ISO 22442-1:2020
(Main)Medical devices utilizing animal tissues and their derivatives — Part 1: Application of risk management
Medical devices utilizing animal tissues and their derivatives — Part 1: Application of risk management
This document applies to medical devices other than in vitro diagnostic medical devices manufactured utilizing materials of animal origin, which are non-viable or have been rendered non-viable. It specifies, in conjunction with ISO 14971, a procedure to identify the hazards and hazardous situations associated with such devices, to estimate and evaluate the resulting risks, to control these risks, and to monitor the effectiveness of that control. Furthermore, it outlines the decision process for the residual risk acceptability, taking into account the balance of residual risk, as defined in ISO 14971, and expected medical benefit as compared to available alternatives. This document is intended to provide requirements and guidance on risk management related to the hazards typical of medical devices manufactured utilizing animal tissues or derivatives such as: a) contamination by bacteria, moulds or yeasts; b) contamination by viruses; c) contamination by agents causing transmissible spongiform encephalopathies (TSE); d) material responsible for undesired pyrogenic, immunological or toxicological reactions. For parasites and other unclassified pathogenic entities, similar principles can apply. This document does not stipulate levels of acceptability which, because they are determined by a multiplicity of factors, cannot be set down in such an international standard except for some particular derivatives mentioned in Annex C. Annex C stipulates levels of TSE risk acceptability for tallow derivatives, animal charcoal, milk and milk derivatives, wool derivatives and amino acids. This document does not specify a quality management system for the control of all stages of production of medical devices. This document does not cover the utilization of human tissues in medical devices. NOTE 1 It is not a requirement of this document to have a full quality management system during manufacture. However, attention is drawn to international standards for quality management systems (see ISO 13485) that control all stages of production or reprocessing of medical devices. NOTE 2 For guidance on the application of this document, see Annex A.
Dispositifs médicaux utilisant des tissus animaux et leurs dérivés — Partie 1: Application de la gestion des risques
Le présent document s'applique aux dispositifs médicaux autres que les dispositifs médicaux de diagnostic in vitro, dans la fabrication desquels entrent des matériaux d'origine animale non viables ou rendus non viables. Associé à l'ISO 14971, il spécifie un mode opératoire permettant d'identifier les dangers et les situations dangereuses associés à de tels dispositifs, d'estimer et d'évaluer les risques qui en découlent, de maîtriser ces risques et de surveiller l'efficacité de cette maîtrise. En outre, il décrit le processus décisionnel relatif à l'acceptabilité du risque résiduel, en tenant compte du rapport entre le risque résiduel, tel que défini dans l'ISO 14971, et le bénéfice médical escompté par rapport aux solutions de remplacement disponibles. Le présent document est destiné à fournir des exigences et des préconisations pour la gestion des risques associée aux dangers typiques des dispositifs médicaux dans la fabrication desquels entrent des tissus ou des dérivés d'origine animale, notamment: a) la contamination par des bactéries, des moisissures ou des levures; b) la contamination par des virus; c) la contamination par des agents responsables d'encéphalopathies spongiformes transmissibles (EST); d) un matériau provoquant des réactions pyrogènes, immunologiques ou toxicologiques indésirables. Des principes similaires peuvent s'appliquer aux parasites et autres entités pathogènes non classées. Le présent document ne stipule pas de niveaux d'acceptabilité qui, du fait qu'ils sont déterminés par de multiples facteurs, ne peuvent s'inscrire dans une telle Norme internationale, excepté pour certains dérivés particuliers mentionnés à l'Annexe C. L'Annexe C stipule des niveaux d'acceptabilité du risque d'EST pour les dérivés du suif, le noir animal, le lait et les dérivés du lait, les dérivés de la laine et les acides aminés. Le présent document ne spécifie pas un système de management de la qualité permettant le contrôle de toutes les étapes de fabrication de dispositifs médicaux. Le présent document ne couvre pas l'utilisation de tissus humains dans les dispositifs médicaux. NOTE 1 Le présent document n'exige pas un système de management de la qualité complet lors de la fabrication. Toutefois, il est préférable de se référer aux Normes internationales relatives aux systèmes de management de la qualité (voir l'ISO 13485) qui contrôlent toutes les étapes de fabrication ou de retraitement des dispositifs médicaux. NOTE 2 Voir l'Annexe A pour les préconisations relatives à l'application du présent document.
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INTERNATIONAL ISO
STANDARD 22442-1
Third edition
2020-09
Medical devices utilizing animal
tissues and their derivatives —
Part 1:
Application of risk management
Dispositifs médicaux utilisant des tissus animaux et leurs dérivés —
Partie 1: Application de la gestion des risques
Reference number
ISO 22442-1:2020(E)
©
ISO 2020
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ISO 22442-1:2020(E)
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© ISO 2020
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
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below or ISO’s member body in the country of the requester.
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Published in Switzerland
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ISO 22442-1:2020(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Risk management process . 3
4.1 General . 3
4.2 Risk analysis . 4
4.2.1 Identification of qualitative and quantitative characteristics related to the
safety of medical devices . 4
4.2.2 Identification of hazards and hazardous situations . 5
4.3 Risk evaluation . 5
4.4 Risk control . 5
4.4.1 General. 5
4.4.2 Risk control for viruses and TSE agents . 5
4.4.3 Risk control of other hazards . 6
4.4.4 Residual risk evaluation . 6
4.5 Evaluation of overall residual risk acceptability . 7
4.5.1 General. 7
4.5.2 Documentation . 7
4.6 Production and post-production information system . 7
Annex A (informative) Guidance on the application of this document . 8
Annex B (informative) Graphical representation of part of the risk management process for
medical devices utilizing animal material . 9
Annex C (normative) Special requirements for some animal materials considering the risk
management for TSE agents .11
Annex D (informative) Information relevant to the management of TSE risk .17
Bibliography .24
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ISO 22442-1:2020(E)
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, Subcommittee SC 1, Tissue product safety, 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 third edition cancels and replaces the second edition (ISO 22442-1:2015), which has been
technically revised.
The main changes compared to the previous edition are as follows:
— 4.4.2 has been updated;
— weblinks in C.2, bullet point 1, C.3.3 and C.4.4 have been updated;
— the weblink in D.3.3 has been updated;
— C.10 has been added;
— the bibliography has been updated.
A list of all parts in the ISO 22442 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.
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ISO 22442-1:2020(E)
Introduction
Certain medical devices utilize materials of animal origin.
Animal 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 non-animal based
materials. The range and quantities of materials of animal origin in medical devices vary. These
materials can comprise a major part of the device (e.g. bovine/porcine heart valves, bone substitutes
for use in dental or orthopaedic applications, haemostatic devices), can be a product coating or
impregnation (e.g. collagen, gelatine, heparin), or can be used in the device manufacturing process (e.g.
tallow derivatives such as oleates and stearates, foetal calf serum, enzymes, culture media).
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 animal 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.
