During the course of manufacturing, packaging, storage, distribution, and administration, dosage forms and/or their formulation constituents contact components and materials of construction of manufacturing and packaging equipment, and primary and secondary packaging components and systems. Such contact may result in interactions between the dosage form and these components and materials. One such interaction is the migration, or leaching, of substances from any of these components and materials into the dosage form. Leachables, which can include both organic and inorganic (i.e., elemental) chemical entities with wide chemical diversity, are of concern due to their potential safety risk to patients and potential compatibility risks for the drug product. In order to assess these risks and manage the potential issues posed by leachables, it is necessary to know their identities and the levels to which they will accumulate in the finished drug product over its shelf-life. These two pieces of information can be used to establish the magnitude of patient exposure (dose) and therefore the safety risk posed by an individual leachable, as well as the likelihood of any drug product compatibility issues.

Regulatory guidelines, requirements, and various best practice recommendations all state that the definitive assessment of the potential impact of contact between a packaging/delivery system and a final dosage form involves testing the final drug product for leachables. In its most essential form, this impact assessment involves performing a migration, or leachables, study whose purpose is to discover, identify, and quantitate leachables that have migrated from the contacted system, components, or materials and accumulated in the finished dosage form under the product's actual manufacturing, storage and clinical use conditions. A leachables study is a laboratory investigation into the qualitative and quantitative nature of a particular leachables profile(s) over the proposed shelf-life of a particular drug product. The purpose of a leachables study is to systematically and rationally identify and quantify (i.e., characterize) drug product leachables to the extent practicable, and within certain defined analytical threshold parameters. The results of leachables studies are used in the overall leachables assessment to understand the impact of leachables on patient safety and drug product quality and stability.

Leachables studies can be used within the context of an overall leachables assessment to:

In these ways, leachables studies and assessments can support Quality by Design (QbD) principles for the development and manufacture of pharmaceutical packaging/delivery systems and drug products.

A complete leachables assessment includes understanding the safety impact of individual leachables, safety qualification of individual leachables, and developing an understanding of the impact of individual leachables on drug product stability (i.e., compatibility) and stability. Although safety qualification is presented in general terms, the details of attaining this goal are beyond the scope of this chapter, which is limited to general scientific principles and best practices for the conduct of leachables studies and the other stated uses of the results of leachables studies within an overall leachables assessment. The reader is directed to authoritative manuscripts on this topic (2,8,9).

Note that certain packaging and combination product medical device components are (or can be) in direct contact with a patient's mouth, nasal mucosa, or other body tissue(s) during normal use of the drug product. Such packaging components include metered dose inhaler and dry powder inhaler mouthpieces, transdermal patches, etc. Patients are potentially exposed to chemical entities by direct contact from such components. Assessment of patient exposure in such direct contact scenarios is best accomplished with appropriate extractables assessments and extraction studies, and the reader is referred to 1663.

Although leachables represent a particular class of drug product impurity, current regulatory guidance for drug product impurities specifically considers leachables to be out of scope (5). Thresholds that have been specifically proposed for drug product leachables are based on either patient safety considerations or the current capabilities of analytical technology. Safety thresholds are particularly important in a leachables assessment because current analytical technology allows detection of trace organic and inorganic chemical entities at extremely low levels (i.e., ng/mL; ng/g). Identification and risk assessment (or qualification) of every individual chemical entity in a typical leachables profile at the limits of current analytical technology is neither necessary from a toxicological perspective nor feasible in a typical drug product. Safety thresholds allow for a science- and risk-based determination of acceptable levels of leachables and can be based on established toxicological information, as well as additional safety risk factors that consider, e.g., route of administration, daily exposure, and treatment duration. Because safety thresholds are derived from exposure data they are considered in terms of units of exposure, such as Total Daily Intake (TDI). Thus, any safety threshold must be converted into units of concentration (e.g., µg/mL) so that it can be applied as an analytical threshold in the laboratory. The analytical threshold is a guide as to which chemical entities in the leachables profile should be considered for chemical characterization (i.e., confirmed identification) and safety evaluation and qualification.

