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General observations regarding USP 232

By Brian W. Alexander, Ph.D.
  1. 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).
  2. 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.
  3. 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."
  4. The Second Supplement had three major changes regarding elemental impurities:
    1. The elemental impurity limits changed.
    2. 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.).
    3. Mn was removed from <232>, and Cr was listed as a safety concern only for inhalation drug products, substances, and excipients.
  5. 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

ORIGINAL PROPOSED

PROPOSED ELEMENTAL IMPURITY LIMITS
Pharmacopeial Forum Vol.36(1) [Jan.–Feb.2010]
     
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
 
 
ElementComponent Limit (µg/g)Oral Daily Dose PDE* (µg/day)Parenteral Component Limit (µg/g)Parenteral Daily Dose PDE (µg/day)
Chromium252502.525
Copper250250025250
Manganese250250025250
Molybdenum252502.525
Nickel252502.525
Palladium10100110
Platinum10100110
Vanadium252502.525
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 USP <232> Elemental Impurities – Limits

FIRST REVISION

REVISED ELEMENTAL IMPURITY LIMITS
DRUG PRODUCTSDRUG SUBSTANCE AND EXCIPIENTS
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)ElementOral Drug Products (µg/g) with max Daily dose < 10 g/dayParenteral Drug Products (µg/g) with max Daily dose < 10 g/dayParenteral Drug Products (µg/g) with max Daily dose < 10 g/day
  
Exposure Factor10.10.1 Exposure Factor10.10.1
  
Arsenic151.51.50.15Arsenic1.50.150.15
Cadmium50.50.50.05Cadmium0.50.050.05
Lead101.010.1Lead10.10.1
Mercury151.51.50.15Mercury1.50.150.15
Chromium25025252.5Chromium252.52.5
Copper250025025025Copper2502525
Manganese250025025025Manganese2502525
Molybdenum25025252.5Molybdenum252.52.5
Nickel25025252.5Nickel252.52.5
Vanadium25025252.5Vanadium252.52.5
Palladium10010101.0Palladium1011
Platinum10010101.0Platinum1011
Osmium10010101.0Osmium1011
Rhodium10010101.0Rhodium1011
Ruthenium10010101.0Ruthenium1011
Iridium10010101.0Iridium1011
IV-STOCK-37
IV-STOCK-38

Second Supplement USP <232> Elemental Impurities – Limits

SECOND SUPPLEMENT

SECOND SUPPLEMENT ELEMENTAL IMPURITY LIMITS
DRUG PRODUCTSDRUG SUBSTANCE AND EXCIPIENTS
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)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
  
Arsenic1.51.51.50.15Arsenic0.150.150.15
Cadmium252.51.50.25Cadmium2.50.250.15
Lead5550.5Lead0.50.50.5
Mercury151.51.50.15Mercury1.50.150.15
Chromium**25*Chromium**2.5
Copper10001007025Copper100107
Manganese1Manganese1
Molybdenum100102501.0Molybdenum101.025
Nickel500501.55.0Nickel505.00.15
Vanadium10010301.0Vanadium1001030
Palladium100101.51.0Palladium101.00.15
Platinum100101.51.0Platinum101.00.15
Osmium100101.51.0Osmium101.00.15
Rhodium100101.51.0Rhodium101.00.15
Ruthenium100101.51.0Ruthenium100101.5
Iridium100101.51.0Iridium101.00.15

* Not a safety concern
1 removed

As stated earlier IV-STOCK-37 and IV-STOCK-38 were created to conform to these recommendations. With the most recent revision IV-STOCK-39 has been added to our stock products. However, we recommend requesting a custom for your current USP <232> standard needs. When filling out your custom form please state that this request is for USP <232> to receive 25% OFF your custom. This information will in return support us in designing a complete USP <232> standard set.

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