) the strategy and planned content for the biological evaluation report of the medical device, including any requirements for additional data generation;
10. j) criteria to evaluate the overall biological safety conclusions for the medical device;
11. k) aspects of the biological evaluation requiring specific technical competencies (e.g. analytical testing, biological testing, toxicology, engineering); and
12. l) the personnel responsible for the biological evaluation.

NOTE 2

A plan can be an evolving document, which starts as an outline and is refined as information is gathered (see 6.2, 6.3 and 6.6).

6.1 General approach

The biological evaluation shall address the medical device life cycle from design and development through initial use to final decommissioning or withdrawal from use (see 4.3). This evaluation shall take all available relevant information into account, including intended use, reasonably foreseeable misuse, physical and chemical information, preclinical tests, clinical investigations, post-market experience, and any other relevant information.

Consideration of sources of data should be broadly based. Data can be drawn from raw material supplier information, information held by the manufacturer such as customer feedback and test reports, or from publicly available information such as adverse event databases, toxicology databases or scientific and clinical literature. Information can include data on relevant medical devices. Where sources of data are incomplete or less informative, the quality and relevance of the data should be justified and documented.

NOTE 1

The activities described in 6.2 to 6.5 can be conducted in parallel.

NOTE 2

The scope of the biological risk analysis can be broad (as for the development of a new medical device with which a manufacturer has little or no experience) or the scope can be limited (as for analysing the impact of a change to an existing medical device for which information already exists in the manufacturer’s files).

6.2 Identification of characteristics related to biological safety

The information needed for the biological evaluation is principally determined by the type, frequency and duration of contact (see 6.4) and the biological hazards identified for the medical device or material (see 6.5).

When identifying characteristics related to biological safety, consideration shall also be given to the following:

1. a) the device design and materials of construction (i.e. all materials with direct contact or indirect contact) and their interactions;
2. b) physical characteristics, including but not limited to, porosity, particle size, shape and surface morphology (see ISO/TS 10993-19);

   NOTE 1

   Nanomaterials can pose specific challenges to the biological evaluation of a medical device due to their potentially unique properties (see ISO/TR 10993-22).

3. c) impact of manufacturing processes on materials of construction (e.g. passivation, laser marking, sterilization);
4. d) introduction of additional constituents during manufacturing and reprocessing activities if applicable (e.g. additives, process contaminants or sterilization residues);

   NOTE 2

   ISO 10993-7 includes requirements for ethylene oxide sterilization residuals.

5. e) primary packaging materials, which can transfer constituents to the medical device;

   NOTE 3

   In some cases, constituents from other packaging components (e.g. glues, adhesives) can be introduced through the primary packaging and impact biological risk;

6. f) interactions with other medical devices or medicines which contact the device, which can transfer constituents to or impact the physical characteristics of tissue-contacting components of the medical device;
   EXAMPLE

   Parenteral container with liquids contained within, ultrasound transducer with lubricating gel, bearing surface interactions, cardiac leads interaction with pacemaker, prosthetic heart valve loading tools, crimping or refolding tools.

7. g) constituents which are available on the device surface or as constituents released from the finished medical device (see ISO 10993-18 and ISO 10993-17);
8. h) where applicable, potential degradation products (see ISO 10993-9 for general principles, and ISO 10993-13, ISO 10993-14 and ISO 10993-15 for degradation products from polymers, ceramics, and metals and alloys, respectively); and

   NOTE 4

   Degradation can be intentional or unintentional.

9. i) consequences of changes in the performance and characteristics of the finished medical device over its life cycle (see 4.3 and Clause 10).

Further information on material characterization can be found in Annex A, ISO 10993-18 and ISO/TS 10993-19.

NOTE 5

ISO/TR 24971:2020 includes further information on identifying hazards and characteristics related to safety.

6.3 Identification of biological hazards, biologically hazardous situations and potential biological harms

Gathering physical and chemical information on the medical device or component and on the materials used in the manufacturing processing (including sterilization) is a crucial first step in the biological evaluation.

The extent of physical and chemical information required depends on the type and duration of contact and the biological hazards presented. At a minimum, the chemical characterization shall address the materials of construction and processing aids or additives used in manufacturing. In addition, it is possible that some physical characterization information will be needed, especially for implanted medical devices or medical devices in contact with tissues including blood. At a minimum, physical characterization shall address general surface characteristics and potential hazardous attributes if they can induce biological risk.

This information allows identification of biological hazards in the form of the presence of constituents at potentially toxic levels or hazardous physical characteristics of the device.

All known and foreseeable biological hazards shall be identified from the medical device characterization data. This involves:

If medical device characterization data indicates the presence of a known hazardous constituent (e.g. sensitizer, carcinogen or neurotoxin) then the risk shall be evaluated in addition to the other biological effects appropriate to the device categorization (as indicated in Table 1, Table 2, Table 3 and Table 4).

Biological hazards associated with physical attributes can be more difficult to quantify and characterize than constituents (where an estimate of the available mass provides quantification). Possible factors to consider include the number and size of particulates released into the tissue and metrics such as porosity, texture and overall surface area of the physical attribute, as well as the specific tissue contact.

For the identified biologically hazardous situations, the use of quantitative information allows a quantitative estimate of biological risks (see 6.9), however, qualitative information can be adequate for biological risk assessment.

Chemical characterization shall be conducted in accordance with ISO 10993-18. Relevant physical attributes shall be characterized. ISO/TS 10993-19 provides information on physical characterization.

