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 will officially be replacing the long standing USP method Heavy Metals Limit test.

This chapter is being 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 is being proposed to include additional elements and their specific limits in this chapter. Additional changes are made to provide clarity on the topic of risk assessment.

Compliance to these new revisions will take effect by 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 soon to be replaced USP Heavy Metals Limit test has 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 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 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.

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
Aresnic 1 15 15 2
Mercury 1 30 3 1
Cobalt 2A 50 5 3
Vanadium 2A 100 10 5
Nickel 2A 200 20 1
Thallium 2B 8 8 1
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
Table 2. Permitted Concentrations of Elemental Impurities for Individual Component Option
(Assuming A 10g Daily Serving Size)

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

 

 

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