EN ISO 22442-1:2015

SLOVENSKI STANDARD
01-februar-2016
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SIST EN ISO 22442-1:2008
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8SRUDEDREYODGRYDQMDWYHJDQMD,62
Medical devices utilizing animal tissues and their derivatives - Part 1: Application of risk
management (ISO 22442-1:2015)
Tierische Gewebe und deren Derivate, die zur Herstellung von Medizinprodukten
eingesetzt werden - Teil 1: Anwendung des Risikomanagements (ISO 22442-1:2015)
Dispositifs médicaux utilisant des tissus animaux et leurs dérivés - Partie 1: Application
de la gestion des risques (ISO 22442-1:2015)
Ta slovenski standard je istoveten z: EN ISO 22442-1:2015
ICS:
11.120.01 Farmacija na splošno Pharmaceutics in general
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

EN ISO 22442-1
EUROPEAN STANDARD
NORME EUROPÉENNE
November 2015
EUROPÄISCHE NORM
ICS 11.100.99 Supersedes EN ISO 22442-1:2007
English Version
Medical devices utilizing animal tissues and their
derivatives - Part 1: Application of risk management (ISO
22442-1:2015)
Dispositifs médicaux utilisant des tissus animaux et Tierische Gewebe und deren Derivate, die zur
leurs dérivés - Partie 1: Application de la gestion des Herstellung von Medizinprodukten eingesetzt werden -
risques (ISO 22442-1:2015) Teil 1: Anwendung des Risikomanagements (ISO
22442-1:2015)
This European Standard was approved by CEN on 1 November 2015.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION

EUROPÄISCHES KOMITEE FÜR NORMUNG

CEN-CENELEC Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2015 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 22442-1:2015 E
worldwide for CEN national Members.

Contents Page
European foreword . 3
Relationship between this European Standard and the Essential Requirements of
EU Directive 93/42/EEC. 5

European foreword
This document (EN ISO 22442-1:2015) has been prepared by Technical Committee ISO/TC 194
"Biological evaluation of medical devices" in collaboration with Technical Committee CEN/TC 316
“Medical devices utilizing tissues” the secretariat of which is held by DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by May 2016 and conflicting national standards shall be
withdrawn at the latest by May 2016.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent
rights.
This document supersedes EN ISO 22442-1:2007.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EU Directive(s).
For relationship with EU Directive, see informative Annex ZA, which is an integral part of this
document.
The following referenced documents are indispensable for the application of this document. For
undated references, the latest edition of the referenced document (including any amendments) applies.
For dated references, only the edition cited applies. However, for any use of this standard ‘within the
meaning of Annex ZA’, the user should always check that any referenced document has not been
superseded and that its relevant contents can still be considered the generally acknowledged state-of-
art.
When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a
normative reference to the corresponding EN standard, if available, and otherwise to the dated version
of the ISO or IEC standard, as listed below.

NOTE The way in which these referenced documents are cited in normative requirements determines the
extent (in whole or in part) to which they apply.

Table 1 – Correlation between normative references and dated EN and ISO standards

Normative references Equivalent dated standard
as listed in Clause 2 of the ISO
EN ISO
standard
ISO 10993-1 EN ISO 10993-1:2009 ISO 10993-1:2009
ISO 14971 ISO 14971:2012 ISO 14971:2007
ISO 22442-2 EN ISO 22442-2:2016 ISO 22442-2:2016
ISO 22442-3 EN ISO 22442-3:2007 ISO 22442-3:2007

According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and the United Kingdom.
Endorsement notice
The text of ISO 22442-1:2015 has been approved by CEN as EN ISO 22442-1:2015 without any
modification.
Annex ZA
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC

This European Standard has been prepared under a mandate given to CEN by the European
Commission and the European Free Trade Association to provide a means of conforming to the
Essential Requirements of Directive 93/42/EEC, concerning medical devices, as amended by
Commission Regulation (EU) No722/2012 in relation to detailed specifications regarding requirements
for medical devices utilizing tissues of animal origin.

