ISO CD 10993-18
Revised after May 1998 Meetings
Chemical Characterisation of Materials
Contents
ISO 10993-1: 1996, Biological evaluation of medical devices Part 1: Evaluation and testing provides a framework for a structured programme of assessment for the evaluation of biological safety. ISO 10993-1 Clause 3 General principles applying to the biological evaluation of materials and devices states that in the selection of materials to be used for device manufacture the first consideration should be fitness for purpose. This should have regard to the characteristics and properties of the material which include chemical, toxicological, physical, electrical, morphological and mechanical properties. This information is necessary prior to any biological evaluation. ISO 10993-1 Clause 7.2 notes that the continuing acceptability of a biological evaluation is an aspect of a quality management system.
Also ISO14971-1, Medical devices - Risk management - Part 1: Application of risk analysis, points out that a toxicological risk analysis should take account of the chemical nature of the materials.
The requirements specified in this document are intended to yield the following information:
Note: This does not cover industrial hygiene aspects which are covered
by other regulations.
The compositional characteristics of the materials of manufacture are mainly under the control of the suppliers of these materials. However other characteristics are chiefly influenced by the requirements to be met by the finished medical device as well as the processes used by the medical device manufacturer.
Chemical Characterisation of Materials
This document describes a framework for the identification and, where necessary, quantification of the chemical constituents of a material to provide information required for inclusion in an assessment of the biological safety of medical devices.
This part of ISO 10993 does not address the identification or quantification of degradation products, which are covered in ISO 10993 part 9, 13, 14 and 15.
ISO 10993-18 is intended for suppliers of materials and manufacturers of medical devices, when carrying out a biological safety assessment.
The following standards contain provisions which, through reference in this text, constitute provisions of this International Standard. At the time of publication, the editions indicated were valid. All standards are subject to revision, and parties to agreements based on this International Standard are encouraged to investigate the possibility of applying the most recent editions of the standards indicated below. Members of IEC and ISO maintain registers of currently valid International Standards.
ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation
and testing.
ISO 10993-12 Biological evaluation of medical devices - Part 12: Sample
preparation and
reference materials.
ISO/DIS 10993-17 Biological evaluation of medical devices - Establishment
of permissible limits
for sterilisation and process residues using health-based risk assessment.
For the purposes of this standard the definitions given in ISO 10993 Part 1 and the following additional definitions apply.
The person who manufactures and/or supplies the basic starting materials to be used in the manufacture of a medical device
The natural or legal person with responsibility for the design, manufacture, packaging and labelling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party.
An item which is manufactured from a basic starting material but is not itself a medical device, since it forms only one part of a medical device.
A person who converts a basic raw material into a semi-finished product, for example: lengths of rod, tubing or lay-flat film.
Identification and quantification of the chemicals present in materials or finished medical devices and their predicted biological exposure.
Any synthetic or natural polymer, metal, alloy, ceramic, or other nonviable substance, including tissue rendered nonviable, used as a medical device or any part thereof (definition from ISO 10993-1: 1997)
Consideration of the chemical characterisation of the materials from which a medical device is made is a necessary first step in assessing the biological safety of the device. It is also important in judging equivalence of (a) a raw material with a clinically established material and (b) a prototype device with a final device. An overview of the chemical characterisation procedure outlined in this document and its relationship to risk assessment is given in Annex A.
Qualitative data shall be obtained to describe the chemical composition
of a material. When relevant to biological safety quantitative data shall
also be obtained. Further guidance is given in Annex B.
The degree of chemical characterisation required should reflect the nature and duration of the clinical exposure and shall be determined by the risk assessor based on the data necessary to evaluate the biological safety of the device. It will also depend on the nature of the materials used, e.g. liquids, gels, polymers, metals, ceramics, composites or biologically sourced material (see Annex C).
The successful completion of the characterisation outlined in this document requires the close collaboration of analytical chemists and toxicological risk assessors. In this partnership, the analytical chemist provides the neccessary qualitative and quantitative data that the risk assessor uses to determine device safety.
The characterisation procedure is summarised in a flowchart in Annex A and the requirements and guidance at each step are specified here. At each step of the procedure, a risk-assessment decision on the adequacy of the data shall be made in accordance with ISO 10993-1, ISO 10993-17 and ISO 14971-1 to determine whether all biological hazards can be identified (clause 3.5 of ISO 10993-1) sufficient for a risk analysis. This procedure is required for each of the materials used in a medical device in addition to the characterisation of the finished device.
