General Observations Regarding USP 232

By Brian W. Alexander, Ph.D.

USP <232> Elemental Impurities — Limits and USP <233> Elemental Impurities — Procedures were proposed to replace the general test chapter Heavy Metals <231>, as reported in Pharmacopeial Forum Vol. 36(1), [Jan.-Feb. 2010]. USP <232> focuses on the four most toxic and best understood metals: Pb, Hg, Cd, and As, as well as twelve additional elements (Cr, Cu, Mn, Mo, Ni, V, and Ir, Pd, Pt, Os, Ru, Rh).

  1. Following the introduction of the proposed <232> in 2010, and subsequent commentary period and review, the initial revision of USP <232> was introduced in May 2011. This version of USP <232> included detailed elemental impurities for both drug products and drug substances/excipients. IV-STOCK-37 and IV-STOCK-38 were created to conform to these recommendations.
  2. In April 2012, the "Final approved General Chapter <232> Elemental Impurities–Limits as it will appear in the Second Supplement to USP 35–NF 30"1 was posted on the U.S. Pharmacopeial Convention website (www.usp.org), with an official publication date for the Second Supplement to USP 35–NF 30 of Dec. 1, 2012. The U.S. Pharmacopeial Convention website (www.usp.org) states that "…while <232> and <233> will be official on December 2, 2012, the date on which conformance with these chapters will be required will be May 1, 2014, when the General Notices provision making them applicable becomes official."
  3. The Second Supplement had three major changes regarding elemental impurities:
  4. The elemental impurity limits changed.
  5. The Exposure Factor ratios between different dosage categories are no longer constant for all listed elements. The effect of this change is that a single elemental impurity standard is no longer suitable for testing Permissible Daily Exposure (PDE) in individual dosage categories (e.g., Oral Daily Dose PDE, Parenteral Daily Dose PDE, etc.).
  6. Mn was removed from <232>, and Cr was listed as a safety concern only for inhalation drug products, substances, and excipients.
  7. The U.S. Pharmacopeial Convention website (www.usp.org) also states (as of July 2012): "At a future date, the Expert Panel intends to revisit General Chapter <232> relative to the Step 4 outcome of ICH Q3D deliberations. At that time, the Expert Panel may add additional elements and limits to General Chapter <232> based on ICH Q3D, or may develop an informational chapter to incorporate elements of low toxicity."

Original Proposed USP <232> *Elemental Impurities — Limits

PROPOSED ELEMENTAL IMPURITY LIMITS

ElementComponent Limit (µg/g)Oral Daily Dose PDE* (µg/day)Parenteral Component Limit (µg/g)Parenteral Daily Dose PDE (µg/day)
Arsenic1.5150.151.5
Cadmium0.550.050.5
Lead1100.11
Mercury1.5150.151.5
Chromium252502.525
Copper250250025250
Manganese250250025250
Molybdenum252502.525
Nickel252502.525
Palladium10100110
Platinum10100110
Vanadium252502.525
ElementComponent Limit (µg/g)Oral Daily Dose PDE* (µg/day)Parenteral Component Limit (µg/g)Parenteral Daily Dose PDE (µg/day)
Osmium10 (combination not to exceed)100 (combination not to exceed)1.0 (combination not to exceed)10 (combination not to exceed)
Rhodium
Ruthenium
Iridium

Revised Elemental Impurity Limits

Drug Products

ElementOral Daily Dose PDE* (µg/day)Parenteral Daily Dose PDE (µg/day)Inhalational Daily Dose PDE (µg/day)Large Volume Parenteral (LVP) Component (µg/g)
Exposure Factor10.10.1
Arsenic151.51.50.15
Cadmium50.50.50.05
Lead101.010.1
Mercury151.51.50.15
Chromium25025252.5
Copper250025025025
Manganese250025025025
Molybdenum25025252.5
Nickel25025252.5
Vanadium25025252.5
Palladium10010101.0
Platinum10010101.0
Osmium10010101.0
Rhodium10010101.0
Ruthenium10010101.0
Iridium10010101.0

Drug Substance and Excipients

Second Supplement USP <232> Elemental Impurities – LimitsIV-STOCK-37 IV-STOCK-38 SECOND SUPPLEMENT

