ISO/TS 10993-19:2006
(Main)Biological evaluation of medical devices — Part 19: Physico-chemical, morphological and topographical characterization of materials
Biological evaluation of medical devices — Part 19: Physico-chemical, morphological and topographical characterization of materials
ISO/TS 10993-19:2006 provides a compilation of parameters and test methods that can be useful for the identification and evaluation of the physico-chemical, morphological and topographical (PMT) properties of materials in finished medical devices. Such an assessment is limited to those properties that are relevant to biological evaluation and the medical device's intended use (clinical application and duration of use) even if such properties overlap with clinical effectiveness.
Évaluation biologique des dispositifs médicaux — Partie 19: Caractérisations physicochimique, morphologique et topographique des matériaux
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TECHNICAL ISO/TS
SPECIFICATION 10993-19
First edition
2006-06-01
Biological evaluation of medical
devices —
Part 19:
Physico-chemical, morphological and
topographical characterization of
materials
Évaluation biologique des dispositifs médicaux —
Partie 19: Caractérisations physicochimique, morphologique et
topographique des matériaux
Reference number
ISO/TS 10993-19:2006(E)
©
ISO 2006
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ISO/TS 10993-19:2006(E)
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ISO/TS 10993-19:2006(E)
Contents Page
Foreword. iv
Introduction . vi
1 Scope.1
2 Normative references.1
3 Terms and definitions .1
4 Symbols and abbreviated terms .2
5 General principles.2
6 Characterization procedure.3
6.1 General.3
6.2 Qualitative information.4
6.3 Material equivalence.4
6.4 Quantitative information .4
6.5 Quantitative assessment.4
7 Characterization parameters and methods.5
8 Reporting of data obtained .8
Annex A (informative) Principles for judging material equivalency .9
Annex B (informative) Nanoparticles — Special consideration in judging material equivalency and
biological evaluation .10
Bibliography .11
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ISO/TS 10993-19:2006(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
(ISO member bodies). The work of preparing International Standards is normally carried out through ISO
technical committees. Each member body interested in a subject for which a technical committee has been
established has the right to be represented on that committee. International organizations, governmental and
non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the
International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
In other circumstances, particularly when there is an urgent market requirement for such documents, a
technical committee may decide to publish other types of normative document:
⎯ an ISO Publicly Available Specification (ISO/PAS) represents an agreement between technical experts in
an ISO working group and is accepted for publication if it is approved by more than 50 % of the members
of the parent committee casting a vote;
⎯ an ISO Technical Specification (ISO/TS) represents an agreement between the members of a technical
committee and is accepted for publication if it is approved by 2/3 of the members of the committee casting
a vote.
An ISO/PAS or ISO/TS is reviewed after three years in order to decide whether it will be confirmed for a
further three years, revised to become an International Standard, or withdrawn. If the ISO/PAS or ISO/TS is
confirmed, it is reviewed again after a further three years, at which time it must either be transformed into an
International Standard or be withdrawn.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO/TS 10993-19 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical
devices.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
⎯ Part 1: Evaluation and testing
⎯ Part 2: Animal welfare requirements
⎯ Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
⎯ Part 4: Selection of tests for interactions with blood
⎯ Part 5: Tests for in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 9: Framework for identification and quantification of potential degradation products
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ISO/TS 10993-19:2006(E)
⎯ Part 10: Tests for irritation and delayed-type hypersensitivity
⎯ Part 11: Tests for systemic toxicity
⎯ Part 12: Sample preparation and reference materials
⎯ Part 13: Identification and quantification of degradation products from polymeric medical devices
⎯ Part 14: Identification and quantification of degradation products from ceramics
⎯ Part 15: Identification and quantification of degradation products from metals and alloys
⎯ Part 16: Toxicokinetic study design for degradation products and leachables
⎯ Part 17: Establishment of allowable limits for leachable substances
⎯ Part 18: Chemical characterization of materials
⎯ Part 19: Physico-chemical, morphological and topographical characterization of materials
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices
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ISO/TS 10993-19:2006(E)
Introduction
ISO 14971 points out that a toxicological risk analysis should take account of the nature of the materials.
