The USP (United States Pharmacopoeia) test for heavy metals <231> is to undergo a proposed change with replacement by spectroscopy methods in the new elemental impurities chapters USP <232>, <2232> and <233>. The US Pharmaceutical Convention proposes that these changes are implemented by 1 December 2015. In the current Ph Eur (European Pharmacopoeia) the 2.4.8 heavy metals test will be replaced by two elemental impurities procedures. This is reflected in the general chapters 5.20 where limits are imposed for metal catalysts and in 2.4.20 which provides suitable sample preparation and measurement techniques.
This will have an impact on the testing and development of drugs and dietary supplements for consumption in the US and European marketplace. Currently the test (USP <231>) is a colorimetric procedure based on the precipitation of heavy metals that is sensitive enough only for certain elements (Pb, Hg, Bi, As, Sb, Sn, Cd, As, Cu and Mo). The test is not specific nor does it provide adequate measurement of the elements being tested for. The test was developed more than 100 years ago and since then the drug development process has changed with the chemical synthesis of Active Pharmaceutical Ingredients (APIs).
Currently the test (USP <231>) is a colorimetric procedure based on the precipitation of heavy metals that is sensitive enough only for certain elements
In the manufacturing process sources of heavy metals include those that are deliberately added to the process (e.g. catalysts), those that are carried through a process that is conducted according to good manufacturing practices (e.g. undetected contaminants from starting materials or reagents), those coming from the process (e.g. leaching from pipes and other equipment), and those that occur naturally (e.g. from naturally derived plant or mineral sources).
Modern drug manufacture APIs involving the use of metal catalysts or metal processing equipment can become contaminated, as can the formulation. Chromium and nickel are potential contaminants from modern stainless steel processing equipment and are not detected by USP<231>.
Both the Ph Eur and the USP define levels of heavy metal residuals allowable in the manufacture process in a series of classes. Currently the goal is to harmonise the USP, Ph Eur and ICH (International Conference on Harmonisation).
The proposed USP methods would test for Class 1 (As, Cd, Hg and Pb) and Class 2 (Cu, Cr, Ir, Mo, Ni, Os, Pd, Pt, Rh, Ru and V) elemental impurities. The suggested Ph Eur methods would test for class 1A (Pt and Pd), Class 1B (Ir, Rh, Ru, Os), Class 1C (Mo, Ni, Cr, B), Class 2 (Cu and Mn) and Class 3 (Fe and Zn) elemental impurities. Lastly, the proposed ICH methods would test for Class 1 (As, Pb, Cd, and Hg), Class 2A (V, Mo, Se and Co), Class 2B (Ag, Au,Tl, Pd, Pt, Ir, Os, Rh and Ru), Class 3 (Sb, Ba, Li, Cr, Cu, Sn and Ni) and Class 4 (B, Fe, Zn, K, Ca, Na, Mn, Mg, W and Al) elemental impurities – different in range from the heavy metals detect by the classical USP heavy metals method <231>.
The above will call for a paradigm shift in technology to achieve the required accuracy, range, specificity and limits of detection. The USP proposed <232> and <233> changes will require new methods of sample preparation such as acid digestion followed by analysis using ICP and ICP-MS instrumentation. This will insist on methodology expertise, as well as a broad depth of sample preparation knowledge.
Instrument set-up, the system for sample introduction and plasma discharge are all integral aspects of accurate and representative analysis that is fit for purpose. These changes will entail a considerable investment by pharmaceutical companies in the drug development process. As it takes many years to bring a product to the marketplace, companies have to be made aware of the proposed changes now and start to develop testing of their product to comply with future regulations. The new technology will involve necessary validation of the methodology for each particular pharmaceutical API and/or formulation as required.
For many of the small- to medium-sized organisations the changes will necessitate a considerable investment
For many of the small- to medium-sized organisations the changes will necessitate a considerable investment in training staff in the required technology and investment in equipment such as ICP and ICP-MS to perform this testing in house. This will remove valuable resources from the pharmaceutical value chain and limit the focus on future research and developments, which could in turn have a considerable impact on the pharmaceutical development market.
Therefore now is the time to seek out a partner contract research organisation (CRO) with the capabilities, knowledge and resources to perform this for them. Without the large capital investment required from the pharmaceutical company, the CRO partner can develop and validate methodology for the detection and quantification of the particular heavy metals used in the drug development process at an fraction of the cost of keeping the analysis in house.