ElementOral Drug Products (µg/g) with max Daily dose < 10 g/dayParenteral Drug Products (µg/g) with max Daily dose < 10 g/dayInhalation Drug Products (µg/g) with max Daily dose < 10 g/day
Arsenic1.50.150.15
Cadmium0.50.050.05
Lead10.10.1
Mercury1.50.150.15
Chromium252.52.5
Copper25025025
Manganese2502525
Molybdenum2502525
Nickel252.52.5
Vanadium252.52.5
Palladium1011
Platinum1011
Osmium1011
Rhodium1011
Ruthenium1011
Iridium1011

Second Supplement Elemental Impurity Limits

Drug Products

ElementOral Daily Dose PDE* (µg/day)Parenteral Daily Dose PDE (µg/day)Inhalational Daily Dose PDE (µg/day)Large Volume Parenteral (LVP) Component (µg/g)
Arsenic1.51.51.50.15
Cadmium252.51.50.15
Lead5550.5
Mercury151.51.50.15
Chromium**25*
Copper10001007025
Manganese
Molybdenum100102501.0
Nickel500501.55.0
Vanadium10010305.0
Palladium100101.51.0
Platinum100101.51.0
Osmium100101.51.0
Rhodium100101.51.0
Ruthenium100101.51.0
Iridium100101.51.0

Drug Substance and Excipients

ElementOral Drug Products (µg/g) with max Daily dose < 10 g/dayParenteral Drug Products (µg/g) with max Daily dose < 10 g/dayInhalation Drug Products (µg/g) with max Daily dose < 10 g/day
Arsenic0.150.150.15
Cadmium2.50.250.15
Lead0.50.50.5
Mercury1.50.150.15
Chromium**2.5
Copper100107
Manganese
Molybdenum101.025
Nickel505.00.15
Vanadium1001030
Palladium101.00.15
Platinum101.00.15
Osmium101.00.15
Rhodium101.00.15
Ruthenium100101.5
Iridium101.00.15

USP <232> Elemental Impurities — Limits and USP <233> Elemental Impurities — Procedures were proposed to replace the general test chapter Heavy Metals <231>, as reported in Pharmacopeial Forum Vol. 36(1), [Jan.-Feb. 2010]. USP <232> focuses on the four most toxic and best understood metals: Pb, Hg, Cd, and As, as well as twelve additional elements (Cr, Cu, Mn, Mo, Ni, V, and Ir, Pd, Pt, Os, Ru, Rh).

  1. Following the introduction of the proposed <232> in 2010, and subsequent commentary period and review, the initial revision of USP <232> was introduced in May 2011. This version of USP <232> included detailed elemental impurities for both drug products and drug substances/excipients. IV-STOCK-37 and IV-STOCK-38 were created to conform to these recommendations.
  2. In April 2012, the "Final approved General Chapter <232> Elemental Impurities–Limits as it will appear in the Second Supplement to USP 35–NF 30"1 was posted on the U.S. Pharmacopeial Convention website (www.usp.org), with an official publication date for the Second Supplement to USP 35–NF 30 of Dec. 1, 2012. The U.S. Pharmacopeial Convention website (www.usp.org) states that "…while <232> and <233> will be official on December 2, 2012, the date on which conformance with these chapters will be required will be May 1, 2014, when the General Notices provision making them applicable becomes official."
  3. The Second Supplement had three major changes regarding elemental impurities:
  4. The elemental impurity limits changed.
  5. The Exposure Factor ratios between different dosage categories are no longer constant for all listed elements. The effect of this change is that a single elemental impurity standard is no longer suitable for testing Permissible Daily Exposure (PDE) in individual dosage categories (e.g., Oral Daily Dose PDE, Parenteral Daily Dose PDE, etc.).
  6. Mn was removed from <232>, and Cr was listed as a safety concern only for inhalation drug products, substances, and excipients.
  7. The U.S. Pharmacopeial Convention website (www.usp.org) also states (as of July 2012): "At a future date, the Expert Panel intends to revisit General Chapter <232> relative to the Step 4 outcome of ICH Q3D deliberations. At that time, the Expert Panel may add additional elements and limits to General Chapter <232> based on ICH Q3D, or may develop an informational chapter to incorporate elements of low toxicity."

Original Proposed USP <232> *Elemental Impurities — Limits

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