Pharmacopoeias diverging on heavy metals testing?
While the US Pharmacopeia seems to be favouring a general screening approach to testing, the European Pharmacopoeia (Ph. Eur.) and Japanese Pharmacopoeia (JP) would prefer to adopt a risk-management method.
This is an important topic are routine testing of raw and auxiliary materials, active ingredients, as well as intermediate and end products for heavy metals contamination can be a significant cost and time factor for pharmaceutical manufacturers.
Moreover, there are well-recognised problems with the heavy metal testing methods outlined in Ph. Eur. (section 2.4.8). The analytical procedures require extensive sample preparation, suffer from a lack of sensitivity and do not provide reproducible results.
“The compendial tests for heavy metals have come under a lot of criticism in recent months,” according to Susanne Keitel, director of the European Directorate on the Quality of Medicines (EDQM) which publishes Ph. Eur. “We have to acknowledge they are not the most favoured methods.”
Speaking at a recent meeting of the European chapter of the International Pharmaceutical Excipients Council (IPEC Europe), Keitel noted that these methods are in essence wet chemical tests for lead.
“Companies have been telling us they test batch after batch and hardly ever come across a positive result,” she said. “So the question is – why test at all?”
One specific problem with the Ph. Eur. tests is the loss of analyte that can occur during the ignition phase. For example one method (Method C) leads to a loss of mercury.
EDQM published a proposal last year to include a new analytical method (H) for heavy metal contaminant testing, with the aim of minimising loss of analyte during the ignition stage. Ignition should no longer be necessary at all for a broad range of heavy metals, and a more objective record of the experiment is obtained as filters can be photographed.
However, it acknowledges that more sweeping changes are needed.
Last November, the US Pharmacopeia lodged a proposal at the Pharmacopoeial Discussion Group – a forum for all three pharmacopoeia to try to bring their requirements into line – to change the requirement for heavy metals from wet chemical testing a general instrument-based screen.
Keitel said that both Ph. Eur. and JP are not comfortable going down that route.
In the EU, she noted, the Quality Working Party and Safety Working Party recently developed a guideline on residues of metal catalysts and reagents which came into force in September 2008 and according to EDQM policy the principles of this new document should be incorporated into Ph. Eur.
But this guidelines has also been criticised by industry as it does not cover all the elements – for example, it is missing aluminium, silver, boron and lithium.
“We’d like to take a similar approach to that taken with residual solvents,” said Keitel.
That would involving different classes of heavy metal residues depending on their safety concerns (taking into account the class, source and origin of the materials) and importance from a quality perspective, and she believes this risk-management approach is preferable to establishing a general screening method.
Keitel said EDQM is setting up a working party to look into the issue in 2009.
