Iso 22442-1-2015

INTERNATIONAL ISO
STANDARD 2 2 442 -1
Second edition
2 01 5-1 1 -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 2 2 442 -1 : 2 01 5 (E)
I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n

© ISO 2 01 5
ISO 2 2 442 -1:2 015(E)
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ii
© ISO 2015 – All rights reserved
ISO 2 2 442 -1:2 015(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 Identi fication of qualitative and quantitative characteristics related to the
safety of medical devices .......................................................................................................................................... 3
4.2.2 Identi fication 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 2 2 442 ........................................................ 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 ............................................................................................................................................................................................................................. 2 5
© ISO 2 01 5 – All rights reserved

iii
ISO 2 2 442 -1:2 015(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 identi fied 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 speci fic 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 2 2442 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 oftransmissible spongiform encephalopathy (TSE)
agents and validation assays for those processes [Technical Report]
iv
ISO 2 2 442 -1:2 015(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
material s . T he range and quantities of materials of animal origin in medical devices var y. T hese
material s can comprise a maj or p ar t of the device (e. g. b ovine/p orcine hear t valves , b one s ub s titutes
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. tal low derivatives s uch as oleates and s tearates , fo etal calf serum, en z ymes , cu lture media) .
I S O 149 71 is a general s tandard which s p eci fies a proces s for a manufac turer by identifying haz ards
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 effec tivenes s of the control throughout the li fe c ycle. T his p ar t of I SO 2 2 4 42 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 2 2442 is intended to cover medical devices including active implantable medical
devices such as implantable infusion pumps.
T his p ar t of I SO 2 2 4 42 do es 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 p ar t of I SO 2 2 4 42 , its s p eci fied requirements shou ld b e fu l fi l led. T he
guidance given in the Notes and informative annexes is not normative and is not provided as a checklist
for auditors.

v
INTERNATIONAL STANDARD ISO 2 2 442 -1:2 015(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 speci fies, 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 de fined in ISO 14971,
and expected medical bene fit 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 unclassi fied 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 2 2442 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 1 3 485 ) that control all stages of production or reprocessing of medical devices.
NOTE 2 For guidance on the application of this part of ISO 2 2442 , 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 109 93 -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 2 2 442 -1:2 015(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 de finitions 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 2 2442-3: 20 07, 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 speci fic purpose(s):
— diagnosis, prevention, monitoring, treatment or alleviation of disease;
— diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury;
— investigation, replacement, modi fication, or support of the anatomy or of a physiological process;
— supporting or sustaining life;
— control of conception;
— disinfection of medical devices;
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ISO 2 2 442 -1:2 015(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
Note 1 to entry: This de finition has been developed by the Global Harmonization Task Force (GHTF) [40]
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 unclassi fied 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 bene fit, as compared to available alternatives.
The requirements of ISO 14971 and 4. 2 to 4. 5 apply. Compliance with these requirements shall be
veri fied by inspection of the risk management file.
NOTE Further discussion of medical bene fits and the risk/bene fit analysis can be found in
ISO 14971: 20 07, 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 s traps 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 10 9 93 (all parts) for the evaluation of such effects.
NOTE 3 The s tructure 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.

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ISO 2 2 442 -1:2 015(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, veri fication 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 puri fied 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 identi fied 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.
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ISO 2 2 442 -1:2 015(E)
4.3 Risk evaluation
In accordance with ISO 14971, all identi fied 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. A n ne x B
identi fies the main categories of risk that should be considered. Regarding the TSE risk, compliance
with requirements speci fied in for certain animal materials can indicate risk acceptability.
A n ne x C
NO TE A n n e x C c o m b i ne s e l e m e n t s o f r i s k e va l u ati o n a n d r i s k c o n tr o l .
4.4 Risk control
4.4.1 General
The risk control options shall be documented and justi fied.

The flowchart in A n ne x B g i ve s an o ve r vi e w o f the ri sk m a n a ge me n t p ro c e s s . I f add i tio n a l r i s ks a re
identi fied 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 justi fied 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 de fining the characteristics of the product, the medical device manufacturer
shall comply with the relevant requirements of both I S O 2 2 4 42 -2 a nd I S O 2 2 4 42 -3 , e xcep t where ei ther
the animal species is such that manufacturers cannot fully meet the requirements of I S O 2 2 4 42 -2 or an
i n ac ti vatio n p ro ce s s i n acco rd a nce w i th I S O 2 2 4 42 -3 wo u ld c au s e u n accep tab le de g rad atio n .
Ta l l o w de r i vati ve s , animal ch a rc o a l , a nd a m i no ac id s th at a re acc e p tab l e fo r TSE risk as discussed in
A n ne x C , due to the i r p ro c e s s i n g a nd no t the i r s o u rc i n g , s h a l l a l s o b e c o n s ide re d to h ave ac ce p tab le r i s k
re ga rd i n g vi r u s e s .
Regarding TSE risk, risk control measures speci fied in A n ne x C fo r ce r t a i n animal m ate r i a l s shall be
applied where relevant. If the manufacturer considers any requirement not to be relevant, the rationale
and justi fication shall be documented.
Fo r me d ic a l de v ic e s whe re an i n ac ti vatio n p ro c e s s c au s e s u n ac ce p tab le de g rad atio n , m a nu fac tu re r s
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 de mo n s trate th at the le ve l o f i n ac ti vati o n o f tra n s m i s s i b le a ge n ts in a va l id ate d m a nu fac tu r i n g
process, as required in ISO 22442-3, is sufficient to achieve an acceptable level of risk.

NO TE C r i te r i a a nd p r i nc ip l e s r e l e va n t to th e m a n a ge m e n t o f T S E r i s ks a re de s c r i b e d in A n ne x D . A n ne x D
c o n t a i n s i n fo r m ati o n o n r e l e va n t r i s k c o n tr o l m e a s u r e s
4.4.3 Risk control of other hazards
Risk control related to bacteria, moulds and yeasts, as well as undesired pyrogenic, immunological and
to x ic o lo g ic a l re ac tio n s s h a l l b e i mp le me n te d ac co rd i n g to ava i l ab le s ta nd a rd s .
Ta l l o w de r i vati ve s , animal ch a rc o a l , a nd a m i no ac id s th at a re acc e p tab l e fo r TSE risk as discussed in
A n ne x C , due to the i r p ro c e s s i n g a nd no t the i r s o u rc i n g , s h a l l a l s o b e c o n s ide re d to h ave ac ce p tab le r i s k
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
b i o b u rde n o f the i nc o m i n g a n i m a l m ate r i a l fo r the p ro duc tio n o f the me d ic a l de v ic e .
NOTE The following International Standards may be relevant:
© I S O 2 0 1 5 – Al l ri gh ts re s e rve d
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ISO 2 2 442 -1:2 015(E)
a) ISO 11135 , ISO 11137, ISO 11737-1 , ISO 1 3 40 8, ISO 14160, ISO 14937, ISO 1766 4 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 bene fit 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 speci fic 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, speci fic 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 bene fit 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 bene fit, as
compared to available alternatives. Where residual risks exist with regard to the contamination with
transmissible agents, the evaluation should speci fically discuss the risks and bene fits 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 bene fit and
feasibility considerations.
4.5.2 Documentation
The rationale that the risk is acceptable shall be documented in the risk management file.
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ISO 2 2 442 -1:2 015(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
s o u rc e o f a n i m a l m ate r i a l s .
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ISO 2 2 442 -1:2 015(E)
Annex A
(informative)
Guidance on the application of this part of ISO 2 2 442
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 2 2 442 -1:2 015(E)
Annex B
(informative)
Graphical representation of part of the risk management process

for medical devices utilizing animal material
See Figure B .1 overleaf.