Once this standard is cited in the Official Journal of the European Union under that Directive and has
been implemented as a national standard in at least one Member State, compliance with the normative
clauses of this standard given in Table ZA.1 confers, within the limits of the scope of this standard, a
presumption of conformity with the corresponding Essential Requirements of that Directive and
associated EFTA Regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the
risk management process needs to be in compliance with Directive 93/42/EEC, as amended by
2007/47/EC. This means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest
possible level’, ‘minimized’ or ‘removed’, according to the wording of the corresponding essential
requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with
essential requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.

NOTE 3 This Annex ZA is based on normative references according to the table of references in the
European foreword, replacing the references in the core text.

NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed
by this European Standard.
Table ZA.1 — Correspondence between this International Standard and Directive 93/42/EEC as
amended by Commission Regulation (EU) No 722/2012
Essential Requirements
(ERs) of Directive
93/42/EEC as amended
Clause(s)/subclause(s) of this Qualifying
by Commission
European Standard remarks/notes
Regulation (EU) No
722/2012
4.1, 4.2, 4.3, 4.4, 4.5, 4.6 and
7.1
Annex C
4.1, 4.2, 4.3, 4.4, 4.5, 4.6 and
7.2
Annex C
4.1, 4.2, 4.3, 4.4, 4.5, 4.6 and
8.1
Annex C
4.1, 4.2, 4.3, 4.4, 4.5, 4.6 and
8.2
Annex C
Annexes C and D Annex I of Commission Annexes C and D are
Regulation (EU) No dedicated to TSE risk,

722/2012 but 4.1, 4.2, 4.3, 4.4 are
also relevant.
WARNING — Other requirements and other EU Directives may be applicable to the product(s)
falling within the scope of this standard.

INTERNATIONAL ISO
STANDARD 22442-1
Second edition
2015-11-01
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 22442-1:2015(E)
©
ISO 2015
ISO 22442-1:2015(E)
© ISO 2015, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
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written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of
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ii © ISO 2015 – All rights reserved

ISO 22442-1:2015(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 . 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 . 6
4.6 Production and post-production information system . 7
Annex A (informative) Guidance on the application of this part of ISO 22442 .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
Bibliography .25
ISO 22442-1:2015(E)
Foreword
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
electrotechnical standardization.
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
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO’s adherence to the WTO principles in the Technical
Barriers to Trade (TBT), see the following URL: Foreword — Supplementary information.
The committee responsible for this document is ISO/TC 194, Biological and clinical evaluation of medical
devices, SC 1, Tissue product safety.
This second edition cancels and replaces the first edition (ISO 22442-1:2007), of which it constitutes a
minor revision.
ISO 22442 consists of the following parts, under the general title Medical devices utilizing animal tissues
and their derivatives:
— Part 1: Application of risk management
— Part 2: Controls on sourcing, collection and handling
— Part 3: Validation of the elimination and/or inactivation of viruses and transmissible spongiform
encephalopathy (TSE) agents
— Part 4: Principles for elimination and/or inactivation of transmissible spongiform encephalopathy (TSE)
agents and validation assays for those processes [Technical Report]
iv © ISO 2015 – All rights reserved

