History of elemental impurities
The starting point for USP's new elemental impurities chapters were challenges to the accuracy and recovery of the existing
pharmacopeial methods for heavy metals. USP General Chapter <231> Heavy Metals provides three methods, all based on the precipitation of metal ions by a sulfide reagent
(4). In 1995, a report was published in the USP Pharmacopeial Forum showing very poor recovery from Method 2, which uses an ignition technique for sample preparation in some excipients (7).
Follow-up articles in the literature investigating these tests concluded that the methods were poorly suited for effective
quantification of the level of metal impurities, due to lack of specificity as well as poor recovery (8).
Over several years, USP made efforts to improve the existing sulfide precipitation methods. USP 28–NF 23 Supplement 1, effective April 1, 2005, for example, added monitor solutions to check the recovery and require rejection
of results if the standard was not met. These approaches did not work well and were withdrawn in USP 30–NF 25, effective May 1, 2007.
The European Pharmacopoeia (Ph.Eur.) also made attempts to improve the existing methods, but with greater success. Using a technique of standard addition, the
performance of the method was confirmed with greater confidence. In addition, Ph. Eur. developed several new methods, including methods F–H in EP 7.5, Chapter 2.4.8 Heavy Metals using organic solvents to dissolve samples, and detection using filter papers to concentrate
precipitate for better visualization (9). Current Ph.Eur. policy is not to accept new monograph submissions using the ignition method because there are concerns over the robustness
of the test.
When USP reached its final conclusions on replacements for the heavy metals tests, the sulfide precipitation test was abandoned
in favor of modern techniques, most specifically inductively coupled plasma (ICP), which are now included in the new USP General Chapter <233>.
This change further complicated the new limits to be adopted, because it is virtually impossible to correlate the current
limits based on sulfide precipitation of several metals with limits for specific metals detected by newer technology, such
as ICP. The USP expert panel working on the chapter revisions resolved this disconnect between the current limits and the
new methodology by developing new limits for the specific metal impurities based on toxicology considerations.
It is important to realize that the USP's terminology switch from "Heavy Metals" to "Elemental Impurities" was prompted by
analytical issues (10, 11) as described above. Although the new methodology proposed in USP represents a significant advance from an analytical standpoint, the driver is not, and has never been, a clearly identified
risk to patients in current pharmaceutical products.
Implementation plans and timelines
The plan being pursued by USP to update its elemental impurities limits and procedures represents years of consideration and
discussion. Although the industry in general supports the goals of improving test methodology and providing an extra measure
of assurance of product safety, as seen in the USP "Commentary–Second Supplement to USP 35–NF 30" (12) for proposed General Chapter <232> where of the 39 comments submitted, USP chose to only incorporate five of them,
there is widespread concern that USP has not adequately considered the impact of its implementation plan. USP stakeholders
have been vocal in citing the potential that currently approved, and safe, drug products may be pushed out of compliance or
forced to reformulate, and that drug shortages may result. There is also concern that a substantial increase in routine testing,
without a commensurate increase in product quality or safety, will result unless manufacturers and suppliers are provided
with adequate options for using risk assessment. (Risk assessment is expected to be a major topic in the ICH Q3D guideline.)
Although the current test requirements in USP General Chapter <231> Heavy Metals require improvement, industry believes that an effective public standard should focus
more on improving control rather than simply adding routine tests. Testing may be used to confirm appropriate controls, but
knowledge of material sources, supply chains, and processes—while applying the tool of risk assessment—should be the basis
of control to ensure patient safety.
Because of the wide use of the heavy metals test by sulfide precipitation, for example, simple replacement with ICP for multiple
metals would represent a huge increase in test load and expense. From the beginning of USP's project, many members of the
industry have anticipated that much of the existing, unnecessary testing of heavy metals could be eliminated. The use of quality
by design (QbD) and risk-based analysis should allow manufacturers to qualify materials and the supply chain in order to remove
testing which does not add value.
The primary driver for USP's implementation timelines of the new chapters seems to be to replace older methods with more modern
methodology; however, this methodological problem is not believed by the coalition to reflect a deeper issue of unsafe products
reaching consumers. A recent paper by FDA representatives surveyed 45 pharmaceutical products to determine lead concentrations
by ICP and found lead concentrations far below currently acceptable levels (13).