Please note that the present document is a working document. It will
therefore be subject to further changes resulting from the ongoing process of
consultation. Once finalized, the present guidelines are part of a set of guidelines
relating to questions of application of EC Directives on medical devices.
The guidelines have been carefully drafted through a process of consultation with
various interested parties during which intermediate drafts were circulated and comments
were taken up in the document. Therefore this document reflects positions taken in
particular by representatives of Competent Authorities and Commission Services, Notified
Bodies, industry and other interested parties in the medical devices sector.
These guidelines are legally not binding. It is recognised that under given
circumstances, for example, as a result of scientific developments, an alternative
approach may be possible or appropriate to comply with the legal requirements.
TABLE OF CONTENTS
INTRODUCTION
…………………………………………………………………………
SECTION NUMBER
1. MEETING THE ESSENTIAL REQUIREMENTS -
RELEVANT STANDARDS AND OTHER DOCUMENTS ……….
2. DOCUMENTATION REQUIREMENTS
2.1 Manufacturer's documentation
……………………………….
2.2 Documentation provided to the Notified Body
by manufacturers
……………………………………………..
2.3 Specific Guidance for the Notified Body
…………………….
3. CONDUCT OF CONFORMITY ASSESSMENT …………………..
4. NOTIFIED BODY'S SPECIFIC PROCEDURES AND EXPERTISE
4.1 Notified bodies internal procedures
………………………….
4.2 Expertise
……………………………………………………..
5. FRAMEWORK FOR AN ASSESSMENT PROGRAM………………….
6. BIBLIOGRAPHY
…………………………………………………………
APPENDICES
Appendix 1
…………………………………………………………..
Appendix 2…………………………………………………………...
Appendix 3
…………………………………………………………...
Appendix 4
……………………………………………………………
Appendix 5
……………………………………………………………
INTRODUCTION
This document has been elaborated to provide guidance to Notified Bodies, manufacturers
and interested parties on the assessment of medical devices incorporating materials of
animal origin. This principally relates to class III devices and associated conformity
assessment procures shall apply. Its use should also be considered where materials of
animal origin are used in manufacturing processes but where the materials is not included
in the final device.
1. MEETING THE ESSENTIAL REQUIREMENTS – RELEVANT STANDARDS AND OTHER DOCUMENTS.
1.1 Essential requirements 1 - 6 of Directive 93/42/EEC of 14 June 1993 stipulate
the requirements for the safety of the device, more specific requirements regarding
'Infection and microbial contamination' are detailed in essential requirements 8.1, 8.2
and 8.4. (see Appendix 1). The primary principle is to 'eliminate or reduce risk as far as
possible' and 'provide optimal security'; these concepts are paramount during assessment.
Where relevant and taking into account the risk analysis and management, identified
residual risks shall be mentioned in the information provided with the device as required
in essential requirements 13.
[To be further considered : indication on presence of material of animal origin in
the labelling].
1.2 In order to provide optimal security minimisation of risks shall address all
relevant aspects including those in relation to :
- source animal,
- nature of animal tissue,
- production processes, including those in relation to elimination and/or inactivation
of viruses and transmissible agents and,
- conditions of use of the finished products.
No single approach will necessarily establish the safety of a device and therefore the
approach cited above will need to be complementary to each other for minimizing the risks.
Furthermore as part of the risk analysis and risk management it shall be considered to
what extent alternative materials to those of animal origin and in particular ruminant
origin are available and can be used.
For medical devices which cannot withstand an inactivation process without undergoing
unacceptable degradation, taking account of the current state of the art, it is necessary
to rely principally on sourcing, controls, collection and handling. This approach shall be
justified in the documentation submitted to a Notified Body and be explicitly addressed in
the overall risk analysis and management.
1.3 Drafts of harmonised standards addressing the use of animal materials (see
definition of 'animal' in Appendix 2) in medical devices are available :
* pr EN 12442 Animal tissues and their derivatives utilised in the manufacture of
medical devices -
- Part 1: Analysis and management of risk -
- Part 2: Sourcing, controls, collection and handling
- Part 3: Validation of the elimination and/or inactivation of viruses and other
transmissible agents).
