Issue Date: December 8, 2008
Improving Metal Detection In Drugs
A 100-YEAR OLD wet chemistry procedure based on precipitating metal sulfide is the current standard method for testing for metals in pharmaceutical ingredients and products. It's a test that nearly everyone in the industry agrees doesn't work, or at least doesn't work well.
As a result, U.S. Pharmacopeia (USP), the pharmaceutical standards-setting organization in the U.S., will be replacing the method with an instrument-based approach. As part of the effort, USP will also revise the permissible limits of metals in pharmaceutical products. The organization aims to have the new methodology finalized by early 2010, with implementation to take several years beyond that.
The changes will require major adjustments by the pharmaceutical industry. It will have to implement new and potentially expensive methodology, report levels of individual metals when previously a simple total had sufficed, and potentially be held to tighter standards. But "it is important to recognize that it is irresponsible for the industry to continue to perform tests that are neither accurate nor meaningful, when the patients believe that the testing is both accurate and meaningful," says Nancy S. Lewen, USP inorganic impurities advisory panel chair and a Bristol-Myers Squibb analytical chemist.
Founded in 1820, USP became the country's official standard-setting agency for pharmaceuticals through the federal Food & Drugs Act of 1906 and the Food, Drug & Cosmetic Act of 1938. A nongovernmental, nonprofit agency, USP sets standards that are then enforced by the Food & Drug Administration. USP publishes the book "United States Pharmacopeia-National Formulary" (USP-NF), which sets packaging, storage, labeling, testing, and acceptance standards for drug ingredients and products.
Metals can wind up in pharmaceutical ingredients through a number of sources: naturally derived plant or mineral raw materials; other starting materials or reagents; catalysts; or reactors, pipes, and other equipment used in manufacturing. The current USP protocol for testing for metals in pharmaceutical ingredients dates to around 1905.
The wet chemistry technique involves precipitating metal sulfides out of an aqueous solution, then visually comparing the color of the test sample with that of a standard lead solution. But the colors of the metal sulfides that arise in a test solution can be white, yellow, orange, brown, or black, complicating comparison to dark brown lead sulfide, according to a paper by Tiebang Wang and colleagues at Merck Research Laboratories (J. Pharm. Biomed. Anal. 2000, 23, 867).
Additionally, samples frequently require ignition and charring before they can be analyzed, making the analysis far from quantitative—especially where volatile elements such as mercury and selenium are concerned. "Although still widely accepted and used in the pharmaceutical industry, these methods based on the intensity of the color of sulfide precipitation are nonspecific, insensitive, time-consuming, labor intensive, and, more often than hoped, yield low recoveries or no recoveries at all," Wang and colleagues comment.
And so, eight years ago, USP embarked on an effort to update how drugmakers detect metal impurities in their products. "Over the last few decades, there have been progressive advances in methodologies and techniques that allow one to do a much better and more comprehensive evaluation of metals in substances," says Darrell R. Abernethy, USP's chief science officer.
Within the proposed changes, however, lie two big switches for USP and the pharmaceutical industry: First, rather than giving pharmaceutical manufacturers a wet chemistry recipe, USP will allow manufacturers to use whatever method or instrument they wish, as long as they can demonstrate accuracy, sensitivity, and specificity. Second, limits will be established for individual metals and based on toxicology rather than the capability of the testing methodology.
USP describes the new testing approach in a recent Pharmacopeial Forum article (2008, 34, 1345) and suggests that plasma spectrochemistry and atomic absorption spectroscopy are likely to be top contenders. Whatever method manufacturers choose, USP plans to develop reference standards that pharmaceutical manufacturers can use to qualify their instruments and methods. In particular, the proposed general requirement is that procedures provide "measurement values within ??20% of the certified concentration for each element." This would be a significant improvement over the current wet chemistry method, which researchers at Bristol-Myers Squibb demonstrated recovers merely 50% or less of 13 metals spiked into drug samples (J. Pharm. Biomed. Anal. 2004, 35, 739).