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INTERNATIONAL STANDARD ISO 22442-1:2020(E)
Medical devices utilizing animal tissues and their
derivatives —
Part 1:
Application of risk management
1 Scope
This document applies to medical devices other than in vitro diagnostic medical devices manufactured
utilizing materials of animal origin, which are non-viable or have been rendered non-viable. It
specifies, in conjunction with ISO 14971, a procedure to identify the hazards and hazardous situations
associated with such devices, to estimate and evaluate the resulting risks, to control these risks,
and to monitor the effectiveness of that control. Furthermore, it outlines the decision process for the
residual risk acceptability, taking into account the balance of residual risk, as defined in ISO 14971, and
expected medical benefit as compared to available alternatives. This document is intended to provide
requirements and guidance on risk management related to the hazards typical of medical devices
manufactured utilizing animal tissues or derivatives such as:
a) contamination by bacteria, moulds or yeasts;
b) contamination by viruses;
c) contamination by agents causing transmissible spongiform encephalopathies (TSE);
d) material responsible for undesired pyrogenic, immunological or toxicological reactions.
For parasites and other unclassified pathogenic entities, similar principles can apply.
This document does not stipulate levels of acceptability which, because they are determined by a
multiplicity of factors, cannot be set down in such an international standard except for some particular
derivatives mentioned in Annex C. Annex C stipulates levels of TSE risk acceptability for tallow
derivatives, animal charcoal, milk and milk derivatives, wool derivatives and amino acids.
This document does not specify a quality management system for the control of all stages of production
of medical devices.
This document does not cover the utilization of human tissues in medical devices.
NOTE 1 It is not a requirement of this document to have a full quality management system during manufacture.
However, attention is drawn to international standards for quality management systems (see ISO 13485) that
control all stages of production or reprocessing of medical devices.
NOTE 2 For guidance on the application of this document, see Annex A.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 14971, Medical devices — Application of risk management to medical devices
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ISO 22442-1:2020(E)
ISO 22442-2, Medical devices utilizing animal tissues and their derivatives — Part 2: Controls on sourcing,
collection and handling
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
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 14971 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .iso .org/ obp
3.1
animal
vertebrate or invertebrate [including amphibian, arthropod (e.g. crustacean), bird, coral, fish, reptile,
mollusc and mammal] excluding humans (Homo sapiens)
3.2
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
3.3
derivative
substance obtained from an animal (3.1) material which is involved directly in the manufacturing
process of the medical device or is part of the final medical device
EXAMPLE Hyaluronic acid, collagen, gelatine, monoclonal antibodies, chitosan and albumin.
3.4
elimination
removal
process by which the number of transmissible agents is reduced
Note 1 to entry: The effectiveness of the process for the elimination of viruses and TSE agents should be expressed
mathematically in terms of a reduction factor (see C.2 and ISO 22442-3:2007, Annex F).
Note 2 to entry: Elimination aims to prevent infection or pathogenic reaction caused by transmissible agents.
3.5
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 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.
3.6
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,
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ISO 22442-1:2020(E)
— investigation, replacement, modification, or support of the anatomy or of a physiological process,
— supporting or sustaining life,
— control of conception,
— disinfection of medical devices,
— 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 may 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 (3.1) and/or human tissues;
— devices for in vitro fertilization or assisted reproduction technologies.
[SOURCE: ISO 13485:2003, 3.7]
3.7
non-viable
having no potential for metabolism or multiplication
3.8
technical agreement
binding contract between two or more parties that assigns responsibilities for technical requirements
3.9
tissue
organization of cells (3.2) and/or extra-cellular constituents
3.10
transmissible agents
bacteria, mould, yeast, parasites, viruses, TSE agents and unclassified pathogenic entities
4 Risk management process
4.1 General
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 justify the use of animal material (including the choice of animal species and
tissues) based on the residual risk acceptability, taking into account the balance of residual risk and
expected medical benefit, as compared to available alternatives.
NOTE Further discussion of medical benefits and the benefit-risk analysis can be found in ISO 14971.
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ISO 22442-1:2020(E)
4.2 Risk analysis
4.2.1 Identification of qualitative and quantitative characteristics related to the safety of
medical devices
4.2.1.1 Does the device come into contact with the patient or other persons?
The quantity of material, the contact surface area and the type(s) of material coming into contact with
body tissues or fluids as well as the type of body tissue or fluid it comes into contact with, shall be
addressed in the risk analysis. For TSE, guidance can be found in D.3.7.
NOTE 1 Medical devices such as orthopaedic shoes or components such as leather straps that come into
contact only with intact skin represent a low infective risk.
NOTE 2 The quantity of material coming into contact is one of the factors in producing biological effects. See
ISO 10993 (all parts) for the evaluation of such effects.
NOTE 3 The structure of animal tissues 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 animal
tissues and derivatives being processed.
4.2.1.2 What materials and/or components are incorporated in the medical device or are used
with, or are in contact with, the medical device?
The following factors shall be addressed, if applicable:
a) if viable animal materials are utilized in the manufacture of the medical device, verification that
the final medical device contains no viable animal material;
b) the intended use of any animal tissue or derivative;
c) geographical source, species, age and feeding (including use of animal-derived protein) of animals;
d) veterinary control, conditions under which the animal materials are recovered, potential for cross-
contamination;
e) the type and anatomical source of tissue;
f) the production process, particularly if it uses materials pooled from more than one animal;
g) the nature of material utilized in the medical device (e.g. intact tissue, highly purified derivative);
h) the method of utilization or incorporation into the medical device.
In the case of medical devices utilizing several relevant constituents (e.g. from various species, origin
or tissues) or several similar types of constituents produced using different methods, each individual
constituent should be analysed separately.
4.2.1.3 Is the device supplied sterile or intended to be sterilized by the user or are other
microbiological controls applicable?
Given the biological nature of animal tissues or derivatives, variations in the bioburden of bacteria,
mould and yeast of the animal material shall be estimated.
NOTE See also ISO 11737-1 and ISO 14160.
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ISO 22442-1:2020(E)
4.2.1.4 Are there 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 animal tissues or derivatives.
NOTE See also ISO 10993-1, ISO 10993-9, ISO 10993-17, ISO 10993-18 and ISO/TS 10993-19.
4.2.2 Identification of hazards and hazardous situations
The possible hazards associated with animal tissues or derivatives shall be identified and documented.
Particular attention shall be applied to possible hazards posed by animal tissues or derivatives with
regard to:
— potential contamination by 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.
4.3 Risk evaluation
In accordance with ISO 14971, all identified risks shall be evaluated. Biological safety shall be evaluated
in accordance with 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. Regarding the TSE risk, compliance
with requirements specified in Annex C for certain animal materials can indicate risk acceptability.
NOTE Annex C combines elements of risk evaluation and risk control.
4.4 Risk control
4.4.1 General
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.
4.4.2 Risk control for viruses and TSE agents
Risk control shall be implemented by separately addressing the risks related to different categories
of viruses and TSE agents. After defining the characteristics of the product, the medical device
manufacturer shall comply with the relevant requirements of both ISO 22442-2 and ISO 22442-3. If
exceptions to ISO 22442-2 and ISO 22442-3 are made, these exceptions shall be documented and
justified.