9
ISO 2 2 442 -1:2 015(E)
Start
Identify hazard and

determine risk using
ISO 1 4971 and
ISO 2 2 442 -1
Risk related to
undesired:
Risk related to Risk related to:
- pyrogenic reaction
parasites and - bacteria Risk related Risk related to
- immunological
unclassiϐied - moulds to viruses TSE agents
reaction
pathogenic entities - yeasts
- toxicological
reaction
ISO 1 1 1 3 4, ISO 1 1 1 3 5 ,
ISO 1 1 1 3 7, ISO 1 1 73 7-1 ,
Relevant parts of
ISO 1 3 408, ISO 1 3 683 , ISO 2 2 442 series
ISO 1 099 3 series
ISO 1 41 60, ISO 1 493 7, or other risk
or other risk
ISO 1 7664, ISO 1 7665 control options
control options
(see also 4.4.3 )
or other risk control
options
Have
risk reduction
measurements been
identiϐied?
Is the
balance between
No Yes
medical beneϐit and Reassess proj ect?
residual risk
acceptable?
Yes No
Prepare risk
management report NON-ACCEPTABLE
(see ISO 1 4971 , DEVICE
Clause B)
Collect production
and post production
information
Figure B.1 — Graphical representation of part of the risk management process
T h i s c h a r t i l l u s trate s p a r t o f the r i s k m a n a ge me n t p ro c e s s i n ac c o rd a nc e w i th I S O 14 9 71 a n d th i s p a r t
o f I S O 2 2 4 42 . T he r i s k m a n a ge me n t p ro c e s s s ho u l d add re s s a l l re l e va n t r i s ks s ho w n i n th i s c h a r t.
10
ISO 2 2 442 -1:2 015(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 C lause 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 2 2442-2:2015 , 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 justi fied by reference to
other applicable risk control measures (see ISO 2 2442-2: 2015, Annex A) . Bone shall not be sourced
from countries where infection with the BSE agent is con firmed at a higher level, unless from a low
risk herd as de fined in ISO 22442-2.
— For collagen produced from bones, the manufacturing conditions speci fied for gelatine are
applicable (see below) .
— Collagen produced from hides and skins does not usually present a signi ficant 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 technical agreement between the collagen
supplier and the medical device manufacturer to prevent such cross-contamination.
Collagen shall be obtained from animals declared as fit for human consumption (see ISO 22442-2).

11
ISO 2 2 442 -1:2 015(E)
Source countries with “Minimal exposure to BSE ” should be interpreted as countries with negligible
BSE risk1) 2 ) 3)
, or countries on the APHIS List4) or from low risk herds as de fined in ISO 22442-2.
Source countries with “Limited exposure to BSE” should be interpreted in the same way as countries
with controlled BSE risk.
C.3 Gelatine derived from hides and bones
C.3 .1 General
Gelatine is a natural, soluble protein, gelling or non-gelling, obtained by the partial hydrolysis of
collagen produced from bones, hides and skins, tendons and sinews of animals.
For gelatine, documentation to demonstrate compliance with this part of ISO 22442 shall be provided,
taking into account the relevant requirements listed in this Annex.
Gelatine shall be obtained from animals declared as fit for human consumption.
When completing the risk evaluation and control required by this part of ISO 22442, consider C . 3 . 2 to
C . 3 .4.
C.3 .2 Hides as the starting material
On the basis of current knowledge, hides used for gelatine production represent a safer source material
when compared to bones.
Gelatine produced from hides does not usually present a signi ficant 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 to prevent such cross-contamination in the technical
agreement between the gelatine supplier and the medical device manufacturer.
C.3 .3 Bones as the starting material
Where bones are used to manufacture gelatine, the quality of the starting materials is the primary
parameter that will ensure the safety of the final product. Therefore, the following shall be applied.
— Subject to national legislation, bone shall be sourced from countries with minimal or limited
exposure to BSE . Bone shall not be sourced from countries where infection with the BSE agent is
con firmed at a higher level, unless from a low risk herd as de fined in ISO 22442-2.
— Skulls and spinal cords shall be removed from the collected bones (raw/starting material) from
cattle of a speci fic age as de fined in national legislation.
— Additionally, vertebrae shall be removed from the raw/starting materials from cattle of all ages
from countries with limited exposure to BSE .
1) The World Organisation of Animal Health (OIE) maintains a list of OIE Member Countries officially
recognised as having a negligible or controlled BSE risk status, available on the OIE Web site at
http: //www.oie.int/en/animal-health-in-the- world/official -disease-status/bse/list-of-bse-risk-status/
2) The European Union has published documents on Geographical BSE Risks for a number of countries,
available on the Web site of the Scienti fic Steering Committee of the Commission of the European Union:
http: //ec.europa.eu/food/fs/sc/ssc/outcome_en.html
3) The EFSA permitted list can be found at http: //www.efsa.europa.eu/en/topics.htm
4) The permitted list published by the Animal and Plant Health Inspection Service can be found at
http: //www.aphis.usda.gov/wps/portal/aphis/home/
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ISO 2 2 442 -1:2 015(E)
C.3 .4 Manufacturing methods
No speci fic measures with regard to the processing conditions are required for gelatine produced from
hides provided that control measures be put in place to avoid cross-contamination both during the
sourcing of the hides and during the manufacturing process (see C . 3 . 2) .
Where bones are used as the starting material, use one of the manufacturing methods described below.
— Although the alkaline extraction process (prior to the finishing steps) has shown a slightly
higher inactivation/elimination capacity compared to the acid process, both the acid and the
alkaline manufacturing methods to produce the final gelatine have shown similar overall
inactivation/elimination of TSE infectivity in the gelatine validation experiments. Studies have
shown that an additional alkaline treatment (pH 13 , 1 h) of the bones/ossein further increases the
TSE inactivation/elimination capacity of the acid manufacturing process.
— For a typical alkaline manufacturing process, bones are finely crushed, degreased with hot water
and demineralized with diluted hydrochloric acid (at a minimum of 4 % and pH <1,5) over a period
of at least two days to produce the ossein. This is followed by an alkaline treatment with saturated
lime solution (at least pH 12,5) for a period of at least 20 d. The gelatine is extracted, washed, filtered
and concentrated. A flash heat treatment step using 138 °C to 140 °C for 4 s is applied. Bovine bones
may also be treated by an acid process. The liming step is then replaced by an acid pre-treatment
where the ossein is soaked overnight at pH <4. In the heat/pressure process, the dried, degreased,
crushed bones are autoclaved with saturated steam at a pressure greater than 3 bar and a minimum
temperature of 133 °C for at least 20 min, followed by extraction of the protein with hot water. The
finishing steps for both the acid and heat/pressure process are similar to the alkaline process.
C.4 Bovine blood derivatives
C.4.1 General
Foetal bovine serum is commonly used in cell cultures. Foetal bovine serum should be obtained from
foetuses harvested in abattoirs from healthy dams fit for human consumption and the womb should
be completely removed. The foetal blood shall be harvested in a dedicated space or area by cardiac
puncture into a closed collection system using an aseptic technique.
New born calf serum is obtained from calves aged less than 20 d; calf serum from animals aged less
than 12 months. In the case of donor bovine serum, given that it can be derived from animals less than
36 months old, the BSE status of the donor herd shall be well de fined and documented. In all cases,
serum shall be collected according to speci fied protocols by personnel trained in these procedures and
the precautions necessary to avoid cross-contamination with higher risk tissues.
For bovine blood derivatives, documentation to demonstrate compliance with this part of ISO 22442
shall be provided, taking into account the relevant requirements listed in this Annex. When completing
the risk management required by this part of ISO 22442, consider C .4. 2 to C .4.4.
C.4.2 Traceability
Traceability to the slaughterhouse shall be ensured for each batch of serum or plasma. Slaughterhouses
shall have available lists of farms from which the animals are sourced. If serum is produced from living
animals, records shall be available for each serum batch to ensure traceability to the farms and to the
individual animal. When traceability to the individual animal is not possible, this shall be justi fied in
the risk management file.
C.4.3 Geographical origin
Bovine blood shall be sourced from countries with minimal exposure to BSE unless otherwise justi fied
and authorized.

