The Impact of Impurity Analysis on Future Regulations

As technology for impurity analysis improves, scientists are gaining better information and asking for more regulatory guidance.
Feb 02, 2007



Even at minute quantities, unwanted chemicals present in pharmaceutical ingredients may greatly influence a drug product's efficacy and safety. While researchers strive to eliminate or control impurities, they rely on fast analytical tools with high sensitivity and specificity to better detect, identify, quantitate, and characterize impurities. The technology for impurity analysis has improved beyond the traditional chromatographic (e.g., high-performance liquid chromatography [HPLC] and gas chromatography [GC] for volatile impurities) and spectroscopic methods (e.g, GC–mass spectrometry [GC–MS]). Scientists are gaining an ever-clearer picture of their materials' constituents. In some cases, technology is revealing never-before-seen impurities even in compounds thought to be well understood.


Qualification of Impurities in ANDAs
Along with improving analytical tools comes a growing concern about genotoxins—molecules that may bind or break DNA even in parts-per-million concentrations—which are only now practical to monitor.

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.


Figure 1: Scientists are increasingly relying on hyphenated and tandem techniques to analyze their compounds, thereby enabling them to better detect and identify impurities (Waters Quattro Micro LC–MS–MS instrument with Waters Alliance 2695 HPLC).
Hyphenated techniques, including LC–MS, GC–MS (accounting for 8% and 2%, respectively, of the methods used in 1999–2001), and chromatography tandem mass-spectrometry (LC–MS–MS) are more sensitive and can provide better separation (see Figure 1) (1). In addition, MS–MS yields more accurate information about the structure of impurities.

"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).