Extractables / leachables analysis

Note that accurate mass measurements can be obtained for El and Cl as well as ESI and APCI spectra. This relatively simple example gives some idea of the power of modem MS for extractables/leachables testing, and trace organic analysis in general. Using state-of-the-art instruments, such as hybrid TOF and Fourier Transform mass... 

Numerous examples exist in the literature for LC/MS applications in pharmaceutical development, but only a few for the analysis of extractables and leachables. Of note are the works of Wu et al. who used ESI LC/MS to identify extractables from stoppers in biotech products. Tiller et alP who used data-dependent LC/MS/MS to identify leachables from adhesives used in pharmaceutical products, Castner, Williams, and Bresnick who used LC/MS to identify BHT (butyla-tedhydroxytoluene) in a lyophilized drug product, and Yu, Block, and Balagh who identified and quantified polymer additives by LC/MS. Other examples, as well as the numerous applications of HPLC to extractables/ leachables testing, have been reviewed by Jenke. " ... 

Inorganic extractables/leachables would include metals and other trace elements such as silica, sodium, potassium, aluminum, calcium, and zinc associated with glass packaging systems. Analytical techniques for the trace analysis of these elements are well established and include inductively coupled plasma—atomic emission spectroscopy (ICP-AES), ICP-MS, graphite furnace atomic absorption spectroscopy (GFAAS), electron microprobe, and X-ray fluorescence. Applications of these techniques have been reviewed by Jenke. " An example of an extractables study for certain glass containers is presented by Borchert et al. ". ... 

Extractables, leachables and outgassing analysis from leather, textiles, car interior materials or food... 

Two different approaches have been taken by researchers to determine the secondary mineralogy of CCBs (1) direct observation, which is accomplished via analysis of weathered ash materials, and (2) prediction, based on chemical equilibrium solubility calculations for ash pore-waters and/or experimental ash leachate or extractant solutions. Because the secondary phases are typically present in very low abundance, their characterization by direct analysis is difficult. On the other hand, predictions based on chemical equilibrium modelling or laboratory leaching experiments may not be reliable indicators of element leachability or accurately indicate the secondary phases that will form under field conditions (Eighmy et al. 1994 Janssen-Jurkovicova et al. 1994). 

The results showed that there was no increase in leachate metals concentration after ten extractions. Most of the metal concentrations remained the same or decreased during the total MEP run. This proves the long term stability of the CHEMFIX product since the MEP was designed to simulate conditions of 1000 years of acid rain exposure. In addition, throughout the entire MEP analysis the leachable metals concentrations were all below the regulatory limits. Thus once the soil is treated by the CHEMFIX process it remains non-hazardous for extended periods of time. 

Figure 6.44 Chromatograms from the LC/UV/ion trap MS analysis of leachables that were extracted from a test adhesive with deionized water at 50°C for 3 days. (A) UV chromatogram at 220nm. (B) TIC full-scan MS chromatogram. (Reprinted with permission from Tiller et al., 1997a. Copyright 1997 John Wiley Sons.)...

Leachables in orally inhaled and nasal drug products (OINDP) are compounds which are present in the drug product due to leaching from container closure system components. Extractables are compounds that can be extracted from OINDP device components, or surfaces of the OINDP container closure system when in presence of an appropriate solvent(s) and/or condition(s). Leachables are often a subset of, or are derived directly or indirectly from, extractables. Extractables may, therefore, be considered as potential leachables in OINDPs. Some leachables may affect product quality and/or present potential safety risks, therefore regulatory guidance has provided some recommendations regarding the analysis and toxicological safety assessment (i.e., qualification) of such compounds. 

As described above, individual packaging components will invariably contain complex mixtures of chemical entities (e.g., additives and oligomers), many if not most of which are at relatively trace levels (i.e., pg/g and lower). The principles of Trace Organic Analysis, as developed in the environmental, geochemical, and bioanalytical fields, can be applied to the problem of identification and quantification of these individual chemical entities, whether as extractables or as leachables.f The general process is as follows ... 

To be amenable to gas chromatographic analysis, a compound must volatilize without thermal decomposition and not interact with the analytical system in such a manner so as to cause irreversible surface adsorption or surface catalyzed decomposition. In addition, the polarities of the various chemical entities to be analyzed must be considered so that an appropriate GC separation mechanism (i.e., partitioning, adsorption, etc.) can be chosen. Although these factors might seem to suggest that GC is a very selective analytical technique, in fact a wide variety of chemical entities which can appear as extractables and leachables are amenable to GC separation and analysis. ... 

GC/MS can also be used to quantitate extractables and leachables with extremely high selectivity, specificity, and sensitivity. For example, Norwood et al. used GC/MS with selected ion monitoring to quantitate polycyclic aromatic hydrocarbons (PAHs) as leachables in suspension MDI drug products. The analytical method employed a cold filtration technique to remove suspended drug substance and excipients, followed by GC/MS analysis. Stable isotope labeled... 

Physicochemical testing is performed to characterize the physical and chemical properties of a plastic to insure that the composition of the synthetic medium will not compromise the quality of the drug being stored within it. To perform these tests, samples of plastic identical to the material being used in the primary package are subjected to an extraction procedure—to dissolve in an extraction solution leachable compounds that are at risk of entering the pharmaceutical preparation. This extraction solution is then subjected to analysis to evaluate the identity and quantity of leachants. For most plastics, the appropriate extraction medium is purified water, but elastomeric closures for use with injections should include extraction with three different extraction... 

Environmental applications of ICP-MS are numerous, and include analysis of water, wastewater, soil, sediment, air particulates, and so on. A typical environmental analysis is to determine the leachable metals from soil or sediment the sohd is not dissolved but leached or extracted to determine labile elements. These labile or leachable elements are the ones that might be mobilized from a landfill into a drinking water supply, for example. Figure 10.39 gives an example of determining leachable metals from an NIST Standard Reference Material (SRM) soil sample by ICP-MS. 

As discussed in an earlier section of this Handbook, additives may eontribute to extraetable and leachable compounds. Other sources include base polymer breakdown produets and/or primary formulation ingredients and flieir breakdown products. These and other extraneous eompounds comprise the basis for the extraction, analysis, and identification methods described in this ehapter. 

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