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ISO 2 2 442 -1:2 015(E)
C.4.4 Stunning methods
If blood is obtained from slaughtered animals, the method of slaughter is of importance to ensure
the safety of the material. It has been demonstrated that stunning by a captive bolt stunner with or
without pithing, as well as by pneumatic stunner, especially if it injects air, can destroy the brain and
disseminate brain material into the blood stream. There is evidence that non-penetrative stunning can
cause some Central Nervous System (CNS) embolism. The stunning methods shall be described for the
bovine blood collection process unless the material is sourced from a country of negligible geographical
BSE risk (see ISO 2 2442-2: 2015 , A. 3 .1) .
Where sourcing of blood is from countries with limited exposure to BSE , a non-penetrative stunner
or electro-narcosis shall be used for slaughter of animals over 1 2 months of age. The use of non-
penetrative stunning shall be justi fied on the basis of an estimate of the risk of dissemination of brain
particles into the blood.
NOTE Additional information on stunning techniques can be found in SSC opinion on s tunning
methods and BSE risk (The risk of dissemination of brain particles into the blood and carcass when applying
certain stunning methods) adopted at the meeting on 10-11 January 2002 ( http://ec.europa.eu/food/fs/sc/
ssc/out245 _en.pdf) and Report of the EFSA Working Group on BSE risk from dissemination of brain particles in blood
and carcass. Question N° EFSA-Q-2003–122 adopted on 21 October 2004 ( http://www.efsa.europa.eu/en/
scdocs/doc/1 23 .pdf) .
C.5 Tallow derivatives
Tallow is fat obtained from tissues including subcutaneous, abdominal and inter-muscular areas and
bones.
Tallow derivatives, such as glycerol and fatty acids, manufactured from tallow by rigorous processes,
are thought unlikely to be infectious. For this reason, such materials manufactured under the conditions
at least as rigorous as those given below shall be considered as presenting an acceptable TSE risk,
irrespective of the geographical origin and the nature of the tissues from which tallow derivatives are
derived. The following are examples of rigorous processes:
a) trans-esteri fication or hydrolysis at not less than 200 °C for not less than 20 min under pressure
(glycerol, fatty acids and fatty acid esters production);
b) saponi fication with sodium hydroxide solution, at a concentration of 12 mol/ l (glycerol and
so ap production) :
1) batch process: at not less than 95 °C for not less than 3 h;

2) continuous process: at not less than 140 °C, under pressure for not less than 8 min, or equivalent;
c) distillation at 200 °C.
C.6 Animal charcoal
Animal charcoal is prepared by carbonization of animal tissues, such as bones, using a

temperature >800 °C.
Irrespective of the geographical origin and the nature of the tissue, animal charcoal prepared under
these conditions shall be considered as presenting an acceptable TSE risk.
C.7 Milk and milk derivatives
Certain materials, including lactose, are extracted from whey, the spent liquid from cheese production
following coagulation. Coagulation can involve the use of calf rennet, an extract from abomasums,
or rennet derived from other ruminants. A risk assessment for lactose and other whey derivatives
14
ISO 2 2 442 -1:2 015(E)
produced using calf rennet was performed 5 ) and concluded that the TSE risk is negligible if the calf
rennet is produced in accordance with the proces s described in the C PM P risk assessment report[4 4] .
Subject to national legislation, milk derivatives manufactured according to the conditions below are
considered as presenting an acceptable TSE risk:
— the milk is sourced from healthy animals under the same conditions as milk collected for human
consumption;
— no other ruminant- derived materials, with the exception of calf rennet, are used in the preparation
of such derivatives (e.g. pancreatic enzyme digests of casein).
C.8 Wool and its derivatives
Wool and its derivatives, s uch as lanolin and wool alcohols , shall be cons idered in compliance with this
part of ISO 22442, provided the wool is sourced from live healthy animals.
Wool derivatives produced from wool that is sourced from slaughtered animals declared “fit for human
cons umption” are considered as presenting an acceptable TSE risk if the manufacturing process in
relation to pH , temperature and duration of treatment meets at leas t one of the s tipulated processing
conditions lis ted below:
— treatment at pH ≥13 (initial; corresponding to concentrations of sodium hydroxide ≥0,1 mol/l) at