Where the potential for degradation exists under the conditions of manufacture, sterilization, transport, storage, reprocessing or intended use of the medical device, the presence and characteristics of degradation products shall be assessed, as applicable, to identify biological hazards associated with degradation (see 6.5.11.6).

The presence of a biological hazard does not necessarily lead to a biological harm. Determination of biological risk requires assessment of whether a biologically hazardous situation exists.

6.4.1 General

The intended use of the medical device under evaluation shall be documented. The intended use should include the intended medical indication, patient population, part of the body or type of tissue interacted with, use environment and operating principle. This information shall be used to categorize the medical device in terms of the type and duration of body contact. The categorization enables the identification of potential biological effects and the selection of appropriate data sets for biological risk estimation and evaluation of the biological response.

Categorization of the medical device shall also consider the potential impact of reasonably foreseeable misuse in accordance with ISO 14971, where there is information available (e.g. post-market surveillance data, clinical literature) to suggest that the device can be used outside of its intended use, and this misuse is identified as being systematic.

Body contact can be either direct contact or indirect contact. Direct contact can occur with physical contact in or on the body (e.g. a hip implant or wound dressing), or outside the body (e.g. a blood oxygenating circuit, devices intended for temporary storage and transport of organs for transplantation). Indirect contact can occur by means of transport of constituents within a fluid (gas or liquid) or semi-solid which passes from the medical device to the tissues (e.g. infusion equipment, ventilators).

NOTE

The ISO 18562 series addresses the biological evaluation for gas pathway devices or components.

Some medical devices, such as those with multiple intended uses, can fall into more than one body contact or duration category. In those instances, evaluation appropriate to all applicable categories shall be carried out or the worst-case category shall be justified.

For medical devices that include components that fall into different categories (e.g. both a long-term duration component, and a limited duration delivery system that is used only during a surgical procedure to place the long-term component), either the components shall be categorised separately or, alternatively, the worst-case category shall be applied to all components if justified.

6.4.2 Exposure duration categories

Medical devices shall be categorized in accordance with the anticipated duration of direct contact or indirect contact. With multiple exposures to a device, the duration category shall be based on the total exposure period on a single patient.

If a material or medical device can be placed in more than one duration category, requirements applicable to the longest contact duration shall apply.

Duration categories shall be determined as follows:

1. a) limited exposure: a medical device that has a total exposure period of less than or equal to 24 h;

   NOTE 1

   Further information on evaluation of medical devices in very brief duration tissue contact is provided in 6.5.11.2.

2. b) prolonged exposure: a medical device that has a total exposure period of more than 24 h but not more than 30 d; and
3. c) long-term exposure: a medical device that has a total exposure period of more than 30 d.

NOTE 2

These time periods are for categorization only, and other durations can be justified for risk assessment (e.g. minutes or hours of use) or testing (e.g. hours of use) if applicable, as described in relevant standards, such as ISO 10993-5, ISO 10993-17 and ISO 10993-18.

The rationale for the approach taken for determination of the total exposure period shall be justified and documented. Where device-specific standards provide guidance for categorization, they should be considered.

NOTE 3

For certain medical devices where constituents can remain after removal of the medical device, recategorization following gap analysis (see 6.6) to consider longer exposure can be needed such as for absorbent creams (see 6.5.11.4) or delivery systems with lubricants or coatings.

6.4.3.1 Daily contact

Daily contact is when a medical device contacts the body every day for any portion of a day. For these medical devices, the total exposure period is the number of calendar days from the first to the last use of the medical device or a replacement of the same medical device on a single patient.

6.4.3.2 Intermittent contact

Intermittent contact is the use of the device where there is a period of at least 24 hours between consecutive tissue contacts. This type of contact can be for the repeated use of one medical device or a replacement of the same medical device under consideration.

For these medical devices, the total exposure period is calculated by adding the number of contact days from the first to the last use of the medical device on a single patient. This calculation of total exposure duration applies regardless of how long a single device is used for on a particular day.

6.4.3.3 Bioaccumulation

The potential for bioaccumulation of medical device constituents shall be considered for all duration categories. Where bioaccumulation is expected (e.g. a raw material contains perfluoro-heptanoic acid, a substance known to bioaccumulate in humans), the contact duration of the medical device shall be long-term unless otherwise justified.

During the subsequent biological evaluation of the medical device, where risk for bioaccumulation is identified, the contact duration of the medical device shall be long-term unless otherwise justified.

6.4.4.1 General

Medical devices shall be categorized in accordance with their type and duration of body contact. The associated biological effects are outlined in 6.4.4.2 to 6.4.4.6.

6.4.4.2 Non-contacting medical devices

Non-contacting medical devices are medical devices (or components) which have neither direct contact nor indirect contact with the body. Absence of body contact means that no biological evaluation is required.

NOTE 1

Medical devices used to collect a tissue sample, such as needles, scalpels or lancets are considered to be body contacting.

NOTE 2

Medical devices used to store a tissue sample or body fluid, that is intended to have subsequent body contact, such as organ perfusion systems, are considered to have indirect contact with the body.

6.4.4.3 Medical devices in contact with intact skin

Medical devices in contact with intact skin are medical devices which have only direct contact or indirect contact with intact, uncompromised skin.

For these medical devices, the biological effects listed in Table 1 shall be evaluated.

6.4.4.4 Medical devices in contact with intact mucosal membrane

Medical devices in contact with intact mucosal membrane are surface-contacting medical devices having direct contact or indirect contact with intact mucosal membranes.