Tallow derivatives, animal charcoal, and amino acids that are acceptable for TSE risk as discussed in
Annex C, due to their processing and not their sourcing, shall also be considered to have acceptable risk
regarding viruses.
Regarding TSE risk, risk control measures specified in Annex C for certain animal materials shall be
applied where relevant. If the manufacturer considers any requirement not to be relevant, the rationale
and justification shall be documented.
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ISO 22442-1:2020(E)
For medical devices where an inactivation process causes unacceptable degradation, manufacturers
may rely on ISO 22442-2 in order to meet the requirements of this document.
If the animal species is such that manufacturers cannot provide information on the animal sourcing,
to fully meet the requirements of ISO 22442-2, they shall demonstrate that the level of inactivation of
transmissible agents in a validated manufacturing process, as required in ISO 22442-3, is sufficient to
achieve an acceptable level of risk.”
NOTE Criteria and principles relevant to the management of TSE risks are described in Annex D. Annex D
contains information on relevant risk control measures.
4.4.3 Risk control of other hazards
Risk control related to bacteria, moulds and yeasts, as well as undesired pyrogenic, immunological and
toxicological reactions shall be implemented according to available standards.
Tallow derivatives, animal charcoal, and amino acids that are acceptable for TSE risk as discussed in
Annex C, due to their processing and not their sourcing, shall also be considered to have acceptable risk
regarding bacteria, moulds and yeasts, subject to maintenance of proper storage conditions.
The manufacturer shall conduct periodic microbiological studies to identify and quantify the initial
bioburden of the incoming animal material for the production of the medical device.
NOTE The following international standards can be relevant:
a) ISO 11135, ISO 11137 (all parts), ISO 11737-1, the ISO 13408 (all parts), ISO 14160, ISO 14937, ISO 17664 and
ISO 17665-1, 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, 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.
4.4.4 Residual risk evaluation
4.4.4.1 General
Residual risk evaluation shall be performed for each risk.
4.4.4.2 TSE risk
The TSE risk 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 risk has been controlled at an acceptable level;
b) the medical 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 D. Acceptability can be based
on conformity with requirements specific to some animal materials given in Annex C or requirements relevant to
sourcing, collection and handling of bovine materials given in ISO 22442-2:2020, Annex A.
Regarding the TSE residual risk, specific considerations are provided in Annex C. Some derivatives such
as tallow derivatives, animal charcoal, milk derivatives, wool derivatives and amino acids manufactured
according to conditions mentioned in Annex C are considered as presenting an acceptable TSE risk.
Where the TSE 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.
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ISO 22442-1:2020(E)
4.5 Evaluation of overall residual risk acceptability
4.5.1 General
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 other animal species, 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.
4.5.2 Documentation
The rationale that the risk is acceptable shall be documented in the risk management file.
4.6 Production and post-production information system
Manufacturers shall ensure that the system identifies changes in the zoonosis status of the chosen
source of animal materials. Any change in zoonotic status of the source material shall be considered in
the risk management evaluation.
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ISO 22442-1:2020(E)
Annex A
(informative)
Guidance on the application of this document
A.1 General
Wherever in this document it is stated that something “be addressed”, the reader should either take
action
...
NORME ISO
INTERNATIONALE 22442-1
Troisième édition
2020-09
Dispositifs médicaux utilisant des
tissus animaux et leurs dérivés —
Partie 1:
Application de la gestion des risques
Medical devices utilizing animal tissues and their derivatives —
Part 1: Application of risk management
Numéro de référence
ISO 22442-1:2020(F)
©
ISO 2020
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ISO 22442-1:2020(F)
DOCUMENT PROTÉGÉ PAR COPYRIGHT
© ISO 2020
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ISO 22442-1:2020(F)
Sommaire Page
Avant-propos .iv
Introduction .v
1 Domaine d’application . 1
2 Références normatives . 1
3 Termes et définitions . 2
4 Processus de gestion des risques . 3
4.1 Généralités . 3
4.2 Analyse du risque . 4
4.3 Évaluation des risques. 5
4.4 Maîtrise des risques . 5
4.4.1 Généralités . 5
4.4.2 Maîtrise des risques liés aux virus et agents EST . 5
4.4.3 Maîtrise des risques liés à d’autres dangers . 6
4.4.4 Évaluation du risque résiduel . 6
4.5 Évaluation de l'acceptabilité du risque résiduel global . 7
4.5.1 Généralités . 7
4.5.2 Documentation . 7
4.6 Système d’informations de production et de postproduction . 7
Annexe A (informative) Préconisations concernant l’application du présent document .8
Annexe B (informative) Représentation graphique d’une partie du processus de gestion des
risques pour les dispositifs médicaux utilisant un matériau d’origine animale .9
Annexe C (normative) Exigences particulières applicables à certains matériaux d’origine
animale en rapport avec la gestion des risques pour les agents EST .11
Annexe D (informative) Informations relatives à la gestion du risque d’EST .17
Bibliographie .26
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ISO 22442-1:2020(F)
Avant-propos
L'ISO (Organisation internationale de normalisation) est une fédération mondiale d'organismes
nationaux de normalisation (comités membres de l'ISO). L'élaboration des Normes internationales est
en général confiée aux comités techniques de l'ISO. Chaque comité membre intéressé par une étude
a le droit de faire partie du comité technique créé à cet effet. Les organisations internationales,
gouvernementales et non gouvernementales en liaison avec l'ISO participent également aux travaux.
L'ISO collabore étroitement avec la Commission électrotechnique internationale (IEC) en ce qui
concerne la normalisation électrotechnique.
Les procédures utilisées pour élaborer le présent document et celles destinées à sa mise à jour sont
décrites dans les Directives ISO/IEC, Partie 1. Il convient, en particulier de prendre note des différents
critères d'approbation requis pour les différents types de documents ISO. Le présent document a été
rédigé conformément aux règles de rédaction données dans les Directives ISO/IEC, Partie 2 (voir www
.iso .org/ directives).
L'attention est attirée sur le fait que certains des éléments du présent document peuvent faire l'objet
de droits de propriété intellectuelle ou de droits analogues. L'ISO et l'IEC ne sauraient être tenues pour
responsables de ne pas avoir identifié de tels droits de propriété et averti de leur existence. Les détails
concernant les références aux droits de propriété intellectuelle ou autres droits analogues identifiés
lors de l'élaboration du document sont indiqués dans l'Introduction et/ou dans la liste des déclarations
de brevets reçues par l'ISO (voir www .iso .org/ brevets) ou dans la liste des déclarations de brevets
reçues par l’IEC (voir http:// patents .iec .ch).
Les appellations commerciales éventuellement mentionnées dans le présent document sont données
pour information, par souci de commodité, à l’intention des utilisateurs et ne sauraient constituer un
engagement.