An example of a safety threshold concept that has been practically applied in pharmaceutical development is the Threshold of Toxicological Concern (TTC) approach (6). The TTC concept was adopted by the European Medicines Agency (EMA) to evaluate genotoxic impurities, using an excess cancer risk factor of 105 (1 in 100,000) (7). The EMA's proposed safety threshold for genotoxic impurities using the TTC approach is 1.5 µg/day TDI. Other examples of safety thresholds include the Product Quality Research Institute (PQRI) Safety Concern Threshold (SCT) and Qualification Threshold (QT), derived and proposed for individual organic leachables in Orally Inhaled Nasal Drug Products (OINDP) (2,8,9). The SCT is 0.15 µg/day TDI, and the QT is proposed at 5 µg/day TDI for an individual organic leachable. The development of the TTC approach provided a foundation, precedent, and guide for derivation of the PQRI SCT, which incorporates a 106 (1 in 1,000,000) risk factor rather than the 105 value used for the EMA threshold. This lower threshold was considered appropriate for leachables in OINDP because of considerations regarding the direct delivery of some of these dosage forms to diseased organs of a sensitive patient population, and assuming lifetime exposure. In addition, leachables are typically industrial chemicals with no direct structural relationship to any active ingredient or other formulation constituent. Below the SCT, identification and safety evaluation of leachables generally would not be required. Below the QT, leachables without structure alerts for carcinogenicity or irritation would not require compound-specific safety risk assessment. Note that neither the SCT nor the QT is a control threshold or safety-driven limit. Rather, they are leachables evaluation thresholds. The SCT in particular is designed to establish a threshold for characterization of unknown drug product leachables. Individual levels of safety concern, different from the SCT value, could be determined for known leachables and potential leachables (i.e., extractables).

For OINDP there are certain “special case” compounds and compound classes, that due to particular safety concerns (e.g., carcinogenic) were deemed to require lower thresholds based on the capabilities of specific analytical technologies and methods. These special case compounds for OINDP include: polyaromatic hydrocarbons or polynuclear aromatics (PAHs or PNAs), N-nitrosamines, and the individual chemical entity 2-mercaptobenzothiozole (see Orally Inhaled and Nasal Drug Products 1664.1).

To successfully manage leachables throughout the drug product lifecycle, it is critical to establish close and regular communication among those stakeholders throughout the development and drug product lifecycle responsible for the quality of the drug product: chemists, toxicologists, packaging engineers, manufacturing operations, procurement, etc. With respect to leachables, communication between the analytical chemist and toxicologist is critical. For example, if a leachable is found to be above an accepted limit, or a new leachable is found, a safety evaluation will need to be performed. The chemist will need to provide the toxicologist with information that will help to qualify the leachable, including the identity of the leachable, which may include compound class or more specific information, such as chemical formula and structure; and the amount and concentration of the leachable in the drug product.

Information sharing between packaging component manufacturers/suppliers and drug product developers/manufacturers is also important in order to guide packaging component and materials of construction selection, provide knowledge of potential extractables and leachables, and facilitate leachables–extractables correlations via knowledge of packaging component chemical compositions, etc. (also see 1663).

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 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.

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:

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 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.

Validation of quantitative leachables methods should be accomplished according to industry accepted practices, criteria, and standards, such as Validation of Compendial Procedures 1225 and (11). The extent of validation required depends on the goals of the leachables study in which the analytical method is being utilized. Validation parameters may include: accuracy, precision (repeatability, intermediate precision), specificity, limit-of-detection, limit-of-quantitation, linearity and range, and robustness. System suitability tests and criteria should also be developed for each leachables method. Special considerations for individual validation parameters relative to leachables methods are as follows:

Several examples of validated leachables methods from the scientific literature have been documented in the chemical literature (12–17).

Occasions may arise in which it is not analytically feasible (due to challenging thresholds, for example) to successfully discover and identify all actual leachables in a drug product leachables study. This circumstance can be managed if the activities of discovery and identification of probable leachables are accomplished in an extraction study, where samples and analyte concentrations are more easily manipulated to achieve the necessary analytical performance. In such a circumstance, the actual drug product leachables assessment is simplified to a high-sensitivity quantitation of targeted leachables that have been discovered and identified as part of this extraction study.

