However, there are frequently end points that cannot be satisfied without studies on animals (commonly, those end points relating to local toxicity effects). These studies are usually required as part of the Toxicological Risk Assessment, in order to address any concerns raised by the Chemical Analysis.
MET have the capabilities to cover all ISO 10993 and ISO 18562 in vitro testing requirements.
For direct contacting devices, the authorities are expecting to see Chemical Analysis. Chemical Analysis is designed to simulate potential extractable and leachable (E&L) conditions found in both the body and in more extreme environments, to show which materials can be released by the devices. The E&L studies are designed bespoke for teach device, in order to detect all residuals left behind from manufacturing, cleaning and sterilisation, as well as other unexpected impurities that could harm the patient.
The main difference between the ISO 10993 and ISO 18562 standards is that direct contact medical devices must be scanned for any expected and unexpected volatile, semi-volatile, non-volatile and non-organic materials while, for breathing devices, the ISO 18562 standards are focusing mostly on the volatile compounds released from the gas pathway and the particulates that are being released at the beginning of the medical device use. Only in situations where there is a risk of condensation occurring from gas pathway devices, ISO 18562-4 applies (this describes the methodologies of assessing semi-volatiles and metals from the components exposed to the condensation, as well as cytotoxic effects and sensitizers).
Extractable and leachable studies simulate the real life and worst-case scenarios of clinical use by using a range of organic solvents of different polarities and temperatures to achieve simulated, exaggerated and aggressive extractions. Simulated extractions are mainly used to release the leachable substances from the product under real clinical use conditions, while extractable studies use aggressive and exaggerated extractions.
For implants where there is a potential of degradation of the medical devices that are introduced into the human body and are intended to remain in place after a procedure, degradation studies are also performed in addition to the extractable and leachable studies. The degradation studies are also designed based on the material of construction of the devices (e.g. polymeric, ceramic, metallic. etc.). Degradation studies are performed under real life conditions and this type of degradation is designed to prove what reactions and processes the device will undergo in real life. This 'real life' degradation is performed in parallel with accelerated degradation, which has the goal of highlighting the worst-case scenario of the degradation products. The first analysis in the accelerated degradation should be gravimetric, in order to evaluate the mass of the degradation product. The gravimetric analysis must be performed at defined periods of time, in order to see if the product is degrading further or if it has reached an equilibrium.
Once the product mass is not changing under the accelerated degradation conditions, the real life degradation extractions may be stopped (as no further changes are expected). The degradation studies for polymeric implants must be performed in oxidative and hydrolytic extraction solutions at body temperature (37°C), as well as at a higher temperature (70°C) as per ISO 10993-13: Biological Evaluation of medical devices - Part 13: Identification and quantification of degradation products from polymeric medical devices.