Note: The supplier may be a useful source of appropriate analytical methods.
In the absence of any initial compositional data, a literature study to
establish the likely nature of the starting material and any additives
is recommended to assist in the selection of the most appropriate methods
of analysis for the material concerned.
Determine whether the device contacts the body directly or indirectly.
If the material or device does not contact the body directly or indirectly
then this procedure is not required (clause 4. l . l of ISO 10993-1).
Describe the material / device and its intended purpose. A full, documented,
qualitative description of the composition of the finished device, including
additives and processing residues for each material used in the device
(clause 3.3 of 10993-l) (see Annex E), is required.
This description shall include details of batch or lot, supplier and material specification for each material. The level of qualitatitive data provided / required shall reflect the category of medical device in terms of degree of invasiveness and clinical exposure duration as well as the nature of the materials and shall be justified. The use of a standardised material (e.g. ISO 5832-l) in its intended use shall meet this requirement.
Medical device manufacturers should preferably obtain qualitative and quantitative compositional information from the supplier of the starting material. Qualitative information about any additional processing additives (for example, mould release agents) should also be obtained from appropriate members of the manufacturing chain, including convertors and component manufacturers. The composition of materials may be in accordance with applicable materials standards, and/or it may be specified by the manufacturer. However in order to obtain full qualitative and quantitative compositional details it may be necessary to request these from the supplier or manufacturer of the starting material and also from component manufacturers to ensure processing aids are also identified.
As a part of risk assessment, a comparison of these data shall be made to determine whether this material is equivalent to that utilised in a device with the same clinical exposure / use and having had the same manufacturing and sterilization processes applied.
Where qualitative analysis alone has not provided sufficient data for a risk analysis to be completed, quantitative chemical composition shall be established and documented.
Analytical methods used shall be appropriate to the material under investigation and shall be justified and reported.
By reference to existing toxicological information, a risk assessment shall be made.
If the quantity of any chemical present, according to the risk assessment, remains a clinical concern, the total dose and rate of exposure of that chemical shall be established. The extraction conditions used shall be documented and justified.
Note: Where a material is for use in a surface-contacting device with < 30 days clinical exposure, extraction conditions as described in ISO 10993-12 may be appropriate. For long-term, more invasive exposure devices, a more exhaustive extraction will better estimate the total dose to the patient but this must be combined with an assessment of the rate of exposure clinically (i.e. kinetics of extraction).
The extract shall be analysed using sensitive and selective methods and the levels of chemicals of concern quantified.
As before, an evaluation for unacceptable toxicological risks shall be carried out.
Where the evaluation indicates that there are still unacceptable risks
then appropriate biological evaluation tests shall be considered in line
with ISO 10993-1 with test selection based on clauses 5.1 and 6 of 10993-1.
The data shall be reported in a standardised format which enables data
entry to a materials file. (See Appendix E).
Test reports shall include the following:
a) Test material description, batch or lot number, and sample dimensions
or weight.
b) Description of origin of compositional data, for example: supplied by
material/finished
product manufacturer, or by analysis.
c) Sample pretreatment (e.g. sterilization).
d) Detailed description of analytical methods used including specificity,
sensitivity, limits of
detection and limits of quantification; also standards and reference materials
where used.
e) List of all chemical components identified including quantitative data
where possible.
a) Test material description, batch or lot number, and sample dimensions
or weight.
b) Sample pretreatment (e.g. sterilization).
c) Extractant solution details including chemical identity and volume used.
Justification shall
be provided for the choice of extractant.
d) Duration and temperature of extraction including justification for their
selection.
e) Detailed description of analytical methods used including specificity,
sensitivity, limits of
detection and limits of quantification; also standards and reference materials
where used.
f) List of all chemical components identified including quantitative data
where possible.
Note: Quantitative data must permit calculation of human exposure
Flowchart summarising the use of material characterisation
data in risk assessment (See 4.1 for related text}
Guidance on Chemical Characterisation
For some materials compositional information may be readily available as part of the material specification. Materials such as polymers may possess more complex formulations and compositional details should be obtained from the supplier of the material. In the absence of such details appropriate analytical techniques should be applied to a material to yield compositional data.