≥60 °C for at least 1 h; this normally occurs during the re flux stage of the organic-alkaline treatment;
— molecular distillation at ≥220 °C under reduced pressure.
C.9 Amino acids
Amino acids can be obtained by hydrolysis of animal materials from various sources.
Amino acids prepared using the following proces sing conditions are considered as presenting an
acceptable TSE risk:
— amino acids produced from hides and skins by a process which involves exposure of the material to
a pH of 1 to 2, followed by a pH >11, followed by heat treatment at 140 °C for 30 min at 3 bar;
— the resulting amino acids or peptides shall be filtered after production;
— analysis shall be performed using a validated and sensitive method to control any residual intact
macromolecules with a justi fied limit set.
5) The committee for Proprietary Medicinal Products and its Biotechnology Working Party conducted a risk and
regulatory assessment of lactose prepared using calf rennet. The risk assessment included the source of the animals,
the excision of the abomasums and the availability of well-de fined quality assurance procedures. The quality of any
milk replacers used as feed for the animal from which abomasums are obtained is particularly important.
© ISO 2 0 1 5 – All rights reserved
15
ISO 2 2 442 -1:2 015(E)
Annex D
(informative)
Information relevant to the management of TSE risk
D.1 General
The naturally occurring transmissible spongiform encephalopathies (TSE) include scrapie (in sheep
and goats), chronic wasting disease (in mule-deer and elk), bovine spongiform encephalopathy (BSE)
in cattle as well as kuru and Creutzfeldt-Jakob disease (CJD) in humans. It is difficult to detect agents
causing these diseases After latency periods of up to many years the agents cause disease and,
in vivo .
finally, lead to death. No means of therapy is known.
Current information on the characteristics of the causative agents is limited. These agents are extremely
resistant to most of the chemical and physical procedures that inactivate conventional viruses. They do
not induce a detectable immune response. There are natural barriers which limit their interspecies
spread of transmissible agent, but they can be crossed under appropriate circumstances. This is usually
dependent upon strain, dose, route of exposure and the species barrier. Studies in laboratory animals
have shown that intracerebral inoculation is the most efficient route of transmission.
D.2 Risks for humans
There is considerable circumstantial evidence that the variant form of human CJD (vCJD) arose from
BSE and it is prudent to accept that the BSE agent can be transmitted to man. This part of ISO 22442
therefore contains a number of requirements to ensure that risks are controlled if biological materials
from species susceptible to TSE are used for the manufacture of medical devices. This Annex
provides guidance that should be followed to minimize the risks of contamination. It identi fies where
requirements elsewhere in this part of ISO 22442 are applicable and where information from other
sources is relevant. All devices should be considered on a case-by-case basis.
D.3 Risk management for TSE agents
D.3 .1 Principle
The safety of a medical device, in terms of its potential for passing on a TSE agent, is dependent on a
number of factors. The eight most important factors below should be analysed, evaluated and managed:
— animal species used (see D. 3 . 2 );
— geographical sourcing (see D. 3 . 3 );
— nature of starting tissue (see D. 3 .4 );
— slaughtering and processing controls to prevent cross-contamination (see D. 3 . 5 );
— methods used to inactivate or remove TSE agents (see D. 3 .6 );
— quantities of animal starting material required to produce one unit of the medical device (see D. 3 .7.1 );
— quantities of material of animal origin coming into contact with the patients and users (see D. 3 .7.2 );
— route of administration (see D. 3 .7. 3) .
16
ISO 2 2 442 -1:2 015(E)
When manufacturers have the choice, the use of materials from non-TSE relevant animal species or
non-animal origin is preferred.
D.3 .2 Animal species used (see ISO 2 2 442 -2 )
The TSE risk is related to the source species, strains and nature of the starting tissue.
As the accumulation of TSE infectivity occurs over an incubation period of several years, sourcing from
young, healthy animals is considered to be a factor reducing the risk. The use of older animals can
increase the risk. Sourcing from animals under the age of 6 months can provide a reduced level of risk.
The use of fallen stock, emergency-slaughtered and TSE-suspected animals might substantially increase
the risk and should be excluded. Risks of this nature are addressed by demonstrating conformity with
requirements in ISO 22442-2:2015, Annex A.
D.3 .3 Geographical sourcing (see ISO 2 2 442 -2 )
Certain factors in fluence the geographical risk of BSE infection associated with the use of raw tissues
or derivatives from individual countries. They will apply particularly to BSE but can also be used to
determine risk from TSEs in other species.
Manufacturers should take into account published assessments relating to BSE risks associated with
speci fic countries. For example, the OIE has published documents on the BSE status for a number of
countries (the OIE Terrestrial Code relating to BSE is available at http://www.oie.int/international-
standard-setting/terrestrial-code/ ) . The United States Department of Agriculture has published a list
of permitted and unauthorized source countries (see Annex C , Footnote 5). Japan’s Ministry of Health,
Labour and Welfare has also published a similar list of permitted and unauthorized source countries
(see Reference [47 ] ) .
D.3 .4 Nature of starting tissue
The manufacturer should take into account the classi fication of the hazards relating to different types
of starting tissue. Sourcing of animal tissue should be subject to control and individual inspection by
a veterinarian and the animal carcass should be certi fied as fit for human consumption, whenever
possible, according to local custom and practice. The manufacturer should not source animal tissue
classi fied as having potentially high TSE infectivity. The only exception is if there is an absence of an
alternative starting tissue and there are signi ficant medical bene fits for the patient.
A classi fication of the hazards relating to different types of animal starting material has been
established and approved by the World Health Organization[42 ] . Tables D.1 to D. 3 are based on the WHO
classi fication of tissues in 2006, and WHO Tables on Tissue Infectivity Distribution in TSE updated
2010 [43] . Risk assessments should be revised in the light of more recent information, as it becomes
available, and should take into account the level of uncertainty inherent in the data available.

17
ISO 2 2 442 -1:2 015(E)
In Tables D.1, D. 2 and D. 3 , the following data entry symbols are used:
+ presence of infectivity or PrP TSE a ;
− absence of detectable infectivity of PrP TSE ;
NT not tested;
NA not applicable;
? uncertain interpretation;
() limited or preliminary data;
[] infectivity or PrP TSE data based exclusively on bioassays in transgenic (Tg) mice over-ex-
pressing the PrP-encoding gene or PrP TSE ampli fication methods.
a PrP TSE = prion protein — TSE infectious isoform
The placement of a given tissue in one or another category can be disease-speci fic and subject to
revision as new data accumulate from increasingly sensitive tests. In fact, it is conceivable that the
detection of infectivity using transgenic mice that over-express genes encoding various prion proteins,
or the detection of PrP TSE using some newly developed ampli fication methods, might prove to be more
sensitive than transmission studies in wild-type bioassay animals, and thus may not correlate with
disease transmission in nature.
It is critically important to understand that categories of infectivity are not the same as categories of
risk, which require consideration not only of the level of infectivity in tissue, but also of the amount
of tissue to which a person or animal is exposed, and the route by which infection is transmitted. For
example, although the level of tissue infectivity is the most important factor in estimating the risk of
transmission by instrument cross-contamination during surgical procedures (e.g. neurosurgery versus
general surgery), it will be only one determinant of the risk of transmission by blood transfusions, in
which a large amount of low-infectivity blood is administered intravenously, or the risk of transmission
by foodstuffs that, irrespective of high or low infectivity, involves a comparatively inefficient oral route
of infection.
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ISO 2 2 442 -1:2 015(E)
Table D.1 — Category A: High-infectivity tissues
CNS tissues that attain a high titre of infectivity in the later stages of all TSEs
and certain tissues that are anatomically associated with the CNS
Humans Cattle Sheep and goats
Tissues vCJD Other TSEs BSE Scrapie
Infectiv-
Infectivitya PrP TSE Infectivitya PrP TSE
itya PrP TSE Infectivitya PrP TSE
Brain + + + + + + + +
Spinal cord + + + + + + + +
Retina NT + + + + NT NT +
O ptic nerve b NT + NT + + NT NT +
Spinal ganglia + + NT + + NT + +
Trigeminal ganglia + + NT + + + NT +
Pituitary glandc NT + + + − + + +
Dura mater c NT (+) + − NT NT NT NT

a Infectivity bioassays of human tissues have been conducted in either primates or mice (or both); bioassays of cattle
tissues have been conducted in either cattle or mice (or both); and most bioassays of sheep and/or goat tissues have been
conducted only in mice. In regard to sheep and goats not all results are consistent for both species; for example, two goats
(but no sheep) have contracted BSE naturally.
b I n experimental models of TSE , the optic nerve has been shown to be a route of neuroinvasion and contains high titres
of infectivity.
c No experimental data about infectivity in the human pituitary gland or dura mater have been reported, but cadaveric
dura mater allograft patches, and growth hormone derived from cadaveric pituitaries have transmitted disease to hundreds
of people and therefore must be included in the category of high risk tissues.