Pour une explication de la nature volontaire des normes, la signification des termes et expressions
spécifiques de l'ISO liés à l'évaluation de la conformité, ou pour toute information au sujet de l'adhésion
de l'ISO aux principes de l’Organisation mondiale du commerce (OMC) concernant les obstacles
techniques au commerce (OTC), voir le lien suivant: www .iso .org/ iso/ fr/ avant -propos.
Le présent document a été élaboré par le comité technique ISO/TC 194, Évaluation biologique et clinique
des dispositifs médicaux, sous-comité SC 1, Sécurité des produits tissulaires, en collaboration avec le
comité technique CEN/TC 206, Évaluation biologique et clinique des dispositifs médicaux.
Cette troisième édition annule et remplace la deuxième édition (ISO 22442-1:2015), qui a fait l'objet
d'une révision technique.
Les principales modifications par rapport à l'édition précédente sont les suivantes:
— mise à jour du paragraphe 4.4.2;
— mise à jour des hyperliens en C.2, point 1, C.3.3 et C.4.4;
— mise à jour de l’hyperlien en D.3.3;
— ajout de la section C.10;
— mise à jour de la Bibliographie.
Une liste de toutes les parties de la série ISO 22442 se trouve sur le site web de l’ISO.
Il convient que l'utilisateur adresse tout retour d'information ou toute question concernant le présent
document à l'organisme national de normalisation de son pays. Une liste exhaustive desdits organismes
se trouve à l'adresse www .iso .org/ fr/ members .html.
iv © ISO 2020 – Tous droits réservés
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ISO 22442-1:2020(F)
Introduction
Certains dispositifs médicaux utilisent des matériaux d’origine animale.
Des tissus d’origine animale et leurs dérivés sont utilisés dans la conception et la fabrication de
dispositifs médicaux pour obtenir des caractéristiques de performance présentant des avantages
par rapport à celles offertes par des matériaux d’origine non animale. La diversité et la quantité de
matériaux d’origine animale utilisés dans les dispositifs médicaux sont variables. Ces matériaux peuvent
constituer une partie importante du dispositif (par exemple, les valves cardiaques d’origine bovine/
porcine, les substituts osseux destinés à être utilisés dans des applications dentaires ou orthopédiques,
les dispositifs hémostatiques), peuvent être un revêtement ou une enduction du produit (par exemple, le
collagène, la gélatine, l’héparine) ou peuvent être utilisés dans le processus de fabrication du dispositif
(par exemple, les dérivés du suif tels que les oléates et les stéarates, le sérum de veau fœtal, les enzymes,
les milieux de culture).
L’ISO 14971 est une norme générale qui spécifie un processus permettant au fabricant, par une
identification des dangers et des situations dangereuses associés aux dispositifs médicaux, y compris
les dispositifs médicaux in vitro, d’estimer et d’évaluer les risques associés à ces dangers, de maîtriser
ces risques et de surveiller l’efficacité de cette maîtrise tout au long du cycle de vie. Le présent document
fournit des exigences et des préconisations complémentaires pour l’évaluation de dispositifs médicaux
dans la fabrication desquels des tissus ou des dérivés d’origine animale non viables ou rendus non
viables sont utilisés.
Le présent document est destiné à couvrir les dispositifs médicaux, y compris les dispositifs médicaux
implantables actifs comme les pompes à perfusion implantables.
Le présent document ne s’applique pas aux dispositifs de diagnostic in vitro.
Le présent document ne peut être utilisé qu’associé à l’ISO 14971 et n’est donc pas une norme « qui se
suffit à elle-même ».
NOTE Afin d’assurer la conformité avec le présent document, il convient que les exigences spécifiques soient
respectées. Les préconisations données dans les Notes et dans les annexes informatives ne sont pas normatives
et ne constituent pas une liste de contrôle pour les auditeurs.
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NORME INTERNATIONALE ISO 22442-1:2020(F)
Dispositifs médicaux utilisant des tissus animaux et leurs
dérivés —
Partie 1:
Application de la gestion des risques
1 Domaine d’application
Le présent document s’applique aux dispositifs médicaux autres que les dispositifs médicaux de
diagnostic in vitro, dans la fabrication desquels entrent des matériaux d’origine animale non viables
ou rendus non viables. Associé à l’ISO 14971, il spécifie un mode opératoire permettant d’identifier les
dangers et les situations dangereuses associés à de tels dispositifs, d’estimer et d’évaluer les risques qui
en découlent, de maîtriser ces risques et de surveiller l’efficacité de cette maîtrise. En outre, il décrit
le processus décisionnel relatif à l’acceptabilité du risque résiduel, en tenant compte du rapport entre
le risque résiduel, tel que défini dans l’ISO 14971, et le bénéfice médical escompté par rapport aux
solutions de remplacement disponibles. Le présent document est destiné à fournir des exigences et des
préconisations pour la gestion des risques associée aux dangers typiques des dispositifs médicaux dans
la fabrication desquels entrent des tissus ou des dérivés d’origine animale, notamment:
a) la contamination par des bactéries, des moisissures ou des levures;
b) la contamination par des virus;
c) la contamination par des agents responsables d’encéphalopathies spongiformes
transmissibles (EST);
d) un matériau provoquant des réactions pyrogènes, immunologiques ou toxicologiques indésirables.
Des principes similaires peuvent s’appliquer aux parasites et autres entités pathogènes non classées.
Le présent document ne stipule pas de niveaux d'acceptabilité qui, du fait qu'ils sont déterminés par
de multiples facteurs, ne peuvent s'inscrire dans une telle Norme internationale, excepté pour certains
dérivés particuliers mentionnés à l’Annexe C. L’Annexe C stipule des niveaux d'acceptabilité du risque
d'EST pour les dérivés du suif, le noir animal, le lait et les dérivés du lait, les dérivés de la laine et les
acides aminés.
Le présent document ne spécifie pas un système de management de la qualité permettant le contrôle de
toutes les étapes de fabrication de dispositifs médicaux.
Le présent document ne couvre pas l’utilisation de tissus humains dans les dispositifs médicaux.
NOTE 1 Le présent document n’exige pas un système de management de la qualité complet lors de la fabrication.
Toutefois, il est préférable de se référer aux Normes internationales relatives aux systèmes de management de
la qualité (voir l’ISO 13485) qui contrôlent toutes les étapes de fabrication ou de retraitement des dispositifs
médicaux.
NOTE 2 Voir l’Annexe A pour les préconisations relatives à l’application du présent document.
2 Références normatives
Les documents suivants cités dans le texte constituent, pour tout ou partie de leur contenu, des
exigences du présent document. Pour les références datées, seule l’édition citée s’applique. Pour les
références non datées, la dernière édition du document de référence s'applique (y compris les éventuels
amendements).
