ISO/DIS 21762:2025(en)

ISO/TC 194

Secretariat: DIN

Date: 2025-07-21

Medical devices utilizing non-viable human materials — Risk management

Dispositifs médicaux utilisant des matériaux humains non viables — Gestion des risques

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Contents Page

Foreword 5

Introduction 6

1 Scope 1

2 Normative references 1

3 Terms and definitions 2

4 General requirements for risk management system 4

4.1 Risk management process 4

4.2 Management responsibilities 4

4.3 Competence of personnel 5

4.4 Risk management plan 5

4.5 Risk management file 5

5 Risk analysis 5

5.1 Risk analysis process 5

5.2 Intended use and reasonably foreseeable misuse 5

5.3 Identification of characteristics related to safety 5

5.4 Identification of hazards and hazardous situations 6

5.5 Risk Estimation 7

6 Risk evaluation 7

7 Risk control 7

7.1 Risk control option analysis 7

7.2 Implementation of risk control measures 7

7.2.1 General 7

7.2.2 Risk control for viruses and TSE agents and other transmissible agents 7

7.2.3 Risk control of other hazards 7

7.3 Residual risk evaluation 8

7.3.1 General 8

7.3.2 Risks for TSE agents and other transmissible agents 8

7.4 Benefit-Risk analysis 8

7.5 Risks arising from risk control measures 8

7.6 Completeness of risk control 8

8 Evaluation of overall residual risk acceptability 9

8.1 General 9

8.2 Documentation 9

9 Risk management review 9

10 Production and post-production activities 9

Annex A (informative) Guidance on the application of this document 10

A.1 General 10

A.2 Application to materials from human sources 10

A.3 Application to materials supplied by third parties 10

Annex B (informative) Graphical representation of part of the risk management process for medical devices utilizing human material 11

Annex C (informative) Information relevant to the management of TSE risk and other transmissible agents 12

C.1 General 12

C.2 Risk management for TSE agents 12

C.2.1 Principle 12

C.2.2 Nature of starting tissue 12

C.2.3 Methods used to inactivate or remove TSE agents (see ISO 22442-3) 13

C.2.4 Exposure to TSE risk 13

C.2.4.1 Quantities of human starting material required to produce one unit of the medical device 13

C.2.4.2 Quantities of material of human origin coming into contact with the patients and users over lifetime 13

C.2.4.3 Route of administration 13

C.2.4.4 Estimate of exposure risk 14

Bibliography 15

Foreword

ISO (the International Organization for Standardization) and IEC (the International Electrotechnical Commission) form the specialized system for worldwide standardization. National bodies that are members of ISO or IEC participate in the development of International Standards through technical committees established by the respective organization to deal with particular fields of technical activity. ISO and IEC technical committees collaborate in fields of mutual interest. Other international organizations, governmental and non-governmental, in liaison with ISO and IEC, also take part in the work.

The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of document should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO and IEC shall not be held responsible for identifying any or all such patent rights. Details of any patent rights identified during the development of the document will be in the Introduction and/or on the ISO list of patent declarations received (see www.iso.org/patents) or the IEC list of patent declarations received (see http://patents.iec.ch).

Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO's adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see www.iso.org/iso/foreword.html.

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, Biocompatibility of medical and dental materials and devices, in accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).

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

Certain medical devices utilize materials of human origin.

Human tissues and their derivatives are used in the design and manufacture of medical devices to provide performance characteristics that have been chosen for advantages over options which are lower risk from a transmissible agent perspective. The range and quantities of materials of human origin in medical devices vary. These materials can comprise a major part of the device e.g. demineralised or mineral sintered bones, heart valves, acellular cornea, placenta and amniotic membranes, dermis, tendons).

ISO 14971 is a general standard which specifies a process for a manufacturer by identifying hazards and hazardous situations associated with medical devices, including in vitro medical devices, to estimate and evaluate the risks associated with those hazards, to control these risks and to monitor the effectiveness of the control throughout the life cycle. This document provides additional requirements and guidance for the evaluation of medical devices manufactured utilizing human tissues or derivatives which are non-viable or rendered non-viable.

