| Part B: Supplementary Information Sheet (SIS) |
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FR Recognition List Number
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059
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Date of Entry 12/19/2022
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FR Recognition Number
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2-298
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| Standard | |
ISO 10993-18 Second edition 2020-01 Amendment 1 2022-05
Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process [Including Amendment 1 (2022)]. |
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Scope/AbstractThis document specifies a framework for the identification, and if necessary, quantification of constituents of a medical device, allowing the identification of biological hazards and the estimation and control of biological risks from material constituents, using a generally stepwise approach to the chemical characterization which can include one or more of the following:
- the identification of its materials of construction (medical device configuration);
- the characterization of the materials of construction via the identification and quantification of their chemical constituents (material composition);
- the characterization of the medical device for chemical substances that were introduced during manufacturing (e.g. mould release agents, process contaminants, sterilization residues);
- the estimation (using laboratory extraction conditions) of the potential of the medical device, or its materials of construction, to release chemical substances under clinical use conditions (extractables);
- the measurement of chemical substances released from a medical device under its clinical conditions of use (leachables).
This document can also be used for chemical characterization (e.g. the identification and/or quantification) of degradation products. Information on other aspects of degradation assessment are covered in ISO 10993-9, ISO 10993-13, ISO 10993-14 and ISO 10993-15.
The ISO 10993 series is applicable when the material or medical device has direct or indirect body contact (see ISO 10993-1 for categorization by nature of body contact).
This document is intended for suppliers of materials and manufacturers of medical devices, to support a biological evaluation. |
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Extent of Recognition
| Partial recognition. The following part(s) of the standard is (are) not recognized: |
Clause 5.5 second and third sentences.
Clause 7, second paragraph, phrase "to assist in any toxicological risk assessment"
Table D.3 in Clause D.5 of Annex D
Clause E3 of Annex E, 5th paragraph, 4th sentence, "For example, a UF value of 2 has been proposed[39][45] as being appropriate, in certain situations, to the screening of extracts for semi-volatile extractables via GC-FID or GC-MS, as analytical FID or MS response factors for extractables are somewhat consistent, extractable to extractable"
Clause E3 of Annex E, paragraph before the last paragraph, the last two sentences "The use of multiple analytical methods can reduce response factor variation and can be considered in the determination of the necessary UF that is then applied to all the complementary methods. See References [56] and [57]. "
Example C2 in Clause E.4 of Annex E
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Rationale for Recognition
This standard is relevant to medical devices and is recognized on its scientific and technical merit and/or because it supports existing regulatory policies.
This standard is recognized in part because:
Clause 5.5 second and third sentences are in conflict with published literature articles, see reference #1-2 listed below.
Clause 7, second paragraph, phrase "to assist in any toxicological risk assessment" is in conflict with published literature, see reference #3-5 listed below.
Table D.3 in Clause D.5 of Annex D is not supported by the cited article and in conflict with published document, see reference #6.
Clause E3 of Annex E, 5th paragraph, 4th sentence, "For example, a UF value of 2 has been proposed[39][45] as being appropriate, in certain situations, to the screening of extracts for semi-volatile extractables via GC-FID or GC-MS, as analytical FID or MS response factors for extractables are somewhat consistent, extractable to extractable" is in conflict with the publication [39] cited in the standard, see reference #10 listed below, which states "Estimated AET that encompasses 90% of the data population would require a factor of approximately 4 to establish the Final AET."
Clause E3 of Annex E, paragraph before the last paragraph, the last two sentences "The use of multiple analytical methods can reduce response factor variation and can be considered in the determination of the necessary UF that is then applied to all the complementary methods. See References [56] and [57]. " is in conflict with the published literature article, see reference #11 listed below, which states "The value of the UF depends on the analytical method and accounts for variation in the response factors (RFs) of individual analytes" and "Additional work using expanded databases is needed to characterize coverage rates for low-RF analytes that are detected only on a single analytical system. Existing work has not specifically explored this subset of analytes, which would be most vulnerable to under-reporting in a combined-UF multidetector approach."
Example C2 in Clause E.4 of Annex E is in conflict with another recognized standard, see clause 5.2 and Table 1 of ISO TS 21726 listed below. |
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Transition Period
| FDA recognition of ISO 10993-18 Second edition 2020-01 [Rec# 2-276] will be superseded by recognition of ISO 10993-18 Second edition 2020-01 Amendment 1 2022-05 [Rec# 2-298]. FDA will accept declarations of conformity, in support of premarket submissions, to [Rec# 2-276] until December 21, 2025. After this transition period, declarations of conformity to [Rec# 2-276] will not be accepted. |
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Relevant FDA Guidance and/or Supportive Publications*
1. Luis Cuadros-Rodríguez, Marta Lazúen-Muros, Cristina Ruiz-Samblás, Natalia Navas-Iglesias, Leachables from plastic materials in contact with drugs. State of the art and review of current analytical approaches, International Journal of Pharmaceutics 583 (2020),119332.
2. Moyer, J. Scull, Extractables and leachables, Book title "Specification of Drug Substances and Products: Development and Validation of Analytical Methods", Maryville, 2014, ch. 13, pp. 265-289.
3. OECD (2014) Guidance on grouping of chemicals. Series on Testing & Assessment. No. 194. JOINT MEETING OF THE CHEMICALS COMMITTEE AND THE WORKING PARTY ON CHEMICALS, PESTICIDES AND BIOTECHNOLOGY. ORGANISATION FOR ECONOMIC CO-OPERATION AND DEVELOPMENT
4. Broschard, T.H. et al. Assessing safety of extractables from materials and le.achables in pharmaceuticals and biologics - Current challenges and approaches, Regulatory Toxicology and Pharmacology, 81(2016), 201-211.
5. Escher, S.E. et al. (2019) Towards grouping concepts based on new approach methodologies in chemical hazard assessment: the read-across approach of the EU-ToxRisk project. Arch Toxicol, 93 (2019), 3643-3667.
6. Guidance for Industry: Preparation of Premarket Submissions for Food Contact Substances (Chemistry Recommendations), Issued 2007.
7. ISO 10993-12 Biological evaluation of medical devices - Part 12: Sample preparation and reference materials.
8. Guidance for Industry and Food and Drug Administration Staff: Use of International Standard ISO 10993-1, "Biological evaluation of medical devices--Part 1: Evaluation and testing within a risk management process", Issued September 2023.
9. ISO TS 21726 First edition 2019-02 Biological evaluation of medical devices - Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents.
10. Jenke D., Odufu A., Utilization of internal standard response factors to estimate the concentration of organic compounds leached from pharmaceutical packaging systems and application of such estimated concentrations to safety assessment. J. Chromatogr. Sci. 2012; 50:206-212
11. Sussman E., Oktem O., Isayeva I., Liu Ji., Wickramasekara S., Chandrasekar V., Nahan K., Shin H., Zheng J., Chemical Characterization and Non-targeted Analysis of Medical Device Extracts: A Review of Current Approaches, Gaps, and Emerging Practices. ACS Biomater. Sci. Eng. 2022, 8, 939−963
Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices - Guidance for Industry and Food and Drug Administration Staff, issued September 2018. |
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| FDA Technical Contacts
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| Standards Development Organization
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| FDA Specialty Task Group (STG)
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| *These are provided as examples and others may be applicable. |
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