OINDP are generally categorized as high-risk dosage forms due to safety considerations related to the route of administration and high probability of packaging component interaction with the formulation (see Table 1 in <1664>). The packaging systems used in these drug products incorporate components of various types, including components composed of polymeric (plastic or elastomeric) raw materials with complex chemical compositions and therefore a variety of potential leachables. Chemical entities may migrate (i.e., leach) into the formulation when there is direct contact with the primary packaging and delivery components for extended periods of time. In certain cases, there is also the potential for leaching from secondary and tertiary packaging. In addition, for OINDP, contact of the delivery device with mucosal tissue (mouth or nasal) is generally expected. Leachables studies for some OINDP may be considered separately for packaging components that are in continuous contact with the formulation (e.g., vials, bottles, blisters, metering valve components) versus those that are only in transient contact (e.g., DPI mouthpiece, MDI mouthpiece).OINDP typically require:

  • A leachables stability study for drug product registration that supports intended storage and use conditions throughout the proposed shelf-life (see Table 1), ideally on primary drug product stability batches manufactured with the same lots of packaging components used in extraction studies (in order to facilitate a leachables–extractables correlation)
  • Sensitive, selective, and fully validated leachables analytical methods
  • Leachables assessments based on safety thresholds [Safety Concern Threshold (SCT): 0.15 µg/day, and Qualification Threshold (QT): 5 µg/day total daily intake (TDI) for an individual organic leachable; however, for exceptions see Special Case Compounds]
  • Complete qualitative and quantitative leachables–extractables correlations (which require that extractables assessments be accomplished on all critical packaging components; see Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems <1663>)
  • Leachables specifications including acceptance criteria (assumes a complete extractables assessment for each critical packaging component). (Note that in many cases routine extractables testing for release of critical components can be used to control drug product leachables in lieu of routine drug product leachables testing, providing that a comprehensive leachables–extractables correlation is established.)

For OINDP dosage forms based on formulations with relatively lower leaching potential for organic compounds (e.g., aqueous formulations, dry powder formulations), the above requirements should be considered and evaluated on a case-by-case basis, including consultations with the appropriate regulatory authorities.

Table 1. Example Stability Storage Conditions and Testing Time Points for an OINDP Registration Leachables Study (5)

(temperature/relative humidity)
Time Points
25 ± 2℃/60 ± 5%RH
3, 6, 12, 18, 24, 36 (to end of shelf-life)
30 ± 2℃/65 ± 5%RH
3, 6, 12, 18, 24, 36 (to end of shelf-life)
40 ± 2℃/75 ± 5%RH
3, 6