This document is intended to cover medical devices including active implantable medical devices such as implantable infusion pumps.

This document does not apply to in vitro diagnostic devices.

This document can only be used in combination with ISO 14971 and is not a “stand-alone” standard.

NOTE Compliance to this document is shown by fulfilling its specified requirements. The guidance given in the notes and the informative annexes is not normative and is not provided as a checklist for auditors.

Medical devices utilizing non-viable human materials —Risk management

This document applies to medical devices other than in vitro diagnostic medical devices manufactured utilizing human materials which are non-viable or have been rendered non-viable. The document 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 determining the acceptability of residual risks, taking into account the risk profile and expected benefit as compared to available alternatives, in line with ISO 14971. This document is intended to provide requirements and guidance on risk management related to the hazards typical of medical devices manufactured utilizing human materials such as:

a) contamination by bacteria, moulds, yeasts or parasites;

b) contamination by viruses;

c) contamination by agents causing transmissible spongiform encephalopathies (TSEs) and other transmissible agents;

d) material responsible for undesired pyrogenic, immunological or toxicological reactions.

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.

This document does not specify a quality management system for the control of all stages of production of 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 does not address requirements for consent to donation of human materials.

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 14971:2019, Medical devices — Application of risk management to medical devices

ISO 22442‑3, Medical devices utilizing animal tissues and their derivatives — Part 3: Validation of the elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents

For the purposes of this document, the terms and definitions given in ISO 14971 and the following apply.

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

— ISO Online browsing platform: available at https://www.iso.org/obp

— IEC Electropedia: available at https://www.electropedia.org/

3.1

human

Homo sapiens

3.2

animal

vertebrate or invertebrate [including amphibian, arthropod (e.g. crustacean), bird, coral, fish, reptile, mollusc and mammal] excluding humans (Homo sapiens)

3.3

cell

smallest organized unit of any living form which is capable of independent existence and of replacement of its own substance in a suitable environment

[SOURCE: ISO 22442-1:2020, 3.2]

3.4

derivative

substance obtained from processed human material

EXAMPLE Collagen, human serum albumin, thrombin, urokinase.

Note 1 to entry: Some materials included in this definition may be considered to be derivatives in some jurisdictions but not in others.

3.5

human material

cells, tissues or exudates obtained from a human (3.1) donor which have been rendered non viable

Note 1 to entry: Human DNA extracted for genetic purposes is excluded.

3.6

exudate

substance that is made by the human body that are not tissues or cells

EXAMPLE Hair, urine, bile, milk.

3.7

elimination

removal

process by which the number of transmissible agents is reduced

[SOURCE: ISO 22442-1:2020 3.4]

Note 1 to entry: The effectiveness of the process for the elimination of viruses and TSE and other transmissible agents should be expressed mathematically in terms of a reduction factor (see clause C.2 and ISO 22442-3:2007, Annex F).

Note 1 to entry: Elimination aims to prevent infection or pathogenic reaction caused by transmissible agents.

3.8

inactivation

process by which the ability to cause infection or pathogenic reaction by a transmissible agent is reduced

Note 1 to entry: The effectiveness of the process for inactivation of viruses and TSE and other transmissible agents should be expressed mathematically in terms of a reduction factor (see ISO 22442-3:2007, Annex F).

Note 2 to entry: Inactivation aims to prevent infection by, and replication of, transmissible agents.

3.9

medical device

instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software, material or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings, for one or more of the specific medical purpose(s) of

— diagnosis, prevention, monitoring, treatment or alleviation of disease,

— diagnosis, monitoring, treatment, alleviation of or compensation for an injury,

— investigation, replacement, modification, or support of the anatomy or of a physiological process,

— supporting or sustaining life,

— control of conception,

— disinfection of a medical device,

— providing information by means of in vitro examination of specimens derived from the human body,

and which does not achieve its primary intended action by pharmacological, immunological or metabolic means, in or on the human body, but which can be assisted in its function by such means

Note 1 to entry: Products which could be considered to be medical devices in some jurisdictions but not in others include:

— disinfection substances;

— aids for persons with disabilities;

— devices incorporating animal (3.2) and/or human (3.1) tissues;

— devices for in vitro fertilization or assisted reproduction technologies.