ISO 22442-1:2015(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 part of ISO 22442 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 part of ISO 22442 is intended to cover medical devices including active implantable medical
devices such as implantable infusion pumps.
This part of ISO 22442 does not apply to in vitro diagnostic devices.
This part of ISO 22442 can only be used in combination with ISO 14971 and is not a “standalone” standard.
To show compliance with this part of ISO 22442, 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.
INTERNATIONAL STANDARD ISO 22442-1:2015(E)
Medical devices utilizing animal tissues and their
derivatives —
Part 1:
Application of risk management
1 Scope
This part of ISO 22442 applies to medical devices other than in vitro diagnostic medical devices
manufactured utilizing materials of animal origin, which are non-viable or have been rendered non-
viable. It specifies, in conjunction with ISO 14971, a procedure to identify the hazards and hazardous
situations associated with such devices, to estimate and evaluate the resulting risks, to control these
risks, and to monitor the effectiveness of that control. Furthermore, it outlines the decision process for
the residual risk acceptability, taking into account the balance of residual risk, as defined in ISO 14971,
and expected medical benefit as compared to available alternatives. This part of ISO 22442 is intended
to provide requirements and guidance on risk management related to the hazards typical of medical
devices manufactured utilizing animal tissues or derivatives such as
a) contamination by bacteria, moulds or yeasts;
b) contamination by viruses;
c) contamination by agents causing Transmissible Spongiform Encephalopathies (TSE);
d) material responsible for undesired pyrogenic, immunological or toxicological reactions.
For parasites and other unclassified pathogenic entities, similar principles can apply.
This part of ISO 22442 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 part of ISO 22442 does not specify a quality management system for the control of all stages of
production of medical devices.
This part of ISO 22442 does not cover the utilization of human tissues in medical devices.
NOTE 1 It is not a requirement of this part of ISO 22442 to have a full quality management system during
manufacture. However, attention is drawn to International Standards for quality management systems
(see ISO 13485) that control all stages of production or reprocessing of medical devices.
NOTE 2 For guidance on the application of this part of ISO 22442, see Annex A.
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
ISO 22442-1:2015(E)
ISO 22442-2, Medical devices utilizing animal tissues and their derivatives — Part 2: Control 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.
3.1
animal
any 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 material by a manufacturing process
EXAMPLE Hyaluronic acid, collagen, gelatine, monoclonal antibodies, chitosan, 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
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
in combination, for human beings for one or more of the specific purpose(s):
— diagnosis, prevention, monitoring, treatment or alleviation of disease;
— diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury;
— investigation, replacement, modification, or support of the anatomy or of a physiological process;
— supporting or sustaining life;
— control of conception;
— disinfection of medical devices;
2 © ISO 2015 – All rights reserved

ISO 22442-1:2015(E)
— providing information for medical purposes by means of in vitro examination of specimens derived
from the human body;
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
[40]
Note 1 to entry: This definition has been developed by the Global Harmonization Task Force (GHTF)
Note 2 to entry: This part of ISO 22442 does not apply to in vitro diagnostic devices.
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 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 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.
The requirements of ISO 14971 and 4.2 to 4.5 apply. Compliance with these requirements shall be
verified by inspection of the risk management file.
NOTE Further discussion of medical benefits and the risk/benefit analysis can be found in
ISO 14971:2007, D.6.
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 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
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.
ISO 22442-1:2015(E)
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.
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 © ISO 2015 – All rights reserved

ISO 22442-1:2015(E)
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 part of ISO 22442, 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, 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 degradation.
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.
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 part of ISO 22442.
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
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:
ISO 22442-1:2015(E)
a) ISO 11135, ISO 11137, ISO 11737-1, ISO 13408, ISO 14160, ISO 14937, ISO 17664 and ISO 17665-1, which can
be relevant for bacteria, moulds and yeasts (see References [19] to [33]);
b) all relevant parts of ISO 10993, which can be used to manage risks related to undesired pyrogenic,
immunological or toxicological reactions (see References [1] to [18]).
The use of these International Standards 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.
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.
6 © ISO 2015 – All rights reserved

ISO 22442-1:2015(E)
4.6 Production and post-production information system
Manufacturers shall ensure that the system will identify changes in the zoonosis status of the chosen
source of animal materials.
ISO 22442-1:2015(E)
Annex A
(informative)
Guidance on the application of this part of ISO 22442
A.1 General
Wherever in this part of ISO 22442 it is stated that something “be addressed”, the reader should either
take action to control the risk or justify in the risk management report why they have not done so.
A.2 Application to materials from animal sources
This International Standard is applicable to materials such as
— porcine heart valves, bovine bones, cattle ligaments and bovine pericardium;
— derivatives of animal tissues, such as chondroitin sulfate obtained from shark and collagen derived
from hides, and of animal blood or serum;
— materials produced in vivo by relevant animals, e.g. antibodies utilized in the manufacturing process;
— starting materials such as bovine serum albumin, enzymes, culture media including those used to
prepare working cell banks, master cell banks or master seeds for products such as hyaluronic acid.
A.3 Application to materials supplied by third parties
This part of ISO 22442 can be applied when the materials used by medical device manufacturers
have been prepared from animal sources by third parties or subcontractors. An example is gelatine
derived from animal hides or bones. In considering the risks associated with the use of these products,
the medical device manufacturers should seek evidence from their suppliers as to whether relevant
requirements of this International Standard have been applied in assessing the suitability of the
animal material or whether alternative approaches were applied. The information obtained should be
incorporated in the risk management report relating to the medical device, as appropriate, but may
need to be supplemented by information supplied by the third party or subcontractor.
8 © ISO 2015 – All rights reserved

