Implementation realities
As noted, in addition to USP's changes, both ICH and EMA are drafting plans for the bio/pharmaceutical industry to develop
methods and establish compliance limits to meet defined metal impurity specification limits for drug products and drug product
components. It is the industry's hope that these various organizations would work to harmonize with the ICH Q3D guidelines;
however, there currently appears to be significant differences in what and when materials will be required to comply. It should
also be noted that until the Ph. Eur. and Japanese Pharmacopeia are updated to reflect the new ICH Q3D guideline, the older tests for heavy metals within those pharmacopeias will still be
required. Any benefits of test reduction will not be gained until the ICH Q3D guideline is fully implemented and the compendia
are harmonized.
Table I: Comparison of USP and ICH implementation plans for elemental impurities.
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Affected products.
As shown in Table I, USP implementation plans have been defined differently in the new USP chapter <232> Elemental Impurities—Limits than those found in the preliminary pre-step ICH Q3D guideline. The differences
in scope between USP and ICH create serious implementation difficulties for industry. The new USP chapters <232> and <233> encompass all products, new and existing, which presents industry with an impractical compliance
task by the May 2014 date. The greater number of elements in the ICH scope forebodes either a doubling of implementation efforts
to achieve compliance by the USP timeline for all 27 elements, or the prospect of duplicating implementation efforts to include
elements not covered by USP once the ICH guideline is completed.
Implementation timelines.
As noted, the ICH Q3D working group is at the pre-step 2 (of 5) stage of development for its guideline on metal impurities
and plans to finalize the document by mid-2014. USP has already published its two new elemental impurities chapters in the
second supplement to USP 35–NF 30, which becomes official Dec. 1, 2012. In addition, USP is planning to implement the new tests and specifications
contained in the new General Chapters through General Notices, with a planned implementation date of May 1, 2014. Finally,
all references to USP General Chapter <231> Heavy Metals are scheduled to be removed from the monographs in USP 37–NF 32.
Full implementation of the new USP chapters would therefore be required before the ICH Q3D guideline is complete, which as
noted is likely to result in duplicative efforts among the industry.
Figure 1: USP implementation limits for elemental impurities, based on USP <232>. Adjusted duration is in weeks.
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Test adoption.
The use of tools such as that illustrated in Figure 1 have highlighted just how difficult it is to estimate the resources and time needed to change elemental impurities limits
in final product, regardless of whether one is considering USP or ICH methods. This complexity is a consequence of the large
number of unknowns that require consideration. Pharmaceutical excipients and APIs have never been routinely tested for the
specific metals proposed by USP and ICH Q3D. The nonspecific limit test has been the standard for many years. It is the coalition's
view that it will take industry a long time to compile enough data to understand the levels of these specific metals actually
present and then implement appropriate testing and/or controls.
A key factor in the USP implementation timeline is that some suppliers may not be aware of these pending requirements, and
many do not have sufficient information or data on levels of metal impurities in their products. IPEC–Americas has developed
an Information Exchange Request Form (available online at http://ipecamericas.org/content/ich-q3d-information-exchange-request/) designed to initiate an exchange of information between drug product manufacturers and suppliers of the ingredients used
in those formulations to bring awareness to the proposed ICH Q3D guideline and to gain a better understanding of the potential
metal impurities, and their normal variation in the ingredients used in those drug formulations.
Whereas a few companies may already have well-established laboratories fully equipped with appropriate analytical instruments
(e.g., ICP–mass spectrometry [MS]) and procedures developed for sample preparation and analysis, many excipient manufacturers
and some drug companies currently do not. As a result, some companies may require more than 18 months to fully implement testing
for a few drug products, and the time required would be much greater if they have a large number of products involved.
Additional concerns.
As companies begin to work through the process of completing their impact assessments, installing and validating equipment,
developing, validating and transferring methods, generating and assessing data, and documenting results/establishing limits,
it is expected that there are other potential issues which may arise. For example:
- Sample preparations will likely take longer and require more time to develop than sample analysis.
- Sample preparation for each type of material or material family could be significantly different and will require time to
develop.
- Certain materials (e.g., talc, silica, silicones, as well as formulations containing these ingredients) require digestion
with hydrofluoric acid (HF) prior to ICP–MS analysis. HF digestion is hazardous and the total elemental results obtained are
not related to the bioavailability of these metals in the human body.
- If permissible daily exposures (PDEs) are exceeded, reformulation of the drug product may be necessary if the level of the
metal cannot be reduced in the finished dosage form.
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