[SOURCE: ISO/IEC Guide 63:2019, 3.7]

3.10

non-viable

having no potential for metabolism or multiplication

3.11

supplier agreement

binding contract between two or more parties that assigns responsibilities for technical requirements

3.12

tissue

organization of cells (3.3) and/or extra-cellular constituents

Note 1 to entry: Some materials included in this definition may be considered to be tissues in some jurisdictions but not in others.

3.13

transmissible agents

bacteria, mould, yeast, parasites, viruses, TSE agents and unclassified pathogenic entities

The requirements of ISO 14971 apply. Compliance with these requirements shall be verified by inspection of the appropriate documents, e.g. the risk management file.

The manufacturer shall document the rationale for the use of human material (including the choice of tissues).

The organization responsible for manufacturing the medical device, shall specify, in a supplier agreement, the principles to be applied, in line with this document, for the sourcing of human material, including:

— Technical specifications;

— Donor screening and assessment;

— Clinical assessment and disease status;

— Informed consent;

— Ethical conduct;

— Anonymisation and traceability;

— Certification of origin;

— Audit of sourcing procedures.

The organization responsible for sourcing human material shall conduct and document sourcing in line with the terms and conditions of the supplier agreement and maintain and document traceability of the human material to the donor.

NOTE National or regional regulations can apply.

A process shall be established to verify and document the provenance of human material to provide evidence of ethical and regulatory compliance.

ISO 14971:2019, 4.3 applies.

ISO 14971:2019, 4.4 applies.

ISO 14971:2019, 4.5 applies.

ISO 14971:2019, 5.1 applies.

ISO 14971:2019, 5.2 applies.

5.3.1.1 Contact with the patient or other person

The following factors shall be addressed, if applicable:

a) the quantity of human material considering the lifetime of the device and cumulative effect i.e. the number of devices which could be used in a single procedure and over the lifetime of the patient;

b) the contact surface area;

c) the type(s) of human material coming into contact with body tissues or fluids;

d) the type of body tissue or fluid it comes into contact with.

NOTE 1 The quantity of human material coming into contact is one of the factors in producing biological effects. See ISO 10993 series for the evaluation of such effects.

NOTE 2 The structure of human material being processed can affect the inactivation and/or elimination of transmissible agents, and the potential for retaining viable cells can be affected by the structure of the human tissues and derivatives being processed.

5.3.1.2 Materials and/or components incorporated in the medical device or used with, or in contact with, the medical device

The following factors shall be addressed, if applicable:

a) if viable human materials are utilized in the manufacture of the medical device, verification that the final medical device contains no viable human material;

b) the intended use of any human material and its expected function in the device;

c) age of the donors;

d) known health conditions of the donor(s) which could present a risk;

e) the type and anatomical source of the human material;

f) the production process, particularly if it uses human materials pooled from more than one donor;

g) the nature of human material utilized in the medical device (e.g. intact tissue, decellularized tissue, derivative);

h) the method of utilization or incorporation into the medical device;

i) the evaluation of the production process in regards to the potential to concentrate levels of transmissible agents potentially present in the starting tissues or derivatives;

j) the potential bioburden in the human material;

k) the potential cross contamination during collection of the human material, transportation, storage and processing and utilization in the medical device;

In the case of medical devices utilizing several relevant constituents (e.g. from various origins or tissues) or several similar types of constituents produced using different methods, each individual constituent should be analysed separately.

5.3.1.3 Devices supplied sterile or intended to be sterilized by the user

Given the biological nature of human materials or derivatives, variations in the bioburden of the medical device shall be estimated.

NOTE See also ISO 11737-1 and ISO 14160.

5.3.1.4 Unwanted outputs of substances

The possible presence of toxic residue related to the manufacturing process utilized or degradation by-products shall be addressed taking into account the physical characteristics (e.g. porosity, heterogeneity) and chemical composition of human materials or derivatives.

NOTE See also ISO 10993-1, ISO 10993-9, ISO 10993-17, ISO 10993-18 and ISO/TS 10993-19.