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ISO 22442-1:2020(F)
ISO 10993-1, Évaluation biologique des dispositifs médicaux — Partie 1: Évaluation et essais au sein d'un
processus de gestion du risque
ISO 14971, Dispositifs médicaux — Application de la gestion des risques aux dispositifs médicaux
ISO 22442-2, Dispositifs médicaux utilisant des tissus animaux et leurs dérivés — Partie 2: Contrôles de
l'origine, de la collecte et du traitement
ISO 22442-3, Dispositifs médicaux utilisant des tissus animaux et leurs dérivés — Partie 3: Validation de
l'élimination et/ou de l'inactivation des virus et autres agents responsables d'encéphalopathie spongiforme
transmissible (EST)
3 Termes et définitions
Pour les besoins du présent document, les termes et définitions donnés dans l’ISO 14971 ainsi que les
suivants s’appliquent.
L’ISO et l’IEC tiennent à jour des bases de données terminologiques destinées à être utilisées en
normalisation, consultables aux adresses suivantes:
— IEC Electropedia: disponible à l’adresse http:// www .electropedia .org/
— ISO Online browsing platform: disponible à l’adresse http:// www .iso .org/ obp
3.1
animal
vertébré ou invertébré [y compris les amphibiens, arthropodes (par exemple, crustacés), oiseaux,
coraux, poissons, reptiles, mollusques et mammifères] à l’exclusion des humains (Homo sapiens)
3.2
cellule
plus petite unité organisée de toute forme de vie capable d’avoir une existence indépendante et de
renouveler ses propres composants dans un environnement adapté
3.3
dérivé
substance obtenue à partir d’un matériau d’origine animale (3.1) qui est directement impliquée dans le
processus de fabrication du dispositif médical ou qui est une partie du dispositif médical final
EXEMPLE Acide hyaluronique, collagène, gélatine, anticorps monoclonaux, chitosane et albumine.
3.4
élimination
processus de suppression permettant de réduire le nombre d’agents transmissibles
Note 1 à l'article: Il convient que l’efficacité du processus d’élimination des virus et des agents EST soit exprimée
mathématiquement par un facteur de réduction (voir en C.2 et l’ISO 22442-3:2007, Annexe F).
Note 2 à l'article: L’élimination a pour but de prévenir l’infection ou la réaction pathogène due à des agents
transmissibles.
3.5
inactivation
processus permettant de réduire le potentiel infectieux ou pathogène d’un agent transmissible
Note 1 à l'article: Il convient que l’efficacité du processus d’inactivation des virus et des agents EST soit exprimée
mathématiquement par un facteur de réduction (voir l’ISO 22442-3:2007, Annexe F).
Note 2 à l'article: L’inactivation a pour but de prévenir l’infection et la multiplication d’agents transmissibles.
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ISO 22442-1:2020(F)
3.6
dispositif médical
instrument, appareil, équipement, machine, dispositif, implant, réactif destiné à une utilisation in vitro,
logiciel, matériel ou autre article similaire ou associé, dont le fabricant prévoit qu’il soit utilisé seul ou
en association chez l'être humain pour une ou plusieurs fins médicales spécifiques suivantes:
— diagnostic, prévention, contrôle, traitement ou atténuation d'une maladie;
— diagnostic, contrôle, traitement, atténuation ou compensation d'une blessure;
— étude, remplacement, modification ou entretien de l'anatomie ou d'un processus physiologique;
— entretien (artificiel) ou maintien de la vie;
— maîtrise de la conception;
— désinfection des dispositifs médicaux;
— communication d'informations par un examen in vitro de prélèvements provenant du corps humain;
et dont l’action principale voulue n’est pas obtenue par des moyens pharmacologiques ou
immunologiques ni par métabolisme, dans le corps humain ou à la surface de celui-ci, mais dont la
fonction peut être assistée par de tels moyens
Note 1 à l'article: Les produits susceptibles d’être considérés comme des dispositifs médicaux dans certaines
juridictions mais pas dans d’autres incluent:
— les produits désinfectants;
— les aides pour les personnes handicapées;
— les dispositifs intégrant des tissus animaux (3.1) et/ou humains;
— les dispositifs pour les technologies de fécondation in vitro ou de reproduction assistée.
[SOURCE: ISO 13485:2003, 3.7]
3.7
non viable
ne possédant pas de potentiel de métabolisme ou de multiplication
3.8
cahier des charges technique
contrat liant deux parties et plus, qui assigne les responsabilités associées aux exigences techniques
3.9
tissu
organisation de cellules (3.2) et/ou de composants extracellulaires
3.10
agents transmissibles
bactéries, moisissures, levures, parasites, virus, agents EST et entités pathogènes non classées
4 Processus de gestion des risques
4.1 Généralités
Les exigences de l’ISO 14971 s’appliquent. La conformité à ces exigences doit être vérifiée par inspection
des documents appropriés, par exemple le dossier de gestion des risques.
Le fabricant doit, sur la base de l’acceptabilité du risque résiduel, justifier l’utilisation de matériau
d’origine animale (y compris le choix de l’espèce animale et des tissus d’origine animale) en tenant
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ISO 22442-1:2020(F)
compte du rapport entre le risque résiduel et le bénéfice médical escompté par rapport aux solutions de
remplacement disponibles.
NOTE Les bénéfices médicaux et l’analyse du rapport risque/bénéfice sont traités dans l’ISO 14971.
4.2 Analyse du risque
4.2.1 Identification des caractéristiques qualitatives et quantitatives relatives à la sécurité des
dispositifs médicaux
4.2.1.1 Le dispositif entre-t-il en contact avec le patient ou d’autres personnes?
La quantité de matériau, la surface de contact et le(s) type(s) de matériau entrant en contact avec
les tissus ou les fluides corporels ainsi que la nature du tissu ou du fluide corporel avec lequel il
entre en contact, doivent être pris en compte dans l’analyse du risque. En ce qui concerne l’EST, des
préconisations sont fournies en D.3.7.
NOTE 1 Les dispositifs médicaux tels que les chaussures orthopédiques ou les composants tels que les lanières
de cuir qui entrent en contact uniquement avec une peau saine représentent un risque infectieux faible.
NOTE 2 La quantité de matériau entrant en contact est l’un des facteurs susceptibles de produire des effets
biologiques. Voir l’ISO 10993 (toutes les parties) pour l’évaluation de ces effets.
NOTE 3 La structure des tissus d’origine animale traités peut avoir un effet sur l’inactivation et/ou
l’élimination des agents transmissibles, et la possibilité de persistance de cellules viables peut aussi être affectée
par la structure des tissus d’origine animale et des dérivés traités.
4.2.1.2 Quels sont les matériaux et/ou les composants incorporés dans, utilisés avec ou en
contact avec le dispositif médical?
Le cas échéant, les facteurs suivants doivent être pris en compte:
a) si des matériaux d’origine animale viables sont utilisés dans la fabrication du dispositif médical,
vérifier que le dispositif médical final ne contient pas de matériaux d’origine animale non viables;
b) l’usage prévu du tissu ou du dérivé d’origine animale;
c) l’origine géographique, l’espèce, l’âge et l’alimentation des animaux (y compris l’utilisation de
protéines animales);
d) le contrôle vétérinaire, les conditions dans lesquelles les matériaux d’origine animale sont
récupérés, la possibilité de contamination croisée;
e) le type et l’origine anatomique du tissu;
f) le processus de production, en particulier s’il utilise des matériaux rassemblés en provenance de
plusieurs animaux;
g) la nature du matériau utilisé dans le dispositif médical (par exemple, tissu sain, dérivé hautement
purifié);
h) la méthode d’utilisation ou d’incorporation dans le dispositif médical.
