oSIST prEN ISO 22442-1:2018

SLOVENSKI STANDARD
oSIST prEN ISO 22442-1:2018
01-november-2018

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Medical devices utilizing animal tissues and their derivatives - Part 1: Application of risk

Dispositifs médicaux utilisant des tissus animaux et leurs dérivés - Partie 1: Application

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting

on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address

Foreword ..........................................................................................................................................................................................................................................v

Introduction ................................................................................................................................................................................................................................vi

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 ............................................................................................................................................................3

4.2.1 Identification of qualitative and quantitative characteristics related to the

safety of medical devices .................................................................................................................3

4.2.2 Identification of hazards and hazardous situations .............................................................4

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 .........................................................................................................5

4.4.4 Residual risk evaluation ...................................................................................................................6

4.5 Evaluation of overall residual risk acceptability .....................................................................................6

4.5.1 General...................................................................................................................................................................................... 6

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 ........................................16

Annex ZA (informative) Relationship between this European Standard and the Essential

(EU) No 722/2012 ............................................................................................................................................................................................23

Bibliography .............................................................................................................................................................................................................................25

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

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 ISO documents 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 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

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

For an explanation on 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 the following

This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of

This third edition cancels and replaces the second edition (EN ISO 22442-1:2015), which has undergone

— Update of weblinks in C.2 Collagen, bullet point 1, C.3.3 Bones s the starting material and C.4.4

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

This document is intended to cover medical devices including active implantable medical devices such

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

NOTE To show compliance with this document, its specified requirements should be fulfilled. The guidance

given in the Notes and informative annexes is not normative and is not provided as a checklist for auditors.

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

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

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

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

ISO 22442-2:2015, Medical devices utilizing animal tissues and their derivatives — Part 2: Controls on

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

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:

any vertebrate or invertebrate [including amphibian, arthropod (e.g. crustacean), bird, coral, fish,

smallest organized unit of any living form which is capable of independent existence and of replacement

substance obtained from an animal material by a manufacturing process which is directly involved in

the production of the medical device or which is a final part of the medical device

EXAMPLE Hyaluronic acid, collagen, gelatine, monoclonal antibodies, chitosan, albumin.

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.

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

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

any instrument, apparatus, implement, machine, appliance, implant, in vitro reagent or calibrator,

software, material or other similar or related article, intended by the manufacturer to be used, alone or

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

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

— providing information for medical purposes by means of in vitro examination of specimens derived

and which does not achieve its primary intended action in or on the human body by pharmacological,

immunological or metabolic means, but which may be assisted in its intended function by such means

Note 1 to entry: This definition has been developed by the Global Harmonization Task Force (GHTF).

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

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

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

The requirements of ISO 14971 apply. Compliance with these requirements shall be verified by

NOTE Further discussion of medical benefits and the risk/benefit analysis can be found in ISO 14971.

4.2.1 Identification of qualitative and quantitative characteristics related to the safety of

The quantity of material, the contact surface area and the type(s) of the 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

NOTE 1 Medical devices such as orthopaedic shoes or components such as leather straps that come into

NOTE 2 The quantity of material coming into contact is one of the factors in producing biological effects. See

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

4.2.1.2 What materials and/or components are incorporated in the medical device or are used

a) if viable animal materials are utilized in the manufacture of the medical device, verification that

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-

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);

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

4.2.1.3 Is the device supplied sterile or intended to be sterilized by the user or are other

Given the biological nature of animal tissues or derivatives, variations in the bioburden of bacteria,

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,

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

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

— potential contamination by transmissible agents and their susceptibility to elimination and/or

— potential for contaminants on the finished material which can cause an undesired pyrogenic,

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

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.

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.

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,

except where either the animal species is such that manufacturers cannot fully meet the requirements

of ISO 22442-2 or an inactivation process in accordance with ISO 22442-3 would cause unacceptable

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 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

For medical devices where an inactivation process causes unacceptable degradation, manufacturers

If the animal species is such that manufacturers cannot 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

Risk control related to bacteria, moulds and yeasts, as well as undesired pyrogenic, immunological and

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.

a) ISO 11135, ISO 11137, ISO 11737-1, ISO 13408, ISO 14160, ISO 14937, ISO 17664 and ISO 17665-1, which can

b) all relevant parts of ISO 10993, which can be used to manage risks related to undesired pyrogenic,

The TSE risk may be judged acceptable if the following criteria are both met, taking into account the

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

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

The evaluation of the overall residual risk acceptability shall take into account the balance between