shutterstock_582653683Trace Elements in Pharmaceuticals – The Details on USP <232> and ICH Q3D

The arrival of 2017, following as it does on the back of a politically momentous 2016, heralds the start of the one year countdown to the implementation of the U.S. Pharmacopeial Convention (USP) <232> and International Conference on Harmonisation (ICH) Q3D trace elemental impurities in pharmaceuticals protocols. As those of you who work in the pharmaceutical industry will know, USP <232> and ICH Q3D are already implemented for new pharmaceutical products (as of June 2016) but in January 2018, these rules are going to be extended to all pharmaceutical preparations. In practice, USP <232> and ICH Q3D apply to the final pharmaceutical product, but the implications of these new rules stretch beyond that, encompassing the excipients as well as the active pharmaceutical ingredients (API’s). There has been and continues to be considerable debate on how to assess the trace elemental impurity risk with regard to each component in any given product and who should be responsible for measuring, validating, reporting and storing data for each product involved in the process. One thing is certain though, come January 1st 2018, pharmaceutical manufacturers across the world will need to have in place a mechanism – either in-house or sub-contracted – for measuring and reporting a range of trace elements in their products when a risk of elemental impurity contamination has been identified.

Which elements need to be quantified and how should they be measured?

USP <232> and ICH Q3D have been aligned such that both protocols specify the same element classification and required maximum impurity levels. The elements required to be measured are broken down into three classes:  Class 1, Class 2(a) & Class 2(b) and Class 3.

  • Class 1 includes the so-called ‘Big Four’ — As, Cd, Hg and Pb– which must be measured in all pharmaceutical products where a risk of contamination has been identified.
  • Class 2(a) and 2(b) require measurement if they have a high probability of being present in the products (e.g. are used as catalysts during the manufacture of the API). Class 2(a) includes Co, Ni and V (these are considered to have a higher probability of occurrence) and Class 2(b) covers Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl (these are considered to be less likely to be present).
  • Finally, Class 3 covers elements regarded as having low toxicity via oral ingestion, but higher toxicity via inhalation or parenteral administration. Class 3 elements, which include Ba, Cr, Cu, Li, Mo, Sb, and Sn, are only required to be measured for products taken orally if they are intentionally added during the manufacturing process.

The recommended analytical techniques for measuring elemental impurities in pharmaceutical products are given in the procedures protocol that accompanies USP <232>, namely USP <233>. This protocol describes the use of ICP-OES or ICP-MS for elemental impurity measurements but also states that other techniques can be used if they are shown to meet the required limits given in USP <232>. In practice, most pharmaceutical laboratories who have already implemented USP <232> or ICH Q3D have adopted ICP-MS as the preferred technique on the basis of its higher sensitivity which future proofs the analysis, should the impurity levels be reduced from where they are currently set.

The Rules for Dietary Supplements (nutraceuticals) – USP 2232

The United States Pharmacopeia (USP) has published a dedicated chapter for elemental impurity limits in dietary supplements, USP <2232>, but, as with USP <232>, the analytical methodology for measuring those impurities is outlined in USP <233>. In contrast to USP <232>, USP <2232> focuses solely on the ‘Big Four’ elements mentioned above (namely As, Cd, Hg and Pb), as these are of the greatest toxicological concern. USP <2232> describes two options to test for elemental impurities, either analyzing the product directly, or by using the individual component option for dietary supplements which have a maximum daily dosage of less than 10 grams. In the latter case, it is sufficient for manufacturers to prove that the individual components do not exceed certain target limits for compliance. This offers the inherent advantage that if a compound is used for several products, analysis is required only once.

ICP-MS is the preferred technique, but which type of ICP-MS is best?

There are 4 basic types of ICP-MS instruments: single quadrupole (SQ), triple quadrupole (TQ), high resolution (magnetic sector field) (HR) and time-of-flight (TOF). Of these, SQ and TQ are the most commonly used for trace elemental analysis in pharmaceutical products.

SQ-ICP-MS is suitable for the majority of pharmaceutical analyses as it offers the sensitivity and interference removal capability required for meeting the impurity limits in most pharmaceutical products. However, there are some products which introduce new interferences which cannot be effectively removed using SQ-ICP-MS.  As unexpected as it might be, seemingly innocuous Vitamin B12 supplements provide a real challenge for accurately measuring As. The cause of the problem is the high level of Co present in this vitamin (approximately 3% of the total mass of Vitamin B12). When high concentrations of Co enter the ICP-MS, the 59Co16O spectral interference, which directly interferes with 75As, becomes significant. Since As is monoisotopic at mass 75, there is no other non-interfered isotope available. Furthermore, since Co is monoisotopic at mass 59 and O is mostly (99.8%) 16O, the CoO interference is relatively large (typically 1 to 2% of the 59Co signal).

Fortunately, this problem can be easily overcome using TQ-ICP-MS.  The solution is based on transmitting mass 75 through the first quadrupole, then reacting the target 75As isotope with O2 inside the second quadrupole (the CoO interference on 75As doesn’t react) to generate 75As16O at mass 91 and finally selectively transmitting the AsO product through the third quadrupole to the detector. Using this approach, the CoO interference on As is effectively eliminated enabling accurate results to be obtained for As. More details on this analysis and other challenging analyses for which TQ-ICP-MS provides an elegant solution can be found at http://www.thermofisher.com/iCAPTQ.

When USP <232>, ICH Q3D and USP <2232> are fully implemented on January 1st, 2018, we’ll be here to help you with our complete range of elemental impurity analysis solutions. In the meantime, if you have any questions on methods, workflows or our trace elemental analysis products, just let us know via the comments box below.

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Additional Resources

ICH Q3D protocol description and training modules (listed under the heading ‘Q3A – Q3D Impurities’)

Downloadable QC Primer for USP <232>, <233>, <2232> and ICH Q3D (registration required)

Application note AN 43149: Analysis of elemental impurities in drug products using the Thermo Scientific iCAP 7600 ICP-OES Duo (downloadable PDF)

Application note AN43325:  Analysis of Pharmaceutical Products for their Elemental Impurities with the Thermo Scientific iCAP RQ ICP-MS (downloadable PDF)

Technical Note 43106: Qtegra Intelligent Scientific Data Solution (ISDS) for 21 CFR Part 11 Compliant Laboratories (downloadable PDF)

Further applications notes, posters, videos and more can be found at the Thermo Scientific Elemental Impurities Information Learning Center