<1664> ASSESSMENT OF DRUG PRODUCT LEACHABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS 

KEY TERMS

This general chapter uses the following key terms (1,2; also see Packaging and Storage Requirements 659). Note that the terms Packaging System, Packaging Component, Primary Packaging Component, Secondary Packaging Component, and Materials of Construction are also defined in 659, and the definitions below are intended for clarification purposes within the context of this chapter and are not intended to supersede those provided in 659.

Packaging Systems are the sum of packaging components that together contain and protect the dosage form. Packaging systems are also referred to as Container Closure Systems and may include primary, secondary, and tertiary packaging.

A Container is a receptacle that holds an intermediate compound, active pharmaceutical ingredient, excipient, or dosage form and is in direct contact with the product.

A Closure is a material that seals an otherwise open space on a container and provides protection for the contents. It also provides access to the contents of the container.

A Packaging Component is any single part of the package or container–closure system including the container (e.g., ampuls, prefilled syringes, vials, bottles), closures (e.g., screw caps, stoppers), ferrules and overseals, closure liners, inner seals, administration ports, overwraps, adminstration accessories, labels, cardboard boxes, and shrink wrap.

A Primary Packaging Component is in direct contact or may come into direct contact with the product (e.g., IV bag).

A Secondary Packaging Component is in direct contact with a primary packaging component and may provide additional protection of the product (e.g., overpouch or dustcover for an IV bag).

A Tertiary Packaging Component is in direct contact with a secondary packaging component and may provide additional protection of the product during transportation and/or storage (e.g., shipping carton for an overpouched IV bag).

An Ancillary Component is a component or entity that may come into contact with a tertiary packaging component during the distribution, storage, and transportation of the packaged product (e.g., pallets, skids, shrink wrap, active containers).

Packaging Materials of Construction are substances used to manufacture packaging components. These are also referred to as Raw Materials.

A Delivery System is the sum of components and materials that are used to transport a drug product from its packaging to the point of administration into the patient. For example, an administration set is a delivery system that is used to transfer liquid drug products from their plastic packaging system to the site of administration to the patient.

Extractables are organic and inorganic chemical entities that can be released from a pharmaceutical packaging/delivery system, packaging component, or packaging material of construction and into an extraction solvent under laboratory conditions. Depending on the specific purpose of the extraction study (discussed below), these laboratory conditions (e.g., solvent, temperature, stoichiometry, etc.) may accelerate or exaggerate the normal conditions of storage and use for a packaged dosage form. Extractables themselves, or substances derived from extractables, have the potential to leach into a drug product under normal conditions of storage and use and become leachables. Thus extractables are potential leachables.

Leachables are foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies. Because leachables are derived from the packaging or delivery system, they are not related to either the drug product itself or its vehicle and ingredients. Leachables are present in a packaged drug product because of the direct action of the drug product on the source of the leachable. 

Thus leachables are typically derived from primary and secondary packaging, because the primary and secondary packaging can serve as a barrier between the packaged drug product and other potential sources of foreign chemical entities (e.g., tertiary packaging and ancillary components). In certain circumstances, packaging may directly contact the patient under typical clinical conditions of use (e.g., the mouthpiece of a metered dose inhaler). As a result of this contact, patients may be exposed to leachables from the packaging without the action of the drug product. Leachables are typically a subset of extractables or are derived from extractables. Note that chemical entities can also migrate from packaging/delivery systems to patients via direct contact.

Migrants are also foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies. However, migrants are differentiated from leachables by the circumstance that migrants accumulate in the packaged drug product after the migrant has crossed a physical barrier, such as that provided by primary and secondary packaging. Because migrants cross a physical barrier, they are not present in the packaged drug product due to direct action of the drug product on the source of the migrant because the barrier prevents such direct action. Thus migrants are derived from secondary and tertiary packaging and ancillary components.

Regardless of whether a substance is a leachable or migrant, it is still a foreign substance in the packaged drug product, and thus its impact must be assessed in the same manner. However, as the means by which a leachable and a migrant become entrained in a packaged drug product may be different, extractables studies meant to address leachables may be designed and implemented differently than extractables studies meant to address migrants.

Leachables Studies are laboratory investigations into the qualitative and quantitative nature of a particular leachables profile(s) over the proposed shelf-life of a particular drug product.

Characterization is the discovery, identification, and quantitation of each individual organic and inorganic leachable present in a drug product formulation above a predetermined level or threshold. Such thresholds should be based mainly on patient safety considerations, with consideration also given to the capabilities of analytical technology, and other related issues.

Identification is the process of assigning a molecular structure to an organic leachable, or assigning constituent elements in the case of an inorganic leachable.

Quantitation is the process of measuring the level, or concentration, of an individual organic or inorganic leachable contained in a drug product formulation.

Leachables Profiles are qualitative and/or quantitative analytical representations of the leachables content of a particular drug product formulation.

Leachables–Extractables Correlations are established when observed drug product leachables are linked both qualitatively and quantitatively to extractables from associated packaging/delivery systems, packaging components, or materials of construction.

Threshold of Toxicological Concern (TTC) is a level of exposure for all chemicals, whether or not there is specific toxicity data, below which there would be no appreciable risk to human health (6). The TTC approach is a form of risk characterization in which uncertainties arising from the use of data on other compounds are balanced against the low level of exposure.

Safety Concern Threshold (SCT) is the threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and noncarcinogenic toxic effects.

Qualification Threshold (QT) is the threshold below which a given noncarcinogenic leachable is not considered for safety qualification (toxicological assessments) unless the leachable presents structure-activity-relationship (SAR) concerns.

Analytical Evaluation Threshold (AET) is the threshold at or above which a leachable should be characterized and reported for toxicological assessment. The AET can be mathematically derived from the SCT (or other threshold concepts) based on factors that include the dosing parameters of the drug product.

As noted, additional terminology and associated definitions are available (1,2; see also 659).