<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). 

Any analytical method for leachables that is used for drug product stability studies in support of product registration, establishing leachables–extractables correlations for high-risk dosage forms, or the development of leachables specifications and acceptance criteria must be subject to complete validation using industry-accepted validation practices.

Preparing the Drug Product for Analysis—Sample Preparation

Sample preparation for leachables characterization is a function of the chemical nature of the potential leachables, the chemical nature of the drug product sample matrix, and the analytical technique(s) to be applied. The drug product matrix can present a significant challenge for organic leachables characterization. 

Drug product matrices contain the active pharmaceutical ingredient and excipients, which are typically present at high levels relative to leachables (except in certain high potency drug products). Analytical methods for organic leachables usually incorporate sample preparation procedures to separate leachables from the drug product matrix and concentrate them for analysis. The exact details of sample preparation procedures are unique to the individual drug product and while it is impossible to anticipate every scenario, the following general statements can be made:

• Aqueous dosage form (e.g., inhalation solutions, small and large volume parenterals, ophthalmic solutions, etc.) leachables can be recovered using liquid-liquid extraction with water immiscible organic solvents, such as dichloromethane, hexane or petroleum ether, etc. The pH of the aqueous sample can be manipulated (i.e., raised or lowered) in order to enhance extraction of weakly acidic or basic leachables, or reduce extraction problems caused by the relatively high concentration of active pharmaceutical ingredient and excipients. The resulting organic extract can be dried if required (e.g., with magnesium sulfate drying agent) and concentrated if required by techniques that remove the solvent, such as evaporation with a gentle stream of dry nitrogen, rotary evaporation, or a Kuderna-Danish concentrator, etc. Concentrated organic extracts can be analyzed directly by GC-based methods; however, for HPLC-based methods using aqueous mobile phases the organic extract can be reduced to dryness (or near dryness) and the resulting residue of leachables taken up in a water miscible solvent (e.g., acetonitrile, methanol, etc.). Volatile leachables (e.g., solvents) can be analyzed directly from aqueous drug product samples with GC combined with headspace sampling. Note that recoveries of certain leachables can be affected by extraction and extract concentration procedures.

• Solid dosage form (e.g., solid orals, inhalation powders, lyophilized powders, etc.) leachables can be recovered (for example) by dissolving the drug product with an aqueous solution and applying liquid-liquid extraction and extract concentration, as above. Headspace sampling and GC analysis of volatile leachables can be accomplished on the aqueous samples or, in some cases, directly on the solid dosage form. It is also possible to dissolve the drug product sample in another appropriate and analytically expedient medium (e.g., an organic solvent) for direct analysis by GC; however it is possible that matrix effects and interferences from the active ingredients and excipients could result.

• Oral liquid dosage form leachables can be recovered by diluting the drug product sample in aqueous solution and applying liquid-liquid extraction and extract concentration, as above. Headspace sampling and GC analysis of volatile leachables can be accomplished on the aqueous samples or, in some cases, directly on the oral liquid dosage form. It is also possible to dissolve the drug product sample in another appropriate and analytically expedient medium (e.g., an organic solvent) for direct analysis by GC; however, it is possible that matrix effects and interferences from the active ingredients and excipients could result.

• Cream and ointment dosage form leachables can be recovered by dissolving the drug product sample in an aqueous solution, filtering, and applying liquid-liquid extraction and extract concentration, as above. Headspace sampling and GC analysis of volatile leachables can be accomplished on the aqueous samples. It is also possible to dissolve the drug product sample in another appropriate and analytically expedient medium (e.g., an organic solvent) for direct analysis by GC; however, it is possible that matrix effects and interferences from the active ingredients and excipients could result.

• 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.

Development of sample preparation methods for leachables characterization can be accomplished through the use of appropriate test samples, such as accelerated drug product samples that have been aged under accelerated conditions (e.g., 40/75%RH on 3-month storage), drug product or placebo samples spiked with known potential leachables, and/or a simulated drug product matrix spiked with known potential leachables. Recoveries of spiked potential leachables should be assessed and optimized during method development. Internal standards can be included to improve quantitative accuracy and precision.

Note that the sample preparation for leachables characterization must create a test sample in a form amenable to the analytical technique to be applied, and appropriately concentrated so that individual leachables can be characterized relative to the selected threshold.

Analytical Techniques

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. 

Other detection systems for both GC and HPLC that are not compound specific (e.g., FID, UV, etc.) are potentially useful for leachables discovery and quantitation, but not in general for identification. The combination of GC and HPLC techniques has the sensitivity and specificity required to characterize the diversity of chemical compounds found in many leachables samples. Analytical methods for leachables should be capable of characterizing target as well as new (or unspecified) leachables (e.g., scanning GC/MS or LC/MS); however, when additional sensitivity is required due to the use of analytically challenging thresholds, dedicated target compound methods (e.g., GC/MS with selected ion monitoring) can be used. It is also possible, with appropriate validation, to use methods based on techniques that are not compound specific (i.e., GC/FID, HPLC/UV, etc.).

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.