For these medical devices, the biological effects listed in Table 2 shall be evaluated.

6.4.4.5 Medical devices in contact with either breached or compromised surfaces (skin or mucosal membranes) or internal tissues other than circulating blood

Medical devices in contact with either breached or compromised surfaces (skin or mucosal membranes) or internal tissues other than circulating blood are:

For these medical devices, the biological effects listed in Table 3 shall be evaluated.

6.4.4.6 Medical devices in contact with circulating blood

Medical devices in contact with circulating blood are medical devices having direct contact or indirect contact with circulating blood, including medical devices that store blood for human use or act as conduits to deliver fluids to or from blood.

This category is not intended to include devices only in contact with bleeding tissue (e.g. a hernia repair graft), which should be categorized as having contact with internal tissues (see 6.4.4.5).

For medical devices in contact with circulating blood, the biological effects listed in Table 4 shall be evaluated.

6.5.1 Overall approach

This subclause provides guidance on the approach to evaluation of each separate biological effect identified and on circumstances which can require modifications in the approach to biological evaluation.

For a specified medical device, all biological effects identified in the relevant table shall be addressed in the biological evaluation and the approach taken shall be justified and documented.

Table 1, Table 2, Table 3 and Table 4 provide a framework for the biological evaluation of a medical device. Where these tables indicate a biological effect for evaluation, existing data sets relevant to that effect should be reviewed to determine if they are adequate to estimate biological risks, or whether additional information or testing is required to obtain reliable biological risk estimates (see 6.9).

If there are device-specific standards that include specific requirements or recommendations regarding biological evaluation or potential biological harms to be assessed, these should be considered in developing the approach to evaluation.

Rationales for changes to the requirements for evaluation of some biological effects included in Tables 1, Table 2, Table 3 and Table 4, compared to the previous version of this document, are provided in Annex B.

6.5.2 Cytotoxicity

Cytotoxicity evaluation is an initial screen for the presence of potential adverse biological effects from the medical device. Therefore, all medical devices having direct contact or indirect contact with the body, irrespective of contact duration, shall be evaluated for potential for cytotoxicity.

NOTE 1

A non-cytotoxic determination in this initial evaluation would not rule out the need for evaluation of other identified biological effects.

NOTE 2

Cytotoxicity data are assessed in relation to other biocompatibility data and the intended use of the product. Any cytotoxic effect can be of concern. However, it is primarily an indication of potential for in vivo toxicity and the device cannot necessarily be determined to be unsuitable for a given clinical application based solely on cytotoxicity data (see ISO 10993-5).

6.5.3 Sensitization

Exposure to constituents that are sensitizers can result in the induction of sensitization or the elicitation of an allergic response in sensitized individuals. Therefore, all medical devices having direct contact or indirect contact with the body, irrespective of contact duration, shall be evaluated for sensitization.

NOTE

Additional information on allergic responses is contained in 6.5.10.2 on immunotoxicity.

6.5.4 Irritation

Irritation can occur either because of the presence of an irritant constituent in or on the medical device, or as a result of a physical interaction, for example, from contact with particles released from a device or from physical interactions with the surface of a medical device. Therefore, all medical devices with direct contact or indirect contact with the body, irrespective of contact duration, shall be evaluated for irritation.

For example, components with indirect contact with blood (e.g. infusion systems) can introduce irritants into the blood stream. These components should be addressed as part of the biological risk assessment.

6.5.5 Systemic toxicity

Medical devices which can introduce constituents or particulates into systemic circulation, lymphatic system or cerebrospinal fluid shall be evaluated for the biological risk of harm from systemic toxicity.

The evaluation of systemic toxicity shall address the potential for adverse biological responses in tissues throughout the body. This evaluation shall include organ systems relevant to the clinical use of the medical device and other organs where chemical-specific toxicities can be relevant.

The duration of body contact is an important determinant of systemic toxicity and more extensive evaluation is required as duration of body contact increases (e.g. acute, sub-acute, sub-chronic and chronic). The approach to the evaluation for systemic toxicity shall be justified and documented.

Unless manufactured from novel materials or intended for use in certain sensitive populations, the evaluation for systemic toxicity is not usually required for medical devices:

However, if other factors apply to the medical device (see 6.5.11), an evaluation for systemic toxicity can be necessary.

Systemic toxicity can be evaluated in a toxicological risk assessment of chemical information. Any toxicological risk assessment shall be conducted in accordance with the requirements of ISO 10993-17 unless otherwise justified.

However, when testing is determined to be necessary, information obtained from comprehensive implantation assessments can also be appropriate to evaluate systemic toxicity if sufficient animals, dosing and timepoints are included and assessed. It is not always necessary to perform separate studies for acute, sub-acute, sub-chronic and chronic systemic toxicity. Such investigations, if appropriately designed and justified, can also combine evaluation of reproductive toxicity and local effects after tissue contact.

6.5.6 Local effects after tissue contact

If a medical device has direct contact with specific tissues or organs, then the local tissue responses to the medical device (including particulates) on those tissues or organs should be evaluated.

The duration of contact is important in the evaluation of local effects after tissue contact and more extensive evaluation is required as duration of body contact increases.

Unless manufactured from novel materials or intended for use in certain sensitive populations, an evaluation for local effects after tissue contact is not usually required for medical devices:

An evaluation for local effects after tissue contact is required for medical devices in prolonged or long-term contact with tissues, except intact skin.

