Drug substances impurity profile

Nicolas, E. C. Scholz,T. H. 1998. Active drug substance impurity profiling part II. LC/MS/MS fingerprinting. J. Pharm. Biomed. Anal., 16, 825-836. 

E. C. Nicolas and T. H. Scholz, Active drug substance impurity profiling. Part I. LC/UV diode array spectral matching,/. Pharm. Biomed.Anal. 16 (1998),813-824. 

FIGURE 7 (a) Impurity profile of Intermediate produced by the new process. Peaks after 8 min were impurities that were not previously observed when the Intermediate was produced via the old process, (b) Chromatogram of the drug substance made from intermediate of poor quality. Peak at 22 min retention time is the drug substance Impurity at 36 min retention time was a new impurity and failed specifications. 

Impurity testing is pivotal in pharmaceutical development for establishing drug safety and quality. In this chapter, an overview of impnrity evaluations of drug substances and products by HPLC is presented from both the laboratory and regulatory standpoints. Concepts from the development of impurity profiles to the final establishment of public specifications are described. Useful strategies in the identification and quantification of impurities and degradation products are summarized with practical examples to illustrate impurity method development. 

The generic representation in Figure 1 illustrates the various types of impurities that may arise during the production of a dosage form. It is not all inclusive, as each dosage form has unique sources of impurities, but it includes most of the important ones. The sources of impurities increase with the increase in the number of components and the number of steps in the process. Each drug substance and excipient has its own impurity profile and the potential for interactions and reactions. 

Several dosage forms carry an increased risk of degradation or adjunct formation. Products such as injections and aerosols are more likely to interact with volatiles or extractables from packaging and closure systems. Tablets have the potential to form adjuncts with excipients (specifically, lactose has been shown to form adjuncts in tablets). Non-CFC propellants in aerosols have a large number of impurities that typically do not interact with drug substances, but the potential for these interactions does still exist. Creams, ointments, lotions, and other such products will each have specific interactions that should be considered while evaluating the impurity profile of a drug product. 

The development of an impurity profile for a dosage form follows many of the same principles as in the drug substances however, instead of identifying all precursors and intermediates, the analyst will identify and place all of the components of the dosage form (excipients, preservatives, and others) and their affiliated impurity profiles within a master profile. Here again additional method development may be needed to... 

VIII. IMPURITY PROFILING FOR DRUG SUBSTANCES AND PHARMACEUTICAL PRODUCTS... 

During the course of chemical development, impurity profiles in drug substances may change due to changes in synthetic route and changes in the size of the batch. ICH guidelines for Impurities in New Drug Substances (ICH Q3A), require that impurity test results for... 

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