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U.S. Department of Health and Human Services

Recognized Consensus Standards: Medical Devices

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Part B: Supplementary Information Sheet (SIS)
FR Recognition List Number 044 Date of Entry 07/26/2016 
FR Recognition Number 2-243
ISO  /TR 10993-33 First Edition 2015-03-01
Biological evaluation of medical devices - Part 33: Guidance on tests to evaluate genotoxicity - Supplement to ISO 10993-3
There are differences between the views of regulatory bodies on the subject of genotoxicity testing. The purpose of this Technical Report is to provide background information to facilitate the selection of tests and guidance on the performance of tests.
Extent of Recognition
Partial recognition. The following part(s) of the standard is (are) not recognized:
Clause 6.3.2, Sentence, "A DRF study may be conducted prior to the main study if cytotoxicity of the test sample is expected to be significant, e.g. cytotoxicity or growth inhibition greater than 50%,"
Clause 6.5.3, Paragraph 2, First bullet, "reduction greater than 50% with dose-dependency in the mean number of revertants per plate as compared to the mean corresponding solvent control."
Clause 7.3.2., Paragraph 4, Phrase, "degree of confluency"
Clause, Paragraph 2, Second Sentence, "Low spontaneous mutant frequencies, i.e. 20 to 34 mutants per 106 surviving cells, are considered acceptable if small colony recovery is demonstrated, see Reference"
Clause, Paragraph 3, First bullet "4 h: >=100 mutants over the negative control".
Annex A
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 6.3.2, 6.5.3, and 7.3.2 "degree of confluency" contains a test method that conflicts with published literature. See reference below.
Annex A contains a test method that is in conflict with published literature. See references below.
Clause contains a test method that is not scientifically acceptable. See OECD guideline 490.
Public Law, CFR Citation(s) and Procode(s)*
21 CFR 58 Good Laboratory Practice for Nonclinical Laboratory Studies
Relevant FDA Guidance and/or Supportive Publications*
Mortelmans, K. and Zeiger, E. (2000). The Ames Salmonella/microsome mutagenicity assay. Mutation Research, Vol 455 (1 ), pp 29-60.

Przygoda, R.T., Safety Assessment and Global Regulatory Requirements for Genetic Toxicity Evaluations of Medical Devices. Environmental and Molecular Mutagenesis, Vol 58, pp 375-379.

Peng et al. (2018). "Evaluation of Sample Preparation Methods in the ISO 10993-12 Standard: problems Associated with Exhaustive Extraction of Polymeric materials for Biological Evaluation," SOT poster.

ISO 10993-12:2012 Biological evaluation of medical devices - Part 12: Sample preparation and reference materials.

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.

Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices - Guidance for Industry and Food and Drug Administration Staff, issued September 2018.
FDA Technical Contacts
 Aprajita Garg
 Pushya Potnis
 Chandramallika (Molly) Ghosh
Standards Development Organization
ISO International Organization for Standardization https://www.iso.org/
FDA Specialty Task Group (STG)
*These are provided as examples and others may be applicable.