この文書は、ISO 10993-8: Sample Preparation and Reference Materials
の付属ガイダンス文書で、ISO Technical Reportの位置づけにある。
生物試験における標準物質・材料の要件を示す。
コメント期限・提出先：
1998.2.28
中村晃忠 FAX 03-3707-6950
E-mail: nakamura@nihs.go.jp
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 main task of technical committees is to prepare International Standards, but in exceptional circumstances a technical committee may propose the publication of a Technical Report of one of the following types:
Technical Reports of types 1 and 2 are subject to review within three years of publication, to decide whether they can be transformed into International Standard, Technical Reports of type 3 do not necessarily have to be reviewed until the data they provide are considered to be no longer valid or useful.
This Technical Report of type 3. was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This document is not to be regarded as in "International Standard". It is proposed for provisional application so that information and experience of its use in practice may be gathered. Comments on the content of this document should be sent to the ISO Central Secretariat.
A review of this Technical Report will be carried out not later than two
years after its publication with the options of: extension for another
two years; conversion into an International Standard; or withdrawal.
. .
1 Scope
This information should be considered as a supplement to ISO 10993-12 which
specifies requirements and gives guidance on procedures to be followed
in the preparation of samples of medical devices for testing in biological
systems in accordance with one or more parts of the ISO 10993 series.
In clause 4, there is a discussion of the use of reference materials as
experimental controls. When ISO 10993-12 was published, Annex A provided
specific information regarding the sources of materials that were available
at that time.
2 Normative references
The following standards and guides contain provisions which, through
reference in this text, constitute provisions of this Technical Report.
At the time of publication, the edition indicated was valid. All standards
are subject to revision, and parties to agreements based on this Technical
Report are encouraged to investigate the possibility of applying the most
recent edition of the standard indicated below. Members of lEC and ISO
maintain registers of currently valid International Standards.
The ISO Guides listed below provide material, which will enable the reader
to place into context. the discussion m this Technical Report.
ISO/IEC Directives, Part 2: 1992, Methodology for the development of international
Standards, Annex B - Mention of reference materials
ISO 10993-12: 1996, Biological evaluation of medical devices - Part 12.
Sample preparation and reference materials.
ISO Guide 30:1992. Terms and definitions used in connection with reference
materials.
ISO Guide 31 :1981, Contents of certificates of reference materials.
ISO Guide 33:1989, Uses of certified reference materials.
ISO Guide 35: 1989, Certification of reference materials - General and
statistical principles.
3 Definitions
3.1 certified reference material (CRM): Reference material,
accompanied by a certificate, one or more of whose property values are
certified by a procedure which establishes its traceability to a an accurate
realization of the unit in which the property values are expressed, and
for which each certified value is accompanied by an uncertainty at a stated
level of confidence (see ISO Guide 30).
3.2 reference material (RM): Material or substance one or more of
whose property values are sufficiently homogeneous and well established
to be used for the calibration of an apparatus. the assessment of a measurement
method, or for assigning values to materials (see ISO Guide 30).
3.3 reference method: Thoroughly investigated test method, clearly
and exactly describing the necessary conditions and procedures, for the
evaluation of a specific biological endpoint. that has been shown to have
accuracy and precision commensurate with its intended use and that can?
therefore, be used to characterize a RM (see ISO Guide 30).
3.4 standard reference material (SRM): A trade mark protected
certification supplied by the National Institutes for Standards and l Technology,
Gaithersburg, MD, USA.
4 Reference materials are test
method specific
Reference materials or certified reference materials may be used in biological
tests as control materials. As control materials, when tested by the biological
test procedure described, the material demonstrates the suitability of
the procedure to yield a reproducible' predictable response, either positive
or negative. Use of a reference material as a positive or negative control
would insure the comparability of the response between laboratories. What
is inherent in this discussion is that any material used in this way must
be evaluated with each biological test procedure for which the use of the
material is desired. It is not sufficient to qualify a material for one
type of reference test method or response, e.g. sensitization, and declare
it a reference material for another, e.g. cytotoxicity, without additional
qualification testing.
5 Characteristics of reference materials
5.1 One or more property values
Working Group 12, during the development of this Technical Report,
emphasized the statements in clause 4. RMs or CRMs used to determine the
biological response in this way must be evaluated with each biological
test procedure for which the use of the material is desired. It is not
sufficient to qualify a material for one type of reference test method
or response. e.g. sensitization, and declare it a reference material for
another. e.g. cytotoxicity, without additional qualification testing.
5.2 Homogeneous
The homogeneity of a material is its condition of being of uniform structure
or composition with respect to the biological endpoint under study. The
RM is said to be homogeneous if the biological response to a specific test
is found to lie within the specified uncertainty limits, irrespective of
the site in the batch or lot material from where the test sample is taken.
5.3 Stability of property
This characteristic of a material is its ability, when stored under
specified conditions, to maintain the stated biological response, within
specified limits, for a specific period of time (see ISO Guide 30).
5.4 Stability of the source of the material
Working Group 12, during the discussion of this Technical Report, became
concerned about the future availability of reference materials for determination
of biological response The Working Group discussed the desirability of
obtaining a commitment of not less than 5 years from suppliers of the RMs
or CRMs. A second, but less desirable, option discussed was the publication
of an "open formulation" for the material, i.e. publication
of the sot source materials and details of the processing needed
to insure uniform batches of RM.
5.5 Number of points on the standard curve
Working Group 12 noted that the reference materials currently described
in Annex A of ISO 10993-1 12 are currently only available in single strength
levels. Good laboratory practice suggests that these materials should be
supplied in a second potency level for the proper development of a standard
curve. Experimenters should strive to insure that the highest point on
the standard curve should be at or near the upper end of the expected biological
response.
5.6 Certification of reference materials
Certification of a reference material is a procedure that establishes
the value of the biological response of tile material under the test
conditions specified, ensuring a traceability of the response, that
leads to the issuance of a certificate by the certified reference material
producer. Working Group 12, during the discussion of this Technical Report,
expressed the desirability, but not the requirement, that tile biological
response of the material be established through an international interlaboratory
test.
6 Use of reference materials as experimental
controls
6.1 Material screening versus medical device biocompatibility
The use of tile reference materials described in ISO 10993-12 and elsewhere
in this document are limited to biological screening testing of the materials
intended for use in the manufacture of medical devices. However, while
not intended for the purpose, they are often used in the performance assessment
of the finished device. The vertical standard for the device, when available,
must address the biological testing of the product in the performance environment
of the device. Biological testing described III the vertical standard takes
precedent over testing performed to screen the materials for suitability.
6.2 Misuse of CRMs
The attention of the users of this Technical Report is directed to the
discussion of "proper use" and "misuse" of CRMs in
the introduction to ISO Guide 33. This discussion points out areas of both
potential under and over utilization of RMs and CRMs. Users of this Technical
Report should also note that the use of classical calibration materials
to evaluate the biological response of materials under investigation within
a single laboratory is often sufficient.