S. Krylov. On Toxicological Testing of Medical Devices for Pyrogenicity
Pyrogens
Pyrogens are substances capable of causing fever.
From a chemical point of view, pyrogens are lipopolysaccharides, that is, substances of a non-protein nature that are adsorbed on a protein carrier. There are:
- endogenous pyrogens (cell and tissue products)
- exogenous pyrogens (of bacterial origin)
In the manufacture of medicines, it is exogenous pyrogens that matter. Their sources are aerobic bacteria, which are carriers of endotoxin, as well as fungi and viruses.
It is the presence of endotoxin that determines whether an object is pyrogenic, both in the presence of the microorganisms themselves and of their fragments.
- Pyrogenicity: the property of a chemical substance or other agent to cause a febrile response
- Febrile response: a temperature above the normal range resulting from an elevation of the body temperature set point
Based on the origin of the pyrogen, the febrile response can be divided into three groups:
- material-mediated pyrogenicity, caused by chemical agents
- endotoxin-mediated pyrogenicity
- pyrogenicity mediated by microbial components other than endotoxin.
Apyrogenicity is the absence of a pyrogenic reaction in a medical device.
There are three methods for testing pyrogenicity:
- Bacterial endotoxin test (BET)
- Human cell-based pyrogen test (HCPT)
- Rabbit pyrogen test
The in vivo rabbit pyrogen test is the only one of the three methods that measures the febrile response in a living organism as its endpoint, in accordance with the definition of a pyrogen.
Pyrogens are heat-stable substances. They are destroyed only by heating in dry-air sterilizers at a temperature of 250°C for 30 minutes.
- Under steam pressure (autoclaving at 120°C), pyrogens in solutions are destroyed only after 5 hours.
- Consequently, it is practically impossible to rid water and liquid implantable medical devices of pyrogenic substances by thermal sterilization.
Thus, every medical device is sterile after proper sterilization, but not every sterile medical device is apyrogenic.
According to the pharmacopoeial method (State Pharmacopoeia XIV), the pyrogenicity of medical devices is determined by a biological method:
- based on the change in a rabbit's body temperature after administration of a test solution obtained by extracting the device under test (prepared in a 0.9% sodium chloride solution).
- The extract is injected into the ear vein of three rabbits at a dose of 10 ml per 1 kg of the rabbit's weight.
- Body temperature is measured twice before the test and then every 30 minutes for 3 hours after the intravenous injection.
A medical device is considered apyrogenic if:
- the sum of the individual maximum temperature rises for the three rabbits does not exceed 1.2 °C
- and the individual temperature rise in none of the three rabbits exceeds 0.5 °C.
Sterility and apyrogenicity are different concepts, and one cannot be substituted for the other.
The following medical devices are subject to pyrogenicity testing:
- those for which apyrogenicity requirements are set by regulatory documents
- or by the manufacturer (on the labeling, in the technical documentation, in the operating documentation).
Regulatory documents
Eurasian Economic Union:
- Clause 6.23 of Recommendation of the Board of the EEC of 8.10.2019 No. 29 "On Methodological Recommendations on the Content and Structure of the Documents of the Registration Dossier of a Medical Device" sets the requirement to describe the pyrogenicity properties of a medical device in the registration dossier.
- In accordance with Table 2, clause 27 of Recommendations of the Board of the EEC of 21.05.2019 No. 14 "On Methodological Recommendations for Conducting the Expert Evaluation of the Safety, Quality and Efficacy of Medical Devices", for the purposes of their registration within the EAEU the recommendations on the structure of the clinical evidence and performance report for a medical device require the classification features of the device (namely, pyrogenic or apyrogenic) to be stated.
- The requirement to conduct pyrogenicity testing was set out in clause 16 of Decision No. 38 in its previous version of 16.05.2016 for medical devices in contact with human blood and its components, implantable devices, and devices intended for injection. However, in the current version of 17.02.2022 this requirement was removed (the version took effect on 14.09.2022).
Russian Federation:
- Requirements for pyrogenicity testing are absent from Order of 30.08.2021 No. 885n "On Approval of the Procedure for Conformity Assessment of Medical Devices in the Form of Technical Testing, Toxicological Studies and Clinical Trials for the Purposes of State Registration of Medical Devices".
Standards:
- GOST R 52770-2016 Medical devices. Safety requirements. Methods of sanitary-chemical and toxicological testing, clause 5.5.2 contains a list of medical devices subject to pyrogenicity testing
- GOST ISO 10991-11-2021 Medical devices. Biological evaluation of medical devices. Part 11. Tests for systemic toxicity, Annex G Material-mediated pyrogenicity
- GOST R ISO 15223-1-2020 Medical devices. Symbols to be used with medical device labels, labelling and information to be supplied. Part 1. General requirements, contains symbol 5.6.3 Non-pyrogenic
International standards:
ISO/TR 21582:2021 Pyrogenicity. A draft standard, GOST ISO/TR 21582-2021 Biological evaluation of medical devices. Pyrogenicity. Principles and methods for pyrogenicity testing of medical devices, has now been published.
The draft standard includes:
- a list of medical devices subject to pyrogenicity testing
- methods
- equipment
International standards:
ISO/TR 21582:2021 Pyrogenicity.
Draft standard:
A draft standard, GOST ISO/TR 21582-2021 Biological evaluation of medical devices. Pyrogenicity. Principles and methods for pyrogenicity testing of medical devices, is currently being developed.
The draft standard includes:
- a list of medical devices subject to pyrogenicity testing
- methods
- equipment
Author of the article: Sergey Krylov
