Laboratory Testing Blog

Review of Proposed USP Changes to Heavy Metals Testing

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In moving from a chemical to an instrument-based methodology, the USP has taken great care to allow for a flexible approach and is working closely with both the FDA and industry to ensure widespread agreement on interpretation of the revisions.  Following are brief descriptions of the techniques and methodologies being proposed by USP:

• Graphite Furnace Atomic Absorption (GFAA)

• Flame Atomic Absorption (FLAA)

• Cold Vapor Atomic Absorption (CVAA)

• Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP/OES)

• Inductively Coupled Plasma-Mass Spectrometry (ICP/MS)

Careful examination of each application must be completed from a quality assurance perspective.  There are situations when multi-element techniques that utilizes plasma as an ion source is capable of producing values that appear to be valid for identification or from a limit test control standpoint, but on the other hand is invalid from a quality assurance standpoint.

Verification of the compendial testing procedures illustrated in USP<233> will be required prior to use.  This can be completed by meeting the “Procedure Validation Requirements” outlined in General Chapter USP<233>.  Two types of validations, limit and quantitative will be permitted and both types of validations will have to be verified experimentally.

The limit test validation will include performing:

The quantitative test validation will include performing:

Perhaps the main criticism of the revised testing protocols relates to the associated cost of new instrumentation and/or outsourcing for testing.  Because Inductively Coupled Plasma spectrometry is not yet widely used in the pharmaceutical industry, smaller manufacturers and excipient companies may not yet have the instrumentation in place and will need to either purchase the new equipment or send their testing to contract testing laboratories.

Atomic Absorption and Inductively Coupled Plasma each include advantages and disadvantages with respect to cost, sensitivity, selectivity, and ease of use.  In some cases Atomic Absorption is a best suited for certain elements, but not for others.  The same is true for certain sample matrices.  For example, the analysis for lead and arsenic by ICP/OES frequently represents a poor choice because of the associated high detection limits (DL).  With these elements, sample preparation would have to be more complicated in order to offset relatively high DL for the instrumentation.  For these situations, GFAA or ICP/MS would be preferable choices.