Identification of the constituents of a material intended for use in the manufacture of a medical device enables the intrinsic toxicity of each constituent to be investigated. The data obtained is intended to be used by the medical device manufacturer as part of the overall biological safety evaluation of the medical device. It is therefore important that a material supplier should not be permitted to change the composition of a material supplied under a specific commercial trade-name or supply agreement without prior notification to the medical device manufacturer. The manufacturer should assess the consequences of any notified changes on the biological safety of the product.
Any of the constituents of a material or additives used in the process of manufacture of a medical device are potentially big-available. However it is necessary to obtain information demonstrating the extent to which the constituents will be available under the actual conditions of use of the finished product to estimate the risk arising from them. This can be determined experimentally through extraction tests on the material. Appropriate extraction conditions are used to ensure that any constituent which is likely to be released during finished product use will be released into the extraction media The extract obtained is analysed qualitatively and quantitatively and physico-chemical tests are used to generate data that can then be used in the biological safety evaluation of the medical device.
An illustration of the wide variety of extraction conditions and extractant test methods which currently exist is found by reference to the documents listed in Annex D and guidance is given in ISO 10993-12.
Identification of appropriate biological toxicity testing required for the medical device concerned is assisted by use of the information obtained from the chemical characterisation procedure.
This standard does not attempt to identify and quantify any degradation products which may be formed. The potential for degradation is addressed separately by ISO Standards 10993-13, 1099314 and 10993-15 concerned respectively with polymeric, ceramic and metallic materials, and also ISO 10993-9.
Test reports containing the information described in section 9 of this standard can be submitted for inclusion in toxicological risk analysis procedures for biological hazards of the medical device/finished product concerned. (For example, see EN 1441 clause 4.2 and revised ISO 10993-1 clause 3).
Qualitative compositional data for the material itself enables the intrinsic toxicity of the chemical constituents to be established by reference to existing data or through toxicity studies. Quantitative data for the material itself and the extract from the material permits the potential biological exposure of each constituent to be assessed. The risk of toxic effects arising from exposure to the constituent during use of the device can be estimated from intrinsic toxicity and exposure data.
Categorisation of Materials
The first consideration should be the physical form of the material. For the purpose of this standard the materials encompassed by the definition may be conveniently divided into several categories. This division is related to the complexity of the chemical composition of the material.
Synthetic polymers will usually contain a larger number of components such as unreacted monomer residue, catalyst and solvent residues, oligomers, production aids and modifying additives including pigments. Many of these will be present at very low levels. Polymers may also occur as liquids, gels or solids with or without association of other formulation chemicals.
Natural polymers may vary significantly dependent on the biological source and may contain impurities and residues resulting from that source.
NOTE: This standard does not cover risks of infection associated with the biological source. Draft European Standards which address these issues should be consulted (prEN 12442, Parts 1-3).
These materials are normally less complex in terms of the number of chemical constituents and these will be present in significant proportions.
These materials are normally less complex in tams of the number of chemical constituents and these will be present in significant proportions.
These can be combinations of the above. Composites which include polymers should be considered as for 1 and 2.
It should be noted that during manufacture and assembly of medical devices from materials in all of the above categories, additional chemical components may be acquired due to the use of processing aids such as lubricants or mould release agents. As well as the chemical components of the starting material and the manufacturing process aids, adhesive/solvent residues from assembly and also sterilant residues or reaction products resulting from the sterilisation process may also be present in a finished product.
Bibliography of International and National Standards and Regulations
Note: This list is not exhaustive but gives examples of some standards
and regulations which may be applicable. A range of materials product specific
standards exists and may be obtained from the relevant standards development
body, e.g., ISO, DIN, ASTM, etc. and may be accessible via the standard
body's website.
ISO 1135 Transfusion equipment for medical use
Part 3: Blood-taking set.
Part 4: Transfusion sets for single use.
ISO 3826 Plastics collapsible containers for human blood and blood components.
ISO 7886 Sterile hypodermic syringes for single use
Part 1: Syringes for manual use.
ISO 8536 Infusion equipment for medical use
Part 4: Infusion sets for single use.
Part 5: Burette type infusion sets.
