Although leachables studies may be accomplished at any time during the drug product development/manufacturing lifecycle, leachables studies are especially relevant during late stage product development or during formal product stability assessment. Ideally, leachables assessment is conducted as follows:

  • The assessment is performed on the actual drug product and not simulations thereof (however, see Simulation Studies).

  • The assessment is performed with the actual packaging and delivery system in the form it will be commercialized, not with a prototype or on system components.

  • The related extractables assessments are accomplished on the same lots of packaging components used to manufacture the drug product lots on which the leachables assessments are performed.

  • The assessment is performed on a product that is manufactured under conditions that reflect the actual commercial processes of production of the drug product and the packaging/delivery system, filling of the drug product into the packaging/delivery system, post-filling treatment of the filled packaging (e.g., terminal sterilization), distribution, storage, and clinical use of the drug product. Although leachables studies may include accelerated storage conditions, they cannot be limited to accelerated conditions and must include real-time assessment.

Leachables studies can also be performed early in the drug product development process (e.g., preclinical stage) in order to facilitate the selection of packaging components and their materials of construction. Such leachables studies are particularly useful for certain “high-risk” dosage forms (see Table 1) where selecting appropriate packaging components and materials of construction is critical. A variety of packaging components and materials of construction can be evaluated at the same time and drug product leachables profiles determined and evaluated for each configuration. 

For primary packaging systems or combination drug/device products this can be accomplished by using either the drug product formulation or a placebo formulation in contact with the proposed packaging system. In the latter case, the placebo formulation can be considered as a simulating solvent to characterize extractables as probable leachables (see Simulation Studies). In either case, the leachables study conditions (i.e., time, temperature, etc.) should be based on conditions that are relevant for either the use-life or shelf-life of the drug product. Preclinical development stage leachables studies can be designed in a systematic way in order to support QbD processes and principles. It is important to also note that during early stage drug product development for high-risk dosage forms, leachables characterization is recommended for any drug product batches that are used as test articles in any definitive toxicology or clinical studies. For “low-risk” dosage forms (e.g., solid orals, topical powders) leachables studies conducted throughout development might be appropriate in order to assess, and thereby avoid, problems with packaging systems that might appear either in later stage development or marketed product.

During later stage development of high-risk dosage forms in support of product registration, when the final market form of the packaged drug product is available, leachables studies may be accomplished on definitive registration batches of drug product during the course of overall product stability studies. The results of these leachables stability studies can be used to establish leachables–extractables correlations, identify trends in leachables accumulation levels, evaluate individual leachables and qualify them on a safety basis, and develop leachables specifications with acceptance criteria (should these be required). For inhalation aerosols and other OINDP, leachables testing should be an integral part of the larger ICH registration stability program (2), and storage conditions and stability time points should be planned accordingly. For cases where a packaging/delivery component is in direct contact with the patient (e.g., a metered dose inhaler or dry powder inhaler actuator mouthpiece), chemical entities that a patient might be exposed to can be evaluated as extractables (i.e., potential leachables) using appropriate simulating fluids under time/temperature exposure conditions relevant to the intended use (see 1663).

Additionally leachables assessments may be appropriate on certain occasions post-market. For example, drug product leachables studies may also be appropriate in many cases where necessary or desired changes in a marketed drug product are made. Such leachables studies are normally required to support change-control processes for many high-risk dosage forms, particularly those with in-place leachables specifications and acceptance criteria, and could also be appropriate for other dosage form types, drug/device combination products, etc. Changes may include but are not limited to: composition of the drug formulation; manufacturing processes for the drug product; primary and secondary packaging components or their materials of construction; manufacturing or assembly processes for primary and secondary packaging components or their materials of construction; and delivery system(s) that are part of the drug product labeling. Any change that results in the patient being exposed to a different leachables profile than the one approved during registration will require leachables studies as part of any change-control process unless adequate scientific justification is provided to the contrary.