19
ISO 2 2 442 -1:2 015(E)
Table D.2 — Category B: Lower-infectivity tissues
Peripheral tissues that have tested positive for infectivity and/or PrP TSE in at least one form of TSE
I n fe c tivity PrP TSE I n fec tivity PrP TSE I n fec tivity PrP TSE I n fe c tivity PrP TSE
Peripheral nervous
system
Peripheral nerves + + (−) + [+] + + +
Autonomic ganglia a NT + NT (−) NT + NT +
Lymphoreticular tissues
Spleen + + + + − − + +
Lymph no des + + + − − − + +
Tonsil + + NT − + − + +
Nictitating membrane NA NA NA NA + − [+] +
T hymus NT + NT − − NT + +
Alimentary tractb
Oesophagus NT − NT − − NT [+] +
Fore-s tomach c NA NA NA NA − NT [+] +

(r um i nants on ly)
Stomach/abomasum NT − NT − − NT [+] +
Duodenum NT − NT − − − [+] +
Jej unum d NT + NT − − + [+] +
I leum d NT + NT − + + + +
Appendix (−) + NT − NA NA NA NA
Colon/caecum d NT + NT − − − + +
Rectum [+] + NT NT NT NT NT +
Reproductive tissues
Placenta e NT − (+) − − NT + +
O var y f NT − (+) NT − − NT − −
Uterus f NT − (+) NT − − NT − −
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ISO 2 2 442 -1:2 015(E)
Table D.2 — (continued)
Peripheral tissues that have tested positive for infectivity and/or PrP TSE in at least one form of TSE
Infectivity PrP TSE Infectivity PrP TSE Infectivity PrP TSE Infectivity PrP TSE
Other tissues
Mammary gland/udder f, g NT − NT − − NT − +
Skin f, h NT − (+) NT − − NT − +
Adipose tissue NT − (−) − − NT NT NT
Heart/pericardium NT − − − − NT − NT
Lung NT − + − − NT − −
Liver f NT − (+) + − − NT + −
Kidney f, i NT − (+) + − − - [+] +
Adrenal NT + − − [+] + + −
Pancreas f NT − (+) NT − − NT + NT
Bone marrow j − − (−) − (+) NT + NT
Skeletal muscle k NT + (−) + (+) NT + +
Tongue l NT − NT − − NT [+] +
Blood vessels NT + NT + − NT NT +
Nasal mucosa m, l NT NT NT + − NT + +
Salivary gland NT − NT − − NT + NT
Cornea n NT − + − NT NT NT NT
Body fluids
CSF − − + − − NT + −
Blood o + ? − ? − ? + ?
Saliva NT − − NT NT NT − NT
Milk p NT NT (−) NT − − + [+]
Urine q NT − − − − NT − −
Faeces q NT NT − NT − NT − NT
a In cattle, PrP TSE is reported to be inconsistently present in the enteric plexus in the distal ileum, but immu -
nohis tochemical examination of tissues from a single “fallen s tock” case of BSE in Japan sugges ted (albeit
equivocally) involvement of myenteric plexuses throughout the small and large intestine.
b In vCJD, PrP TSE is limited to gut-associated lymphoid and nervous tissue (mucosa, muscle, and serosa are
negative) .
c Ruminant forestomachs (reticulum, rumen, and omasum) are widely consumed, as is the true stomach (abo -
masum) . The abomasum of cattle (and sometimes sheep) is also a source of rennet.
d When a large BSE oral dose was used to infect cattle experimentally, infectivity was detected in the jejunum
and the ileo-caecum junction in Tg mice overexpressing PrP. PrP TSE was detected at low incidence in lymphoid
tissue of ileum and has been detected at an even lower frequency in jejuna lymphoid tissue of cattle similarly
infected by the oral route.
e A single report of transmission of sporadic CJD infectivity from human placenta has never been con firmed
and is considered improvable.

