<1664> ASSESSMENT OF DRUG PRODUCT LEACHABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS
LEACHABLES CHARACTERIZATION
The primary goal of any leachables study is leachables characterization; i.e., the discovery, identification, and quantitation of leachables present in a particular drug product. Analytical methods for leachables characterization are developed based on the nature of the drug product matrix, the identities and possible accumulation levels of potential leachables, and the required sensitivity based on an adopted leachables evaluation threshold and the capabilities of the analytical methods employed.
Unlike a typical drug product impurity method where target analytes are related to the drug substance, leachables have a wide chemical diversity and can come from various sources in the packaging/delivery system. Leachables also have a wide range of possible accumulation levels in a drug product. Taken in total, these factors present a significant challenge for trace analysis, especially in the case of organic leachables identification. Under certain circumstances, this challenge can be mitigated by performing the process of potential leachables identification outside of the leachables assessment, for example via extractables assessment in simulated extractables studies (see Simulation Studies).
Before describing the processes, analytical techniques, and methods involved in leachables characterization, it is appropriate to state that the ultimate objective of thorough leachables characterization as defined above cannot be realized in all cases, even when state-of-the-art analytical chemistry is practiced with best available skill and diligence. It is a reality that there is no analytical technique or combination of analytical techniques that is capable of the discovery, identification, and quantitation of any and all organic and inorganic leachables.
For example, authentic reference compounds for organic leachables may not be available in all cases for confirmation of identifications or for quantitative instrument calibration. Given these circumstances, the practical objective of leachables characterization must therefore be the discovery, identification, and quantitation of individual leachables present in a drug product above a predetermined level, or “threshold”, to a reasonable degree of scientific certainty and exercised with appropriate due diligence.
Analytical Thresholds
The starting action in leachables method development is to establish the level at which the method must perform at to accomplish the appropriate leachables characterization functions. This level is known as the analytical threshold. Minimally, an appropriate method must function at all levels greater than or equal to the analytical threshold. As discussed previously, such an analytical threshold can be based on various criteria, including safety considerations. An example of a safety-based threshold is the SCT as established for OINDP.
In order to define the SCT in terms that facilitate laboratory analysis, it must be converted from units of exposure (i.e., µg/day) to units of concentration (e.g., µg/mL, µg/g, µg/canister, µg/vial, etc.). This is accomplished by considering the dose parameters for a given drug product per the drug product's label claim. The resulting analytically useful threshold is termed the Analytical Evaluation Threshold (AET) (2). Previously characterized target leachables will have known safety profiles and previously established leachables thresholds. In any event, thresholds can be used for the basis for analytical method development unless other product considerations, such as compatibility, dictate a lower level is necessary.
A general formula for converting the SCT (0.15 µg/day) to an AET is as follows:
Further, for liquid dosage forms:
Further, for solid dosage forms:
This AET establishes the level at which unknown leachables should be identified and quantified in a particular drug product, and can therefore be used as a basis for analytical method development.
Analytical Method Requirements
Analytical method requirements for leachables characterization are based on the determined AET (or an alternative valid threshold concept), and information on potential leachables obtained from extractables assessments of packaging components and materials, including information from component/material suppliers. Since leachables are typically a subset of extractables or chemically linked to extractables, it may be the case that analytical methods used for leachables characterization can be based on those used for extractables characterization (see 1663).
Preparing the Drug Product for Analysis—Sample Preparation
- Dosage forms with nonaqueous drug product vehicles (e.g., metered dose inhalers with organic solvent propellants) require special sample preparation procedures, which are discussed in 1664.1.
Analytical techniques applied to leachables characterization are the same as those applied to extractables characterization, which are summarized and discussed in 1663. Scouting analyses in general are not applied to leachables characterization, as the drug formulation may interfere with the scouting methods (see 1663). The most useful analytical techniques for discovery, identification (either by qualitative or structural analysis), and quantitation of organic leachables are those that combine GC and HPLC with mass spectrometry [i.e., GC/MS and HPLC (or LC)/MS]. Headspace sampling can also be interfaced with GC/MS to address volatile compounds.
Structural analysis of leachables should be accomplished with a systematic process identical to that described in 1663 for extractables, and to a level of confidence sufficient for safety assessment. A discussion of the principles of both gas and liquid chromatography is available in Chromatography 621. A discussion of the principles of mass spectrometry (including both GC/MS and LC/MS) is available in Mass Spectrometry 736. Although chromatographic-based hybrid analytical techniques are most commonly applied to leachables characterization, other analytical techniques with compound-specific detection capability (e.g., nuclear magnetic resonance spectroscopy) can be employed.