The possible hazards associated with human materials or derivatives shall be identified and documented. Particular attention shall be applied to possible hazards posed by human materials or derivatives with regard to:

— potential contamination or cross contamination by viruses and other transmissible agents and their susceptibility to elimination and/or inactivation during processing;

— potential for contaminants on the finished material which can cause an undesired pyrogenic, immunological or toxicological reaction;

— potential for the finished material itself to cause an undesired pyrogenic, immunological or toxicological reaction.

ISO 14971:2019, 5.5 applies.

In accordance with ISO 14971, all identified risks shall be evaluated. Biological safety can be evaluated according to ISO 10993-1. Risk evaluation for transmissible agents shall be implemented by separately addressing the risks related to different categories of transmissible agents. Annex B identifies the main categories of risk that should be considered.

The risk control options shall be documented and justified.

The flowchart in Annex B gives an overview of the risk management process. If additional risks are identified when using this document, the medical device manufacturer may choose to follow any other relevant standard or any other route. The decision should be justified and documented.

ISO 14971:2019, 7.2 applies.

Risk control shall be implemented by separately addressing the risks related to different categories of viruses, TSE agents and other transmissible agents. After defining the characteristics of the product, the medical device manufacturer shall comply with the relevant requirements for procurement. and ISO 22442-3 for guidance in regards to inactivation.

The principles for the conduct of literature review and inactivation studies in ISO 22442-3 shall be considered. If exceptions to ISO 22442-3 are made, these exceptions shall be documented and justified.

For medical devices where an inactivation process causes unacceptable degradation, manufacturers may rely on controls in procurement in order to meet the requirements of this document.

NOTE Criteria and principles relevant to the management of TSE risks are described in Annex C. Annex C contains information on relevant risk control measures.

Risk control related to bacteria, moulds and yeasts, and parasites as well as undesired pyrogenic, immunological and toxicological reactions shall be implemented according to available standards.

The manufacturer shall conduct periodic microbiological studies to identify and quantify the initial bioburden of the incoming human material for the production of the medical device.

NOTE The following international standards can be relevant:

a) ISO 11135, ISO 11137 series, ISO 11737-1, the ISO 13408 series, ISO 14160, ISO 14937, ISO 17664-1 and ISO 17665, which can be relevant for bacteria, moulds and yeasts;

b) ISO 10993‑2, ISO 10993‑3, ISO 10993‑4, ISO 10993‑5, ISO 10993‑6, ISO 10993‑7, ISO 10993‑9, ISO 10993‑10, ISO 10993‑11, ISO 10993‑12, ISO 10993‑13, ISO 10993‑14, ISO 10993‑15, ISO 10993‑16, ISO 10993‑17, ISO 10993‑18, ISO/TS 10993‑19 and ISO/TS 10993‑20, ISO 10993-23 which can be used to manage risks related to undesired pyrogenic, immunological or toxicological reactions.

The use of these documents is illustrated in Annex B.

Residual risk evaluation shall be performed for each risk.

The risks for TSE agents and other transmissible agents may be judged acceptable if the following criteria are both met, taking into account the availability of alternative materials:

a) the residual risk estimate indicates that the TSE and other transmissible agent risk has been controlled at an acceptable level;

b) the benefit arising from the intended use of the device is judged to outweigh the residual risk estimate.

NOTE Guidance on risk management applicable to TSE agents is given in Annex C.

Where the TSE and other transmissible agent risk has not been controlled at a level that presents an acceptable level of risk to users or recipients, the overall risk may only be judged acceptable when balanced by exceptional benefit and feasibility considerations.

ISO 14971:2019, 7.4 applies.

ISO 14971:2019, 7.5 applies.

ISO 14971:2019, 7.6 applies.

The acceptability of the overall residual risk shall be justified taking into account the risk profile and how the chosen human materials support the expected benefits of the medical device, and the acceptability of the residual risks, as compared to available alternatives.

NOTE The term benefit is defined in ISO 14971. Further guidance on benefit-risk analysis, benefit estimation, and the evaluation of overall residual risks can be found in ISO/TR 24971:2020, 7.4 and clause 8.