However, if other factors apply to the medical device (see 6.5.11), an evaluation for local effects can be necessary.

When testing is determined to be necessary, studies can be designed to estimate risks of biological harms related to local effects as well as to assess medical device performance or other biological effects such as systemic toxicity and haemocompatibility. Further information is contained in ISO 10993-6.

6.5.7 Genotoxicity

Genotoxicity evaluation is carried out to determine if constituents are present which can result in adverse effects related to genotoxicity. Duration of contact is important in determining the need for a genotoxicity assessment.

Unless manufactured from novel materials or intended for use in certain sensitive populations, an evaluation for genotoxicity is not usually required for medical devices:

However, if other factors apply to the medical device (see 6.5.11), an evaluation for genotoxicity can be necessary.

Evaluation for genotoxicity is required for medical devices in:

However, if the medical device contains constituents known to be genotoxic, the potential for relevant biological harms should be considered in the biological risk assessment irrespective of the type or duration of body contact. Further information is contained in ISO 10993-3.

Genotoxicity can be evaluated in a toxicological risk assessment of chemical information. Any toxicological risk assessment shall be conducted in accordance with the requirements of ISO 10993-17 unless otherwise justified.

6.5.8 Carcinogenicity

Carcinogenicity can be of concern in medical devices resulting from:

Unless manufactured from novel materials or intended for use in certain sensitive populations, evaluation for carcinogenicity is not usually required for medical devices in contact with intact skin. However, if other factors (see 6.5.11) apply to the medical device, an evaluation for carcinogenicity can be necessary.

Medical devices in long term contact with any other tissues, including circulating blood shall be evaluated for carcinogenicity.

In vivo carcinogenicity tests use a large number of animals and are usually of limited sensitivity and relevance to exposure from medical devices. In the absence of any significant cancer risk, it is rare for carcinogenicity tests to be considered appropriate for medical devices. Chemical information and subsequent toxicological risk assessment can provide a basis for the evaluation of carcinogenicity. If the medical device contains constituents known to be carcinogenic, the potential for these harms should be considered in the biological risk assessment irrespective of the type or duration of body contact. Further information is contained in ISO 10993-3. Any toxicological risk assessment shall be conducted in accordance with the requirements of ISO 10993-17 unless otherwise justified.

6.5.9 Haemocompatibility

Devices having direct contact or indirect contact with circulating blood (irrespective of contact duration) can cause adverse interactions with the blood such as haemolysis and thrombosis and shall be evaluated for haemocompatiblity.

Haemocompatibility is affected by constituents and by the surface characteristics of the medical device, including the impact on blood flow. Therefore, understanding of relevant chemical and physical characteristics is important for blood contacting devices and shall be addressed in the biological risk assessment. Further information is contained in ISO 10993-4.

6.5.10.1 Consideration of other effects

In addition to the specific biological effects described in Table 1, Table 2, Table 3 and Table 4, other biological effects relevant to the medical device shall be considered.

The following are specific examples.

6.5.10.2 Immunotoxicity

Immunotoxicity evaluation shall be considered based on:

Understanding of immunotoxicity is a developing science. ISO/TS 10993-20 provides information on the evaluation of immunotoxicology.

6.5.10.3 Neurotoxicity

Medical devices or their constituents that have direct contact or indirect contact with tissues of the central or peripheral nervous system or cerebrospinal fluid shall be evaluated for potential neurotoxicity. This evaluation should consider potential local neurotoxicity (local effects on the central or peripheral nervous tissue in close proximity to the medical device) as well as potential systemic neurotoxicity (systemic neurological effects not localized to the medical device)^[19^].

6.5.10.4 Reproductive and developmental toxicity

Reproductive and developmental toxicity shall be evaluated for medical devices:

Evaluations shall consider the potential effects of medical devices, materials or their constituents on reproductive function, embryonic development (e.g. from exposure to teratogens), and prenatal and early postnatal development. These biological effects can be addressed with a biological risk assessment including chemical identification of impurities, extractable or leachable constituents, patient exposure to these constituents, weight of evidence and mode of action information, if available.

The evaluation for reproductive and developmental toxicity is not usually required for medical devices in contact with intact skin. However, if other factors (see 6.5.11) apply to the medical device, an evaluation for reproductive and developmental toxicity can be necessary.

Chemical information and subsequent toxicological risk assessment can provide a basis for the evaluation of the presence of potential reproductive or developmental toxicants. If the medical device contains constituents known to cause such adverse effects, the potential for these harms shall be considered in the biological risk assessment irrespective of the type or duration of body contact. Further information is contained in ISO 10993-3.

6.5.10.5 Material-mediated pyrogenicity

Pyrogenicity occurs when certain chemical or biological constituents of medical devices induce a febrile response. Chemically induced material-mediated pyrogenicity is rare and has been shown to occur only in the case of a small number of substances, which are not normally found as constituents.^[20^] Pyrogenicity can occur when medical devices are contaminated with biological or pharmaceutical pyrogens.

Medical devices containing constituents that have previously elicited a pyrogenic response or chemical entities where the pyrogenic potential is unknown (e.g. use of a novel material) should be evaluated for material-mediated pyrogenicity.

In many cases, it can be sufficient to present a rationale that;

Further information on material-mediated pyrogenicity is provided in ISO 10993-11: 2017.

NOTE

The evaluation for the presence of bacterial endotoxins and other microbial pyrogens is outside of the scope of this document and is addressed by ISO 11737-3.