These documents are sufficiently advanced that they should be utilised when performing
an assessment of medical devices containing materials of animal origin. Notified Bodies
should apply the principles described in these documents as the basis for their assessment
methodology. If a manufacturer chooses to follow a different approach its relevance and
adequacy in achieving an equivalent level of safety has to be demonstrated.
Other guidance documents and standards are available from national, European and
international sources, which may provide useful background information, these are detailed
in the bibliography.
The following standards address the essential requirements 8.1, 8.2 and 8.4:
1.3.1 pr EN 12442-1: Animal tissues and their derivatives utilised in the manufacture
of medical devices - Part 1: Analysis and management of risk.
This standard provides requirements and guidance on:
- Definitions,
- Risk analysis: by providing additional requirements and guidance to EN 1441,
- Risk management: by requiring that relevant requirements of both part 2 and part 3 shall
be applied by providing a specific informative guidance on transmissible agents.
1.3.2 pr EN 12442-2: Animal tissues and their derivatives utilised in the manufacture
of medical devices - Part 2: Sourcing, controls, collection and handling.
This standard provides requirements and guidance on:
- Quality system for the collection (including traceability),
- Requirements or guidance on the veterinarian surveillance of the animals and the
slaughter,
- Requirements or guidance to avoid further cross-contamination during dissection, storage
and transport.
1.3.3 pr EN 12442-3: Animal tissues and their derivatives utilised in the manufacture
of medical devices - Part 3: Validation of the elimination and/or inactivation of viruses
and other transmissible agents. This standard provides requirements and guidance on:
- Quality system for the inactivation/elimination studies,
- Requirements or guidance to assess that inactivation/elimination studies' parameters are
equivalent to those of the manufacturing process,
- Requirements or guidance to design and perform inactivation/elimination studies,
- Requirements or guidance on the role of literature search.
1.4 Particular attention is drawn to the decision 96/239/EEC as last amended by
decision 96/362/EEC, taken at Community level in relation to the restriction of use of
defined material from bovine origin for the manufacture of medical devices, as well as to
any subsequent legislation at a Community level in this area.
The manufacturer shall not use Specified Risk Material (SRM) as defined in Commission
Decision 97/534/EEC and as subsequently revised; further conditions of use are described
in these Commission Decisions.
When using gelatine manufacturers shall ensure that SRMs have not been used by the
gelatine processor for gelatine manufacture and that gelatine is manufactured in
accordance with the conditions described in this document.
2. DOCUMENTATION REQUIREMENTS
2.1 Manufacturers' documentation
Examples of documentation are laid down in pr EN 12442-1, pr EN 12442-2 and pr EN
12442-3.
2.2 Documentation provided to the Notified Body by manufacturers
The result of the risk analysis report shall be submitted to the Notified Body (see
directive 93/42/EEC, annex II point 3.2.c and 4.2 or annex III point 3 as appropriate).
The following documentation should also be provided, where appropriate:
- Statement on the presence of animal materials in the finished device and/or utilised
during manufacture.
- Certificates or other documents establishing the origin of the animals,
- Certificates or documents to demonstrate conformance with veterinary inspection criteria
and the nature of this inspection.
- Information about the material used to feed the animals,
- Documentation related to the slaughtering of animals, and contractual arrangements with
the abattoir.
- Documentation and work instructions relating to the collection, transport and storage of
the material.
- Detailed documentation describing the inactivation process and validation of this
inactivation process.
- Manufacturers audit and review of sub-contractors.
[To be further considered : use of material of animal origin for processing only]
Where a part of this documentation is not submitted, a justification shall be
provided.
2.3 Specific guidance for Notified Bodies
Essential Requirements 8.2 requires Notified Bodies to retain information on the
geographical origin of the animals. The concept of geographical origin includes place of
birth, rearing and slaughtering. Special consideration should be given to the feeding
practices for transmissible agent's susceptible species. The depth of information required
should be commensurate with the risk of the material and the reliance on sourcing as a
means of risk management.
Notified Bodies are not required to hold all batch specific information, which should
be available from the manufacturer on request. Nevertheless, the Notified Body should be
aware of how this information is kept by the manufacturer.
The manufacturer shall inform the Notified Body of any change in the geographical
origin of animals, sourcing, processing and use of animal materials.
3. CONDUCT OF CONFORMITY ASSESSMENT
The Notified Body shall review the documentation (see 2.2) as part of the assessment
process (see directive 93/42/EEC).