21
ISO 2 2 442 -1:2 015(E)
Table D.2 — (continued)
f PrP TSE was detected by immunoblot in the dura mater of a vCJD patient who died in the US after an unusually
long incubation period (other positive tissues: skin, kidney, liver, pancreas, ovary and uterus). It must be men -
tioned that earlier studies of numerous cases examined in the UK reported all of these tissues to be negative.
g PrP TSE has been detected in scrapie-infected sheep with chronic mastitis, but not from infected sheep with-
out mas titis.
h Studies in hamsters orally infected with scrapie revealed that PrP TSE deposition in skin was primarily
located within small nerve fibres.
i PrP TSE detected by immunocytochemistry in the renal pelvis of scrapie-infected sheep.
j A single positive marrow in multiple transmission attempts from cattle orally dosed with BSE-infected brain.
k Muscle homogenates have not transmitted disease to primates from humans with sCJD, or to cattle from
cattle with BSE . However, intracerebral inoculation of a semitendinosus muscle homogenate (including nervous
and lymphatic elements) from a single cow with BSE has transmitted disease to PrP over-expressing transgenic
mice at a rate indicative of only trace levels of infectivity. Also, recent published and unpublished studies have
reported the presence of PrP TSE in skeletal muscle in experimental rodent models of scrapie and vCJD, in exper-
imental and natural infections of sheep and goats, in sheep orally dosed with BSE, and in humans with sCJD,
iCJD and vCJD. Bioassays to determine whether PrP TSE is associated with transmissibility in these experimen-
tal or natural infections are in progress.
l In cattle, infectivity bioassay was negative, but the presence of PrP TSE in palatine tonsil has raised concern
about possible infectivity in lingual tonsillar tissue at the base of the tongue that may not be removed at slaugh -
ter. In sheep naturally infected with scrapie, 7 of 10 animals had detectable PrP TSE in the tongue.
m Limited chie fly to regions involved in olfactory sensory reception.
n Because only one or two cases of CJD have been plausibly attributed to corneal transplants among hundreds
of thousands of recipients, cornea is categorized as a lower risk tissue; other anterior chamber tissues (lens,
aqueous humour, iris, conjunctiva) have been tested with a negative result both in vCJD and other human TSEs,
and there is no epidemiological evidence that they have been associated with iatrogenic disease transmission.
o A wealth of data from studies of blood infectivity in experimental rodent models of TSE have been extended
by recent studies documenting infectivity in the blood of sheep with naturally occurring scrapie and in sheep
transfused with blood from BSE infected cattle; and (from epidemiological observations) in the red cell frac-
tion (which includes signi ficant amounts of both plasma and leukocytes) of four blood donors in the pre-clinical
phase of vCJD infections]. Plasma Factor VIII administration has also been potentially implicated in a subclin -
ical case of vCJD in a haemophilia patient. Blood has not been shown to transmit disease from humans with
any form of ‘classical’ TSE or from cattle with BSE (including fetal calf blood). A number of laboratories using
new, highly sensitive methods to detect PrP TSE are reporting success in a variety of animal and human TSEs.
However, several have experienced difficulty obtaining reproducible results in plasma, and it is not yet clear
that positive results imply a potential for disease transmissibility, either because of false positives, or of ‘true’
positives that are due to sub-transmissible concentrations of PrP TSE . Because of these considerations (and the
fact that no data are yet available on blinded testing of specimens from naturally infected humans or animals)
the expert group of WHO felt that it was still too early to evaluate the validity of these tests with sufficient
con fidence to permit either a negative or positive conclusion.
p Evidence that infectivity is not present in milk from BSE-infected bovines includes temporo-spatial epi -
demiologic observations failing to detect maternal transmission to calves suckled for long periods; clinical
observations of over a hundred calves suckled by infected cows that have not developed BSE; and experimental
observations that milk from infected cows reared to an age exceeding the minimum incubation period has not
transmitted disease when administered intracerebrally or orally to mice. Also, PrP TSE has not been detected in
milk from cattle incubating BSE following experimental oral challenge. However, low levels (μg to ng/l) of nor-
mal PrP have been detected in milk from both animals and humans. PrP TSE has been detected in the mammary
glands of scrapie-infected sheep with chronic mastitis, and very recently it has been reported that milk (which
in some cases also contained colostrum) from scrapie-infected sheep transmitted disease to healthy animals.
q Recent bioassays in Tg mice have transmitted disease from both urine and faeces. In addition, mice with
lymphocytic nephritis that were experimentally infected with scrapie shed both PrP TSE and infectivity in
urine, when bioassayed in Tg mice. Very low levels of infectivity have also been detected in the urine (and his -
tologically normal kidneys) of hamsters experimentally infected with scrapie. Finally, in an experimental scra-
pie-hamster model, oral dosing resulted in infectious faeces when bioassayed in Tg mice over-expressing PrP.
22
ISO 2 2 442 -1:2 015(E)
Table D.3 — Category C: Tissues with no detected infectivity or PrP TSE
Tissues vCJD Other TSE BSE Scrapie
Infectivity PrP TSE Infectivity PrP TSE Infectivity PrP TSE Infectivity PrP TSE
Reproductive tissues
Tes tis NT − (−) − − NT − −

Prostate/epididymis/ NT − (−) − − NT − −
seminal vesicle
Semen NT − (−) − − NT − −
Placenta fluids NT NT (−) (−) − NT NT NT
Foetus a NT NT NT NT − NT − −
Embryos a NT NT NT NT − NT ? NT
Musculo-skeletal tissues
Bone NT NT NT − − NT NT NT
Tendon NT NT NT − − NT NT NT
Other tissues
Gingival tissue NT − − − NT NT NT NT
Dental pulp NT − NT − NT NT NT NT
Trachea NT − NT − − NT NT NT
Thyroid gland NT − (−) − NT NT − NT
Body fluids, secretions

and excretions
Colostrum b NT (−) (−) NT (−) − (?) NT
Cord blood b NT (−) (−) NT − NT NT NT
Sweat NT − − NT NT NT NT NT
Tears NT − − NT NT NT NT NT
Nasal mucus NT − − NT NT NT NT NT
Bile NT NT NT NT NT NT NT NT
a Embryos from BSE-affected cattle have not transmitted disease to mice, but no infectivity measurements have been
made on fetal calf tissues other than blood (negative mouse bioassay). Calves born of dams that received embryos from
BSE-affected cattle have survived for observations periods of up to seven years, and examination of the brains of both the
unaffected dams and their offspring revealed no spongiform encephalopathy or PrP TS E .
b Early reports of transmission of sporadic CJD infectivity from human cord blood and colostrum have never been
con firmed and are considered improbable. A bioassay from a cow with BSE in transgenic mice over-expressing bovine PrP
gave a negative result; and PrP TSE has not been detected in colos trum from cattle incubating B SE following experimental
oral challenge.
D.3 .5 Slaughtering and processing controls (see ISO 2 2 442 -2 )
The manufacturer should ensure that all necessary measures are taken to minimize the risk of cross-
contamination at the time of slaughtering and processing.
D.3 .6 Methods used to inactivate or remove TSE agents (see ISO 2 2 442 -3 )
For devices that cannot withstand an inactivation/elimination process without undergoing unacceptable
degradation, the manufacturer should rely principally on the control of sourcing (see ISO 22442-2).
For other devices, if claims are made by the manufacturer for the ability of manufacturing processes
to remove or inactivate TSE agents, these should be substantiated by appropriate documentation.
Relevant information from an appropriate scienti fic literature review can be used to support

