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The US Pharmacopeia (USP) has finalized the revised methods through USP <232> and USP <233> to determine elemental impurities in pharmaceutical products. This new USP Chapter is officially replacing the long standing USP method Heavy Metals Limit test.
This chapter was revised to address comments received and to further align this chapter with ICH Q3D. USP’s Elemental Impurities Expert Panel approved a recommendation to the General Chapters—Chemical Analysis Expert Committee that this chapter be revised to align with the ICH Q3D Step 4 document to the greatest extent possible. Therefore, this revision includes additional elements and their specific limits in this chapter. Additional changes were made to provide clarity on the topic of risk assessment.
Compliance to these new revisions took effect January 1, 2018. Regardless of the approach used, compliance with the limits specified is required for all drug products unless otherwise specified in an individual monograph or specifically excluded.
As most of you are aware, the previous USP Heavy Metals Limit test had been in existence for over 100 years. The USP 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 made the USP <231> obsolete. Now elemental impurities can be isolated and determined at levels unachievable by the previous USP <231> method.
As of April 2016, the new USP <232> (Elemental Impurities-Limits) and USP <233> (Elemental Impurities-Procedures) have given the following proposed regulated guidelines for the determination of elemental impurities in pharmaceutical products.
Guidance: When To Submit EI Data To The FDA
Table 1. Permitted Daily Exposures for Elemental Impurities for Drug Products
| Element | ICH Class | Oral PDE (ug/day) | Parenteral Daily PDE (ug/day) | Inhalation PDE (ug/day) |
| Cadmium | 1 | 5 | 2 | 2 |
| Lead | 1 | 5 | 5 | 5 |
| Arsenic | 1 | 15 | 15 | 2 |
| Mercury | 1 | 30 | 3 | 1 |
| Cobalt | 2A | 50 | 5 | 3 |
| Vanadium | 2A | 100 | 10 | 1 |
| Nickel | 2A | 200 | 20 | 5 |
| Thallium | 2B | 8 | 8 | 8 |
| Gold | 2B | 100 | 100 | 1 |
| Palladium | 2B | 100 | 10 | 1 |
| Iridium | 2B | 100 | 10 | 1 |
| Osmium | 2B | 100 | 10 | 1 |
| Rhodium | 2B | 100 | 10 | 1 |
| Ruthenium | 2B | 100 | 10 | 1 |
| Selenium | 2B | 150 | 80 | 130 |
| Silver | 2B | 150 | 10 | 7 |
| Platinum | 2B | 100 | 10 | 1 |
| Lithium | 3 | 550 | 250 | 25 |
| Antimony | 3 | 1200 | 90 | 20 |
| Barium | 3 | 1400 | 700 | 300 |
| Molybdenum | 3 | 3000 | 1500 | 10 |
| Copper | 3 | 3000 | 300 | 30 |
| Tin | 3 | 6000 | 600 | 60 |
| Chromium | 3 | 11000 | 1100 | 3 |
| Element | ICH Class | Oral Concentration (ug/g) | Parenteral Concentration (ug/g) | Inhalation Concentration (ug/g) |
| Cadmium | 1 | 0.5 | 0.2 | 0.2 |
| Lead | 1 | 0.5 | 0.5 | 0.5 |
| Arsenic | 1 | 1.5 | 1.5 | 0.2 |
| Mercury | 1 | 3 | 0.3 | 0.1 |
| Cobalt | 2A | 5 | 0.5 | 0.3 |
| Vanadium | 2A | 10 | 1 | 0.1 |
| Nickel | 2A | 20 | 2 | 0.5 |
| Thallium | 2B | 0.8 | 0.8 | 0.8 |
| Gold | 2B | 10 | 10 | 0.1 |
| Palladium | 2B | 10 | 1 | 0.1 |
| Iridium | 2B | 10 | 1 | 0.1 |
| Osmium | 2B | 10 | 1 | 0.1 |
| Rhodium | 2B | 10 | 1 | 0.1 |
| Ruthenium | 2B | 10 | 1 | 0.1 |
| Selenium | 2B | 15 | 8 | 13 |
| Silver | 2B | 15 | 1 | 0.7 |
| Platinum | 2B | 10 | 1 | 0.1 |
| Lithium | 3 | 55 | 25 | 2.5 |
| Antimony | 3 | 120 | 9 | 2 |
| Barium | 3 | 140 | 70 | 30 |
| Molybdenum | 3 | 300 | 150 | 1 |
| Copper | 3 | 300 | 30 | 3 |
| Tin | 3 | 600 | 60 | 6 |
| Chromium | 3 | 1100 | 110 | 0.3 |