The processes involved in sourcing control and handling and inactivation of relevant
animal materials are to be considered as "special processes". Notified Bodies
shall give particular attention to manufacturer's control of raw materials and
subcontractors. Where necessary Notified Bodies may need to audit matters relating to
sourcing including subcontractors.
4. NOTIFIED BODY'S SPECIFIC PROCEDURES AND EXPERTISE
4.1 Notified bodies internal procedures
Notified Body shall establish and implement internal policy and procedures for
assessing medical devices manufactured from materials of animal origin.
4.2 Expertise
The Notified Body should possess relevant knowledge in order to:
- Identify the potential hazards and estimate the associated risks arising from the use of
animal materials for the manufacture of medical devices,
- Evaluate the manufacturer's risk analysis and risk management strategy,
- Evaluate information provided by the manufacturer including information referred to in
section 2.2,
- Interpret the results of any inactivation study and literature search .
This knowledge shall reside within the Notified Body, which may be supplemented by
external experts. Such external experts should have the most up to date knowledge in the
field concerned.
The Notified Body shall maintain awareness of legislation relevant to a particular
application.
5. FRAMEWORK FOR AN ASSESSMENT PROGRAM
This Annex provides a framework for the development of an assessment program. Each
medical device should be considered on its own merits and the rationale for selection
and/or waiving of the data should be documented.
NOTE: The table provided in this Annex is not a checklist for auditors.
Guidance for the Risk Management of Medical Devices utilizing
Materials of Animal Origin
1. Only Part 1 shall be applicable to Class 1 products with materials of
animal origin where such devices are intended to come into
contact with intact skin only.
2. The application of referenced process parameters (ie Commission Decision
96/362) may supercede the practicalities of this data
6. BIBLIOGRAPHY
- Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (Official
Journal of European Communities No. L 169/L)
- pr EN 12442-1 : Animal tissues and their derivatives utilized in the manufacture of
medical devices - Part 1 : Analysis and management of risk.
- pr EN 12442-2 : Animal tissues and their derivatives utilized in the manufacture of
medical devices - Part 2 : Sourcing, controls, collection and handling.
- pr EN 12442-3 : Animal tissues and their derivatives utilized in the manufacture of
medical devices - Part 3 : Validating of the elimination and/or inactivation of viruses
and other transmissible agents.
- European guideline CPMP/BWP/268/95, FINAL version 2 «Note for guidance on virus
validation studies: the design, contribution and interpretation of studies validating the
inactivation and removal of viruses.
- Notification on the marketing authorization and registration of drugs, Measures to
avert risks associated with drugs, stage II, of March 28, 1996 of the Bundesinstitut für
Arzneimittel, Germany (BfArM).
- Guidelines for minimizing the risk of transmission of agents causing spongiform
encephalopathies via medicinal products - III/3298/91 - EN FINAL.
- Note for Guidance for minimising the risk of transmitting animal Spongiform
Encephalopathy Agents via medicinal products - EMEA - CPMP/BWP/877/96 - draft of October
1997
- Commission decisions :
- N° 96/239/EEC of 27 March 1996
- N° 96/362/EEC of 11 June 1996
- N° 97/534/EEC of 30 July 1997
- [Processing of gelatin/tallow]
APPENDIX 1
Essential requirements of Directive 93/42/EEC relating to infection and microbial
contamination :
8.1. The devices and manufacturing processes must be designed in such a way as to
eliminate or reduce as far as possible the risk of infection to the patient, user and
third parties. The design must allow easy handling and, where necessary, minimize
contamination of the device by the patient or vice versa during use.
8.2. Tissues of animal origin must originate from animals that have been subjected to
veterinary controls and surveillance adapted to the intended use of the tissues.
Notified Bodies shall retain information on the geographical origin of the animals.
Processing, preservation, testing and handling of tissues, cells and substances of
animal origin must be carried out so as to provide optimal security. In particular safety
with regard to viruses and other transferable agents must be addressed by implementation
of validated methods of elimination or viral inactivation in the course of the
manufacturing process.
........
8.4. Devices delivered in a sterile state must have been manufactured and sterilised by
an appropriate, validated method.
Essential requirements for labelling to be further discussed and included.
