29 Apr 2025
Following submission of a package to a regulatory body, it is typical to receive feedback regarding some portion of the submission, including biocompatibility. Recently, Labcorp provided guidance to a client who needed help responding to a submission finding that we had previously navigated. We share both the finding and response below. Sharing common or important findings, and the responses to them, can help the community and regulators better understand the evaluation methods and ensure that future submissions are as successful as possible.
Deficiency finding
In the rabbit pyrogen test report, please justify why only a polar solvent (NaCl 0.9%) was used for the extraction of the test article as per section 10.3.5 of ISO 10993-12:2021.
Response
ISO 10993-12 is the international standard for the general sample preparation of medical devices for biocompatibility testing. Its guidance and requirements are meant to be horizontally (broad) reaching across the other ISO 10993 standards. There are elements of individual methods contained within other ISO 10993 standards that provide specificity to sample preparation requirements beyond what is contained in part 12. Some examples include ISO 10993-6 for how to approach the implantation evaluation of absorbable materials and ISO 10993-11 regarding material mediated pyrogenicity in rabbits.
Unlike most other extraction-based methods where both polar and non-polar vehicles are required for testing, saline (NaCl) is the only validated extraction vehicle for the material mediated pyrogenicity in rabbits. ISO 10993-11 Annex G on material-mediated pyrogens states that for the rabbit pyrogen test to follow either the United States, European or Japanese Pharmacopoeias. At Labcorp’s North American sites, we follow USP <151> as the method to support the pyrogenicity endpoint. The rabbit pyrogen test has only been validated for and subsequently included in the methods contained within USP and other global pharmacopeia addressing extraction and intravenous dosing of a saline extract. While the majority of medical devices requiring biocompatibility evaluations are constructed of materials which include both polar and non-polar compounds, the rabbit pyrogen method is not compatible with non-polar (e.g., CSO or SSO) vehicles. Vegetable oil extracts have not been validated for use in the method and cannot be dosed intravenously for rapid systemic exposure.
Accordingly, any material mediated pyrogen testing in rabbits using only saline extracts of the test article is considered to conform to ISO 10993-11, ISO 10993-12 and pharmacopeia standards.
Note 1: The rabbit pyrogen test has been removed from the European Pharmacopoeia
Note 2: Alternative and/or supporting methods to the rabbit pyrogen test (e.g., limulus amebocyte lysate [LAL] and monocyte activation test [MAT]) are accepted in certain global regulatory regions
Note 3: Pyrogenic substances include both bacterial endotoxins and substances, such as nickel salts, certain phenols and prostaglandins