Better information about pharmaceutical impurities is generating new questions. What is the best way to handle them? How should we report them? How do they really affect overall product quality? How should control procedures be put in place? Ingredient suppliers are working—and debating—with regulatory agencies to develop guidelines designed to eliminate redundant testing for APIs, explain the composition of excipients, and reasonably control the genotoxic impurities in both.Improving analytical methods
Nongenotoxic impurities. LC and GC techniques with conventional detectors have been the traditional analytical methods for identifying and quantitating nongenotoxic impurities. According to a 2003 survey, HPLC accounted for approximately 53% of the reported analytical separations used in 1999–2001 (1). In these applications, specificity, sensitivity, and matrix interference remain the primary analytical challenges (2). These techniques may not necessarily measure impurity levels accurately. They assume that impurities are structurally related to the drug substance, and therefore have similar detector responses; this is not always the case.
"Incorporating this information with those obtained from NMR and IR techniques, one can identify the impurity with a fairly good degree of accuracy," says Liakatali Bodalbhai, group leader, Analytical Sciences R&D, DPT Laboratories (San Antonio, TX). "However, only by synthesizing the possible molecule and comparing its fragmentation pattern in MS and retention time by HPLC to the impurity of interest can one conclusively identify that impurity."
Bodalbhai points out that the development of multiple ionization modes in LC–MS and LC–MS–MS, namely electrospray ionization, atmospheric pressure chemical ionization, and atmospheric pressure photoionization, has expanded the capabilities of these techniques for a large class of compounds. Newer technologies include fast chromatography data treatment such as signal averaging, new LC–NMR platforms, thermogravimetric–MS for volatile impurities, and LC–MS–NMR (3).