ISO 10993-1 provides a framework for a structured programme of assessment for the evaluation of biological
safety. ISO 10993-1:2003, Clause 3, 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 10993-1:2003, 7.2 notes that the continuing acceptability of a biological evaluation is an aspect of a
quality management system.
The identification and evaluation of the physico-chemical, morphological and topographical properties of
materials used in a finished medical device are important in determining the biological evaluation of that
device and its materials. Such information can be used in:
a) assessing the overall biological evaluation of a medical device (ISO 10993);
b) screening of potential new materials and/or processes for suitability in a medical device for a proposed
clinical application.
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 production processes used by the medical device manufacturer.
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TECHNICAL SPECIFICATION ISO/TS 10993-19:2006(E)
Biological evaluation of medical devices —
Part 19:
Physico-chemical, morphological and topographical
characterization of materials
1 Scope
This Technical Specification provides a compilation of parameters and test methods that can be useful for the
identification and evaluation of the physico-chemical, morphological and topographical (PMT) properties of
materials in finished medical devices. Such an assessment is limited to those properties that are relevant to
biological evaluation and the medical device’s intended use (clinical application and duration of use) even if
such properties overlap with clinical effectiveness.
This part of ISO 10993 does not address the identification or quantification of degradation products, which are
covered in ISO 10993-9, ISO 10993-13, ISO 10993-14 and ISO 10993-15. Chemical characterization of
materials is covered by ISO 10993-18.
The ISO 10993 series of International Standards is not applicable when the material or device does not
contact the body directly or indirectly (see ISO 10993-1:2003, 4.2).
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 10993-1:2003, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-18 and the
following apply.
3.1
physico-chemical
relating to the physical chemistry (of materials)
3.2
morphological
relating to the shape, contours and microstructural organization (of materials)
3.3
topographical
relating to the features of the surface (of materials)
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ISO/TS 10993-19:2006(E)
4 Symbols and abbreviated terms
The following abbreviations are used throughout the document.
• NP: nanoparticle
• PMT: physico-chemical, morphological and topographical
The abbreviations listed in Table 1 are used in Clause 7.
Table 1 — Methodology abbreviations
Abbreviation Analytical method
AES Auger Electron Spectroscopy including scanning tunneling auger
Atomic Force Microscopy/Scanning Probe Microscopy including topographical roughness and phase
AFM/SPM
contrast
BET Brunauer-Emmett-Teller, a porosity measurement methodology
CLSM Confocal Laser Scanning Microscopy
DMTA Dynamic Mechanical Thermal Analysis
DSC Differential Scanning Calorimetry
EPMA Electron Probe Microanalyser
ESC Equilibrium Solvent Content
EWC Equilibrium Water Content
EDX-SEM Energy Dispersive X-ray Analysis — Scanning Electron Microscopy
FTIR Fourier Transform Infra Red (spectroscopy) including microscopy, imaging and diffuse reflectance
FTIR-ATR Fourier Transform Infra Red (spectroscopy) — Attenuated Total Reflectance (multiple internal reflectance)
IR Infra Red (spectroscopy)
OM Optical Microscopy including polarized light and phase contrast microscopy
QCM Quartz Crystal Microbalance (or other microbalance techniques)
SEM/TEM Scanning Electron Microscopy/Transmission Electron Microscopy
SPR Surface Plasmon Resonance
TOF/SIMS Time of Flight — Secondary Ionization Mass Spectroscopy
TMA Thermal Mechanical Analyser
XPS/ESCA X-ray Photoelectron Spectroscopy/ Electron Spectroscopy for Chemical Analysis
5 General principles
Consideration of the PMT characterization of the materials from which a medical device is made, like chemical
characterization of materials (addressed in ISO 10993-18), is a necessary step in assessing the biological
safety and clinical effectiveness of the device. Both types of characterization are also important in judging
equivalence of:
a) a proposed material to a clinically established material,
or
b) a prototype device to a final device.
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ISO/TS 10993-19:2006(E)
The relationship of PMT characteristics of materials used in devices, to their biocompatibility and clinical
effectiveness, is still a developing area. However there are several examples of where these relationships are
becoming better understood, as listed below.
1) The use of certain PMT characteristics of porous materials as surfaces on orthopaedic implants can
encourage tissue in-growth at the surface of the implant and thus result in better integration with the
surrounding tissue.