ISO 22442-1:2015(E)
Annex B
(informative)
Graphical representation of part of the risk management process
for medical devices utilizing animal material
See Figure B.1 overleaf.
ISO 22442-1:2015(E)
Start
Identify hazard and
determine risk using
ISO 14971 and
ISO 22442-1
Risk related to
undesired:
Risk related to Risk related to:
- pyrogenic reaction
parasites and - bacteria Risk related Risk related to
- immunological
unclassiied - moulds TSE agents
to viruses
reaction
pathogenic entities - yeasts
- toxicological
reaction
ISO 11134, ISO 11135,
ISO 11137, ISO 11737-1,
Relevant parts of
ISO 13408, ISO 13683, ISO 22442 series
ISO 10993 series
ISO 14160, ISO 14937, or other risk
or other risk
control options
ISO 17664, ISO 17665
control options
(see also 4.4.3)
or other risk control
options
Have
risk reduction
measurements been
identiied?
Is the
balance between
No Yes
medical beneit and
Reassess project?
residual risk
acceptable?
YesNo
Prepare risk
management report
NON-ACCEPTABLE
(see ISO 14971,
DEVICE
Clause B)
Collect production
and post production
information
Figure B.1 — Graphical representation of part of the risk management process
This chart illustrates part of the risk management process in accordance with ISO 14971 and this part
of ISO 22442. The risk management process should address all relevant risks shown in this chart.
10 © ISO 2015 – All rights reserved

ISO 22442-1:2015(E)
Annex C
(normative)
Special requirements for some animal materials considering the
risk management for TSE agents
C.1 General
The requirements of this Annex do not obviate the need to undertake a risk assessment for TSE risks,
including the requirements in Clause 4, as part of the risk assessment and management process
described in ISO 14971.
Risk management can be addressed by processing, sourcing, or a combination of both. Tallow
derivatives, animal charcoal and amino acids are acceptable for TSE risk due to their processing and
not their sourcing.
ISO 22442-2:2015, Annex A, contains additional requirements relating to the application of this part of
ISO 22442 to bovine-sourced materials.
To demonstrate compliance with the requirements of this part of ISO 22442 it is necessary to implement
a technical agreement between the medical device manufacturer and the animal material/derivative
supplier (see ISO 22442-2:2015, Clause 6).
C.2 Collagen
Collagen is a fibrous protein component of mammalian connective tissue.
For collagen, documentation to demonstrate compliance with this part of ISO 22442 shall be provided,
taking into account the relevant requirements of this Annex.
When completing the risk management required by this part of ISO 22442, consider the following.
— For collagen produced from bone, the bone shall be sourced from countries with minimal exposure
to BSE. Sourcing bone from countries with limited exposure to BSE shall be justified by reference to
other applicable risk control measures (see ISO 22442-2:2015, Annex A). Bone shall not be sourced
from countries where infection with the BSE agent is confirmed at a higher level, unless from a low
risk herd as defined in ISO 22442-2.
— For collagen produced from bones, the manufacturing conditions specified for gelatine are
applicable (see below).
— Collagen produced from hides and skins does not usually present a significant TSE risk provided
that cross-contamination with potentially infected materials, for example central nervous tissues, is
avoided during their procurement. To demonstrate compliance with the requirements of this part of
ISO 22442, it is necessary to incorporate measures to prevent cross-contamination (see ISO 22442-2)
and to document the measures that are adopted in the techn
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