APPENDIX 2
Definition of «Animal from pr EN 12442-1 : «All vertebrates including fish,
amphibians, reptiles, birds and mammals, excluding humans (Homo sapiens).
Definition of «Transmissible agents from pr EN 12442-1: «Unclassified pathogenic
entities, prions and similar entities.
Note: e.g. BSE agent, scrapie agent
Requirements on sourcing from pr EN 12442-2 :
«
«6 Sourcing of animal materials: Inspection, certification and traceability
6.1 Sourcing of animal material shall where technically practicable be subject to
control and individual inspection by a veterinarian. There will however be some source
species where this is not possible (e.g. fish). If individual animals cannot be inspected,
the justification for this shall be documented and a relevant sampling plan provided. To
minimize the potential risk of the causative agents of spongiform encephalopathies in
medical devices the requirements of normative Annex A shall be applied to relevant animal
species.
6.2 Material of animal origin intended for utilization in medical devices shall have
originated from animals confirmed by a veterinarian as being fit for human consumption.
For species not usually consumed by humans a status equivalent to «fit for human
consumption is required. Records to demonstrate conformance with veterinary inspection
criteria at the abattoir, certificate details and source shall be available.
6.3 A certificate relating to the animal material utilized in medical devices (see for
example Annex B.1) signed by a person having personal knowledge of the facts being
declared and a health attestation signed by a veterinarian (see for example Annex B.2)
shall be retained by the manufacturer. In countries where local regulations ensure that
the relevant requirements of this standard are met, the health attestation (see Annex B.2)
may be omitted provided that adequate documentary evidence of compliance is available.
6.4 Depending on the source species of the tissues used, the perceived risk from
pathogens, and the ability to obtain appropriate assurances, it may be necessary to
specify the origin of the animals (such as country, region or farm) and to obtain
additional assurances on their state of health and system of management (see Part 1 of EN
12442). (For bovine species, see Annex A).
NOTE: Whenever practicable, and when necessary information systems are in place,
animals should be individually traceable, where the intended use of the animal material
and the results of the risk analysis indicate that this is necessary.
APPENDIX 3
Requirements on literature search from pr EN 12442-3 :
«5 Literature search
5.1 Conduct of the literature search
A literature search shall be performed as specified in Annex A, to identify and analyze
data on the elimination and/or inactivation of viruses and other transmissible agents (see
Annex C.2).
5.2 Application of literature search output
Technical information from the literature search can assist in optimizing the design of
an inactivation study.
The analysis of the literature search may provide sufficient data to support the design
of the chosen manufacturing process and may justify not undertaking an inactivation study.
Any extrapolation based on the inactivation of viruses and transmissible agents shall
be justified and documented.
NOTE: Intrinsic variability of materials of animal origin utilized in medical devices
and of manufacturing processes may lead to misinterpretation of the validity of published
data.
5.3 Viruses
The literature search may provide an indication of which inactivation and/or
elimination steps are likely to be effective and is a prerequisite to performing a viral
inactivation study. In exceptional cases, if a manufacturer chooses not to perform a study
this shall be justified and documented.
5.4 Transmissible agents
The literature search may provide an indication of which methods are likely to be
effective in the elimination and/or inactivation of transmissible agents. Subject to
confirmation that the materials of animal origin and the identified manufacturing steps
from the literature search are relevant, it may not be necessary to undertake a
transmissible agent inactivation study.
If the available information does not support the elimination and/or inactivation of
transmissible agents, then an alternative risk management strategy shall be implemented
(see Part 1 of EN 12442).+
APPENDIX 4
Requirements and guidance on BSE/TSE risks in pr EN 12442-2 :
«A.1 General aspects
NOTE : The aim should be to source all tissues from countries which present little or
no risk while acknowledging this may not always be achievable. The highest risk will be
represented by high risk tissues (brain, spinal cord and eye) derived from countries of
high incidence. Whether or not a risk is unacceptably high will depend on the use to which
the tissue is put. Risk analysis and risk management are addressed in Part 1 of EN 12442.
The use of tissues of bovine origin shall take into account the following factors:
a) the BSE status of the country, the herd(s) or origin of the animals and the breeding
history (maternal line) (see also Annex A.2) ;
NOTE :a) the prevalence of disease in the country,
b) whether or not there is compulsory notification of disease (official veterinary
surveillance),
c) whether there is compulsory clinical and laboratory verification of suspected cases.
