<1664.1> ORALLY INHALED AND NASAL DRUG PRODUCTS  

ADDITIONAL CONSIDERATIONS

An AET is that concentration above which unknown leachables should be characterized and reported for toxicological assessment. Target leachables (previously characterized as potential or probable leachables from extractables or simulation studies) will have known safety profiles and previously established leachables thresholds. In addition, reference compounds for previously characterized potential leachables will allow for accurate and precise quantitation of those target leachables as actual drug product leachables. Characterization of unknown leachables requires consideration of analytical uncertainty, as the location of an AET in a given leachables profile (e.g., a gas chromatography/mass spectrometry [GC/MS] chromatogram) must be accomplished relative to an internal standard(s) within the leachables profile. Analytical uncertainty for a particular analytical technique or method can be estimated based on the analysis of a series of reference compounds to create a response factor database. The reference compounds included in this database should represent all known potential leachables (i.e., as determined from extractables assessments). For OINDP, it is recommended (3,5) that the estimated AET be lowered by a factor defined as 1% relative standard deviation in an appropriately constituted response factor database, or a factor of 50% of the estimated AET, whichever is greater. Detailed examples of response factor databases and AET determinations are available (3,5).

Polycyclic Aromatic Hydrocarbons (PAHs) or Polynuclear Aromatics (PNAs), N-nitrosamines, and 2-mercaptobenzothiozole (2-MBT) are considered to be “special case” compounds (i.e., compounds with special safety and historical concerns), requiring special characterization studies using specific analytical techniques and methods (1–3,5). Thresholds for characterization of these compounds as extractables or leachables in OINDP are typically based on the limits of these specific analytical techniques and methods. Table 2 lists the PNAs and N-nitrosamines that, along with 2-MBT, are typically investigated as extractables and leachables in OINDP.

PNAs have been associated with carbon black filler used in many types of elastomer. Analysis of PNAs, either as elastomer extractables or as drug product leachables, usually involves quantitative extraction followed by highly specific and sensitive analysis of resulting extracts. GC/MS with selected-ion-monitoring has been reported for analysis of target PNAs as leachables in MDI drug products, for example (6). N-Nitrosamines are reaction products between specific organic precursor molecules, secondary amines (R2NH), and a “nitrosating agent”. In the compounding of rubber, secondary amines are likely formed from certain vulcanization accelerators such as thiurams and dithiocarbamates. Potential nitrosating agents include NO+, N2O3, N2O4, etc., certain of which can be formed from commonly used chemicals such as sodium nitrite (NaNO2), which has many industrial uses. Analysis of N-nitrosamines in rubber as potential leachables involves quantitative extraction followed by analysis of extracts with gas chromatography/thermal energy analysis detection (GC/TEA) (8). Analysis of N-nitrosamines as leachables in MDI drug products using GC/TEA has been reported (7). The 2-MBT is a vulcanization accelerator, which is used in certain sulfur-cured elastomers, and can be analyzed by extraction followed by LC/MS (5).