LEACHABLES STUDY DESIGNAlthough lea

LEACHABLES STUDY DESIGNAlthough leachables studies may be accomplished at any time during the drug product development/manufacturing lifecy- cle, leachables studies are especially relevant during late stage product development or during formal product stability assess- ment. 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 pro- cesses of production of the drug product and the packaging/delivery system, filling of the drug product into the packag- ing/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 orcombination drug/device products this can be accomplished by using either the drug product formulation or a placebo formu- lation in contact with the proposed packaging system. In the latter case, the placebo formulation can be considered as a simu- lating 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 ofthe 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 dos- age forms, leachables characterization is recommended for any drug product batches that are used as test articles in any defin- itive 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.