If a source country cannot comply, a higher level of risk should be assumed.
b) the age of the donor animals ; and the nature of tissues used (see Annex E of Part 1
of EN 12442) ;
NOTE : As clinical BSE has not been diagnosed in young animals (less than 20 months),
sourcing from animals particularly under 6 months of age gives an additional level of
safety.
c) whether or not they will be pooled or derived from single animals, and
d) feeding history (A.3).
Annex F is defining the criteria of a «low risk herd : «low risk herds (sometimes
referred to as closed herds) are herds which have satisfied the following criteria for at
least the previous six years :
- documented veterinary monitoring ;
- no case of BSE ;
- no feeding of ruminant-derived protein ;
- no admission of female cattle from herds which do not satisfy the above criteria,
unless the animal comes from a country complying with the criteria cited in A.1.1 or
A.1.2+ (A.1.1 is defining criteria for country with no recognized case of BSE still having
some official notification of the disease and an adequate veterinary surveillance ; A.1.2
is defining criteria for BSE low incidence country with additional requirements regarding
the killing and the destruction of the BSE-affected individual animals).
APPENDIX 5
Annex A of pr EN 12442-1 stipulates :
«A.1 Management of risks related to viruses and transmissible agents
Risk management shall be implemented by taking into account separately the risks
related to viruses and transmissible agents. After having defined the characteristics of
the product, the medical device manufacturer shall comply with the relevant requirements
of Part 2 and Part 3 of EN 12442 cumulatively. If medical device manufacturers do not
fully comply with relevant requirements, they shall justify and document their rationale.
NOTE 1: For medical devices which cannot withstand an inactivation process, without
undergoing unacceptable degradation, medical device manufacturers may rely principally on
part 2 of EN 12442 in order to meet the requirements of this part.
NOTE 2: If manufacturers cannot fully meet the requirements of Part 2 of EN 12442, they
should demonstrate a very high level of inactivation of viruses and transmissible agents
in a validated manufacturing process, as required in Part 3 of EN 12442.
The safety of the device with regard to its application and intended use shall be
documented in the risk analysis report (see clause 4.9 in this standard).
Clause 4.1 of pr EN 12442-2 provides all requirements and guidance for documentation on
sourcing :«A documented system shall be established and maintained to control the quality
of materials of animal origin. This system shall include at least the following:a)
specification of the geographical origin (such as country or region) of the animal
material, state of health of the animals, and acceptance criteria for animals taking into
account the source species, perceived risk from pathogens and ability to obtain
appropriate assurances;
NOTE: The geographical origin may include the animal's place of birth and the countries
or regions in which it has lived during its lifetime, and its place of slaughter as well.
The manufacturer should document the extent to which the geographical origin of the animal
can be traced taking into account the risk analysis and management (see Part 1 of EN
12442).
b) hygiene and quality assurance requirements to be met by the slaughterer;
c) procedures for the collection, preservation, handling, storage and transport of
materials of animal origin;d) records to be maintained (including as a minimum items a),
b) and c) above; see also 6.2);e) audit of the effectiveness of controls defined in a), b)
and c) above. Clauses 6.2 and 6.3 specify requirements for the certification of the animal
materials (see appendix 2).Clauses 4.2.1, 7 and 8 of pr EN 12442-3 :«4.2.1 Documented
procedures
The documented procedures and requirements of this standard shall be implemented.
Documentation and records shall be reviewed and approved by designated personnel (see
clause 4.2.2).
Procedures for any literature search and/or any inactivation study shall be documented
and records shall be retained for a period defined by the manufacturer.
«7 Final report
A final report shall be compiled containing a critical evaluation of the literature
search (see clause 5 and Annex A) and a critical evaluation of the data obtained during
any elimination and/or inactivation study undertaken (see clause 6) together with a
overall conclusion.
This report shall be signed by persons designated as responsible for its preparation,
review and approval. This report shall be retained (e.g. for re-validation(s), see clause
8). «
«8 Review of final report
Procedures for the review of the final report shall be documented.
The review of the final report shall be conducted when significant changes in the
manufacturing process(es) occur and/or when relevant information, e.g. in the literature,
not previously considered in the final report becomes available.
Records of the review of the final report shall be retained.
