Impurity detection has received heightened attention since the scandals involving lead in toys, glycerin contamination with diethylene glycol, adulterated heparin, and melamine in pet food and infant formula. A strong impurities screening approach is especially important as an increasing amount of drug substances and excipients are imported from regions outside of the United States. "When FDA has to confront these big problems, it has to start using all the tools at its disposal. Eventually manufacturers will have to know more about what they buy," says Luciano Virgili, former director of global testing standards at Bristol Meyers Squibb.
Problems with current methodologyThe USP ‹231› General Chapter screening methods are outdated, nonspecific, and, for the most part, inefficient. The qualitative wet chemistry techniques convert metals to a sulfide and analysts compare the colors of the sample liquid to a standard preparation to determine whether metallic impurities are present. The chapter contains three methods. Method I is used for substances that yield a colorless liquid preparation and involves only dissolving and diluting the substance. Methods II and III, however, are used for substances that do not yield colorless preparations and involve heating the substance, which may result in the loss of some metals and negatively impact the accuracy of the analysis.
"The way the method is run, you can detect 10 different metals while performing the test," says Gayla Velez, director of analytical services at SGS Northview Labs (Northbrook, IL). "But when USP revised the General Chapter a few years ago and they added a monitor to Method II, we found you couldn't recover most of those metals if you spiked it, and then took it through the digestion process. So what concerns me is that we are doing this test on a day-to-day basis, yet we know that we may be losing some of the metals that we are trying to detect."
Industry analysts have reported difficulty with reagents and achieving results with the monitor solutions and standards (2). Moreover, the methods in the current chapter are nonspecific. "One description of it is hitting two rocks together and hoping it's going to tell you the right answer," says Steve Boyajian, business development manager at Activation Labs (Ancaster, Ontario). "You very rarely, if ever, get a positive result from the current test indicating there is metal above the limit. Even if a problem existed, the current test would not be able to detect it."