Impurity levels identification

The identification of process-related impurities can ultimately lead to elucidation of their mechanistic pathways. The first step in this process entails determination of structures for the impurities using tools such as NMR or LC-MS. With an elucidated structure, one can then attempt to propose a mechanism for its formation and to identify the synthetic steps that lead to its formation. This information can then be utilized to manipulate synthetic conditions so as to minimize its formation or develop efficient recrystalfiza-tion procedures to reduce impurity level while stiU maintaining acceptable yield. 

The current manufacturing process for the synthesis of the drug substance in case study A.5 generated an impurity at the 1-2% level. Identification was required for a drug safety assessment on this impurity within a 1-month time line. LC/MS analysis suggested that the impurity had... 

Harmonization of requirements has successfully been made by the International Conference on Harmonisation (ICH), e.g., in guidelines on stability documentation, method validation, and investigation of impurities. Regarding impurities information is given on how the limits should be set and at what level identification is needed. Similar efforts are seen for dissolution testing and how to correlate in vivo and in vitro data. The question of bioavailability and bioequivalence is an important one and has been dealt with as well. As a consequence of the rapid development in chiral separations we can now see a harmonization of requirements also for chiral drugs. 

The USP and NF standards give the basic measures required for medical gas strength, quality, and purity. The United States Pharmacopeia/National Formulary is available from the United States Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, Maryland 20852. The USP and NF standards include requirements for packaging, labeling, identification, impurity levels, and assay procedures for certain medical gases. 

Luminescence spectroscopy is one of the most sensitive techniques for identification of impurities in dyes. The most commonly observed impurities in to-bipyridyl complexes of the type [RuL2X2] are the homoleptic tris-bipyridyl species [RuL3]2+. Since the emission quantum yields of the [RuL3]2+ complexes are significantly higher than those of the [RuL2X2] complexes, one can identify the homoleptic impurities at a level of less than 1%. This does depend, however, on the relative quantum yields, and position of the emission spectral maxima, for the complexes and impurities involved. 

Regulatory bodies such as the Food and Drug Administration (FDA) in the United States require the identification of all impurities above the 0.1% level in formulated pharmaceuticals. Once identified, the structure of the impurity is typically confirmed through synthesis to provide absolute structure identification and for use as standards in subsequent quality assurance analyses. Together, LC-MS and LC-NMR play important roles in stability testing. For example, parallel analysis by LC-NMR and LC-MS was used for the rapid structure elucidation of an unknown impurity in 5-aminosalicylic acid, which is marketed for the treatment of acute ulcerative colitis and Chron s disease [57]. In another study, Fukutsu et al. [58] used a combination... 

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