ISO 10993-9 Biological evaluation of medical devices - Part 9: Degradation
of
materials related to biological testing.
ISO 10993-13 Biological evaluation of medical devices - Part 13: Identification
and quantification of degradation products from polymeric medical devices.
ISO 10993-14 Biological evaluation of medical devices - Part 14: Identification
and quantification of degradation products from ceramics.
ISO 10993-15 Biological evaluation of medical devices - Part 15: Identification
and quantification of degradation products from uncoated or coated metals
and alloys.
ISO TR10451 (Dee 1995)
prEN 12442-1 Animal tissues and their derivatives utilised in the manufacture
of medical devices - Part 1: Risk analysis and management.
prEN 12442-2 Animal tissues and their derivatives derivatives in the manufacture
of medical devices - Part 2: Sourcing, controls, collection and handling.
prEN 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.
3.1. 1 Materials based on plasticised PVC for containers for human
blood and blood components and aqueous solutions for
intravenous infusion.
3.1.2 Materials based on plasticised PVC for tubing used in sets for
transfusion of blood and blood components.
3.1.3 Polyolefines.
3.1.4 Polyethylene-low density for containers for preparations for
parenteral use and ophthalmic preparations.
3.1.5 Polyethylene-high density for containers for preparations for
parenteral use.
3.1.6 Polypropylene for containers for preparations for parenteral use.
3.1.7 Ethylene-vinyl acetate copolymer for containers and tubing for total
parenteral nutrition preparations.
3.1.8 Silicone oil used as a lubricant.
3.1.9 Silicone elastomer for closures and tubing.
3.2.1 Glass containers for pharmaceutical use.
3.2.2 Plastic containers and closures.
3.2.3 Sterile plastic containers for human blood and blood components.
3.2.4 Empty sterile containers of plasticised PVC for human blood and blood
components.
3.2.5 Sterile containers of plasticised PVC for human blood containing
an
anticoagulant solution.
3.2.6 Sets for the transfusion of blood and blood components.
3.2.7 Plastic containers for aqueous solutions for intravenous infusion.
3.2.8 Sterile single-use plastic syringes.
3.2.9 Rubber closures for containers for aqueous preparations for parenteral
use.
European Agreement on the exchange of therapeutic substances of human origin
(As accepted by the EU in January 1987).
United States Pharmacopoeia 23rd Edition Physico- chemical tests -
Plastics.
Japanese Pharmacopoeia Plastic containers for aqueous in fusions.
Nordic Pharmacopoeia
Plastic material for containers and transfusion tubing for blood and blood
fractions
blood fractions and for aqueous solutions for infusion, injection or irrigation.
DIN 13098 Sterile hypodermic syringes for single use.
DIN 58363 Transfusion equipment
Part 15: Infusion containers and accessories, infusion bags and bottles
made of plastic.
BS 2463 Transfusion equipment for medical use
Part 1: Collapsible containers for blood and blood components.
Part 2: Administration sets.
BS 3531 Surgical implants made of heat-vulcanised silicone.
BS 5081 Sterile hypodermic needles and syringes for single use.
Example of the Structure of a Material File
Purpose
The purpose of the layout of this file is to generate a format for
(starting) materials to be used in
medical device applications. These materials are in general supplied to
the medical device
manufacturer.
The device manufacturer relies on the quality and consistency of the supplied
materials to generate
his final product safety profile.
Use
The Material Database can be used to assess whether materials are suitable
for their final application
(design history), and/or inserted in certification files.
