# Presentation: 159750

## FDA Survey of Lead in Pharmaceuticals

- John F. Kauffman, PhD
- R&D Team Leader
- CDER, Division of Pharmaceutical Analysis
- ACPS-CP Meeting
- July 22,2008

**Notes:**
What did we do?

## FDA Survey ofLead in Pharmaceuticals

- How drugs were selected
- Analytical Procedures
- Results
- Predicted BLLs based on daily exposure

**Notes:**
What did we do?

## Drug Selection

- Risk based
- Ibuprofen and analgesics (addresses the Citizen’s Petition)
- Calcium, bismuth and metal containing products
- High volume products for chronic conditions
- Diabetes, cholesterol, asthma, rheumatoid arthritis, vitamins, smoking cessation, common OTCs, etc
- Imports
- API collected by the FDA
- Finished products (difficult to identify)
- Pediatric dosage forms

## Methods of Pb Analysis

- USP Lead <251>
- Dithazone (in chloroform) extraction of aqueous solution
- Dithazone chelates metals to form a homogeneous solution
- Two step, pH controlled process to first concentrate, then analyze metals
- Green  Red upon metal chelation
- visual colorimetric limit test, 1 ppm limit
- Some metal selectivity with pH

## Methods of Pb Analysis

- Problems with USP Lead <251>
- Careful control of pH is required
- Narrow analyte concentration range
- Calcium, magnesium, phosphorous, iron and copper interfere with extraction
- Nonspecific:  same response for several metals
- Hg, Ag, Cu, Bi, Sn, Pb, Zn, Tl, Cd, etc.
- Elaborate wet chemical reagent preparation
- Reagents are heat and light sensitive
- Large sample mass is required (1-5 grams)
- Incompatible with closed vessel digestion methods

## Methods of Pb Analysis

- USP Heavy Metals <231>
- Sulfide precipitation of metals
- Insoluble, colored metal sulfides precipitate from solution
- Clear  Rust upon metal precipitation
- visual colorimetric limit test, 1 ppm limit
- Problems with Heavy Metals <231>
- Lower limit of detection is high (>1 ppm) for many metals
- Nonspecific:  same response for several metals
- Elaborate wet chemical reagent preparation
- Large sample mass is required (1-5 grams)
- Incompatible with closed vessel digestion methods

## Methods of Pb Analysis

- Flame Atomic Absorbance Spectrometry
- 30 part per billion (ppb) detection limit
- inexpensive, widely available instrumental method
- Problems with Flame AA
- interferences can reduce utility in some cases, e.g., vitamins with metals such as iron
- Each metal requires its own specific lamp
- Requires large volume of solution, and therefore large sample mass (1-10 grams)
- Not compatible with closed vessel digestion

## Methods of Pb Analysis

- Inductively coupled plasma Mass Spectrometry
- 1 part per trillion detection limit
- current state of the art for metals analysis
- more expensive than flame AA, but being widely adapted by industry and contract labs
- Instrument prices are dropping
- few interferences due to single atomic mass unit resolution
- Can survey nearly all metals
- Requires low solution volume, and therefore low sample mass. (0.1 grams)
- Compatible with closed vessel digestion methods

## ICP-MS Analysis of Pharmaceuticals:References

- “A multi-element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials”  Wang, et al., Journal of Pharmaceutical And Biomedical Analysis **(2000)** _23_ 867
- “A rapid ICP-MS screen for heavy metals in pharmaceutical compounds”  Lewen, et al., Journal of Pharmaceutical And Biomedical Analysis **(2004)** _35_ 739
- “Lead in pharmaceutical products and dietary supplements” Kauffman, et al., Regulatory Toxicology and Pharmacology **(2007)** _48_ 128

## Scope and Summary of Survey:  Pb in Pharmaceuticals

- Inductively Coupled Plasma Mass Spectrometry
- Limit of detection:  0.5 part per billion (ppb) in product
- Performed in collaboration with the University of Missouri Research Reactor
- Experts in elemental analysis
- 45 Products were analyzed
- None exceeded 500 ppb.
- Average = 48 ppb
- 10 foreign sources of Ibuprofen API
- None exceeded 15 ppb.
- Average = 5 ppb

**Notes:**
45 products:  high volume, analgesics, pediatric products, geriatric products

## Results:Ibuprofen

## Results: Pediatric Products

## Results: Products withHighest Lead Concentrations

## Results: Products withHighest Maximum Daily Intake

## Results: BLLs for Products withHighest Maximum Daily Intake

## Questions?