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LIFE SCIENCE I TECHNICAL BULLETIN ISSUE N28/ SEPTEMBER 2010

USP ELEMENTAL IMPURITIES TO REPLACE


USP <231> HEAVY METALS
AUTHOR: GAYLA VELEZ, DIRECTOR, ANALYTICAL SERVICES, SGS LIFE SCIENCE SERVICES, USA

Our last article on the replacement of USP <231> Heavy Metals (October 2008) focused primarily on Inductively
Coupled Plasma (ICP) and limits under consideration at that time. Since then, the USP has completed its revision
on how heavy metals testing will be performed for drug products, drug substances, excipients and dietary supple-
ments. The classical wet chemistry methods will be replaced by more specific methodology including ICP Spec-
troscopy, Atomic Absorption (AA) Spectroscopy and X-Ray Fluorescence (XRF) Spectroscopy. This has been a hot
topic in the last few years with various Pharmacopeial Forum publications and industry commentary taking place.
Outlined here are the main points and outcome of this highly anticipated change.

The USP has proposed three new gene- is required only if these metals are added product. This calculation may only be
ral chapters to replace the current Heavy during manufacturing. used if the maximum daily dose is
Metals procedure in general chapter not more than 10 grams.
<231>: Specifications are based upon the route
of delivery for the drug product, and the 3. The third calculation method is used
<232> Elemental Impurities Limits USP has proposed limits for oral and pa- when the daily dose is more than
<233> Elemental Impurities renteral dosage forms. The specifications 10 grams/day or if any individual
Procedures are based upon the following assump- component exceeds the component
<2232> Elemental Contaminants in tions: 10 grams/day drug product dose, limit. This calculation is perfor-
Dietary Supplements 50 kg body weight, 70 year lifetime, med on each individual elemental
10% bioavailability for oral dosage forms impurity. The sum of the elemental
<232> ELEMENTAL IMPURITIES and 100% bioavailability for parenteral impurity in each component of the
LIMITS dosage forms. USP has provided three drug product must be less than the
methods for calculating elemental impu- PDE.
USP <232> provides limits for Class 1 rities in drug products:
and Class 2 elemental impurities in drug <233> ELEMENTAL IMPURITIES
substances, drug products and exci- 1. The first calculation method mul-
PROCEDURES
pients. The limits are based upon toxicity tiplies the impurity results from a
and the hazard these impurities may typical dosage unit by the maximum
USP <233> provides methodology for
cause to the environment. The focus is daily dose to determine if it is less
analyzing elemental impurities in drug
on the Class 1 elemental impurities Ar- than the permissible daily exposure
substances, drug products, excipients,
senic, Cadmium, Lead and Mercury. All (PDE).
dietary supplements and dietary ingre-
drug products must comply with Class
dients. Alternate methods may be used,
1 elemental impurity specifications. 2. The second calculation method
but must be validated for each elemen-
Class 2 elemental impurities are metal evaluates each individual compo-
tal impurity. Validation procedures are
catalysts, which include Chromium, Cop- nent in the drug product. If the drug
described for limit tests and quantitative
per, Iridium, Manganese, Molybdenum, substance(s) and all excipients meet
tests.
Nickel, Osmium, Palladium, Platinum, the proposed component limits,
Rhodium, Ruthenium and Vanadium. then these components may be
Limit test validation includes perfor-
Testing for Class 2 elemental impurities used in any proportion in the drug
ming accuracy and repeatability at the
LIFE SCIENCE I TECHNICAL BULLETIN 2

limit, and specificity. Quantitative test <2232> ELEMENTAL required if the results for total Mercury
validation includes performing accuracy met the Methylmercury PDE limit.
CONTAMINANTS IN DIETARY
at 50%, 100%, and 150% of the limit,
repeatability at the limit, specificity, and SUPPLEMENTS Calculating elemental contaminants in
limit of quantitation (at 50% of the limit). dietary supplements can be done using
USP has proposed two referee pro- USP <2232> provides limits for Class 1 the same three scenarios described
cedures. These procedures use ICP- elemental contaminants in dietary sup- under <232>.
OES and ICP-MS methodology. Sample plements and dietary ingredients. Limits
preparation can be performed by diluting for individual components and permis- Trust SGS for Your Elemental Impurity
the test article in an aqueous solution sible daily exposure (PDE) are provided Testing
(dilute acid), diluting in an organic solvent for Arsenic (inorganic), Cadmium, Lead,
or by closed vessel microwave digestion. Mercury (total), and Methylmercury. The The USP changes should become official
Two working standards and a blank are limits are based on the assumptions within the next 12 months. SGS has
analyzed. System suitability using check described under <232> for oral dosage extensive experience with the proposed
standard recovery is outlined within forms. USP methodology and is ready to im-
each method. Prior to analyzing any test plement the new USP requirements to
articles, method verification according to Speciation for Arsenic and Mercury are make a smooth transition for our clients.
USP <1226> Verification of Compendial addressed in this general chapter with Contact SGS Life Science Services to
Procedures must be performed. testing methodology provided for inorga- help you plan your strategy to remain in
nic Arsenic and Methylmercury. The test compliance with Heavy Metals Testing.
for inorganic Arsenic would not be requi-
red if the results from a non-speciated
Arsenic test method met the PDE limit.
The test for Methylmercury would not be

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