General Chapter <232>: New limits
USP General Chapter <232> Elemental Impurities—Limits sets out the acceptable levels of 15 elements in final drug products. These
limits have been evaluated from toxicological data and are expressed in terms of a daily permissible exposure (DPE) limit.
The DPE also takes into consideration the route of administration (e.g., oral, parenteral, or inhalable) with orally administered
drugs having a higher permissible limit than parenteral or inhaled drug products. Where elements on the list are known to
be present or have the potential to be present then compliance with the specifications must be assessed. The 15 elements addressed
in Chapter <232> are based on the International Conference on Harmonization's (ICH) Q3D Elemental Impurities Working Group
pre-Stage 2 draft guideline (2).
Chapter <232> covers arsenic, cadmium, mercury, and lead— all elements that are considered ubiquitous and therefore must be
assessed in all cases. In addition, the chapter covers iridium, osmium, palladium, platinum, rhodium, ruthenium, chromium,
molybdenum, and nickel. The second group of elements may be present in products as a result of being added deliberately, for
instance, in the form of a catalyst or through interactions with metal components through the manufacturing process.
Because the ICH Q3D guideline is still being reviewed and is likely to expand to cover more elements, it has been decided
that a review of Chapter <232> will happen after the deliberations on ICH Q3D guidelines have been completed. At this stage,
the scope of Chapter <232> may be expanded to cover more elements, or an informational chapter may be incorporated to cover
elements of low toxicity.
The outdating of long-standing tests
It is fair to point out that the methods of USP General Chapter <231> were developed before the introduction of modern analytical instruments. These methods were easily
transferable from one laboratory to another and did not require sophisticated instrumentation or specialized expertise. Hence,
a competent laboratory staff member could perform the same techniques with relative ease. The problem was that the methods
themselves were flawed, no matter how competent the analyst.
For example, Chapter <231> methods involved subjective visual examination and comparison of the sample solution with a lead
standard. Similar to the method of 1905, the compendial methods used a reaction to form the sulphide of any metal ions present
and the total metal content was reported against the lead standard response as a limit test.
The validity of this comparison relied on several assumptions, all of which can be questioned. For example, the compendial
method assumed that each of the heavy metals in the sample matrix would react in a like manner to lead to form a sulphide
species. This assumption applied despite many sulphides being known to be insoluble and despite some elements being known
to have a far more intensely colored sulphide than the lead standard against which it was being assessed. Similarly, the compendial
method assumed that the reaction kinetics for lead sulphide would be very similar to that of the other metal sulphides and
that reaction kinetics were not greatly affected by the sample matrix. A final major and unsafe assumption was that the heating
and/or ashing step of the method would have no impact on volatile metals (3).
Work has been carried out that suggests that recovery of mercury can be as little as 2% using the <231> compendial method,
which clearly introduces a massive error in the final result (2). Other laboratories have reported similar poor recovery of
metals such as tin, selenium, and antimony. These examples are by no means the only reasons to challenge the validity, applicability,
and reliability of the compendial methods. In fact, additional chapters for the control of specific metals and other inorganic
impurities have been added to USP over the years. Significant among these additions has been USP Chapter <730> Plasma Spectrochemistry, which gave laboratories the opportunity to use techniques such as inductively coupled
plasma with either mass spectrometry or atomic emission spectroscopy (ICP–MS and ICP–AES).
The advantage of ICP methods is that they can provide specific detection and quantification for each of the elements specified
in Chapter <232>. The subjectivity of the semiquantitative comparison that is required by the compendial methods is eliminated
with ICP. The ICP techniques are also quicker in most cases, requiring a smaller sample size and giving a better detection
limit for all the elements of interest. The sample preparation method for ICP, for example, is less likely to lead to the
loss of the volatile elements.