23
ISO 2 2 442 -1:2 015(E)
inactivation/elimination factors, where the speci fic processes referred to in the literature are
comparable to those used for the device.
When the literature review fails to substantiate the claims, the manufacturer should conduct a speci fic
inactivation and/or elimination study and the following should be addressed by the study:
— the identi fied hazard associated with the tissue;
— identi fication of the relevant model TSE agents;
— rationale for the choice of the particular combinations of model TSE agents;
— identi fication of stage chosen to eliminate and/or inactivate the TSE agents;
— calculation of the reduction factors .
A final report should identify manufacturing parameters and limits that are critical to the effectiveness
of the inactivation or elimination process .
Appropriate documented procedures should be applied to ens ure that the validated proces sing
parameters are applied during routine manufacture.
D.3 .7 Exposure to TSE risk
D.3.7.1 Quantities of animal starting material required to produce one unit of the medical device
The manufacturer should evaluate the quantity of raw tissues or derivatives of animal origin
re qui red to pro duce a s i ngle un it of the medica l device . T he manu fac tu rer shou ld as s es s whether
the pro duc tion pro ces s has the p otential to concentrate level s of TSE agents pres ent in the an i ma l
s tar ti ng tis s ues or derivatives .
D.3 .7.2 Quantities of material of animal origin coming into contact with the patients and users
Manufacturers should consider the maximum quantity of animal material that might come into contact
with the patients and users (including any absorption and/or degradation) . The number of medical devices
that could be used in a given procedure and the number of treatments should be taken into account.
D.3 .7.3 Route of administration
Account should be taken of the route of adminis tration recommended in the product information. From
the highes t risk down to the lowes t, the lis t is
a) products coming into contact with the central nervous system (including intra-ocular route);
b) products coming into contact with the central circulatory system or parenterally administered or
invasive devices or devices used on open wounds, including ulcer preparations;
c) products requiring administration on intact mucous membranes e.g. conjunctival, intranasal,
bronchial, rectal, vaginal, vesical; products required to remain in the mouth (buccal, sublingual) or
to be swallowed;
d) products to be applied to undamaged external skin.
D.3 .7.4 Estimate of exposure risk
The degree of expos ure to TSE risk and the effect of this on the overall TSE risk should be es timated.
24
© ISO 2 0 1 5 – All rights reserved
ISO 2 2 442 -1:2 015(E)
Bibliography
[1] ISO 109 93 -2 , Bio lo gica l e va lu a tio n o f m edica l de vices — Pa rt 2: A n im a l welfa re requ irem en ts
[2] ISO 109 93 -3 , Bio lo gica l e va lu a tio n of m edica l de vice s — Pa rt 3: Te sts for g en o to xicity,
ca rcin o g en icity a n d rep ro du ctive to xicity
[3 ] I SO 10 9 93 - 4, Bio lo g ica l e va lu a tio n of m e dica l de vice s — Pa rt 4: Se le ctio n of te s ts for
in te ra ctio n s with b lo o d
[4] ISO 10993 -5, Bio lo g ica l e va lu a tio n o f m edica l de vice s — Pa rt 5: Te sts fo r in vitro cyto to xicity
[5 ] ISO 109 93 - 6, Bio lo gica l e va lu a tio n of m edica l de vice s — Pa rt 6: Tests for lo ca l effects after
im p la n ta tio n
[6] ISO 109 93 -7, Bio lo gica l e va lu a tio n o f m edica l de vice s — Pa rt 7: Eth ylen e o xide steriliza tio n residu a ls
[7 ] ISO 10993 -9, Biological evaluation of medical devices — Part 9: Framework for identification and
quantification of potential degradation products
[8] ISO 10993 -10, Bio lo gica l e va lu a tio n o f m edica l de vices — Pa rt 1 0: Te sts for irrita tio n an d skin
sen sitiza tio n
[9] ISO 109 93 -11, Bio lo g ica l e va lu a tio n o f m edica l de vice s — Pa rt 1 1 : Tests fo r s ystem ic toxicity
[10] ISO 10993 -1 2 , Bio lo g ica l e va lu a tio n of m edica l de vice s — Pa rt 1 2: Sa m p le p rep a ra tio n an d
referen ce m a teria ls
[11] ISO 10993 -13 , Biological evaluation of medical devices — Part 13: Identification and quantification
o f deg ra da tio n p ro du cts fro m p o lym eric m edica l de vice s
[12] ISO 109 93 -14, Biological evaluation of medical devices — Part 14: Identification and quantification
o f degra da tio n p ro du cts fro m cera m ics
[13] ISO 10993 -15 , Biological evaluation of medical devices — Part 15: Identification and quantification
o f deg ra da tio n p ro du cts fro m m eta ls a n d a llo ys
[14] ISO 10993 -16, Bio lo g ica l e va lu a tio n o f m edica l de vice s — Pa rt 1 6: To xico kin etic stu dy desig n for
deg ra da tio n p ro du cts a n d lea ch a b le s
[15 ] ISO 109 93 -17, Bio lo g ica l e va lu a tio n o f m edica l de vice s — Pa rt 1 7: Esta b lish m en t o f a llo wa b le lim its
fo r lea ch a b le su b sta n ce s
[16] ISO 10993 -18, Bio lo gica l e va lu a tio n o f m edica l de vice s — Pa rt 1 8: Ch em ica l ch a ra cteriza tio n of
m a teria ls
[17 ] ISO 10993 -19, Bio lo gica l e va lu a tio n o f m edica l de vice s — Pa rt 1 9: Ph ysico - ch em ica l, m o rp h o lo g ica l
a n d to p o g ra p h ica l ch a ra cteriza tio n o f m a teria ls
[18] ISO 109 93 -20, Bio lo gica l e va lu a tio n o f m edica l de vice s — Pa rt 20: Prin cip le s an d m eth o ds for
im m u n o toxico lo g y testin g o f m edica l de vice s
[19] ISO 11135 (all parts) , Steriliza tio n o f h ea lth - ca re p ro du cts — Eth ylen e o xide — Requ irem en ts for
th e de velo p m en t, va lida tio n a n d ro u tin e co n tro l o f a steriliza tio n p ro ce ss fo r m edica l de vice s
[20] ISO 11137 (all parts) , Steriliza tio n o f h ea lth ca re p ro du cts — Ra dia tio n
[21] ISO 11737 (all parts) , Steriliza tio n o f m edica l de vice s — Micro b io lo gica l m eth o ds
[2 2] ISO 13 408-1, A sep tic p ro ce ssin g o f h ea lth ca re p ro du cts — Pa rt 1 : Gen era l requ irem en ts

25
ISO 2 2 442 -1:2 015(E)
[23] ISO 13 408-2 , A sep tic p ro ce ssin g o f h ea lth ca re p ro du cts — Pa rt 2: Filtra tio n
[24] ISO 13 408-3 , A sep tic p ro ce ssin g o f h ea lth ca re p ro du cts — Pa rt 3: Lyo p h iliza tio n
[25 ] ISO 13 40 8- 4, A sep tic p ro ce ssin g o f h ea lth ca re p ro du cts — Pa rt 4: Clea n -in -p la ce tech n o lo g ie s
[26] ISO 13 40 8-5 , A sep tic p ro ce ssin g o f h ea lth ca re p ro du cts — Pa rt 5: Steriliza tio n in p la ce
[27 ] ISO 13 408- 6, A sep tic p ro cessin g o f h ea lth ca re p ro du cts — Pa rt 6: Iso la to r s ystem s
[2 8] ISO 13 408-7, A sep tic p ro ce ssin g o f h ea lth ca re p ro du cts — Pa rt 7: A ltern a tive p ro ce sse s fo r m edica l
de vices a n d co m b in a tio n p ro du cts
[2 9] ISO 13 485, Medica l de vices — Qu a lity m a n a g em en t system s — Requ irem en ts fo r regu la to ry p u rp o ses
[30] ISO 14160, Steriliza tio n o f h ea lth ca re p ro du cts — Liq u id ch em ica l sterilizin g a g en ts fo r sin g le- u se
m edica l de vice s u tilizin g a n im a l tissu e s a n d th eir deriva tives — Req u irem en ts fo r ch a ra cteriza tio n ,
de velo p m en t, va lida tio n a n d ro u tin e co n tro l o f a steriliza tio n p ro cess fo r m edica l de vices
[31] ISO 14937, Steriliza tio n o f h ea lth ca re p ro du cts — Gen era l req u irem en ts fo r ch a ra cteriza tio n of a
sterilizin g a g en t a n d th e de velo p m en t, va lida tio n an d ro u tin e co n tro l of a steriliza tio n p ro ce ss for
m edica l de vice s
[32] ISO 17664, Steriliza tio n o f m edica l de vice s — In fo rm a tio n to be p ro vided by th e m an ufa ctu rer for
th e p ro ce ssin g o f re steriliza b le m edica l de vice s
[33] ISO 17665 -1, Steriliza tio n o f h ea lth ca re p ro du cts — Mo ist h ea t — Pa rt 1: Req u irem en ts for th e
de velo p m en t, va lida tio n a n d ro u tin e co n tro l o f a steriliza tio n p ro ce ss fo r m edica l de vice s
[3 4] European Pharmacopoeia, 2 .6. 8 Pyro g en s
[35 ] European Pharmacopoeia, 2 .6.14 Ba cteria l en do to xin s
[36] European Pharmacopoeia, 5.2 .8 Min im izin g th e risk of tra n sm ittin g a n im a l sp o n g ifo rm
en cep h a lo p a th y a g en ts via h um an a n d veterin a ry m edicin a l p ro du cts
[37] US Pharmacopeia <85> Ba cteria l En do toxin s Te st
[38] US Pharmacopeia <151> Pyro g en Te st
[39] Supplement 1, Japanese Pharmacopoeia XI V, 17. Ba sic Requ irem en ts for Vira l Sa fety of
Bio tech n o lo g ica l/Bio lo gica l Pro du cts , listed in Japanese pharmacopoeia, pp. 1618-1631, 2003
[40] G lobal H armonization Task Force (GH TF) — S tudy G roup 1 . (SG1) Document No. N02 9R13 ,
Stage PD dated December 2003 (http://www.ghtf.org)
[41] WHO Guidelines on Transmissible Spongiform Encephalopathies in relation to Biological

