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General observations regarding USP 232

  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 LIMITSPharmacopeial ForumVol.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)
Arsenic 1.5 15 0.15 1.5
Cadmium 0.5 5 0.05 0.5
Lead 1 10 0.1 1
Mercury 1.5 15 0.15 1.5
Chromium 25 250 2.5 25
Copper 250 2500 25 250
Manganese 250 2500 25 250
Molybdenum 25 250 2.5 25
Nickel 25 250 2.5 25
Palladium 10 100 1 10
Platinum 10 100 1 10
Vanadium 25 250 2.5 25
ElementComponent Limit (µg/g)Oral Daily Dose PDE*(µg/day)Parenteral Component Limit (µg/g)Parenteral Daily Dose PDE (µg/day)
Osmium 10 (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 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
Arsenic 15 1.5 1.5 0.15
Cadmium 5 0.5 0.5 0.05
Lead 10 1.0 1 0.1
Mercury 15 1.5 1.5 0.15
Chromium 250 25 25 2.5
Copper 2500 250 250 25
Manganese 2500 250 250 25
Molybdenum 250 25 25 2.5
Nickel 250 25 25 2.5
Vanadium 250 25 25 2.5
Palladium 100 10 10 1.0
Platinum 100 10 10 1.0
Osmium 100 10 10 1.0
Rhodium 100 10 10 1.0
Ruthenium 100 10 10 1.0
Iridium 100 10 10 1.0
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
Exposure Factor10.10.1
Arsenic 1.5 0.15 0.15
Cadmium 0.5 0.05 0.05
Lead 1 0.1 0.1
Mercury 1.5 0.15 0.15
Chromium 25 2.5 2.5
Copper 250 25 25
Manganese 250 25 25
Molybdenum 250 25 25
Nickel 25 2.5 2.5
Vanadium 25 2.5 2.5
Palladium 10 1 1
Platinum 10 1 1
Osmium 10 1 1
Rhodium 10 1 1
Ruthenium 10 1 1
Iridium 10 1 1

Second Supplement USP <232> Elemental Impurities – Limits
IV-STOCK-37

IV-STOCK-38

SECOND SUPPLEMENT

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)
Arsenic 1.5 1.5 1.5 0.15
Cadmium 25 2.5 1.5 0.25
Lead 5 5 5 0.5
Mercury 15 1.5 1.5 0.15
Chromium * * 25 *
Copper 1000 100 70 25
Manganese1
Molybdenum 100 10 250 1.0
Nickel 500 50 1.5 5.0
Vanadium 100 10 30 5.0
Palladium 100 10 1.5 1.0
Platinum 100 10 1.5 1.0
Osmium 100 10 1.5 1.0
Rhodium 100 10 1.5 1.0
Ruthenium 100 10 1.5 1.0
Iridium 100 10 1.5 1.0
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
Arsenic 0.15 0.15 0.15
Cadmium 2.5 0.25 0.15
Lead 0.5 0.5 0.5
Mercury 1.5 0.15 0.15
Chromium * * 2.5
Copper 100 10 7
Manganese1
Molybdenum 10 1.0 25
Nickel 50 5.0 0.15
Vanadium 100 10 30
Palladium 10 1.0 0.15
Platinum 10 1.0 0.15
Osmium 10 1.0 0.15
Rhodium 10 1.0 0.15
Ruthenium 100 10 1.5
Iridium 10 1.0 0.15

* 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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