The evaluation of the overall residual risk acceptability shall take into account the balance between the residual risk after implementation of all risk control measures and the expected medical benefit, as compared to available alternatives. Where residual risks exist with regard to the contamination with transmissible agents, the evaluation should specifically discuss the risks and benefits of

— using alternative materials that do not present the risk of contamination with these transmissible agents, such as synthetic materials, materials from biologic (other than animal or human tissue) origin, materials from animal origin, or materials from human origin, and

— applying whole product alternatives for the same intended purposes.

Where the risk has not been controlled at a level that presents an acceptable level of risk to users or recipients, the overall risk may only be judged acceptable when balanced by exceptional benefit and feasibility considerations.

The rationale that the risk is acceptable shall be documented in the risk management file.

ISO 14971:2019, clause 9 applies.

Manufacturers shall ensure that the quality management system in place periodically identifies changes in the epidemiological status of the chosen source of human materials and documents the results of identification. The periodic frequency needs to be justified according to the overall human material risk evaluation. Any change in epidemiological status of the source material shall be considered in the risk management evaluation in view of the updated risks identified and considering the risk control options implemented. Relevance of the risk management conclusion shall be discussed periodically.

1. 
   (informative)
   
   Guidance on the application of this document
   1. General

Wherever in this document it is stated that something “be addressed”, the reader should either take action to control the risk or justify in the risk management report why they have not done so.

• 1. Application to materials from human sources

This document is applicable to human materials such as:

— heart valves, bones, ligaments, amniotic membranes, cornea

— derivatives of human tissues, such as collagen obtained from human tissue such as skin or tendons;

— materials produced in vivo extracted from human blood, e.g. antibodies utilized in the manufacturing process.

• 1. Application to materials supplied by third parties

This document can be applied when the materials used by medical device manufacturers have been prepared from human sources by third parties or subcontractors. In considering the risks associated with the use of these products, the medical device manufacturers should seek evidence from their suppliers as to whether relevant requirements of this document have been applied in assessing the suitability of the human material or whether alternative approaches were applied. The information obtained should be incorporated in the risk management report relating to the medical device, as appropriate, but may need to be supplemented by information supplied by the third party or subcontractor.

1. 
   (informative)
   
   Graphical representation of part of the risk management process for medical devices utilizing human material

Figure B.1 — Graphical representation of part of the risk management process

This chart illustrates part of the risk management process in accordance with ISO 14971 and this document. The risk management process should address all relevant risks shown in this chart.

1. 
   (informative)
   
   Information relevant to the management of TSE risk and other transmissible agents
   1. General

The naturally occurring TSEs include Kuru and Creutzfeldt-Jakob disease (CJD) in humans. It is difficult to detect agents causing these diseases in vivo. After latency periods of up to many years the agents cause disease and, finally, lead to death. No means of therapy is known.

Current information on the characteristics of the causative agents is limited. These agents are extremely resistant to most of the chemical and physical procedures that inactivate conventional viruses. They do not induce a detectable immune response. There are natural barriers that limit their interspecies spread of transmissible agent, but they can be crossed under appropriate circumstances. This is usually dependent upon strain, dose, route of exposure and the species barrier. Studies in laboratory animals have shown that intracerebral inoculation is the most efficient route of transmission.

• 1. Risk management for TSE agents
     1. Principle

The safety of a medical device, in terms of its potential for passing on a TSE agent, is dependent on a number of factors. The seven most important factors below should be analysed, evaluated and managed:

— Age of the donors and absence of known conditions of the donors;

— nature of starting tissue (see C.2.2);

— compliance to procurement controls;

— methods used to inactivate or remove TSE agents (see C.2.3);

— quantities of human starting material required to produce one unit of the medical device (see C.2.4.1);

— quantities of material of human origin coming into contact with the patients and users (see C.2.4.2) over lifetime;

— route of administration (see C.2.4.3).

• • 1. Nature of starting tissue

The manufacturer should take into account the classification of the hazards relating to different types of starting tissue. The manufacturer should not source human tissue classified as having potentially high TSE infectivity.

