SIST EN ISO 22442-1:2008

SLOVENSKI STANDARD
SIST EN ISO 22442-1:2008
01-april-2008
1DGRPHãþD
SIST EN 12442-1:2001
0HGLFLQVNLSULSRPRþNLNLXSRUDEOMDMRåLYDOVNDWNLYDLQQMLKRYHGHULYDWHGHO
8SRUDEDREYODGRYDQMDWYHJDQMD,62
Medical devices utilizing animal tissues and their derivatives - Part 1: Application of risk
management (ISO 22442-1:2007)
Tierische Gewebe und deren Derivate nutzende Medizinprodukte - Teil 1: Anwendung
des Risikomanagements (ISO 22442-1:2007)
Tissus animaux et leurs dérivés utilisés dans la fabrication des dispositifs médicaux -
Partie 1: Application de la gestion des risques (ISO 22442-1:2007)
Ta slovenski standard je istoveten z: EN ISO 22442-1:2007
ICS:
11.120.01
SIST EN ISO 22442-1:2008 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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EUROPEAN STANDARD
EN ISO 22442-1
NORME EUROPÉENNE
EUROPÄISCHE NORM
December 2007
ICS 11.100.20 Supersedes EN 12442-1:2000
English Version
Medical devices utilizing animal tissues and their derivatives -
Part 1: Application of risk management (ISO 22442-1:2007)
Dispositifs médicaux utilisant des tissus animaux et leurs Tierische Gewebe und deren Derivate, die zur Herstellung
dérivés - Partie 1: Application de la gestion des risques von Medizinprodukten eingesetzt werden - Teil 1:
(ISO 22442-1:2007) Anwendung des Risikomanagements (ISO 22442-1:2007)
This European Standard was approved by CEN on 14 December 2007.
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 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 Management Centre has the same status as the
official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,
Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36  B-1050 Brussels
© 2007 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 22442-1:2007: E
worldwide for CEN national Members.

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EN ISO 22442-1:2007 (E)
Contents Page
Foreword.3

2

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EN ISO 22442-1:2007 (E)
Foreword
This document (EN ISO 22442-1:2007) 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 NBN.
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 June 2008, and conflicting national standards shall be withdrawn at
the latest by June 2008.
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 12442-1:2000.
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 EC Directive(s).
This European Standard has been developed for medical devices regulated by the Medical Device Directive
93/42/EC as amended by 2003/32/EC (see Annex ZA). By analogy, it could be applied for active implantable
medical devices regulated by the Active Implantable Medical Device Directive 90/385/EC.
For relationship with EC Directive(s), see informative Annex ZA, which is an integral part of this document.
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, Cyprus, Czech
Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,
Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain,
Sweden, Switzerland and the United Kingdom.
Endorsement notice
The text of ISO 22442-1:2007 has been approved by CEN as a EN ISO 22442-1:2007 without any
modification.
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EN ISO 22442-1:2007 (E)

Annex ZA
(informative)


Relationship between this European Standard and the Essential Requirements
of EU Directive 93/42/EEC as amended by Commission Directive 2003/32/EC


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 Essential Requirements of the
New Approach Directive 93/42/EEC, concerning medical devices, as amended by Commission Directive
2003/32/EC 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 Communities under that Directive and has
been implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in table ZA confers, within the limits of the scope of this International Standard, a presumption
of conformity with the corresponding Essential Requirements of that Directive and associated EFTA
regulations.

Table ZA — Correspondence between this European Standard and Directive 93/42/EEC as amended by
Commission Directive 2003/32/EC
Clause(s)/subclause(s) of this Essential requirements (ERs) of Qualifying remarks/Notes
International Standard Directive 93/42/EEC as amended
by Commission Directive
2003/32/EC
4.1, 4.2, 4.3, 4.4, 4.5, 4.6, Annex C Annex I, 7.1, 7.2, 8.1, 8.2
Annexes C and D Annex of Commission Directive Annexes C and D are dedicated to
2003/32/EC TSE risk, but clauses 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.

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INTERNATIONAL ISO
STANDARD 22442-1
First edition
2007-12-15

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 22442-1:2007(E)
©
ISO 2007

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ISO 22442-1:2007(E)
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ii © ISO 2007 – All rights reserved

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ISO 22442-1:2007(E)
Contents Page
Foreword. iv
Introduction . v
1 Scope . 1
2 Normative references . 2
3 Terms and definitions. 2
4 Risk management process . 3
4.1 General. 3
4.2 Risk analysis . 4
4.3 Risk evaluation. 5
4.4 Risk control . 5
4.5 Evaluation of overall residual risk acceptability .7
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 . 24

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ISO 22442-1:2007(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.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
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.
ISO 22442-1 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices,
Subcommittee SC 1, Tissue product safety.
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
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ISO 22442-1:2007(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 “stand-alone” Standard.
NOTE 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.

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INTERNATIONAL STANDARD ISO 22442-1:2007(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.


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ISO 22442-1:2007(E)
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management system
ISO 14971:2007, Medical devices — Application of risk management to medical devices
ISO 22442-2:2007, Medical devices utilizing animal tissues and their derivatives — Part 2: Control 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.
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 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 Annex F of ISO 22442-3:2007).
NOTE 2 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 The effectiveness of the process for inactivation of viruses and TSE agents should be expressed
mathematically in terms of a reduction factor (see Annex F of ISO 22442-3:2007).
NOTE 2 Inactivation aims to prevent infection by, and replication of, transmissible agents.
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ISO 22442-1:2007(E)
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;
⎯ 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
[39]
NOTE 1 This definition has been developed by the Global Harmonization Task Force (GHTF)
NOTE 2 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,
Clause D.6.
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ISO 22442-1:2007(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 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 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.
NOTE 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 22442-1:2007(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, -9, -17, -18 and -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 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.
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ISO 22442-1:2007(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 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 maintena
...