IN THEORY, allowing drug manufacturers the ability to choose the test that best fits their processes and products would give them some desired flexibility. It should also allow them easier implementation of less expensive or more efficient technology down the road. At the same time, however, the flexibility opens up manufacturers to questions from FDA or other regulatory agencies because they could lose the protection offered by "safe harbor." Under that concept, manufacturers that follow USP-NF processes exactly will meet all FDA requirements, Abernethy says. Choosing one's own method, however, runs the risk that an auditor or regulator will disagree with the choice, even if the manufacturer has validated the method.
Manufacturers became especially wary after USP recently revised the USP-NF chapter on determining residual solvents in pharmaceutical products. The FDA Office of Generic Drugs interpreted USP's requirements in a different, completely unexpected way than what manufacturers had anticipated on the basis of FDA's prior treatment of New Drug Applications. "It pretty much stymied the entire generic drugs industry," says David R. Schoneker, director of global regulatory affairs for excipient company Colorcon and chairman of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), which represents excipient manufacturers, distributors, and users. Something similar could happen with the heavy metals revisions if USP, FDA, and industry don't communicate better about expectations before the protocols are finalized, he says.
Schoneker is also concerned that the cost of buying and maintaining instrumentation and training personnel may drive some chemical companies out of the pharmaceutical market. Many excipients, for example, are materials produced by chemical companies for other industries, and their pharmaceutical market may be relatively small. Such companies might use Good Manufacturing Practices but may not have a lot of personnel dedicated to the pharmaceutical business. If they're told they have to spend upward of $60,000 to buy an inductively coupled plasma spectroscopy unit, never mind maintenance and training, these companies may well decide the business simply isn't worth the effort.
Then there is the issue of the metal limits themselves. Right now, the heavy metal limits in pharmaceutical ingredients are reported as a total amount of whatever might be in the sample—the current method cannot distinguish, for example, arsenic versus palladium. With the likely instrument-based methods, however, the results can be reported as individual elements.
USP will not require manufacturers to look for every element in the periodic table, Abernethy says. Rather, it will require them to take a risk-based approach. For example, if a raw material comes from a plant that is known to take up arsenic and a process uses a platinum catalyst in a reactor made from an iron alloy, then those are the elements a manufacturer will likely have to test for and control.
Setting the individual limits for those metals will be a much thornier issue, Abernethy says. The considerations include whether a drug is taken for a short period, such as an antibiotic, or a long period, such as insulin; whether a drug is taken orally, injected, or inhaled; how much of the metals people are likely to consume from a typical diet; whether to accommodate sensitive populations such as children; and the speciation of the metal—arsine (AsH3), for example, is highly toxic, whereas arsenocholine ([As(CH3)3CH2CH2OH]+) is considered nontoxic.
USP published a preliminary set of limits for 31 elements in the Pharmacopeial Forum article. Industry is eyeing the list warily, Schoneker says. The list includes iron and aluminum, for example, but iron oxides and aluminum lake compounds are frequently used, with FDA approval, as coloring agents in pharmaceuticals. Products that use such ingredients could exceed the suggested amounts. Schoneker says that IPEC-Americas would like more information as to how USP came up with the limits.
THE CURRENT timeline for the new protocols calls for USP to have the new draft USP-NF chapter published in the summer of 2009, with the final version out by June 2010. Actual implementation will take several years beyond that. Drug manufacturers will have to evaluate their suppliers and processes; purchase equipment; train personnel; develop, validate, and implement new analytical methods in quality-control labs; and document everything for regulatory agencies. And if a drug ingredient has an unacceptably high level of a metal, the manufacturer will have to figure out a way to prevent it or remove it. USP wants to allow manufacturers the time to accomplish all of this without threatening the drug supply, Abernethy says.
For his part, Schoneker thinks USP may have taken on too much too quickly by trying to address so many metals at once. IPEC-Americas would prefer to have USP carve out a smaller set—say, the "big four" of arsenic, cadmium, lead, and mercury, which have well-established safety concerns—to see how the new protocols shake out before expanding to control a larger portion of the periodic table, he says.
"Everyone wants to have good, strong controls on the metals that have safety issues," Schoneker says, adding that IPEC-Americas hopes to work with USP and FDA to develop a system that will not unduly burden industry while still providing maximum safety protection to patients at a reasonable cost.
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