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US Pharmacopeia has finalized the Method Revisions USP <232> and USP <233>

The US Pharmacopeia (USP) has finalized the revised methods for the determination of elemental impurities in pharmaceutical products. The USP <232> and USP <233> will officially be replacing the long standing USP method <231> Heavy Metals Limit test. USP <232> and <233> will be incorporated into the “Second Supplement to USP 25-NF30 on December 1, 2012. Compliance to these new revisions will take effect by May 1, 2014.

As most of you are aware, the soon to be replaced USP <231> Heavy Metals Limit test has been in existence for over 100 years. The USP <231> was not capable of individually determining the concentration of each metal in a specific sample. It was a qualitative analysis. Capable of only giving a combined concentration result of heavy metals at a detection level of a possible 3 to 10 ppm. Within the last 40 years there have been enormous strides in the development of spectroscopy techniques able to be elemental specific with much lower and precise results. The development of ICP-OES and ICP-MS has provided extraordinary leaps into the elemental and trace elemental analysis realm which has made the USP <231> obsolete. Now elemental impurities can be isolated and determined at levels unachievable by the soon to be replaced USP <231>.

As of April 27, 2012, the new USP <232> (Elemental Impurities-Limits) and USP <233> (Elemental Impurities-Procedures) have given regulated guidelines for the determination of elemental impurities in pharmaceutical products.

Trace Metal Analysis by AA and ICP-OES

Metal impurities have historically been monitored in drug articles intended for use by humans and animals. Drug articles include active pharmaceutical ingredients (API),excipients, drug products and dietary supplements along with their ingredients. Some heavy metals, such as arsenic, mercury, cadmium and lead are toxic at very low levels and should be monitored to ensure consumer safety. Sources of metal impurities may include those that are added to the process (such as catalysts), those derived from the process, or undetected contaminants from starting materials or reagents.

Metal impurities test procedures are currently available in the USP under the General Chapter <231> heavy metals as well as specific tests for aluminum, arsenic, iron, lead, and mercury. USP <231> is a limit test, which is qualitative or at best semi-quantitative. It demonstrates the content of metallic impurities by using sulfide ions to produce a colored precipitate, and standard comparisons are made to determine if the samples exceed specified limits. Sample preparation schemes may be utilized in this analysis are:

  • Method I is used for substances that are soluble in water and produce a clear, colorless solution. After addition of a sulfide reagent, the color is compared to both a standard as well as a sample spiked at the limit.
  • Method II is used for aqueous insoluble materials where the solid sample is first carbonized by heating with sulfuric acid, and then the residual carbon is burned off in a muffle furnace. Metals are subsequently extracted from the residue. The analysis is free from any organic interference.
  • Method III is used for solid samples, which are first digested in a mixture of sulfuric and nitric acids. The digestion is followed by oxidation with peroxide.

Method II and III are aggressive treatments and could lead to loss of target analytes, especially for volatile elements such as antimony and mercury, potentially yielding false negative results. In addition, the method detects only metals that are precipitated by sulfide ions, which are the elemental impurities lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper, and molybdenum. It is labor intensive, requires larger sample sizes and are non-specific since individual elements cannot be quantified. This may be impractical for expensive materials such as proteins and peptides.

Because of the limitations of the USP <231> heavy metals general chapter, USP has proposed to replace it with two analytical procedures described in USP <232> and <233>: Inductively coupled plasma mass spectroscopy (ICP-MS), and Inductively coupled plasma optical emission spectroscopy (ICP-OES).

The proposed revisions, set to become effective in September 2013, will eliminate the specificity issues, provide greater sensitivity, and quantify each individual element. All drugs produced and sold in the U.S. will be required to comply with the limits set by USP <232>. Drug substances and excipients will have to be tested for elemental impurities and all drug products will have to comply with the USP limit. In addition, all dietary supplements will have to comply with limits set by USP <2232>. For each drug article, the procedure should be verified to ensure it is appropriate for the sample used (method verification).

QCL Quality Compliance Laboratories offers trace metals analysis in pharmaceutical drug substance, drug products, and dietary supplements of various types ranging from proteins and cytotoxic compounds to peptides and oligomers.

Our trace metals analysis service fall fully in line with the new USP Heavy Metals general chapters as well as client metods. We utilize the latest Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES), Graphite Furnace AA (GF-AA), Cold Vapour (CV) system for Mercury (Hg) determination technologies and microwave digestion sample preparation techniques to meet the requirements set out in the recently published USP Heavy Metals general chapters: USP <232>, USP <233> and USP <2232>. Our highly experienced analysts perform Heavy Metals, Metal Catalysts and other trace elements testing on samples with low detection limits in full compliance with 21 CFR Parts 210 and 211 as well as EMEA and ICH guidelines. We provide Quantitative elemental and heavy metal screening on Class 1 elements, the “Big Four”; Mercury (Hg), Lead (Pb), Arsenic (As) and Cadmium (Cd), as well as Class 2 elements such as Chromium (Cr), Copper (Cu), Manganese (Mn), Molybdenum (Mo), Nickel (Ni), Palladium (Pd), Platinum (Pt), Vanadium (V), Osmium (Os), Rhodium (Rh), Ruthenium (Ru) and Iridium (Ir).