6.5.11.1 Consideration of other factors

The biological risk can be influenced by certain other factors. If any of these apply, the approach taken shall be justified and documented.

Other factors include (but are not limited to) those listed in 6.5.11.2 to 6.5.11.9.

6.5.11.2 Medical devices with very brief tissue contact

For medical devices that have very brief contact with the body, typically for less than one minute (e.g. lancets, hypodermic needles, capillary tubes), it is possible to prepare a written justification regarding the negligible potential for biological harm. For products with repeat use during a single 24 h period, the total exposure should be considered.

However, for medical devices that can leave materials in contact with tissues after the medical device is removed (e.g. coatings, lubricants) a more detailed biological evaluation is required.

6.5.11.3 Low risk intact skin contacting medical devices

A medical device or component which meets the following conditions is considered to have low biological risk if:

For these medical devices, a written justification shall be documented to include the materials, relevant prior use, any identified biological risks (e.g. from clinical use of similar medical devices), and why these biological risks would not apply for the medical device under consideration.

6.5.11.4 Absorption through the skin or mucosal membranes

Medical devices such as creams, drops or other topical preparations can result in substantial absorption of constituents through the skin or mucosal membranes. In this case, the biological evaluation shall consider the potential for systemic exposure to constituents released from the device and whether evaluation for systemic effects is required.

6.5.11.5 Materials that change during clinical use

If a medical device is intended to change during its clinical use, such as materials that polymerize or degrade in situ, the evaluation shall take into account all the different device states. For example, for an absorbable adhesive intended to polymerize in situ, the different device states would include starting components, intermediate reaction products, the fully polymerized material and subsequent degradation products.

6.5.11.6 Material degradation

The impact of degradation whether intended or not, shall be evaluated if:

NOTE 1

Degradation can include chemical breakdown, corrosion or physical breakdown. Degradation products include both constituents and particulates (see 6.5.11.7).

NOTE 2

Further information on degradation related to mechanical wear can be found in device-specific standards (e.g. ISO 21535), as well as ISO/TR 10993-22.

In such cases, degradation products and the parameters that affect the rate and extent of degradation shall be documented. For medical devices intended to degrade, the expected mechanism of degradation shall also be documented.

Specific guidance on degradation testing is provided in 6.8.3.

6.5.11.7 Particulates

If a medical device can release particulate materials into the tissues (e.g. from manufacturing residuals, through degradation or wear processes or by any other means) then the impact on biological safety of those particulate materials shall be considered in the biological evaluation.

For biological risk assessment of particulates, the following local and systemic effects shall be considered:

NOTE

ISO/TS 10993-19 provides information on physico-chemical, morphological and topographic characterization of materials. ISO/TR 10993-22 provides specific information on nanomaterials.

6.5.11.8 Toxicokinetics

The purpose of conducting toxicokinetic studies is to evaluate the absorption, distribution, metabolism and excretion (ADME) of a constituent.

The evaluation of toxicokinetics shall be considered:

1. a) if the medical device is designed to be absorbable,
2. b) if the medical device is a long-term contact implant, and degradation or significant corrosion is known or likely,
3. c) if the medical device is likely or known to release substantial quantities of potentially toxic or reactive degradation products or constituents that can be released into the body during clinical use,
4. d) if substantial quantities of nano-objects are likely or known to be released from a medical device into the body during clinical use, or
5. e) for drug and device combination products.

In this context, substantial quantities of constituents are amounts that can result in a risk of biological harm.

The release of degradation products or other constituents from metals, alloys and ceramics is usually too low to justify toxicokinetic studies, unless the material is designed to degrade.

Toxicokinetic studies are not required if the levels of clinical exposure at the expected rates of release of degradation products or other constituents have been demonstrated to be safe. Clinical experience or toxicological data can be used to support this approach.

Specific guidance on toxicokinetics studies is provided in 6.8.4.

6.5.11.9 Presence of hazardous constituents

If material information indicates that one or more constituents with known toxicities are present in a medical device at levels that can be toxic, the biological evaluation shall address the associated biological risk, regardless of the categorization (see 6.3).

6.6.1 General

A gap analysis is a review of the available information to determine if the information is sufficient to carry out a biological risk assessment according to this document.

The gap analysis is first conducted following the initial data gathering. The gap analysis determines if the available information is sufficient either to demonstrate biological equivalence (see 6.7) or to proceed to biological risk estimation (see 6.9). If the information is not sufficient, additional information shall be gathered or generated, and the gap analysis repeated.

Additional information can include physical or chemical characterization, review of data from clinical use, or biological testing of the finished medical device.

The gap analysis shall be documented.

6.6.2 Medical devices evaluated using previous versions of this document

This document shall not be used to mandate re-testing of medical devices that are already on the market and have established and acceptable safety profiles. Instead, the historical information shall be reviewed and documented to determine whether any differences (e.g. change(s) in the medical device design or use since the prior review, additional biological effects, related literature and adverse events) will impact the conclusion of biological safety for the medical device under evaluation. A history of safe clinical use, that includes information relevant to the biological effects under consideration, can be sufficient such that no further biological evaluation is needed. However, if any of the changes described in production and post-production activities (see Clause 10) occur, an evaluation of the biological risks related to the change shall be performed using the current edition of this document.

If no additional biological effects are applicable (see 6.4.4), the update of prior biological evaluation documentation is not required. This shall be justified and documented as part of the review process.

