Extractables / leachables

Metered-Dose Inhalers and Nasal Aerosols Content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial bioburden, valve delivery, extractables, leachables from plastic and elastomeric components. 

A foundation for consideration of the extractables/ leachables issue is provided by the United States Food and Drug Administration (USFDA) in its Guidance for Industry documents, which define extractables as Compounds that can be extracted from elastomeric or plastic components of the container closure system when in the presence of a solvent. ... 

Note, however, that the chromatogram shows this additive to be in reality a complex mixture of chemical entities, all of which could appear as extractables/ leachables. 

It is clear that to understand extractables and leachables, and to conduct appropriate and successful extractables/leachables studies, a thorough understanding of each container closure system component is required. Such an understanding should include the following ... 

It is important, however, to remember that no analytical method, technique, or combination of methods and techniques can provide complete assurance that every individual extractable/leachable associated with a drug product and its container closure system has been detected and identified. To quote Jenke ... 

MS is not the only highly sensitive and selective detection system that can be interfaced with GC. For example, consider another compound class of special safety concern as extractables/leachables, A-nitrosamines.f A-Nitrosamines are formed during mixing and vulcanization of certain types of rubber, by the reaction of various secondary amines with nitrosating agents " and can be found at trace levels (ng/g) in components fabricated from these rubbers. 

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. " ... 

What does it mean to identify an extractable/ leachable ... 

IPAC-RS goes on to use these criteria to propose identification categories for extractables/leachables ... 

Develop and validate GC/FID methods for routine use when GC/MS was used for extractables/ leachables characterization studies. 

Thus far, this review has focused completely on organic extractables and leachables, however it is also possible to have inorganic extractables and leachables associated with pharmaceutical packaging and drug products. Inorganic extractables/leachables can arise from residual... 

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. ". ... 

Jenke, D. Extractable/leachable substances from plastic materials used as pharmaceutical product containers/ devices. J. Pharm. Sci. Technol. 2002, 56 (6), 332-364. 

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