The examination of extractables and leachables from medical products and devices is growing in importance. This has arisen from ISO 10993 Standard Biological Evaluation of Medical Devices – Part 18 Chemical Characterisation of Materials and also from various guidelines produced by the FDA1,2. These guidelines are concerned with various drug delivery devices, such as meter dose inhalers (MDI) and dry powder inhalers (DPI), and cover a wide range of aspects including extractables and leachables from rubber and plastic components in these devices.
In recent years the PQRIa Leachables and Extractables Working Group has submitted best practice guidelines3 for Extractables and Leachables Testing to the PQRI Drug Product Technical Committee and the U.S. Food and Drug Administration. These guidelines have made an important contribution to Extractables and Leachables Testing of Orally Inhaled and Nasal Drug Products (OINDP).
This paper discusses the importance of Extractables and Leachables testing to Medical and Drug Delivery Devices, firstly considering the testing of inhalation drug delivery devices (OINDP) and then medical devices.
2. EXTRACTABLES AND LEACHABLES TESTING OF OINDP
The assessment of Extractables and Leachables in OINDP, as recommended by the PQRI, has three main parts:
1. Extractables
2. Leachables
3. Routine Extraction Testing
Each of these stages is guided by various safety thresholds.
a Product Quality Research Institute
2.1. Safety Thresholds
The PQRI Leachables and Extractables Working Group have recommended two safety evaluation thresholds which have been justified from a toxicological or safety perspective:
· A Safety Concern Threshold (SCT) of 1.5 µg per day, which is defined as the threshold below which an individual leachable would have a dose so low as to present negligible safety concerns from carcinogenic and non-carcinogenic toxic effects;
· A Qualification Threshold (QT) of 5 µg per day, which 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
These thresholds represent absolute exposures, expressed as total daily intake per day. They need to be converted into relative amounts expressed as an amount of a particular leachable per drug product or extractable per mass of component. This threshold is known as the Analytical Evaluation Threshold (AET). The AET is determined by consideration of the SCT and the specific drug product configuration (e.g. total number of doses in the Drug Product, number of doses per day, mass of individual components).
For an extractables from a device component the AET (µg/g) can be determined using Equation 1:
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Richard Walton –
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