6.7 Biological equivalence

Biological equivalence of a medical device can be demonstrated if the following are shown to be sufficiently similar to another medical device for which there are existing data demonstrating biological safety:

Sufficient similarity is where any differences do not result in any new or increased biological risks.

If biological equivalence is claimed, the demonstration of equivalence shall be documented and justified based on following steps (see Figure 3).

Figure 4 describes the process for determining biological equivalence between two medical devices or materials.

If biological equivalence is demonstrated, then biological safety is established for the new or modified medical device.

Figure 3

Figure 4

6.8.1 General principles

If there are insufficient existing data to demonstrate safety, it can be necessary to carry out testing to obtain reliable estimates of biological risks and to complete the biological evaluation.

The following shall apply when testing of medical devices is considered necessary as part of the overall risk management process.

1. a) Testing shall be performed on the finished medical device, or representative samples from the finished device or materials processed in the same manner as the finished medical device (including sterilization, if applicable). A representative sample can be a worst case taken from a medical device family. The choice of representative sample shall be justified and documented. For example, sample selection should account for process variation or changes that can occur during the medical device life cycle.
2. b) For medical devices with multiple components that are tested separately due to different categorisations (see 6.4), interactions between the components shall be considered (e.g. simulated deployment prior to testing of an implanted component).
3. c) If the medical device includes non-contacting components, the non-contacting components should not be included in the test article, unless justified.
4. d) If the medical device includes both implanted and non-implanted components, and testing is carried out using an extract, the implanted components should not be combined in the same test article with the non-implanted components to prevent dilution of the implanted components, unless justified.
5. e) The choice of test procedures shall consider:

   — type, duration, frequency and conditions of exposure to or contact with the medical device;

   — chemical and physical characteristics of the finished medical device;

   — toxicological activity of any known constituents in the formulation of the finished medical device;

   — the ratio of device surface area to recipient body size and mass;

   — animal welfare provisions (see 4.4); and

   — that in vivo biological tests are not justifiable where valid information related to released constituents and degradation products (including particulates) have been addressed by other means and the constituents have a known and acceptable toxicity profile (see 4.4).

6. f) If extracts of the medical devices are prepared, the solvents and conditions of extraction used should be appropriate to the use of the finished medical device, including consideration for the potential loss of constituents during extraction. Extracts for biological testing shall be prepared in accordance with ISO 10993-12 and extracts for analytical chemistry testing shall be prepared in accordance with ISO 10993-18. Whenever possible, the extraction conditions should represent an exaggeration of use conditions.
7. g) Positive and negative controls should be used where appropriate.

Testing shall be carried out in accordance with appropriate laboratory quality assurance controls [e.g. ISO/IEC 17025, OECD Principals of Good Laboratory Practice (GLP)]. Where test methods not detailed in the ISO 10993 series are used in the biological evaluation, these tests shall be sensitive, precise and accurate.

Where prior testing is considered during initial data gathering (see 6.6), evaluation of that testing shall be conducted and any differences relative to the applicable standards shall be justified and documented.

6.8.2 Biological, physical and chemical testing

If testing is needed, the selection of tests shall be based on device category as determined in accordance with 6.4. A rationale for the testing strategy, as well as for test selection, shall be documented in the biological evaluation plan (see Clause 5). Test protocols, reports and original data, complete to the extent that an independent analysis can be made, shall be evaluated by competent experts and shall be retained.

Any testing shall be performed in accordance with applicable requirements of other parts of the ISO 10993 series as listed in Table 5, unless otherwise justified.

If the characteristics of the device or its use requires a non-standardized test to be used, a scientific justification for the selected alternate test methods shall be documented.

Additional information on testing for materials mediated pyrogenicity is provided in ISO/TR 21582.

6.8.3 Degradation testing

If degradation testing is necessary (see 6.5.11.6), the parameters affecting the rate and extent of degradation shall be described and documented.

Expected degradation mechanisms should be simulated in vitro to estimate the rates of degradation and release of potentially toxic constituents to estimate the exposure. It is also possible that in vivo tests will be required to assess degradation of a material.

In vivo degradation tests can be unnecessary if an in vitro to in vivo comparison has been previously demonstrated and in vitro degradation studies show that only the probable products of degradation are present in the predicted quantities and produced at a rate similar to those that have a history of safe clinical use. When particulate degradation products are generated, tests can be unnecessary if the particulates are present in a quantity and physical state, i.e. size distribution and shape, similar to those with a history of safe clinical use or sufficient degradation data already exist relevant to the constituents and degradation products generated in the intended use.

A general framework for degradation tests is given in ISO 10993-9.

Specific in vitro degradation tests for polymers, ceramics and metals (and alloys) are described in ISO 10993-13, ISO 10993-14 and ISO 10993-15, respectively.

ISO/TS 37137-1 provides information on the evaluation of absorbable medical devices.

When particulate degradation products are present in the form of nanomaterials, tests can be designed considering ISO/TR 10993-22.

6.8.4 Toxicokinetic studies

If toxicokinetic studies are determined to be necessary (see 6.5.11.8), they shall be conducted in accordance with ISO 10993-16.

Where appropriate, theoretical degradation processes shall be investigated using in vitro experiments (e.g. with tissue, homogenates or cells) prior to in vivo toxicokinetic studies. This is for animal welfare reasons as given in ISO 10993-2, and to determine probable rather than possible degradation products.

Specific considerations for toxicokinetic studies with nanomaterials are given in ISO/TR 10993-22.