A classification of the hazards relating to different types of animal starting material has been established and approved by the World Health Organization.^[42] Risk assessments should be revised in the light of more recent information, as it becomes available, and should take into account the level of uncertainty inherent in the data available.

• • 1. Methods used to inactivate or remove TSE agents (see ISO 22442-3)

For devices that cannot withstand an inactivation/elimination process without undergoing unacceptable degradation, the manufacturer should rely principally on the control of sourcing.

For other devices, if claims are made by the manufacturer for the ability of manufacturing processes to remove or inactivate TSE agents, these should be substantiated by appropriate documentation. Relevant information from an appropriate scientific literature review can be used to support inactivation/elimination factors, where the specific processes referred to in the literature are comparable to those used for the device.

When the literature review fails to substantiate the claims, the manufacturer should conduct a specific inactivation and/or elimination study and the following should be addressed by the study:

— the identified hazard associated with the tissue;

— identification of the relevant model TSE agents;

— rationale for the choice of the particular combinations of model TSE agents;

— identification of stage chosen to eliminate and/or inactivate the TSE agents;

— calculation of the reduction factors.

A final report should identify manufacturing parameters and limits that are critical to the effectiveness of the inactivation or elimination process.

Appropriate documented procedures should be applied to ensure that the validated processing parameters are applied during routine manufacture.

• • 1. Exposure to TSE risk
       1. Quantities of human starting material required to produce one unit of the medical device

The manufacturer should evaluate the quantity of raw tissues or derivatives of human origin required to produce a single unit of the medical device. The manufacturer should assess whether the production process has the potential to concentrate levels of TSE agents present in the human starting tissues or derivatives.

• • • 1. Quantities of material of human origin coming into contact with the patients and users over lifetime

Manufacturers should consider the maximum quantity of human material that might come into contact with the patients and users (including any absorption and/or degradation). The manufacturer must consider the period of time the device is intended to remain in contact with the body (including bioresorption effect). The number of medical devices that could be used in a given procedure and the number of treatments should be taken into account or, if possible, over the lifetime of a patient or user.

• • • 1. Route of administration

Account should be taken of the route of administration recommended in the product information. From the highest risk down to the lowest, the list is:

a) products coming into contact with the central nervous system (including intra-ocular route);

b) products coming into contact with the central circulatory system or parenterally administered or invasive devices or devices used on open wounds, including ulcer preparations;

c) products requiring administration on intact mucous membranes e.g. conjunctival, intranasal, bronchial, rectal, vaginal, vesical; products required to remain in the mouth (buccal, sublingual) or to be swallowed;

d) products to be applied to undamaged external skin.

• • • 1. Estimate of exposure risk

The degree of exposure to TSE risk and the effect of this on the overall TSE risk should be estimated.

Bibliography

[1] ISO/TR 24971:2020, Medical devices — Guidance on the application of ISO 14971

[2] ISO 22442‑1, Medical devices utilizing animal tissues and their derivatives — Part 1: Application of risk management

[3] ISO 10993‑1, Biological evaluation of medical devices — Part 1: Requirements and general principles for the evaluation of biological safety within a risk management process

[4] ISO 10993‑2, Biological evaluation of medical devices — Part 2: Animal welfare requirements

[5] ISO 10993‑3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity

[6] ISO 10993‑4, Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood

[7] ISO 10993‑5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity

[8] ISO 10993‑6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation

[9] ISO 10993‑7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals

[10] ISO 10993‑9, Biological evaluation of medical devices — Part 9: Framework for identification and quantification of potential degradation products

[11] ISO 10993‑10, Biological evaluation of medical devices — Part 10: Tests for skin sensitization

[12] ISO 10993‑11, Biological evaluation of medical devices — Part 11: Tests for systemic toxicity

[13] ISO 10993‑12, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials

[14] ISO 10993‑13, Biological evaluation of medical devices — Part 13: Identification and quantification of degradation products from polymeric medical devices

[15] ISO 10993‑14, Biological evaluation of medical devices — Part 14: Identification and quantification of degradation products from ceramics

[16] ISO 10993‑15, Biological evaluation of medical devices — Part 15: Identification and quantification of degradation products from metals and alloys

