"That is where the challenge is," says Virgili. "Not only do you have to buy this instrumentation, but you are looking nonspecifically
for anything. Unless someone tells you, how do you know what to look for? When you buy an excipient that can come from many
different suppliers worldwide, the profile of metal impurities from one supplier may be different from another that may be
using a different manufacturing method. I don't regard ICP as a routine QC tool for everybody but rather as a tool to learn
and monitor. That work does not have to be done in a company laboratory, but it can be delegated to those that can do it better
such as third-party laboratories."
Spectroscopic methods, though substantially more beneficial, are also significantly more expensive. Optical ICP and AA instruments
can cost $60,000–100,000 each. Adding an MS component can raise the price to $130,000–160,000, with annual maintenance costs
between $5000 and $6000. In addition, operators unfamiliar with the equipment would need at least a week or two of intense
training to learn how to find interferences and the relevant emission lines. At a time when companies are cutting their workforce
and scaling back expenses, the investment may be difficult to make.
Moreover, ICP–MS for heavy metals uses USP reference standards. "Sometimes USP reference standards may be on backorder and
they are very expensive," says Velez. "Another expense is that we always need to have argon, that is what keeps the plasma
going, and argon is an expensive gas." SGS now runs ICP for some clients. It currently receives 50–100 samples per month for
heavy metals. "If we went from a wet chemistry method to an ICP method, it would at least double the cost. It may be more
cost effective based on quantity, but it is a significant expense that [USP] is passing along to the companies that are asking
us to do the tests." She adds that conducting an ICP method, however, could eliminate some of the other general chapters that
are already in USP such as running separate tests for iron, zinc, and mercury.
Although Virgili agrees that the ICP and AA methods are more expensive, he argues that with more diffusion through the marketplace,
the costs may become more reasonable. He points out that the use of reagents with ICP is minimal, quite less than high performance
liquid chromatography when the costs to replace the columns, solvents, and recycling these solvents are factored in. "When
you look at it in the perspective of a phased-in implementation over a period of say five years, I don't think it is the biggest
Boyajian also points out that pharmaceutical firms may not realize how far the environmental and geological industries have
come in using these newer techniques. "The drug industry is focused on the tried and true because that is what we focus on—making
sure we are consistent. But some of these cutting-edge techniques are completely ignored for the time being. ICP–MS and ICP
both can be done for less than $100 per sample."
The stimulus article lists the first approximations of the oral limits and parenteral limits for those elements listed in
the sidebar. Within industry, however, there is still confusion as to the origin of these limits and why some of these limits
disagree with limits already established in other references such as the Food Chemicals Codex and the Code of Federal Regulations requirements for food additives. Industry is also discussing whether these limits apply to substances or finished products.
Limits on finished products, for example, would have to take into account dosage, intended use, and the daily exposure information
similar to what is used for evaluating residual solvents limits.
Some of these metals are necessary. Iron in dietary supplements, for example, and alumnium, which may go into a pigment for
a tablet, can be beneficial. Placing a limit on these elements when they are residuals as opposed to when they are intended
components has to be handled separately from limiting metal impurities that are known to be toxic.
"I understand why USP is trying to revise the chapter, but a lot of the limits that USP is proposing are much higher than
what they were in the original monograph, so it doesn't make sense that they now allow more than what was allowed individually,"