6.9 Biological risk estimation

Biological risk estimation is an input to determine biological safety. Biological risk estimation requires consideration of severity and probability of occurrence of harm.

For each biologically hazardous situation, the associated biological risk(s) shall be estimated using the data gathered or generated in accordance with applicable parts of Clause 6. Available information from published standards, literature, test data and clinical evidence can be used to estimate biological risk (see 6.1).

The biological risk can be estimated by assigning qualitative or quantitative values to the severity and probability of occurrence of biological harm. These values can be based on qualitative judgement or quantitative calculation, and they are combined to reach the biological risk estimate (for further information, see ISO/TR 24971:2020). The approach used for qualitative or quantitative estimation of the biological risk shall be documented.

The level of uncertainty inherent in the risk analysis shall be taken into account. If there is significant uncertainty due to limitations in relevant data, the risk estimate can be based on reasonable worst-case assumptions.

7 Biological risk evaluation

The identified and estimated biological risks shall be evaluated against the acceptability criteria defined in the biological evaluation plan (see Clause 5).

Examples of acceptability criteria comparisons can include:

Biological safety is established when acceptability criteria are met.

If one or more biological risks do not meet the acceptability criteria, then the following shall be considered:

1. a) refinement of biological risk estimates which can include:

   — the improvement in constituent quantification in accordance with ISO 10993-18;

   — the selection of more appropriate tolerable intake values based on additional gathered literature in accordance with ISO 10993-17; or

   — biological testing (see 6.8).

2. b) implementation of biological risk controls (see Clause 8).

The risks shall then be re-evaluated for acceptability with the following action outcomes:

8 Biological risk control

If estimates of one or more biological risks do not meet the acceptability criteria, then these biological risks shall be controlled (reduced) to the greatest extent feasible.

Where biological risk control is necessary, one or more of the following risk control options shall be used, in the priority order listed (see ISO 14971: 2019):

1. a) inherently safe design and manufacture (e.g. substitute with a less toxic material);
2. b) protective measures in the medical device itself (e.g. application of a barrier around a toxic material) or in the manufacturing process (e.g. addition of a cleaning step to remove a toxic constituent);
3. c) information for safety and, where appropriate, training to users (e.g. contraindications for susceptible individuals, warnings about biological risks from reasonably foreseeable misuse or a risk of biological harm).

If risk control measures are implemented, they shall be evaluated for acceptability (see Clause 7).

If the overall residual biological risk, after risk control measures, is judged acceptable, the manufacturer shall inform users of significant residual biological risks and shall include the necessary information in the accompanying documentation in order to disclose those residual biological risks (see ISO 14971: 2019).

9 Biological evaluation report

After all information has been obtained in accordance with the biological evaluation plan and any biological risk control measures have been implemented and verified, the findings and conclusions shall be documented in the biological evaluation report.

The report shall be prepared by competent personnel (e.g. lead author, contributors). The evidence of competence shall be documented.

The biological evaluation report shall document, as applicable:

1. a) the criteria for determining the acceptability (see Clause 5) of the medical device or medical device family for the intended use or for reasonably foreseeable misuse, in line with the biological evaluation plan;
2. b) conformity with the biological evaluation plan (see Clause 5);
3. c) how each biological effect applicable to the medical device has been addressed;
4. d) the interpretation and assessment of data including historical information, relevance to the finished medical device and the results of relevant physical, chemical or biological testing;
5. e) the rationale for:

   — the selection of tests or waiving of tests, or both, or

   — the use of non-standard test methods not described in any part of the ISO 10993 series;

6. f) the outcomes of the biological risk evaluation (see Clause 7) and associated biological risk estimations (see 6.9);
7. g) any biological risk control (see Clause 8) measures applied;
8. h) identified residual biological risks and overall biological safety conclusions for the medical device.

10 Production and post-production activities

Biological evaluation is conducted within a total life cycle risk management framework. A system shall be established and maintained to actively collect, document and review information relevant to the biological evaluation of the medical device in the production and post-production phases. Therefore, the biological evaluation shall be reviewed whenever changes to design, production processes or emerging post-market information can impact biological safety.

The biological evaluation documentation shall be reviewed and updated as required if any of the following occur:

The review shall consider:

The review shall be documented and include:

A.1 Background information

The selection and characterization of materials used in a medical device are important aspects of the biological evaluation of a medical device.

A.2 Material selection

Material selection and biological risk analysis are integral components of the design process for medical devices and are considered in parallel throughout product development.

The selection of materials plays a crucial role in controlling the biological risk and, when approached in a systematic way, allows the collection of relevant data. In line with ISO 14971, criteria to define the acceptable biological risk are established at the start of the design process.

When selecting materials for a medical device, their suitability is established based on the intended purpose, taking into account their chemical, toxicological, physical, electrical, morphological and mechanical properties. In addition to material selection, manufacturing processes (including sterilization), packaging, transportation or storage can impact finished medical device biological safety. These additional factors are considered in the biological risk assessment.

The biological evaluation is planned and performed to demonstrate the achievement of specified criteria for safety based on outputs of the biological risk analysis or history of use of the same material.

A.3.1 Chemical characterization

From a practical perspective, chemical characterization information (see ISO 10993-18) are most useful in a biological evaluation when:

A.3.2 Use of chemical characterization data in a biological evaluation

Information on constituents of the medical device is useful in identifying potential biological risks.