2) The use of material scaffolds and meshes, with certain PMT characteristics, as implants into injured
soft or hard tissue can facilitate the beneficial infiltration of certain types of cells which aid the healing
[50]
process (Dexter et al. ).
3) The PMT characteristics of the surfaces of materials used as catheters have a major influence on the
adherence of bacteria and proteins to the inner and outer surfaces, which in turn influences the risk
of infections and blockages.
4) Alterations to the micro-topography of surfaces, e.g. producing microgrooves or other defined
patterns, has been shown to influence the adhesion and direction of movement of certain types of
[46] [49]
cells on that surface (Alaerts et al. ; Dewez et al. ).
5) For certain medical devices e.g. orthopaedic implants and vascular prostheses, mechanical
properties may influence biological responses such as tissue re-modelling.
NOTE The shape and geometric form of medical devices and their components are known to affect the biological
response, e.g. aspect ratio, thickness, form with relation to blood flow. Information on specific devices may be found in the
applicable product standards.
This technical specification provides a range of examples of PMT characterization parameters and methods
which may be usefully applied in the PMT characterization of materials utilized in medical devices.
Medical device manufacturers should select relevant parameters and methods and justify their selection.
Manufacturers should document the level of characterization performed on their medical device and its
component materials, appropriate to its clinical application.
The extent of characterization should reflect the nature and duration of the clinical exposure and may be
useful for risk assessment of the biological safety of the device. The PMT characterization should also reflect
the materials used and their physical form(s), e.g. solid, liquid, gel, polymer, metal, ceramic, composite or
biologically sourced material. Characterization generally requires the close collaboration of material scientists,
analytical scientists and risk assessors.
6 Characterization procedure
6.1 General
The analytical methods should be selected to give the required information for the evaluation. Prior to new
method development, existing standards, monographs, scientific articles or other relevant scientific documents
should be consulted to check for existing appropriate test methods. Methods from the literature may need to
be adapted and validated before use. If suitable methods cannot be identified, appropriate new methods
should be developed.
The analytical methods used should be validated, justified and reported in line with Clauses 7 and 8. The
validation of an analytical method is the process by which it is established that the performance characteristics
of the method meet the requirements for the intended analytical applications. Analytical methods should be
validated as appropriate with respect to the following justified analytical characteristics: accuracy, precision,
specificity, limit of detection, limit of quantification, linearity, range, ruggedness, robustness and system
suitability.
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ISO/TS 10993-19:2006(E)
At each step of the characterization procedure, a decision should be made on the adequacy of the data
obtained, as a basis for the risk analysis. This procedure should consider each of the materials as they appear
in the finished device.
NOTE The supplier may be a useful source of appropriate analytical methods. In the absence of any initial data on
material properties, a literature study is recommended to assist in the selection of the most appropriate methods of
analysis for the material concerned.
6.2 Qualitative information
Describe the material/device and its intended purpose. A documented, qualitative description of the PMT
characteristics of the finished device is recommended, including the characteristics of each material used in
the device (see 3.2 and Clause 4 of ISO 10993-1: 2003) (see Annex A). The level of qualitative data provided
should reflect the category of medical device in terms of degree of invasiveness and clinical exposure
duration, as well as the nature of the materials present.
The qualitative description should, where applicable, include details of batch or lot, supplier and material
specification for each material.
Medical device manufacturers should obtain qualitative and quantitative material characterization information,
relevant to the final product. Such information may be obtained from the supplier of the starting material, the
literature or additional testing. The PMT characteristics of materials should either be in accordance with
applicable materials standards or should be specified by the manufacturer. It is important to obtain as much
information as possible at this early stage to be able to gain a thorough understanding of the hazards
(potential risks) and potential benefits arising from the properties of the material, and to develop an initial
assessment of the fitness for the intended purpose. This assessment will be further refined as additional
information is gained during the product development process.
6.3 Material equivalence
As a part of material suitability assessment, a comparison of these data should be made to determine whether
this material is equivalent to that utilized in a device with the same clinical exposure/use and having had the
same manufacturing and sterilization processes applied, e.g. established safe and effective use of materials in
a product to be used on intact skin. Annex A gives further guidance on judging material equivalency and
Annex B gives information on the special case of material used as nanoparticles (u 100 nm in any one
dimension).
