During its 2008 annual meeting, USP said it is looking into paring the list of elements down and providing guidance that manufacturers
test only for those elements pertinent to their product (2). IPEC–Americas proposes a stepwise approach that focuses on the
metals that have the most safety concern to determine their limits and methodologies. Then analysts would assess what other
metals need controls and establish appropriate limits and methodologies.
"No one questions there need to be tighter controls on some metals with safety concerns. However, if the full list of 31 metals
is incorporated in this initiative all at once, there will be much controversy about whether they all need to be controlled
and what the scientifically justified limits need to be in those cases to provide appropriate levels of safety, especially
where there may be limited literature information concerning any real safety issues. Let's see how this plays out as we implement
the control of the key metals in industry and get everyone on board with thinking about these metals individually and then
learn from that and see how the implementation goes," says Schoneker. "We can then add more metals to the list as needed using
an organized process so that the implementation for these additional metals provides appropriate control but also works for
the industry. Judging from discussions during past stakeholder meetings, we have a sense that USP will not go forward with
the way that was specifically proposed in the stimuli article. USP has indicated they will have an Open Forum style meeting
in the near future to obtain more information from industry before deciding how to proceed. That is certainly our hope."
The proposal in the stimuli article to replace the entire General Chapter has also been debated. Some experts believe only
Methods II and III should be replaced because Method I is still effective for soluble substances. "I think people are saying
where simple works, let simple be," says Schoneker. "To our knowledge, no one has shown that there are any problems with using
Method I. You are not using any heat or other processes in that method to affect the metal recovery. For simple inorganic
material, if you can mix it in water and run a quick sulfide reaction as you do now and you get accurate data that shows you
don't have metals present, why not continue with that where it works."
USP indicates the selection of a method should be based on performance using USP reference standards. In particular, "any
procedure that provides measurement values within ±20% of the certified concentration for each element in the appropriate
USP Reference Standard(s) is considered to be an acceptable procedure to demonstrate compliance" (2).
"USP's intent is not to replace a known specific technology with one that is more specific," says Virgili. "It is just to
introduce ICP as an analytical tool and still allow the use of atomic absorption and other techniques, including some spectroscopic
techniques in the UV or visible region. If you know what you are looking for and you have the sensitivity and specificity,
then it is okay. USP does not exclude anything." However, when it is unknown what, if any, impurities are in a material, such
as for some raw materials, drug substances, and excipients, a broader screening may be needed. In such case, the power of
ICP or X-ray fluorescence technologies may be needed.
One problem is that ICP is not yet a typical analytical instrument. For some Big Pharma companies and firms making drug substances,
where metal impurities may be present, ICP may be a quality control technique, depending on the susceptibility for metal
impurities resulting from the processes (e.g., use of catalysts or present in starting materials) and equipment. Many smaller
excipient companies and contract laboratories, however, may not yet have ICP or AA instruments. It depends on the likelihood
of metals being present in their material, metals that are subject to concern. Some suppliers may have to do a thorough metal
screening. In other cases, they will not get that equipment because the concern is not there. These companies are going to
have limits to what they will be willing to pay or what they will be willing to do to meet this requirement.