Material Database
TABLE OF CONTENTS
1. GENERAL INFORMATION
1.1 GENERAL PRODUCT lNFORMATION
1.2 MANUFACTURING SITE AND CONTACT NAMES
1.3 SPECIFICATION AND ROUTINE TESTS (LARS)
2. PRODUCT NOMENCLATURE AND CHARACTERISATION
2.1 DESCRIPTION
2.2 NOMENCLATURE
2.3 PRODUCT (QUALITATIVE) FORMULATION/COMPOSITION
3. MANUFACTURE
3.1 GENERIC DESCRIPTION OF THE MANUFACTURING PROCESS
3.2 MANUFACTURING QUALITY ASSESSMENT
3.3 ENVIRONMENTAL ASSESSMENT
4. QUALITY CONTROL DURING MANUFACTURING
4.1 RAW MATERIALS DESCRIPTION AND SPECIFICATIONS
4.2 IN-PROCESS SAMPLING AND TESTING
4.3 PACKAGING MATERIAL
5. DEVELOPMENT CHEMISTRY
5.1 EVIDENCE OF THE CHEMICAL STRUCTURE
5.2 PHYSICO-CHEMICAL CHARACTERISTICS OF "PRODUCT NAME"
5.2.1 PHYSICO-CHEMICAL PROPERTIES
5.2.2 FUNCTIONAL PROPERTIES
6. ANALYTICAL DEVELOPMENT AND VALIDATION
7. BATCH STUDIES
8. STABILITY STUDIES
8.1 STABILITY CONTAINERS
8.2 STABILITY RESULTS AND CONCLUSIONS
9. TOXICOLOGY
NOTE: Any lists are only intended to be examples and not meant to be all
inclusive.
A general product history/overview, including raw materials and a brief
chemistry and/or process review should be provided.
Names of manufacturing site(s) and pertinent regulatory contacts should
be included.
- testing as performed and including acceptance limits (Sales specifications)
- Certificates of Analysis
- regulatory references (material(s) compliance to vertical standards,
monographs ).
Regulatory references of compliance to horizontal standards and on Pharmacopoeia's
shall be mentioned. These should reflect the section specification/testing
of the material.
This section deals with the identity, nomenclature and chemical structure
of the product(s) which is (are) the subject of the File. Only brief details
of the physical characteristics should be stated, as full details and proof
of structure are required later.
- physical form(s)
- structural formula(s)
- molecular formula(s)
- relative molecular mass(es)
A brief description should be given of the appearance of the materials(s),
where possible. The structural formula(s) should be given diagrammatically
with all known stereochemistry indicated conventionally, with molecular
formula(s) and relative molecular mass(es). A detailed description of the
nature of the substance(s) should be given.
- international non-proprietary name (INN)
- national approved names, +
- US adopted name (USAN)
- laboratory code(s)
- systemic chemical name(s)
- other names (e.g. internal proprietary, product names, etc.)
- CAS Registry number
example .........
NOTE: Any lists are only intended to be examples and not meant to be all
inclusive.
Provide a list of raw materials used to product the final material.
- A concise but comprehensive account of the manufacture of the product(s)
should be provided.
- Name and address of manufacturing source.
- Quality of production; Quality certificates (ISO 9001, cGMP bulk pharmaceutical,
cGMP Medical Device, etc.
When a complete or partial chemical synthesis is involved, the synthesis should be represented by diagrams of the chemical reactions in the form of a flow sheet. An appropriate description should be given of each stage of the manufacture, including, where applicable:
- solvents and reagents used
- catalysts used
- conditions of reactions where these are critical
- information on intermediates which are isolated and purified
- details of the final purification and the solvents involved.
Reference quality assessments based on ISO 9001, cGMP bulk pharmaceutical, cGMP Medical Device, etc.
Emissions concentrations of all substances to the environment have been evaluated for impact outside of the property line of the facility. Waste generated at the manufacturing facility is managed in accordance with all federal, state and local environmental regulations.
Describe the analytical controls which are applied to ensure that the starting materials, which make a significant contribution to the molecular formula and any reagents, are correctly identified and are shown to be of satisfactory quality. An indication of the content of significant impurities in starting materials should be given. Specifications for solvents used in the final stages of synthesis, crystallisation and/or washing should be submitted.
The criteria for accepting or rejecting batches of these materials should be indicated.
NOTE: Any lists are only intended to be examples and not meant to be all inclusive.
The quality control checks which are carried out at each stage of the process and on the isolated intermediates should be described. A statement of the test procedure(s) and criteria for acceptance should be given for each stage, where appropriate.
Include specifications and routine tests, if applicable, for packaging materials (containers, closures, labels, etc.):
- type of material
- construction
- quality specifications (routine tests) and test procedures
This section should indicate the research and development which was (were) undertaken on the product(s) to demonstrate/investigate the evidence of their structure and chemical and physico-chemical properties.
The findings described in this section should be reflected in the control tests on the product(s) by which batch- to-batch uniformity is controlled.