6.4 Quantitative information
Where qualitative material characterization data alone have not provided sufficient data for a material
suitability assessment to be completed, quantitative material characterization data should be established,
documented and subjected to assessment of suitability and risk.
6.5 Quantitative assessment
Sufficient quantitative characterization information should be obtained in order to permit an assessment of the
fitness of all of the materials in a finished device for their intended purpose as part of the overall biological
evaluation of the medical device. This quantitative characterization information can be usefully compared with
data for materials and/or finished medical devices clinically established as being safe and effective for the
intended use. The characterization information may also be usefully compared to those materials/products
found not to have the required characteristics for this use. This overall evaluation is outside the scope of this
part of ISO 10993 and will combine information gained from many other parts of the ISO 10993 series of
International Standards and will utilize ISO 14971.
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ISO/TS 10993-19:2006(E)
7 Characterization parameters and methods
Clause 6 indicates the generation of qualitative and quantitative PMT characterization data for use in the
suitability/risk assessment. Table 2 summarizes examples of parameters for material characterization and
examples of methods which can be used to provide qualitative and/or quantitative data for these. Relevant
standards and/or references are given for the parameter section, e.g. topography. Not all of the parameters or
the associated methods may be applicable to all types of material. The characterization parameters used
should be selected appropriate to the material or finished medical device. Due to the diversity of medical
devices, it is recognized that not all of the parameters identified for a material will be relevant for all/some
device uses. As noted in 6.2 the extent of characterization which should be considered is determined by the
invasiveness and duration of clinical exposure in the intended use.
The analyst and material scientist in consultation with the manufacturer’s assessor of the material fitness for
use (risk assessor) should determine which parameters are relevant to the assessment of a material or
medical device. Characterization data should be considered for all of the parameters considered relevant by
the manufacturer’s risk assessor.
NOTE For natural macromolecules, it is essential that the source organism (species) and breed/strain be clearly
identified as a first step. The ISO 22442 series of standards covers the safe utilisation of non-human tissues and their
derivatives in the manufacture of medical devices. EN 455-3 covers the assessment of risks associated with protein
residues in natural rubber latex.
Natural macromolecules utilized in medical devices include but are not limited to proteins, glycoproteins, polysaccharides
and ceramics. Examples include gelatine, collagen, elastin, fibrin, albumin, alginate, cellulose, heparin, chitosan,
processed bone, coral and natural rubber. These materials may have been processed, purified and modified to different
extents. Pharmacopoeia monographs exist for many of these materials and several ASTM F04 standards also cover the
characterization of these materials.
Table 2 — Examples of parameters and test methodologies for characterization of materials including
polymers, metals, alloys, ceramics and natural macromolecules
Example methods
Examples of parameters
(not comprehensive or Qualitative Quantitative Standard or reference
to be analysed
exclusive)
Porosity
Classical OM × –
Gas adsorption (BET) – ×
Mercury porosimetry – ×
[39]
Helium pycnometry × –
ASTM F1854-01
[22]
ISO 18754
Connectivity SEM – ×
[23]
ISO 18757
AFM × –
Scaffolds SEM – ×
AFM × –
Morphology
Crystallinity X-Ray Diffraction × ×
OM × –
DSC × ×
SEM/TEM × –
[35]
ASTM F665
AFM × –
[38]
ASTM F754
[42]
Amorphous DMTA × ×
ASTM F2081
AFM × –
[44]
ASTM F2183
Hasegawa and
Multiple phases OM × ×
[55]
AFM × – Hashimoto
[58]
TEM × –
Kajiyama et al.
[59]
Kajiyama et al.
Hard/soft surfaces OM × ×
AFM/SPM × ×
TEM × –
Ultrasound × –
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ISO/TS 10993-19:2006(E)
Table 2 (continued)
Example methods
Examples of parameters
(not comprehensive or Qualitative Quantitative Standard or reference
to be analysed
exclusive)
Surface energy/charge
Hydrophobic Wettability (contact angle) × ×
Hydrophilic Wettability (contact angle) × ×
[27]
Protein adsorption QCM or SPR × × EN 828
[48]
CLSM × ×
Collier et al.
