ISO 19227 Implants for Surgery--Cleanliness of Orthopedic Implants--General Requirements is a long-awaited guidance document that was finalized and published early 2018. This guidance document is intended to assist orthopedic medical device manufacturers address the cleaning of their devices. One of the requirements of the good laboratory practices (GLPs) mandated by FDA is that medical devices be free from manufacturing residuals. Determination of what is needed to fulfill this requirement has largely been up to manufacturers and has been a topic hotly debated across the industry.
Absent of specific guidance on setting acceptance criteria, and what classes of residuals to look for in a cleaning validation, individual manufacturers (and to a limited extent testing laboratories) have defined a set of tests and acceptance criteria to screen for potentially concerning residuals, which are highly variable from company to company.
The tests to be included, and their acceptance criteria, are commonly tied to safety of the device with a risk-based approach using the following four steps:
- Risk analysis of the manufacturing process to identify most concerning potential residuals.
- Selection of analytical tests that are capable of detecting targeted residuals.
- Selection of a sampling strategy that results in a statistically meaningful set of measurements.
- Development of acceptance criteria related to a demonstration or assessment of patient safety, relying on history of device use, toxicological risk assessment, or biocompatibility tests executed in parallel with the cleaning validation.
Determining how clean is clean enough has consistently been the key challenge in the cleaning validation process. The preferred method for setting acceptance criteria is by relating analytical results measuring cleanliness to those tests that provide an indication of device safety (like cytotoxicity testing). The motivation for this practice is understandable, as protecting patient safety is a goal shared universally. However, the difficulty with using a simple biocompatibility test to set acceptance criteria is that there are occasions where a device may be safe, but not clean, and occasions when a device may be clean, but not safe.
It is tempting to equate cleanliness with safety, but the two are not the same. Cytotoxicity testing has commonly been used as an indicator that device cleanliness is acceptable, and because cytotoxicity testing is an extremely sensitive test, this does provide a good general indication of cleanliness. However, it should not be assumed that passing cytotoxicity equals safety. There is, after all, a whole suite of biocompatibility tests addressing biological risks outside of cytotoxicity that are necessary to support safety.
If passing a cleaning validation does not provide an indication of patient safety, and the analytical methods used for cleaning validations are not appropriate or sensitive enough for toxicological risk assessment, perhaps the previous ways of setting acceptance criteria for cleanliness are misguided.
Understanding that demonstrating device safety is a task separate from validating cleanliness, ISO 19227 prescribes a set of tests for demonstrating cleanliness along with acceptance criteria broadly applicable to orthopedic implants. These tests and acceptance criteria (where specified) are outlined below:
- Visual inspection – acceptable when meeting specifications of the manufacturer
- Bioburden – acceptable when the level of specified sterility assurance is met
- Bacterial endotoxin – acceptable when less than 20.0 endotoxin units
- Total organic carbon (TOC) – acceptable when less than 500 µg/device
- Total hydrocarbon content (THC) – acceptable when less than 500 µg/device
- Metals – acceptable when less than limits established by ICH Q3D or 10993-17
- Cytotoxicity – acceptable when passing per 10993-5
The most significant takeaways from ISO 19227 are the suggested acceptance criteria for common analytical tests that have, up to now, been difficult to interpret as they do not have the specificity and sensitivity to adequately indicate safety. Separating the ideas of safety from cleanliness helps to keep the determination of safety within the realm of biocompatibility per ISO 10993 and allows manufacturers to set common sense acceptance criteria in situations where criteria based on biocompatibility do not make sense.
Ultimately, for cleanliness of final finished devices, the points of greatest value of a cleaning validation per ISO 19227 are to demonstrate control over processing, know the level of cleanliness at the time biocompatibility was established, and then track cleanliness looking for unexpected changes using routine monitoring to know when biocompatibility might be in question.