医療用具の生物試験(ISO 10993シリーズ中の各試験）で用いられる
標準材料（陰性対照、陽性対照、その他）に必要な要素を示す文書である。
1998.3.15付けで投票した。
Guidance on the selection and qualification of reference materials for biological tests
1 Scope
This information should be considered as a supplement to ISO 10993-12, Sample preparation and reference materials. ISO 10993 Part 12 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 ISO 10993. In clause 4, there is a discussion of the use of reference materials as experimental controls. Annex A provides specific information regarding the sources of materials which were available at the time Part 12 was published.
2 References
The following ISO Guides provide material which will enable the reader to place into context the discussion in this Guidance.
ISO/IEC Directives - Part 2:1992 Methodology, Annex A - Mention of 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 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 (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 ('SO Guide 30)
3.3 Reference method: A 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 an RM. (see ISO Guide 30)
3.3 Standard reference material (SRM): A trade mark protected certification supplied by the National Institutes for Standards and 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 guidance, emphasized the statements in Clause 4 of this Guidance. 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 Guidance, 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 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 10993-12 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 the 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 Guidance, expressed the desirability, but not the requirement, that the biological response of the material be established through an international interlaboratory test.
6. Use of reference materials as experimental controls
6.1 Material screening vs. medical device biocompatability: The use of the reference materials described in ISO 10993-12 and elsewhere in this document is limited to biological screening testing of the materials intended for use in the manufacture of medical devices. These materials are not intended for the performance assessment of the finished device. The vertical standard for the device must address the biological testing of the product in the performance environment of the device. Biological testing described in 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 Guidance 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. User of this Guidance should also note that the use of classical calibration materials to evaluate the biological response of materials under investigation within a single laboratory are often sufficient.