ISO 10993-15:2019 pdf free download – Biological evaluation of medical devices – Part 15: Identification and quantification of degradation products from metals and alloys.
7.1.1 Test cells of borosilicate glass, of appropriate sizes, in accordance with ISO 3585, with a means of controlling the bath temperature within ±1 °C.
7.1.2 pH-meter with a sensitivity of ±0,1.
7.2 Sample preparation
The test sample shall be placed in a separate glass container. The size of the glass container should be selected so that an electrolyte volume of less than 1 ml/cm2 of sample surface shall completely cover the sample(s). The test sample shall be totally covered by the electrolyte.
Do not risk compromising long-term data through biological (e.g. bacterial, fungal) contamination. For example, the utilized containers may need to be sterile and electrolyte may need to be prepared under aseptic conditions.
The surface area and volume of electrolyte should be sufficient for the intended method of analysis (see Clause 8).
Care should be taken such that the samples do not touch the glass surface except in a minimum support line or point. If the test sample is small, the proper surface area/volume ratio might not be attainable with a single test sample. Therefore, if the test sample shall be made up of two or more pieces, the pieces shall not touch each other.
For test samples with roughened or irregular shapes and therefore difficult to determine the surface area, the user is referred to the discussion in ISO 10993-12 and ISO/TR 10993-2 2 concerning how such differences can impact the risk assessment.
7.3 Immersion test procedure
Measure the pH of the electrolyte containing the test sample at the start of the test. Then tightly close the test cell to prevent evaporation and maintain at (37 ± 1) °C for (7 ± 0,1) d. Then remove the sample and measure the pH of the residual electrolyte. Certain materials can call for the use of tissue culture (i.e. sterile filtered) grade phosphate buffered saline as the immersion electrolyte.
It can be necessary to conduct immersion tests for a longer period of time if all of the following conditions apply:
a) the alloy is used in a permanent implant
b) the alloy contains constituents that are soluble in the use environment
c) the soluble constituents are present at potentially hazardous levels within the device
d) no additional information exists to demonstrate the stability of the constituents of concern (e.g. established surface process and acceptable corrosion resistance)
For devices that meet the above criteria, the release of potentially hazardous constituents shall be quantified over time to determine what short- and long-term exposure to the alloy will present for consideration in the risk analysis. To quantify the time-dependent release rate, successive immersion testing shall be conducted on the same test sample. After each test interval, the immersion procedure should be repeated by removing the test sample from the container, sampling the electrolyte for analysis, and placing the test sample into a container with fresh electrolyte. The pH of the electrolyte should be measured at the beginning and end of each sampling interval. Sampling intervals should be sufficiently frequent such that key release characteristics can be captured (e.g. more frequent sampling at earlier time points to capture the initial bolus of release). For example, sampling intervals for nitinol implants might include at least days 1, 2, 4, 7, 14, 21, and 28 for the first month of cumulative exposure time, and at least bi-weekly thereafter. In a similar manner, time-dependent ion release has been seen from titanium test samples. A justification shall be provided for concluding the testing based on the release of degradation products approaching equilibrium, attaining a steady-state rate and/or falling below a predetermined rate of toxicological concern. The user of this document is alerted to the observation that variations in material lots and manufacturing lots can affect testing results. In addition to the analytical instrumentation, validation of the test protocol over the time frame of the testing shall also be conducted.