Extractables are compounds forcibly extracted from individual device components using a range of solvents combined with a number of extraction techniques. The compounds observed are potential leachables (generally at much higher levels than would be observed in a leachable study) and the information gained is used to create a “library” for use in the leachable study.
“Controlling” the extractables will therefore impact strongly on the levels and types of leachables observed.
The source of extractable compounds can usually be traced to the raw materials used in the device component manufacture. Experience of handling/analyzing raw materials is a significant advantage in extractable studies.
The planning of an extractable study has to consider the leachable study and fundamentally the usage of the device.
As such before starting an extractable study, the following needs to be considered:
- What is the analytical sensitivity required?
- What scientific instrumentation should be used?
- How do we prepare the extract? (Sample size? Extract volume?)
- Should all the extractables observed be fully identified and quantified?
We follow the PQRI guideline to evaluate extractables and leachables, based on 3 concepts:
- SCT – Safety Concern Threshold (0.15 µg/patient/day). The SCT is defined as the threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and non-carcinogenic toxic effects.
- QT – Qualification Threshold (5 µg/patient/day). The QT is defined as the threshold below which a given leachable is not considered for safety qualification (toxicological assessments) unless the leachable presents structure activity relationship (SAR) concerns.
- AET – Analytical Evaluation Threshold. The AET is derived from the SCT based upon the design of the drug product and the dose regime. The AET is defined as the threshold at or above which a chemist should begin to identify a particular leachable and/or extractable and report it for potential toxicological assessment.
With reference to the PQRI guidelines and our long experience in such work, our recommendation for an extractable study would include:
- Vigorous extraction, multiple solvents, varying polarity
- Multiple extraction techniques
- Multiple analytical techniques
- Extraction methods should be optimised when considering the components usage
- As the AET determines the sensitivity requirements, quantitative analysis needs to carefully considered
As devices and their components can cover a very broad range of applications we would strongly recommend discussing your specific requirements, please contact us to enable an appropriate strategy to be devised and implemented.