Impurities identification

Solutions to practical problems rarely depend upon a single technique or a single approach. The following example of an impurity identification in a pharmaceutical product illustrates the key role that LC-MS can play in such an investigation, but also illustrates the limitations of the technique. The identification of this impurity has been published elsewhere in complete detail [75]. The problem and solution is summarized here. The impurity, designated as H3, was observed at 0.15% in a bulk lot of the drug substance in the structure below. The impurity required identification before the bulk lot could be released for use in further studies. 

In comparing the impurity-identification capabilities of these techniques, one important fact stands out the TDH, PC, and absorption methods will normally give information on only one, or at best a few, impurities in the same sample, whereas the TSC, PITS, and OTCS methods often see many. Thus, the latter three techniques are more useful for general survey studies. Unfortunately, however, only a few impurities, and no defects, can be positively identified in GaAs by any of these methods at the present time. This problem must continue to be addressed. 

Sharman GJ, Jones IC. Critical investigation of coupled liquid chromatogra-phy-NMR spectroscopy in pharmaceutical impurity identification. Magn Reson Chem 2003 41 448-454. 

Cummings PG, Offen P, Olsen MA, Kennedy-Gabb S, Zuber G. LC/MS, LC/ NMR, FTIR an integrated approach to impurity identification in pharmaceutical development formulation. Am Pharm Rev 2003 6(3) 88, 90, 92. 

Tollsten L. HPLC/MS for drug impurity identification. In Gorog S, ed. Identification and Determination of Impurities in Drugs. New York Elsevier, 2000 266-297. 

This strategy is highly successful for impurity identification (Kerns et al., 1995) during preclinical development. When information is stored within a comparative database, this approach is also highly effective for protein identification (Arnott et al., 1995). In these applications, the characteristic fragmentation corresponding to amino acid residues provides the searchable template for identification. This approach is particularly useful when identification studies are required for vast numbers of compounds or for samples that contain many analytes of interest. 

Production Impurity identification Data dependent analysis Tiller et al., 1997... 

Impurity Identification Using Data-Dependent Analysis... 

A 0.1% threshold for identification and isolation of impurities from all new molecular entities is under consideration by the International Conference on Harmonization as an international regulatory standard [4,5]. However, where there is evidence to suggest the presence or formation of toxic impurities, identification should be attempted. An example of this is the 1500 reports of Eosinophilia-Mylagia Syndrome and more than 30 deaths associated with one impurity present in L-tryptophan which were present at the 0.0089% level [6]. 

The authors would like to thank Vincent Bobin for the solubility data for Compound A. The authors would also like to thank the following individuals for their work on Compound B described in this chapter Daniel Gierer for manufacture of the placebo tablets Amy Orce for her work on the extraneous syringe peak Thomas Sharp, George Horan, and Ronald Morris for their work on impurity identification and Cheryl Kirkman, Heidi O Donnell, Britt-Marie Otano, Doreathea Roberts, J. Sean Space, and Gregory Steeno for their work on the small volume dissolution method. In addition, the authors would like to thank Amanda Deal and Kelly Field for their work on the HPLC purity method development for the fixed combination tablet. 

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