and Pharmaceutical Products, 2003 (www.who.int/bloodproducts/publications/en/WHO_
TSE _2003 .pdf)
[42] WHO G uidelines on T issue I nfectivity D istribution in T ransmissible S pongiform

E ncephalopathies . 2006 (http://www.who.int/bloodproducts/TSEPUBLISHEDREPORT.pdf)
[43] WHO Tables on T issue I nfectivity D istribution in T ransmissible S pongiform

E ncephalopathies . Updated 2010 (http://www.who.int/bloodproducts/
tablestissueinfectivity.pdf)
[44] EME A/410/01 Rev. 3 — June 2011, Note for guidance on minimising the risk of transmitting
animal spongiform encephalopathy agents via human and veterinary medicinal products
adopted by the Committee for Proprietary Medicinal Products (CPMP) and by the Committee for
Veterinary Medicinal Products (CVMP) — Official Journal of the European Union 5.3.2011
26
ISO 2 2 442 -1:2 015(E)
[45] EMEA/CPMP/571/02 — February 2002, Public statement on Lactose prepared using calf rennet of
the European Agency for the Evaluation of Medicinal Products
[46] T errestrial A nimal H ealth C ode from OIE — O ffice I nternational des E pizooties/World
O rganisation for A nimal H ealth . http://www.oie.int/
[47 ] No N. 177 of the Ministry of Health, Labour and Welfare on the standard for biological
ingredients, 31 March 2005 on Standards for Raw Materials Originating from Living Organisms
(http://www.nihs.go. jp/cgtp/cgtp/guidline/03052001 .pdf) (in Japanese)
[48] MEDDEV 2.11/1, rev 2, January 2008, Guidelines on Medical Devices, Application of Council
Directive 93/42/EEC taking into account the Commission Directive 20 03/32/EC for medical
devices utilising tissues or derivatives originating from animals for which a TSE risk is
suspected, A guide for manufacturers and noti fied bodies ( h t t p : //e c . e u r o p a . e u / h e a l t h /
medical- devices/files/meddev/2_11_1_rev2_bsetse_january2008_en .pdf)
[49] Assessment of Risk of Bovine Spongiform Encephalopathy in Pharmaceutical Products, Part 1,

Pharmaceutical Research and Manufacturers of America (PhRM A) BSE Committee, BioPharm.,
11 , Number 1, pp 20-31, 56, January, 1998
[50] Assessment of Risk of Bovine Spongiform Encephalopathy in Pharmaceutical Products, Part 2,
Example Risk Assessment for a Hypothetical Product, Pharmaceutical Research and Manufacturers
of America (PhRM A) BSE Committee, BioPharm., 11 , Number 3, pp 18-30, March, 1998

27
ISO 2 2 442 -1:2 015(E)
ICS 11.100.20
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INTERNATIONAL ISO

Medical devices utilizing animal

Dispositifs médicaux utilisant des tissus animaux et leurs dérivés —

I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n

COPYRIGHT PROTECTED DOCUMENT

© ISO 2015, Published in Switzerland

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 2

4 Risk management process .......................................................................................................................................................................... 3

Annex D (informative) Information relevant to the management of TSE risk ....................................................... 16

© ISO 2 01 5 – All rights reserved

— Part 1: Application of risk management

— Part 2: Controls on sourcing, collection and handling

Certain medical devices utilize materials of animal origin.

T his p ar t of I SO 2 2 4 42 do es not apply to in vitro diagnostic devices.

© ISO 2 01 5 – All rights reserved

Medical devices utilizing animal tissues and their

a) contamination by bacteria, moulds or yeasts;

ISO 14971, Medical devices — Application of risk management to medical devices

© ISO 2 01 5 – All rights reserved

3 Terms and definitions

4 Risk management process

4.2 Risk analysis

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

© ISO 2 01 5 – All rights reserved

The following factors shall be addressed, if applicable:

4.2 .1.4 Are there unwanted outputs of substances?

4.2.2 Identification of hazards and hazardous situations

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

4.3 Risk evaluation

4.4 Risk control

The risk control options shall be documented and justi fied.

4.4.2 Risk control for viruses and TSE agents

i n ac ti vatio n p ro ce s s i n acco rd a nce w i th I S O 2 2 4 42 -3 wo u ld c au s e u n accep tab le de g rad atio n .

Ta l l o w de r i vati ve s , animal ch a rc o a l , a nd a m i no ac id s th at a re acc e p tab l e fo r TSE risk as discussed in

A n ne x C , due to the i r p ro c e s s i n g a nd no t the i r s o u rc i n g , s h a l l a l s o b e c o n s ide re d to h ave ac ce p tab le r i s k

process, as required in ISO 22442-3, is sufficient to achieve an acceptable level of risk.

4.4.3 Risk control of other hazards

Ta l l o w de r i vati ve s , animal ch a rc o a l , a nd a m i no ac id s th at a re acc e p tab l e fo r TSE risk as discussed in

A n ne x C , due to the i r p ro c e s s i n g a nd no t the i r s o u rc i n g , s h a l l a l s o b e c o n s ide re d to h ave ac ce p tab le r i s k

NOTE The following International Standards may be relevant:

The use of these International Standards is illustrated in Annex B .

4.4.4 Residual risk evaluation

Residual risk evaluation shall be performed for each risk.

4.4.4.2 TSE risk

4.5 Evaluation of overall residual risk acceptability

— applying whole product alternatives for the same intended purposes.

4.6 Production and post-production information system

Guidance on the application of this part of ISO 2 2 442

A.2 Application to materials from animal sources

This International Standard is applicable to materials such as

A.3 Application to materials supplied by third parties

Graphical representation of part of the risk management process

See Figure B .1 overleaf.

© ISO 2 01 5 – All rights reserved

Identify hazard and

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

Special requirements for some animal materials considering the

Risk management can be addressed by processing, sourcing, or a combination of both. Tallow