Pour les dispositifs médicaux utilisant différents composants appropriés (par exemple, de différentes
espèces ou origines ou de différents tissus) ou plusieurs types similaires de composants produits par
différentes méthodes, il convient d’analyser individuellement chaque composant.
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ISO 22442-1:2020(F)
4.2.1.3 Le dispositif est-il fourni stérile ou est-il prévu qu'il soit stérilisé par l'utilisateur, ou
d'autres contrôles microbiologiques sont-ils applicables?
Étant donné la nature biologique des tissus ou des dérivés d’origine animale, la variabilité de la charge
biologique en bactéries, en moisissures et en levures du matériau d’origine animale doit être estimée.
NOTE Voir également l’ISO 11737-1 et l’ISO 14160.
4.2.1.4 Y a-t-il des émissions non souhaitées de substances?
En raison des caractéristiques physiques (par exemple porosité, hétérogénéité) et de la composition
chimique des tissus ou des dérivés d'origine animale, il faut tenir compte de l'éventuelle présence de
résidus toxiques liés au processus de fabrication utilisé ou de sous-produits de dégradation.
NOTE Voir également l’ISO 10993-1, l’ISO 10993-9, l’ISO 10993-17, l’ISO 10993-18 et l’ISO/TS 10993-19.
4.2.2 Identification des dangers et des situations dangereuses
Les dangers potentiels associés aux tissus ou aux dérivés d’origine animale doivent être identifiés et
documentés. Une attention particulière doit être prêtée aux dangers potentiels que présentent les
tissus ou les dérivés d’origine animale en ce qui concerne:
— une contamination éventuelle par des agents transmissibles et leur sensibilité aux étapes
d’élimination et/ou d’inactivation durant le processus de traitement;
— la possibilité d'une présence d'agents contaminants dans le produit fini, pouvant entraîner une
réaction pyrogène, immunologique ou toxicologique indésirable;
— la possibilité pour le produit fini de provoquer lui-même une réaction pyrogène, immunologique ou
toxicologique indésirable.
4.3 Évaluation des risques
Tous les risques identifiés doivent être évalués conformément à l’ISO 14971. La sécurité biologique doit
être évaluée conformément à l’ISO 10993-1. L’évaluation des risques associés aux agents transmissibles
doit être mise en œuvre en traitant séparément les risques liés aux différentes catégories d’agents
transmissibles. L’Annexe B identifie les principales catégories de risque qu’il convient de prendre en
compte. En ce qui concerne le risque d’EST, la conformité aux exigences spécifiées dans l’Annexe C pour
certains matériaux d’origine animale peut indiquer l’acceptabilité du risque.
NOTE L’Annexe C combine les éléments de l’évaluation et de la maîtrise des risques.
4.4 Maîtrise des risques
4.4.1 Généralités
Les options de maîtrise des risques doivent être documentées et justifiées.
Le logigramme de l’Annexe B donne une vue d’ensemble du processus de gestion des risques. Si des
risques supplémentaires sont identifiés en utilisant le présent document, le fabricant du dispositif
médical peut choisir de suivre toute norme appropriée ou toute autre méthode, à condition que cette
décision soit justifiée et documentée.
4.4.2 Maîtrise des risques liés aux virus et agents EST
La maîtrise des risques doit être mise en œuvre en traitant séparément les risques liés aux différentes
catégories de virus et d’agents EST. Après avoir défini les caractéristiques du produit, le fabricant du
dispositif médical doit satisfaire aux exigences applicables de l’ISO 22442-2 et de l’ISO 22442-3. Si des
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ISO 22442-1:2020(F)
exceptions à l’ISO 22442-2 et à l’ISO 22442-3 sont faites, ces exceptions doivent être documentées et
justifiées.
Les dérivés du suif, le noir animal et les acides aminés qui sont acceptables pour le risque d’EST, comme
indiqué à l’Annexe C, en raison de leur processus de fabrication et non de leur origine, doivent également
être considérés comme présentant un risque viral acceptable.
En ce qui concerne le risque d’EST, les mesures de maîtrise des risques spécifiées à l’Annexe C pour
certains matériaux d’origine animale doivent être appliquées le cas échéant. Le fabricant doit justifier
et documenter toute exigence qu'il juge non applicable.
Pour les dispositifs médicaux dans lesquels un processus d’inactivation provoque une dégradation
inacceptable, les fabricants peuvent s’appuyer sur l’ISO 22442-2 pour satisfaire aux exigences du
présent document.
Lorsque l'espèce animale ne permet pas aux fabricants de fournir des informations sur l’origine des
animaux, de satisfaire entièrement aux exigences de l'ISO 22442-2, ces derniers doivent démontrer qu'ils
ont atteint, par un processus de fabrication validé, un niveau d'inactivation des agents transmissibles,
conformément aux exigences de l'ISO 22442-3, suffisant pour atteindre un niveau de risque acceptable.
NOTE Les critères et les principes applicables à la gestion des risques d’EST sont décrits à l’Annexe D, qui
contient des informations sur les mesures de maîtrise des risques applicables.
4.4.3 Maîtrise des risques liés à d’autres dangers
Une maîtrise des risques doit être mise en œuvre pour les bactéries, les moisissures et les levures, ainsi
que pour les réactions pyrogènes, immunologiques et toxicologiques indésirables, conformément aux
normes disponibles.
Les dérivés du suif, le noir animal et les acides aminés qui sont acceptables pour le risque d’EST, comme
indiqué à l’Annexe C, en raison de leur processus de fabrication et non de leur origine, doivent également
être considérés comme présentant un risque acceptable associé aux bactéries, moisissures et levures,
sous réserve du maintien de conditions de stockage appropriées.
Le fabricant doit réaliser des études microbiologiques périodiques afin d’identifier et de quantifier
la charge biologique initiale du matériau d’origine animale réceptionné, en vue de la fabrication du
dispositif médical.
NOTE Les Normes internationales suivantes peuvent être appliquées:
a) l’ISO 11135, l’ISO 11137 (toutes les parties), l’ISO 11737-1, l’ISO 13408 (toutes les parties),
l’ISO 14160, l’ISO 14937, l’ISO 17664 et l’ISO 17665-1, qui peuvent être applicables aux bactéries, aux
moisissures et aux levures;
b) l’ISO 10993-2, l’ISO 10993-3, l’ISO 10993-4, l’ISO 10993-5, l’ISO 10993-6, l’ISO 10993-7, l’ISO 10993-9,
l’ISO 10993-10, l’ISO 10993-11, l’ISO 10993-12, l’ISO 10993-13, l’ISO 10993-14, l’ISO 10993-15,
l’ISO 10993-16, l’ISO 10993-17, l’ISO 10993-18, l’ISO/TS 10993-19 et l’ISO/TS 10993-20, qui peuvent
être utilisées pour la gestion des risques liés aux réactions pyrogènes, immunologiques ou
toxicologiques indésirables.
