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FDA Survey of Lead in Pharmaceuticals

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

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FDA Survey of Lead in Pharmaceuticals

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  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. FDA Survey ofLead in Pharmaceuticals • How drugs were selected • Analytical Procedures • Results • Predicted BLLs based on daily exposure

  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. 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

  5. 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

  6. 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

  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. 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. 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. 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. Results:Ibuprofen

  12. Results: Pediatric Products

  13. Results: Products withHighest Lead Concentrations

  14. Results: Products withHighest Maximum Daily Intake

  15. Results: BLLs for Products withHighest Maximum Daily Intake

  16. Questions?

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