prepFAST Preparing for USP <232> <233> Through Automation

Introduction  |  Oral Drugs by Dilution  |  Oral Drugs by Dissolution  |  Inhalation Undiluted  |  Parenteral Undiluted

The prepFAST inline autodilution system with ICP and ICP-MS, fully automates USP <233> methods. The prepFAST can:

  1. dilute a single stock standard to build linear calibration curves
  2. dilute samples to the appropriate TDS
  3. spikes samples at user defined J values

Benefits include:

  • prepFAST - all flows syringe-driven: Eliminate peripump tubing daily maintenance
  • prepFAST - autocalibration: Single multi-element standard for all J values
  • prepFAST - auto inline dilution: Eliminate final manual dilution step
  • prepFAST - auto J spiking
  • Run undiluted samples up to 1% TDS (ICP)
  • Easy-to-use automated system for USP protocols
  • Pre-developed fully automated methods
  • Exceeds all USP validation criteria: Stability, Repeatability, Ruggedness, and Accuracy

Trace metal impurities in pharmaceutical products are either the direct result of catalysts added during drug formulation or contamination during production. An element's toxicity is a function of exposure (bioavailability) and route of administration. Based on the toxicity of elemental impurities, the United States Pharmacopeia (USP) has set values for their Permissible Daily Exposure (PDE) based on route of administration (Table 1).

Table 1. Maximum Permissible Daily Exposure - PDE
Element Oral Daily Dose
PDE (μg/day)
Parenteral Daily
Dose PDE (μg/day)
Inhalation Daily
Dose PDE (μg/day)
LVP Component
Limit (μg/g)
Cadmium 25 2.5 1.5 0.25
Lead 5.0 5.0 5.0 0.50
Arsenic (Inorganic) 1.5 1.5 1.5 0.15
Mercury (Inorganic) 15 1.5 1.5 0.15
Iridium 100 10 1.5 1.0
Osmium 100 10 1.5 1.0
Palladium 100 10 1.5 1.0
Platinum 100 10 1.5 1.0
Rhodium 100 10 1.5 1.0
Ruthenium 100 10 1.5 1.0
Molybdenum 100 10 250 1.0
Nickel 500 50 1.5 5.0
Vanadium 100 10 30 1.0
Copper 1000 100 70 25
Chromium - - 25 -

The USP Chapter <232> defines a target (J) value as a function of PDE (μg/day) and a drugs daily dose (g/day), whereas Chapter <233> outlines specific protocols for the determination of toxic metals by ICP/ICP-MS. USP <233> requires a calibration curve and a series of QC validation protocols including spike recovery, accuracy, precision and stability tests to be based on the target values (J).

To appropriately determine the J value for analysis, the final dilution factor must be taken into consideration. For simplicity and homogeneity purposes, the adjacent example uses a 1g mass of drug and requires a final diluent volume of 500mL (0.2% TDS). The formula illustrates the calculation of J for Cd (PDE = 25μg/day; Oral) in a drug with a maximum daily dose of 1g/day.

To maximize detection limits, optimize stability and unify sample preparation for all solid (tablets and powders) drugs, a target Total Dissolved Solids (TDS) for ICP and ICP-MS are 1% (100 fold dilution of solid) and 0.2% (500 fold dilution of solid), respectively. By setting the dilution factor constant, for optimal analytical performance, the J value varies inversely with respect to daily dose. Therefore, large daily dose drugs require a lower concentration spike and calibration standard.