L’utilisation de ces documents est illustrée à l’Annexe B.
4.4.4 Évaluation du risque résiduel
4.4.4.1 Généralités
L’évaluation du risque résiduel doit être effectuée pour chaque risque.
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ISO 22442-1:2020(F)
4.4.4.2 Risque d’EST
Le risque d’EST peut être jugé acceptable si les deux critères suivants sont remplis, en tenant compte de
la disponibilité de matériaux de remplacement:
a) l’estimation du risque rési
...
FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 22442-1
ISO/TC 194/SC 1
Medical devices utilizing animal
Secretariat: DIN
tissues and their derivatives —
Voting begins on:
2020-02-10
Part 1:
Voting terminates on:
Application of risk management
2020-04-06
Dispositifs médicaux utilisant des tissus animaux et leurs dérivés —
Partie 1: Application de la gestion des risques
ISO/CEN PARALLEL PROCESSING
RECIPIENTS OF THIS DRAFT ARE INVITED TO
SUBMIT, WITH THEIR COMMENTS, NOTIFICATION
OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPOR TING
DOCUMENTATION.
IN ADDITION TO THEIR EVALUATION AS
Reference number
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO-
ISO/FDIS 22442-1:2020(E)
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN-
DARDS TO WHICH REFERENCE MAY BE MADE IN
©
NATIONAL REGULATIONS. ISO 2020
---------------------- Page: 1 ----------------------
ISO/FDIS 22442-1:2020(E)
COPYRIGHT PROTECTED DOCUMENT
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ISO/FDIS 22442-1:2020(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Risk management process . 3
4.1 General . 3
4.2 Risk analysis . 4
4.2.1 Identification of qualitative and quantitative characteristics related to the
safety of medical devices . 4
4.2.2 Identification of hazards and hazardous situations . 5
4.3 Risk evaluation . 5
4.4 Risk control . 5
4.4.1 General. 5
4.4.2 Risk control for viruses and TSE agents . 5
4.4.3 Risk control of other hazards . 6
4.4.4 Residual risk evaluation . 6
4.5 Evaluation of overall residual risk acceptability . 7
4.5.1 General. 7
4.5.2 Documentation . 7
4.6 Production and post-production information system . 7
Annex A (informative) Guidance on the application of this document . 8
Annex B (informative) Graphical representation of part of the risk management process for
medical devices utilizing animal material . 9
Annex C (normative) Special requirements for some animal materials considering the risk
management for TSE agents .11
Annex D (informative) Information relevant to the management of TSE risk .17
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC as amended by Commission Regulation
(EU) No 722/2012 .24
Bibliography .27
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ISO/FDIS 22442-1:2020(E)
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 jointly by Technical Committee ISO/TC 194, Biological and clinical
evaluation of medical devices, Subcommittee SC 1, Tissue product safety, and Technical Committee EN/TC
206, Biological and clinical evaluation of medical devices.
This third edition cancels and replaces the second edition (ISO 22442-1:2015), which has been
technically revised.
The main changes compared to the previous edition are as follows:
— 4.4.2 has been updated;
— weblinks in C.2, bullet point 1, C.3.3 and C.4.4 have been updated;
— the weblink in D.3.3 has been updated;
— C.10 has been added;
— the bibliography has been updated.
A list of all parts in the ISO 22442 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.
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ISO/FDIS 22442-1:2020(E)
Introduction
Certain medical devices utilize materials of animal origin.
Animal 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 non-animal based
materials. The range and quantities of materials of animal origin in medical devices vary. These
materials can comprise a major part of the device (e.g. bovine/porcine heart valves, bone substitutes
for use in dental or orthopaedic applications, haemostatic devices), can be a product coating or
impregnation (e.g. collagen, gelatine, heparin), or can be used in the device manufacturing process (e.g.
tallow derivatives such as oleates and stearates, foetal calf serum, enzymes, culture media).
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 animal 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.
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FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 22442-1:2020(E)
Medical devices utilizing animal tissues and their
derivatives —
Part 1:
Application of risk management
1 Scope
This document applies to medical devices other than in vitro diagnostic medical devices manufactured
utilizing materials of animal origin, which are non-viable or have been rendered non-viable. It
specifies, in conjunction with ISO 14971, a procedure to identify the hazards and hazardous situations
associated with such devices, to estimate and evaluate the resulting risks, to control these risks,
and to monitor the effectiveness of that control. Furthermore, it outlines the decision process for the
residual risk acceptability, taking into account the balance of residual risk, as defined in ISO 14971, and
expected medical benefit as compared to available alternatives. This document is intended to provide
requirements and guidance on risk management related to the hazards typical of medical devices
manufactured utilizing animal tissues or derivatives such as:
a) contamination by bacteria, moulds or yeasts;
b) contamination by viruses;
c) contamination by agents causing transmissible spongiform encephalopathies (TSE);
d) material responsible for undesired pyrogenic, immunological or toxicological reactions.
For parasites and other unclassified pathogenic entities, similar principles can apply.
This document does not stipulate levels of acceptability which, because they are determined by a
multiplicity of factors, cannot be set down in such an international standard except for some particular
derivatives mentioned in Annex C. Annex C stipulates levels of TSE risk acceptability for tallow
derivatives, animal charcoal, milk and milk derivatives, wool derivatives and amino acids.
This document does not specify a quality management system for the control of all stages of production
of medical devices.
This document does not cover the utilization of human tissues in medical devices.
NOTE 1 It is not a requirement of this document to have a full quality management system during manufacture.
However, attention is drawn to international standards for quality management systems (see ISO 13485) that
control all stages of production or reprocessing of medical devices.
NOTE 2 For guidance on the application of this document, see Annex A.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are
indispensable for its application. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 14971, Medical devices — Application of risk management to medical devices
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ISO/FDIS 22442-1:2020(E)
ISO 22442-2:2015, Medical devices utilizing animal tissues and their derivatives — Part 2: Controls on
sourcing, collection and handling
ISO 22442-3:2007, 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
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 14971 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .iso .org/ obp
3.1
animal
vertebrate or invertebrate [including amphibian, arthropod (e.g. crustacean), bird, coral, fish, reptile,
mollusc and mammal] excluding humans (Homo sapiens)
3.2
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
3.3
derivative
substance obtained from an animal (3.1) material which is involved directly in the manufacturing
process of the medical device or is part of the final medical device
EXAMPLE Hyaluronic acid, collagen, gelatine, monoclonal antibodies, chitosan and albumin.
3.4
elimination
removal
process by which the number of transmissible agents is reduced
Note 1 to entry: The effectiveness of the process for the elimination of viruses and TSE agents should be expressed
mathematically in terms of a reduction factor (see C.2 and ISO 22442-3:2007, Annex F).
Note 2 to entry: Elimination aims to prevent infection or pathogenic reaction caused by transmissible agents.
3.5
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 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.
