There is always a possibility that trace quantities of heavy metal elements may be present in pharmaceutical products. Historically, the biggest risks came from those that might arise from natural sources – arsenic, cadmium, lead and mercury. In the past few decades, however, transition metal catalysts have increasingly been used in the manufacture of APIs, leaving the possibility that traces of more unusual metals might also be present. Metals commonly found in catalysts include palladium, platinum, nickel, rhodium, ruthenium, chromium and copper, among others.
To say that the US Pharmacopeia’s (USP’s) testing protocol for heavy metals is outdated is something of an understatement. The method, enshrined in USP <231> Heavy Metals, prescribes the qualitative method of sulfite precipitation followed by a visual comparison, and requires checks for 10 metals – antimony, arsenic, bismuth, cadmium, copper, lead, mercury, molybdenum, silver and tin – missing out many of those that might be present as catalyst residues. Almost 20 years since the issue was first raised, replacement chapters USP <232> Elemental Impurities – Limits and <233> Elemental Impurities – Procedures are now close to being adopted. USP <232> lays down permitted limits for a range of metals, or elemental impurities, as they are now denoted. USP <233> sets out permitted testing protocols.
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