A stimuli article calling for revised methods for detecting heavy metals impurities in drug substances and drug products has
been applauded for addressing an issue long overdue and has prompted much needed discussion (1). While the details of the
article replacing the nearly 100-year-old USP–NF (231) Heavy Metals General Chapter are debated, industry and regulators are actively keeping an eye on its progress. The
final chapter will affect makers of drug substances, finished drug products, and raw materials. Factors under consideration
include the types of impurities that should be detected, their acceptance limits, and the analytical tools for quantitative
(ILLUSTRATION: M.MCEVOY IMAGES: CASPER BENSON, DAVID FREUND/GETTY IMAGES)
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 methodology
The USP ‹231› General Chapter screening methods are outdated, nonspecific, and, for the most part, inefficient.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."