In order to facilitate the discovery and identification of probable leachables, the extraction study must be similar in design to a drug product leachables study. Such an extraction study seeks to simulate the circumstances experienced by the drug product but should produce a test sample that is easier to characterize than the drug product itself. For such a study to be relevant in establishing appropriate target leachables, the solvent(s) used to generate the test sample must have nearly the identical propensity to leach as the drug product formulation. Such a study should be accelerated versus the leachables study so that the extractables, reflecting potential target leachables, can be discovered and identified in a timely fashion. Differences in the study design between this simulation study and the drug product leachables study are: 1) that the drug product formulation has been replaced with a simulating solvent that mimics the formulation; 2) that the conditions of contact have been accelerated, so as to increase both the concentrations of probable leachables and the rates of migration of probable leachables into the simulating solvent; and 3) that the test article can be either the complete packaging and delivery system or separate components of that system. Factors to consider in designing and justifying the simulating solvent(s), along with recommendations on the analytical approach used to characterize the simulating extract for extractables as potential target leachables are discussed in 1663. Given the intent of the simulation study, which is the discovery and identification of extractables as target leachables, simulation studies must also be driven by relevant thresholds.

It is possible that in cases of very low thresholds (e.g., AETs), quantitation of drug product leachables might still not be analytically feasible, even with high sensitivity target compound analytical methods. In such cases, the results of the simulation study (probable leachables identities and concentrations) may be sufficient to establish patient safety and the quality impact of the actual drug product leachables. To the extent that the simulation study mimics the drug product leachables study, the potential safety or quality impact of a compound as an extractable is an estimate of the potential safety or quality impact of the compound as an actual leachable. If it can be established that a compound quantitated as an extractable under these conditions has an acceptably small impact on safety and quality, then it follows that the same compound as a leachable in the drug product formulation may be assumed to have a similarly low impact on safety and quality as a leachable in the drug product formulation. The acceptability of this approach for any particular drug product needs to be scientifically justified by the drug product applicant.

If a compound is measured as an extractable in a simulation study and targeted as a leachable in a drug product leachables study, the extractables and leachables data for that compound become the basis upon which a leachables–extractables correlation can be made. For such a correlation to be considered to be valid, it is necessary that each leachable concentration in the drug product be less than or equal to the corresponding extractable concentration in the simulated extract, accounting for the uncertainty in the analytical measurements and any justifiable “exaggeration factors” that may have been utilized in the simulation study. Note that in certain justifiable circumstances drug product placebo batches may be used as test articles in drug product leachables studies (stability studies). However, there are also circumstances when placebo batches are not acceptable, such as when there is significant reason to believe that leachables might have an adverse effect on an active pharmaceutical ingredient (e.g., therapeutic proteins).

The topic of leachables as elemental impurities in pharmaceuticals can be addressed within the overall context of elemental impurities in drug products (e.g., Elemental Impurities—Limits 232. Elemental impurities leached from packaging or delivery systems represent only one source of elemental impurities in a drug product, and thus testing a drug product for elemental impurities does not establish that the impurities are leachables.

Testing of the plastic packaging systems and their materials of construction will establish those extractable elemental impurities that are relevant to a particular packaging system, and it may be appropriate to quantify such elemental impurities as leachables in the drug product. Therefore, the results of testing plastic packaging systems should be used to establish those elemental impurities that should be monitored as targeted elemental leachables in the drug product.

In general, guidelines and recommendations about elemental impurities in drug products address safety concerns associated with the elemental impurities. However, it is proper to consider elemental leachables from the broader perspective of the overall quality of the drug product. Thus the process of evaluating elemental leachables may include both the aspects of user safety and product quality.

Note that one of the differences between the testing for organic leachables (and extractables) and for elemental impurities is the nature of the information generated. The testing for organic leachables is based on having established the identity of the chemical compound that is the leachable. Alternatively, the test methods most commonly employed to address elemental impurities (atomic spectroscopy) do not establish the compound, or form, that the detected element is present in. For example, sulfur might be present in the form of elemental sulfur (S8), as the sulfate (SO42), or as a sulfur-containing organic compound (e.g., 2-mercaptobenzothiazole). Also, silicon might be present either as silicone oil or as silicon dioxide (SiO2). As the form of the elemental impurity may have a marked effect on the impurity's impact on product quality or safety, it may be the case that testing beyond elemental impurity profiling may be necessary to establish the exact chemical form of the elemental impurity and thus ascertain its potential safety or product impact.

An important issue to consider in testing drug products for elemental leachables is establishing which elements to measure as leachables. Considering this, it is noted that testing of the plastic packaging systems and their materials of construction will establish those extractable elemental impurities that are relevant to a specific packaging system. Therefore, the results of testing plastic packaging systems should be used as one means of establishing those elemental impurities that should be monitored as targeted elemental leachables.