A scientific discussion of the chemistry of the product(s) should be given and should include, where applicable, unequivocal proof of structure, configuration, conformation and potential isomerism. Where the synthetic route and structure of the intermediates are cited as evidence of structure, references to relevant published papers in the literature would be helpful. Where relevant, the information might include such evidence as:
- elemental analysis with theoretical values
- infra-red spectra with interpretation
- nuclear magnetic resonance spectra with interpretation
- discussion on UV characteristics including pH dependent shifts
- mass spectrum with interpretation and discussion of results
- discussion of the synthetic route as evidence of structure
- evidence of structure of key intermediates of synthesis (e.g. using IR,
NMR, etc.)
- characteristic chemical reactions which are diagnostic of the structure
of the molecule
- X-ray crystallography with interpretation and discussion of results
- optical rotation with discussion of optical purity in the case of isomerism.
(Absence of optical rotation should be reported when this serves to illustrate
that asymmetric molecule is racemic)
- evidence of the indicated relative molecular mass
- the relevance of the isomer to activity should be discussed.
NOTE: Any lists are only intended to be examples and not meant to be all inclusive.
Information set out under the relevant headings below should cover aspects of physico-chemical characteristics which have been investigated, whether or not they are included in the monograph for the active ingredient. Including a schematic of the synthetic reactions is recommended.
The following sections should include specifications and tests for release (at time of manufacture) including both general characteristics and specific for each of the product(s) covered in the Master File. An example of what might be included is shown below .....
Functional tests as well as other test procedures which were used for identification and quantitative determination during the development of the product(s), but which are not routinely performed on each batch of material produced, should be described here. An indication should be given as to whether the product(s) is (are) crystalline, amorphous, etc. and where relevant, information on:
- particle size, salvation, melting point, boiling point, etc.
- the presence of polymorphic forms and the methods of detection and control
should be
discussed, or their absence confirmed
- the pKa values of the product(s) and the pH in solutions of defined concentration
should be
given. In the case of a salt, this information for the corresponding base
or acid should be
given
- oil/water partition coefficients, etc....
The tests applied and the limits thereby imposed should be stated for:
- physical characteristics
- tests for identity
- standards for purity and limitations of impurity.
Discussion of the precession and accuracy of test procedures is particularly applicable to substances where biological control is necessary.
Analytical validation of methods and comments on the choice of routine tests and standards (e.g. working standards) should be described here. Some EXAMPLES are shown below:
Data should be provided in this section to illustrate the actual results which have been obtained from routine quality control of the product(s). Results should be given, if possible for:
- batches of material used in the toxicity tests and clinical trials reported in support of the application
NOTE: Any lists are only intended to be examples and not meant to be all inclusive.
- recent consecutive batches (5) which are representative of the product
which will be supplied for the purpose covered by the marketing authorisation
to show that the proposed methods will give routine production material
which falls within the specification limits cited.
The purpose of stability tests is to obtain information which enables proposals
to be made for the shelf-life.
The purpose of the stability studies is to ascertain how the quality of
a product varies as a function of time and under the influence of a variety
of environmental factors.
On the basis of the information thus obtained, storage conditions are recommended
(the purpose of these studies is to produce recommendations) which will
guarantee the maintenance of the quality of the medicinal product. In relation
to its safety, efficacy and acceptability, throughout the proposed shelf-life.
Details of the packaging should be stated as:
- type(s) of container and closure, and nature of the constituent materials
- nature of any desiccant used.
The interpretation should include:
- the conclusions as to the most appropriate storage conditions for the
product
- recommendations on material shelf-life based on results from stability
lot acceptance studies
- the discussion of the significance of the decomposition products (during
storage), particularly
as regards their potential toxicity.
The conclusion should include:
- the stability data on the product and the development studies enable
a preliminary choice of
the formulation and packaging material to be made. They are enable some
consideration to
be given to the choice of analytical methods and test conditions.
Results from biological testing as performed are summarised. These tests
results give a general degree of assurance that the risk of adverse reactions
during clinical usage is low.
Testing as performed should refer to an accepted toxicological standard.
Depending on the application, it needs to be decided what further (biological/clinical)
testing needs to be performed (for this assessment ISO 10993-1, EN540).
NOTE: May want to consider including section on degradation of materials
per
ISO 10993-(13-16).
NOTE: Any lists are only intended to be examples and not meant to be all
inclusive.