Pharmaceutical heavy metals detection now requires high-technology equipment.
The United States Pharmacopoeia (USP) test for heavy metals (USP 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 1st December 2015. In the current European Pharmacopoeia (Ph Eur), the 2.4.8 heavy metals test will be replaced with 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.
These changes will have an impact on the testing and development of drugs and dietary supplements for consumption in the US and European markets. The USP 231 test is currently a colourimetric procedure based on the precipitation of heavy metals that is only sensitive enough 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, with the chemical synthesis of active pharmaceutical ingredients (APIs), the drug development process has changed.
Modern manufacturing
In the manufacturing process, sources of heavy metals include those that are deliberately added to the process (such as catalysts), those that are carried through a process that is conducted according to good manufacturing practices (undetected contaminants from starting materials or reagents, for instance), those coming from the process (for example, leaching from pipes and other equipment), and those that occur naturally (such as those 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 manufacturing process in a series of classes.
Currently the goal is to harmonise the USP, Ph Eur and International Conference on Harmonisation (ICH).
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. These differ in range from the heavy metals detected by the traditional USP 231 method.
The above changes will call for a paradigm shift in technology to achieve the required accuracy, range, specificity and limits of detection.
Sample preparation
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 require methodology expertise, as well as a broad depth of sample preparation knowledge.
Instrument set-up, what type of system is used 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 must 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 validation of the methodology for each particular pharmaceutical API and/or formulation as required.
The impact on businesses
For many small- to medium-sized organisations the changes will necessitate a considerable investment in training staff in the required technology and investment equipment, such as ICP and ICP-MS to perform this testing in-house.
This will remove important resources from the pharmaceutical value chain and limit the focus on future research and developments, which in turn could have a considerable impact on the pharmaceutical development market.
Therefore it is now the time for such companies to seek out a partner contract research organisation (CRO) with the capabilities, knowledge and resources to perform this for them.
Without any 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 a fraction of the cost of keeping the analysis in house.
Testing services
International Laboratory Services (ILS) is one of the market leaders in the provision of contract laboratory pharmaceutical testing services in the UK, and it provides a wide range ofcGMP-compliant chemical and microbiological testing to both the food and pharmaceutical industries.
For more information at www.scientistlive.com/eurolab
ILS Limited is based in Shardlow, Derbyshire, UK.
