The Impact of Impurity Analysis on Future Regulations - Pharmaceutical Technology

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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.


Pharmaceutical Technology


"Incorporating NMR to LC–MS would make this technique one of the most powerful tools for an analytical chemist," says Bodalbhai. With this technology, scientists can fragment a molecule and obtain structural information as well as map atom-to-atom connectivity of the molecule, thereby generating three-dimensional structures of the isomers.

"On-line implementation of techniques is gaining popularity and the ability to conduct identification, characterization, and quantitative analysis at the same time will be one of the trends of the industry," predicts Qingxi Wang, director of Global Pharmaceutical Globalization, Merck Co., Inc. (Whitehouse Station, NJ). "For example, interfaced LC–MS–NMR could potentially be a widely used technique for the characterization of organic impurities."

Wet chemistry is currently the compendial method for inorganic impurity analysis. However, ICP–AES and ICP–MS are widely used and potentially methods of choice because of their higher sensitivity and selectivity. Other techniques for detection and characterization of inorganic impurities include laser induced bombardment spectroscopy, scanning electron microscopy-energy dispersive X-ray, and X-ray fluorescence (3).


Table I: ICH Q3A (R2) thresholds for impurities in drug substances.
Analysis of genotoxic impurities. In general, impurities should be quantitated at levels ≥0.03 or 0.05% by weight according to ICH guidelines (see Table I). Genotoxic impurities or potential genotoxic impurities must be controlled at levels significantly lower than the 0.03–0.05% levels that are typically reported by an HPLC impurity assay. Typically, developing limit tests (e.g., <50 ppm) for highly toxic impurities is readily achievable, however it can be difficult to develop a test to control a particular genotoxic impurity at 1 ppm (0.0001% w/w).

"There is a huge difference between the two," says Sandeep Modi, director of Quality Management at Bristol-Myers Squibb (New Brunswick, NJ). "For genotoxic impurities we need very sensitive and selective methods. One needs higher sensitivity to determine ppm-level impurities and selective methods to separate low levels of genotoxic impurities from base line noise and other organic impurities. The typical HPLC methods with a nonspecific detector (e.g., UV) that are used to measure organic impurities may not be appropriate to quantitate low ppm levels of genotoxic impurities."

The quantitation of low levels (in the range of ppms) of impurities is the challenging part, notes Modi, and using specific detectors such as MS or MS–MS with LC will significantly improve the method selectivity and the quantitation limit. The goal for scientists is to identify potential genotoxic impurities early in development, develop analytical methods to test for these impurities in the intermediates, and if possible, to demonstrate that the manufacturing process controls them before reaching the final drug substance.

"If you eliminate them early enough, then your actual active drug substance is pure, free of genotoxic impurities," says Modi.

A more flexible USP

Improvements in analytics as well as those in synthetic chemistry also have led to a greater number of synthetic routes discovered. Molecule synthesis has improved with better reagents, better techniques, better reaction types, and better control. As a result, some APIs now have as many as five possible synthetic routes. And APIs produced according to those synthetic routes may have different impurity profiles.


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