Biochemical analysis × ×
[49]
Dewez et al.
RIA × ×
[50]
Dexter et al.
[53]
Protein repulsion QCM or SPR × ×
Ebara and Okahata
[56]
CLSM × ×
Ikada
Biochemical analysis × ×
[57]
Jenney and Anderson
Radioimmunoassay × ×
[60]
Kishida et al.
[65]
Cell attachment
MacDonald et al.
⎯ Human general OM × ×
[69]
Niikura et al.
⎯ Human blood cells QCM × ×
[71]
Quirk et al.
⎯ Human specific cells CLSM × ×
[72]
Senshu et al.
⎯ Bacteria general
[74]
⎯ Bacteria specific class Senshu et al.
[76]
Tamada et al.
Cell repulsion
[77]
Wagner et al.
⎯ Human general OM × ×
[79]
Weber et al.
⎯ Human blood cells QCM × ×
⎯ Human specific cells CLSM × ×
⎯ Bacteria general
⎯ Bacteria specific class
Abrasion resistance
[31]
ASTM D968
Stability of treated surface IR × –
[32]
Surface friction Volume loss, strain gauge ASTM D1044
× ×
[33]
Coefficient of friction
× × ASTM D1894
[34]
AFM/SPM
× × ASTM D4060
[36]
ASTM F732
[37]
ASTM F735
[41]
ASTM F1978
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ISO/TS 10993-19:2006(E)
Table 2 (continued)
Example methods
Examples of parameters
(not comprehensive or Qualitative Quantitative Standard or reference
to be analysed
exclusive)
Topography
[1]
ISO 3274
Surface chemical mapping XPS/ESCA × ×
[2]
ISO 4287
TOF-SIMS × –
[3]
FTIR/ATR
– ISO 4288
×
[4]
FTIR-Microscopy –
ISO 5436-1
×
FTIR-Imaging [5]
–
× ISO 5436-2
EDX-SEM – [11]
× ISO 11562
Raman
–
[12]
×
ISO 12179
EPMA ×
[15]
×
ISO 13565-1
[16]
ISO 13565-2
Roughness
[17]
ISO 13565-3
⎯ smooth SEM – [22]
×
ISO 18754
⎯ pitted AFM/SPM × [23]
×
ISO 18757
⎯ grooved Tribology
–
× [25]
EN 623-4
⎯ irregular terrain Profilometry –
× [46]
Alaerts et al.
(“hills, valleys”)
[56]
Ikada
[58]
Kajiyama et al.
[63]
Kumaki et al.
[72]
Senshu et al.
[73]
Senshu et al.
[74]
Senshu et al.
Particles
[40]
ASTM F1877
Size OM
× ×
[13]
Size distribution Laser diffraction ISO 13319
× ×
[14]
3D shape Image analysis
ISO 13320-1
× ×
[18]
Filters (sieves)
× – ISO/TS 13762
SEM [21]
–
× ISO 17853
[26]
EN 725-5
Shape and Form SEM × ×
AFM/SPM
× ×
OM
× ×
Swelling
Water absorption EWC × ×
Solvent absorption ESC
× ×
Shape change Image analysis
× ×
[20]
ISO 17190-5
Surface crazing OM
× ×
[66]
Moskala and Jones
SEM
× ×
TMA
× ×
Weight gain Microbalance
× ×
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ISO/TS 10993-19:2006(E)
8 Reporting of data obtained
Test reports should clearly state the purpose of the characterization that has been performed and, where
appropriate, should include the following:
a) description and details of material or finished medical device;
b) characterization methods;
c) qualitative data generated;
d) quantitative data generated.
For areas for which no standards exist, the qualitative and quantitative PMT data generated will be collected
and documented for information purposes. These data may be used to assist in the development of
appropriate future standards.
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ISO/TS 10993-19:2006(E)
Annex A
(informative)
Principles for judging material equivalency
In 6.3 characterization data is used in risk assessment to judge equivalency of a proposed material to an
existing clinically established material or finished medical device for the same type of clinical exposure. The
key principle applied in making this judgement is that the proposed material or finished medical device has
equivalent properties in terms of biological safety and
...
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