 Although low-risk dosage forms (e.g., solid orals, topical powders) typically do not rigorously require leachables studies as part of the drug product registration process (Table 1), it is possible that leachables could appear in drug product impurity profiles either during registration stability studies or in marketed products. For example, it has been documented that chemical additives in label adhesives can migrate through plastic primary packaging and appear in impurity profiles of solid oral dosage forms packaged within these containers. Thus, it is appropriate to consider performing leachables studies on “low-risk” dosage forms in certain cases. If leachables assessment is not performed proactively, such an event could lead to an OOS result for a development or marketed product and require an “emergency” leachables study as part of an investigation process. The design of this type of leachables study depends on the particular situation; however, in general it would be necessary to identify and quantify the leachable(s), evaluate safety and possibly qualify the leachable(s), and correlate the leachable(s) with packaging component extractables. It is also possible that leachables could result from contact with manufacturing equipment and tertiary packaging systems (e.g., shipping materials).

The design of a particular leachables study depends on the purpose and goals of the overall leachables assessment. Although the leachables studies described above have different purposes and overall goals, they require similar types of information for their proper design. First, it is important to have information as to the identities and maximum possible accumulation levels of all potential leachables. The packaging component manufacturers may provide chemical composition details for the packaging/delivery system and various materials of construction, as well as details regarding the manufacturing processes for these components and materials. 

Such information may be in the form of material safety data sheets, technical data sheets, test reports, or confidential communications, and can be used to infer potential leachables. An extractables assessment (including an extraction study) can also be accomplished on packaging components and/or their materials of construction to directly assess potential leachables (see 1663). Regardless of how the chemical information is obtained, it is important to ensure that all possible sources of potential leachables from the finished packaging system are considered. These may include chemical entities from any of the primary and secondary packaging components and their materials of construction, coatings, cleaning, lubricating, cutting, sterilization, assembly, or other processes associated with the manufacture of the final packaging/delivery system as used in the drug product. The chemical information on the packaging and delivery system is used to create a list of potential leachables and their possible accumulation levels.

 Potential leachables have a significant chemical diversity, and therefore a diversity of physical and chemical properties, including polarity, volatility, solubility, etc. Whereas relatively volatile compounds can more readily migrate into any type of formulation through indirect contact, nonvolatiles generally require direct contact. Two aspects of formulation contact should be considered: the nature of the formulation contact (i.e., direct or indirect) and the time of contact (transient or continuous). If the formulation is not in direct contact with the packaging component (e.g., inhalation powder in a capsule packaged in a blister) then it is less likely that any relatively nonvolatile compounds would migrate into the formulation from the packaging system; however, volatile compounds might. 

If the formulation is only briefly contacting the packaging component (e.g., an inhaler mouthpiece) it is less likely that any migration of chemicals from the component would occur on this transient timescale. However, if the formulation is in continuous contact with the packaging component (e.g., parenteral in a bag delivered through an administration set) then all types of compounds could potentially migrate into the formulation.

 A rigorous leachables assessment considers leachables from sources other than primary packaging, such as necessary secondary packaging and, in certain situations, tertiary packaging. If the primary packaging consists of a semipermeable polymer (e.g., a low density polyethylene container), then potential leachables from labels, inks, adhesives, etc. that are used in the secondary packaging must be evaluated. Similarly, volatile compounds that are present in tertiary packaging (e.g., wooden pallets, cardboard boxes, plastic overwraps, etc.) could migrate into a formulation contained in such a plastic bottle. These migrants that are derived from tertiary packaging should be considered in the event that an unknown impurity is detected or suspected in the drug product. 

Various characteristics of the drug product formulation must also be considered in designing any leachables study. For example, formulations are typically either solids or liquids, and it is well documented that physical state affects the leaching process. In the event that a formulation has a change in state during the course of production (e.g., lyophilization; liquid to solid) then the leachables study should be designed taking into consideration the time periods that the formulation is expected to be in each physical state. 

In the event that a formulation has a change in state during the course of use (e.g., nebulization of a liquid to vapor) then consideration should be given to both the leachables acquired during storage from the container of the liquid and those acquired during use of the prescribed delivery device. In addition, typically only the final packaged product is evaluated for leachables; however, there may be cases in which an intermediate (e.g., bulk capsule for an inhalation powder) is stored for long periods of time in different primary packaging (e.g., foil pouch) from which compounds may leach. If these compounds that migrate from bulk packaging persist through the drug product's manufacturing process and are entrained in the finished drug product, then they are properly treated as leachables.

 The nature of any contact that the packaging and delivery system has with the patient must also be considered. If the contact is only surface contact, then the likelihood of direct chemical migration to the patient is much less than if the contact is with mucosa, tissue, bone, or dentin. The various contact categories are described in The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants 1031 or ISO 10993 (10).