1. 1 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

2. 2 FDA Survey of Lead in Pharmaceuticals 1.How drugs were selected 2.Analytical Procedures 3.Results 4.Predicted BLLs based on daily exposure

3. 3 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

4. 4 Methods of Pb Analysis USP Lead –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

5. 5 Methods of Pb Analysis Problems with USP Lead –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

6. 6 Methods of Pb Analysis USP Heavy Metals –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 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

7. 7 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

8. 8 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

9. 9 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

10. 10 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

11. 11 Results: Ibuprofen

12. 12 Results: Pediatric Products

13. 13 Results: Products with Highest Lead Concentrations

14. 14 Results: Products with Highest Maximum Daily Intake

15. 15 Results: BLLs for Products with Highest Maximum Daily Intake

16. 16 Questions?