3.6
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,
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ISO/FDIS 22442-1:2020(E)
— investigation, replacement, modification, or support of the anatomy or of a physiological process,
— supporting or sustaining life,
— control of conception,
— disinfection of medical devices,
— 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 may 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 (3.1) and/or human tissues;
— devices for in vitro fertilization or assisted reproduction technologies.
[SOURCE: ISO 13485:2003, 3.7]
3.7
non-viable
having no potential for metabolism or multiplication
3.8
technical agreement
binding contract between two or more parties that assigns responsibilities for technical requirements
3.9
tissue
organization of cells (3.2) and/or extra-cellular constituents
3.10
transmissible agents
bacteria, mould, yeast, parasites, viruses, TSE agents and unclassified pathogenic entities
4 Risk management process
4.1 General
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 justify the use of animal material (including the choice of animal species and
tissues) based on the residual risk acceptability, taking into account the balance of residual risk and
expected medical benefit, as compared to available alternatives.
NOTE Further discussion of medical benefits and the benefit-risk analysis can be found in ISO 14971.
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ISO/FDIS 22442-1:2020(E)
4.2 Risk analysis
4.2.1 Identification of qualitative and quantitative characteristics related to the safety of
medical devices
4.2.1.1 Does the device come into contact with the patient or other persons?
The quantity of material, the contact surface area and the type(s) of material coming into contact with
body tissues or fluids as well as the type of body tissue or fluid it comes into contact with, shall be
addressed in the risk analysis. For TSE, guidance can be found in D.3.7.
NOTE 1 Medical devices such as orthopaedic shoes or components such as leather straps that come into
contact only with intact skin represent a low infective risk.
NOTE 2 The quantity of material coming into contact is one of the factors in producing biological effects. See
ISO 10993 (all parts) for the evaluation of such effects.
NOTE 3 The structure of animal tissues 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 animal
tissues and derivatives being processed.
4.2.1.2 What materials and/or components are incorporated in the medical device or are used
with, or are in contact with, the medical device?
The following factors shall be addressed, if applicable:
a) if viable animal materials are utilized in the manufacture of the medical device, verification that
the final medical device contains no viable animal material;
b) the intended use of any animal tissue or derivative;
c) geographical source, species, age and feeding (including use of animal-derived protein) of animals;
d) veterinary control, conditions under which the animal materials are recovered, potential for cross-
contamination;
e) the type and anatomical source of tissue;
f) the production process, particularly if it uses materials pooled from more than one animal;
g) the nature of material utilized in the medical device (e.g. intact tissue, highly purified derivative);
h) the method of utilization or incorporation into the medical device.
In the case of medical devices utilizing several relevant constituents (e.g. from various species, origin
or tissues) or several similar types of constituents produced using different methods, each individual
constituent should be analysed separately.
4.2.1.3 Is the device supplied sterile or intended to be sterilized by the user or are other
microbiological controls applicable?
Given the biological nature of animal tissues or derivatives, variations in the bioburden of bacteria,
mould and yeast of the animal material shall be estimated.
NOTE See also ISO 11737-1 and ISO 14160.
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ISO/FDIS 22442-1:2020(E)
4.2.1.4 Are there 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 animal tissues or derivatives.
NOTE See also ISO 10993-1, ISO 10993-9, ISO 10993-17, ISO 10993-18 and ISO 10993-19.
4.2.2 Identification of hazards and hazardous situations
The possible hazards associated with animal tissues or derivatives shall be identified and documented.
Particular attention shall be applied to possible hazards posed by animal tissues or derivatives with
regard to:
— potential contamination by 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.
4.3 Risk evaluation
In accordance with ISO 14971, all identified risks shall be evaluated. Biological safety shall be evaluated
in accordance with 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. Regarding the TSE risk, compliance
with requirements specified in Annex C for certain animal materials can indicate risk acceptability.
NOTE Annex C combines elements of risk evaluation and risk control.
4.4 Risk control
4.4.1 General
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.
4.4.2 Risk control for viruses and TSE agents
Risk control shall be implemented by separately addressing the risks related to different categories
of viruses and TSE agents. After defining the characteristics of the product, the medical device
manufacturer shall comply with the relevant requirements of both ISO 22442-2 and ISO 22442-3. If
exceptions to ISO 22442-2 and ISO 22442-3 are made, these exceptions shall be documented and
justified.
Tallow derivatives, animal charcoal, and amino acids that are acceptable for TSE risk as discussed in
Annex C, due to their processing and not their sourcing, shall also be considered to have acceptable risk
regarding viruses.
Regarding TSE risk, risk control measures specified in Annex C for certain animal materials shall be
applied where relevant. If the manufacturer considers any requirement not to be relevant, the rationale
and justification shall be documented.
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ISO/FDIS 22442-1:2020(E)
For medical devices where an inactivation process causes unacceptable degradation, manufacturers
may rely on ISO 22442-2 in order to meet the requirements of this document.
If the animal species is such that manufacturers cannot provide information on the animal sourcing,
to fully meet the requirements of ISO 22442-2, they shall demonstrate that the level of inactivation of
transmissible agents in a validated manufacturing process, as required in ISO 22442-3, is sufficient to
achieve an acceptable level of risk.”
NOTE Criteria and principles relevant to the management of TSE risks are described in Annex D. Annex D
contains information on relevant risk control measures.
4.4.3 Risk control of other hazards
Risk control related to bacteria, moulds and yeasts, as well as undesired pyrogenic, immunological and
toxicological reactions shall be implemented according to available standards.
Tallow derivatives, animal charcoal, and amino acids that are acceptable for TSE risk as discussed in
Annex C, due to their processing and not their sourcing, shall also be considered to have acceptable risk
regarding bacteria, moulds and yeasts, subject to maintenance of proper storage conditions.
The manufacturer shall conduct periodic microbiological studies to identify and quantify the initial
bioburden of the incoming animal material for the production of the medical device.
NOTE The following international standards may be relevant:
a) ISO 11135, ISO 11137, ISO 11737-1, the ISO 13408 (all parts), ISO 14160, ISO 14937, ISO 17664 and ISO 17665-1,
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 10993-19 and ISO 10993-20, 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.
4.4.4 Residual risk evaluation
4.4.4.1 General
Residual risk evaluation shall be performed for each risk.
4.4.4.2 TSE risk
The TSE risk 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 risk has been controlled at an acceptable level;
b) the medical 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 D. Acceptability can be based
on conformity with requirements specific to some animal materials given in Annex C or requirements relevant to
sourcing, collection and handling of bovine materials given in ISO 22442-2:2015, Annex A.
Regarding the TSE residual risk, specific considerations are provided in Annex C. Some derivatives such
as tallow derivatives, animal charcoal, milk derivatives, wool derivatives and amino acids manufactured
according to conditions mentioned in Annex C are considered as presenting an acceptable TSE risk.
Where the TSE 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.
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ISO/FDIS 22442-1:2020(E)
4.5 Evaluation of overall residual risk acceptability
4.5.1 General
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 other animal species, 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
...
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