General observations regarding USP 232
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).
- 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.
- 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."
-
The Second Supplement had three major changes regarding elemental impurities:
- The elemental impurity limits changed.
- 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.).
- Mn was removed from <232>, and Cr was listed as a safety concern only for inhalation drug products, substances, and excipients.
- 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] | ||||
| Element | Component 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 |
| Element | Component Limit (µg/g) | Oral Daily Dose PDE* (µg/day) | Parenteral Component Limit (µg/g) | Parenteral Daily Dose PDE (µg/day) |
| 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 |
| 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 | DRUG SUBSTANCE AND EXCIPIENTS | |||||||
| Element | Oral Daily Dose PDE* (µg/day) | Parenteral Daily Dose PDE (µg/day) | Inhalational Daily Dose PDE (µg/day) | Large Volume Parenteral (LVP) Component (µg/g) | Element | Oral Drug Products (µg/g) with max Daily dose < 10 g/day | Parenteral Drug Products (µg/g) with max Daily dose < 10 g/day | Parenteral Drug Products (µg/g) with max Daily dose < 10 g/day |
| Exposure Factor | 1 | 0.1 | 0.1 | Exposure Factor | 1 | 0.1 | 0.1 | |
| Arsenic | 15 | 1.5 | 1.5 | 0.15 | Arsenic | 1.5 | 0.15 | 0.15 |
| Cadmium | 5 | 0.5 | 0.5 | 0.05 | Cadmium | 0.5 | 0.05 | 0.05 |
| Lead | 10 | 1.0 | 1 | 0.1 | Lead | 1 | 0.1 | 0.1 |
| Mercury | 15 | 1.5 | 1.5 | 0.15 | Mercury | 1.5 | 0.15 | 0.15 |
| Chromium | 250 | 25 | 25 | 2.5 | Chromium | 25 | 2.5 | 2.5 |
| Copper | 2500 | 250 | 250 | 25 | Copper | 250 | 25 | 25 |
| Manganese | 2500 | 250 | 250 | 25 | Manganese | 250 | 25 | 25 |
| Molybdenum | 250 | 25 | 25 | 2.5 | Molybdenum | 25 | 2.5 | 2.5 |
| Nickel | 250 | 25 | 25 | 2.5 | Nickel | 25 | 2.5 | 2.5 |
| Vanadium | 250 | 25 | 25 | 2.5 | Vanadium | 25 | 2.5 | 2.5 |
| Palladium | 100 | 10 | 10 | 1.0 | Palladium | 10 | 1 | 1 |
| Platinum | 100 | 10 | 10 | 1.0 | Platinum | 10 | 1 | 1 |
| Osmium | 100 | 10 | 10 | 1.0 | Osmium | 10 | 1 | 1 |
| Rhodium | 100 | 10 | 10 | 1.0 | Rhodium | 10 | 1 | 1 |
| Ruthenium | 100 | 10 | 10 | 1.0 | Ruthenium | 10 | 1 | 1 |
| Iridium | 100 | 10 | 10 | 1.0 | Iridium | 10 | 1 | 1 |
IV-STOCK-37
IV-STOCK-38
IV-STOCK-38
Second Supplement USP <232> Elemental Impurities – Limits
SECOND SUPPLEMENT
| SECOND SUPPLEMENT ELEMENTAL IMPURITY LIMITS | ||||||||
| DRUG PRODUCTS | DRUG SUBSTANCE AND EXCIPIENTS | |||||||
| Element | Oral Daily Dose PDE* (µg/day) | Parenteral Daily Dose PDE (µg/day) | Inhalational Daily Dose PDE (µg/day) | Large Volume Parenteral (LVP) Component (µg/g) | Element | Oral Drug Products (µg/g) with Max Daily dose < 10 g/day | Parenteral Drug Products (µg/g) with Max Daily dose < 10 g/day | Inhalation Drug Products (µg/g) with Max Daily dose < 10 g/day |
| Arsenic | 1.5 | 1.5 | 1.5 | 0.15 | Arsenic | 0.15 | 0.15 | 0.15 |
| Cadmium | 25 | 2.5 | 1.5 | 0.25 | Cadmium | 2.5 | 0.25 | 0.15 |
| Lead | 5 | 5 | 5 | 0.5 | Lead | 0.5 | 0.5 | 0.5 |
| Mercury | 15 | 1.5 | 1.5 | 0.15 | Mercury | 1.5 | 0.15 | 0.15 |
| Chromium | * | * | 25 | * | Chromium | * | * | 2.5 |
| Copper | 1000 | 100 | 70 | 25 | Copper | 100 | 10 | 7 |
| Manganese1 | Manganese1 | |||||||
| Molybdenum | 100 | 10 | 250 | 1.0 | Molybdenum | 10 | 1.0 | 25 |
| Nickel | 500 | 50 | 1.5 | 5.0 | Nickel | 50 | 5.0 | 0.15 |
| Vanadium | 100 | 10 | 30 | 1.0 | Vanadium | 100 | 10 | 30 |
| Palladium | 100 | 10 | 1.5 | 1.0 | Palladium | 10 | 1.0 | 0.15 |
| Platinum | 100 | 10 | 1.5 | 1.0 | Platinum | 10 | 1.0 | 0.15 |
| Osmium | 100 | 10 | 1.5 | 1.0 | Osmium | 10 | 1.0 | 0.15 |
| Rhodium | 100 | 10 | 1.5 | 1.0 | Rhodium | 10 | 1.0 | 0.15 |
| Ruthenium | 100 | 10 | 1.5 | 1.0 | Ruthenium | 100 | 10 | 1.5 |
| Iridium | 100 | 10 | 1.5 | 1.0 | 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.