[17] ISO 10993‑16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for degradation products and leachables

[18] ISO 10993‑17, Biological evaluation of medical devices — Part 17: Toxicological risk assessment of medical device constituents

[19] ISO 10993‑18, Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process

[20] ISO/TS 10993‑19, Biological evaluation of medical devices — Part 19: Physico-chemical, morphological and topographical characterization of materials

[21] ISO/TS 10993‑20, Biological evaluation of medical devices — Part 20: Principles and methods for immunotoxicology testing of medical devices

[22] ISO 10993‑23, Biological evaluation of medical devices — Part 23: Tests for irritation

[23] ISO 11135, Sterilization of health-care products — Ethylene oxide — Requirements for the development, validation and routine control of a sterilization process for medical devices

[24] ISO 11137 (all parts), Sterilization of health care products — Radiation

[25] ISO 11737‑1, Sterilization of health care products — Microbiological methods — Part 1: Determination of a population of microorganisms on products

[26] ISO 13408 (all parts), — Aseptic processing of health care products

[27] ISO 13485, Medical devices — Quality management systems — Requirements for regulatory purposes

[28] ISO 14160, Sterilization of health care products — Liquid chemical sterilizing agents for single-use medical devices utilizing animal tissues and their derivatives — Requirements for characterization, development, validation and routine control of a sterilization process for medical devices

[29] ISO 14937, Sterilization of health care products — General requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices

[30] ISO 17664‑1, Processing of health care products — Information to be provided by the medical device manufacturer for the processing of medical devices — Part 1: Critical and semi-critical medical devices

[31] ISO 17665, Sterilization of health care products — Moist heat — Requirements for the development, validation and routine control of a sterilization process for medical devices

[32] European Pharmacopoeia, General chapter 2.6.30. Monocyte-activation test (MAT)

[33] European Pharmacopoeia, 2.6.14 Bacterial endotoxins

[34] European Pharmacopoeia, 5.2.8 Minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products

[35] US Pharmacopeia <85> Bacterial Endotoxins Test

[36] US Pharmacopeia <151> Pyrogen Test

[37] US Pharmacopeia<86> Bacterial Endotoxins Test using Recombinant Reagents

[38] Supplement 1, Japanese Pharmacopoeia XIV, 17. Basic Requirements for Viral Safety of Biotechnological/Biological Products, listed in Japanese pharmacopoeia, pp. 1618-1631, 2003

[39] Global Harmonization Task Force (GHTF) — Study Group 1 (SG1) Document No. N071:2012 (http://www.ghtf.org)

[40] WHO Guidelines on Transmissible Spongiform Encephalopathies in relation to Biological and Pharmaceutical Products, 2003 (https://www.who.int/bloodproducts/publications/en/WHO_TSE_2003.pdf)

[41] WHO Guidelines on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies. 2006 (https://www.who.int/bloodproducts/TSEPUBLISHEDREPORT.pdf)

[42] WHO Tables on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies. Updated 2010 (https://www.who.int/bloodproducts/tablestissueinfectivity.pdf)

[43] EMEA/410/01 Rev.3 — June 2011, Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee for Veterinary Medicinal Products (CVMP) — Official Journal of the European Union 5.3.2011

[44] Terrestrial Animal Health Code from OIE — Office International des Epizooties/World Organisation for Animal Health. https://www.oie.int/

[45] No N. 177 of the Ministry of Health, Labour and Welfare on the standard for biological ingredients, 31 March 2005 on Standards for Raw Materials Originating from Living Organisms (in Japanese)

[46] Assessment of Risk of Bovine Spongiform Encephalopathy in Pharmaceutical Products, Part 1, Pharmaceutical Research and Manufacturers of America (PhRMA) BSE Committee, BioPharm., 11, Number 1, pp 20-31, 56, January, 1998

[47] Assessment of Risk of Bovine Spongiform Encephalopathy in Pharmaceutical Products, Part 2, Example Risk Assessment for a Hypothetical Product, Pharmaceutical Research and Manufacturers of America (PhRMA) BSE Committee, BioPharm., 11, Number 3, pp 18-30, March, 1998