Evaluation of such information can be used to focus the biological evaluation strategy to address the relevant biological effects for the finished medical device.

Chemical characterization data can also be useful for biological risk estimation. If data are available on the rate at which a constituent is released from the medical device under conditions that simulate the in-use environment, and if sufficient data are available to derive a relevant safety threshold or chemical specific limit, then it is possible to compare the dose received to the relevant threshold or limit in assessing probability of adverse effects.

Analytical chemistry testing is not always necessary if there is sufficient information for biological risk estimation. Additionally, in some cases analytical chemistry testing is not appropriate (e.g. when the medical device is incompatible with extraction solvents or other methods are available to evaluate the biological effect). For example, carcinogenicity evaluation can be performed using available genotoxicity and carcinogenicity information, including from the literature, relevant to the materials of construction and manufacturing processes.

A.3.3 Proprietary material information

Where the necessary data (e.g. complete formulation and manufacturing information) are not available to a manufacturer because of confidentiality of proprietary information, enquiries can be made with the materials supplier as to the availability of biological evaluations for the material, which can be relevant to the proposed application. In some cases, it is possible to manage confidentiality of proprietary formulations by means of separate submission by the owner of the biological evaluation data to an independent assessor or regulatory agency. These data can then be referenced in a regulatory submission by the medical device manufacturer and confidentially reviewed by the relevant conformity assessment body or regulatory agency in conjunction with the medical device submission review. If these methods to obtain relevant proprietary information are not successful, testing can be needed as described in the rest of this document.

A.3.4 Physical characterization

Physical characteristics (e.g. configuration, particle size, porosity, surface texture) can have a substantial effect on biological interactions with the medical device and can impact safety. It is important to consider such aspects as part of the biological evaluation. If there are insufficient data available from literature or other sources to estimate biological risks, then it is possible that further investigations using appropriate functional models or other investigations of the effect of physical characteristics will be necessary. Examples include:

For particulates and nanomaterials (when used in medical devices), physical characterization is necessary, as described for nanomaterials in ISO/TR 10993-22.

A.3.5 Effects of manufacturing processes

It is important to consider the effect of manufacturing conditions on materials and the use of additives or presence of contaminants. In general, to support biological safety, testing is performed on test samples processed and sterilised (if applicable) in equivalent ways to the finished medical device. Where the material processing differs from that used to produce test articles to generate the test data, a justification is required to explain why the differences are not significant to the determination of biological safety. Particular aspects to consider include:

B.1 Background information

This Annex summarizes the key changes between the fifth edition of this document (i.e. ISO 10993-1:2018) and this edition of this document in device categorization and in biological effects to be considered for evaluation and provides the rationale for these changes.

B.2 Changes to device contact categories

In this document, the number of contact categories has been simplified to four groups of devices in contact with:

Externally communicating medical devices are no longer a separate contact category and are not separately referenced in this document as the term externally communicating was challenging to translate in some regions. The recommended biological effects for externally communicating medical devices for the relevant type and duration of contact are now included either:

B.3 Changes to the presentation of systemic toxicity

The prior edition of this document (i.e. ISO 10993-1:2018) included acute, subacute, sub-chronic and chronic toxicity in Table A.1. This current edition of this document includes a general category of systemic toxicity and indicates in the table footnotes that the evaluations for systemic toxicity should reflect the duration of use.

B.4.1 Overview

The prior edition of this document (i.e. ISO 10993-1:2018) did not include consistent recommendations for genotoxicity and carcinogenicity evaluation for medical device categories with the same types and durations of contact. This current edition of this document has introduced some changes to address these inconsistencies as indicated in B.4.2 to B.4.3.

B.4.2 Genotoxicity evaluation of prolonged contact (>24 h to 30 d) medical devices

A genotoxicity evaluation has been added for medical devices contacting mucosal, breached or compromised surfaces and having indirect contact with blood (see Table 2, Table 3 and Table 4). Genotoxicity assessment is now applicable for all medical devices with prolonged contact, except for medical devices with only intact skin contact.

The development of cancer is considered a multistage process.^[21^][22^] Each additional exposure to a genotoxic constituent increases the risk for cancer development. When the exposure is systemic, a genotoxic constituent can reach multiple tissues increasing the risk. Therefore, a genotoxicity evaluation is applicable for all prolonged contact medical devices requiring a systemic toxicity evaluation.

A genotoxicity evaluation can be used as a potential screen for carcinogens.^[23^] Therefore, if the outcome of the genotoxicity evaluation indicates that a genotoxic constituent is present, an evaluation for genotoxic carcinogenicity is applicable.

The development of cancer by a non-genotoxic mechanism requires long-term exposure and is not expected to occur in prolonged contact.^[16^] Therefore, for prolonged contact, an evaluation for non-genotoxic carcinogenicity is considered unnecessary.

B.4.3 Carcinogenicity evaluation of long-term contact (>30 d) medical devices

A carcinogenicity evaluation is applicable for all long-term contact medical devices where chronic toxicity is evaluated. Therefore, a carcinogenicity evaluation has been added for medical devices with long-term mucosal contact (see Table 2).

B.5 Omission of material-mediated pyrogenicity from Table 1 to Table 4

Material-mediated pyrogenicity has been removed from Table 1, Table 2, Table 3 and Table 4 because this biological effect is rare and has been shown to occur only in the case of a small number of constituents. Guidance on material-mediated pyrogenicity is now located in 6.5.10.5 as part of other biological effects for evaluation.

Bibliography