1. Welcome to the USP User Forum Istanbul, Turkey January 17, 2013

2. Elemental Impurities: Recent Changes

3. Heavy Metals - Background  Introduced in USP VIII (1905)  Consists of three procedures, all involving –Sulfide precipitation of metals –Visual comparison to lead standards  Methods in the EP and JP are similar to the USP methods

4. Heavy Metals - Issues  Difficulties in reproducibility –Monitor solutions/standards change with time, recovery issues  Difficulties with reagents – safety issues –All procedures generate H 2 S (USP via thioacetamide reaction with base). H 2 S more toxic than cyanide –Thioacetamide not allowed in California and several European countries (EP uses Na 2 S)  Nondiscriminatory screening test –Not element specific –Sensitivity varies by element –Only a few elements respond at required sensitivities  Visual comparison test –Limits based on visual acuity, not toxicology

5. Heavy Metals Background Comparisons Between Instrumental Methods and (Lewen, N. et al J. Pharm. & Biomed. Anal. 35 (2004) 739-752)

6.  USP is proposing an approach to elemental impurity control that is both health based and risk based  Control metals that are toxic  At limits that are toxicologically relevant  At all times during a drug product’s shelf life  With a risk-based approach as to what and when to test Toxicology

7. : Elements  Elements in the environment – critical contaminant are Lead, Arsenic, Mercury and Cadmium (the “Big Four”)  EMEA Guideline on the Specification Limits for Residues of Metal Catalysts (CPMP/SWP/4446/00) lists 14 catalysts used in pharmaceutical synthesis –Exclude zinc and iron, which are not toxic at levels relevant in pharmaceuticals  Need to control in drug products if presence is possible –Deliberately added (catalyst) –Possible supply-chain contaminant or adulterant –Process issue (equipment)

8. : Basics  Applies to: –Drug products, but levels in excipients and API’s must be known and reported –Veterinary products, l evels must be adjusted based on species, dosage, and toxicology  Does not apply to dietary supplements  Speciation is not addressed in this Chapter  Procedures are specified in Elemental Impurities – Procedures

9. 9 Elemental Impurities Element Oral Daily Dose PDE (µg/day) Parenteral Daily Dose PDE (µg/day) Inhalational Daily Dose PDE (µg/day) LVP Component Limit (µg/g) Inorganic Arsenic 1.5 0.15 Cadmium252.51.50.25 Lead5550.5 Inorganic Mercury 151.5 0.15

10. 10 Elemental Impurities Element Oral Daily Dose PDE (µg/day) Parenteral Daily Dose PDE (µg/day) Inhalational Daily Dose PDE (µg/day) LVP Component Limit (µg/g) Chromium**25* Copper10001007025 Molybdenum10010 1.0 Nickel500501.55.0 Palladium100101.51.0 Platinum100101.51.0 Vanadium10010301.0 Osmium100101.51.0 Rhodium100101.51.0 Ruthenium100101.51.0 Iridium100101.51.0

11.  Drug Product Analysis Option –Sample and measure dosage form –Scale results to daily dose  Summation Option –Sample and measure all components –Validate process will add no additional impurities –Sum each metal and scale to daily dose  Individual Component Approach for LVP Options to Determine Content

12. : Basics  Applies to Dietary Supplements –Dietary Ingredients –Excipients  Does not apply to drug products  Procedures in Elemental Impurities – Procedures are specified  Speciation is critical for Dietary Supplements –Arsenic and Mercury procedures addressed in this Chapter  Only “the big four” Elemental Impurities considered

13. Elemental Impurities - Procedures  Elemental Impurities - Procedures  Definitions  Compendial Procedures Procedure 1: ICP-OES Procedure 2: ICP-MS  Validation Limit Procedures Quantitative Procedures  Calculations and Reporting  Comment on Method Verification per

14. Key Issues Page on www.usp.org www.usp.org

15. Implementation and Postponement Chapters and appear in Second Supplement to USP35 (official Dec 1, 2012), but… –The official dates of these chapters have been postponed via Revision Bulletin The postponement will allow the Executive Committee of the Council of Experts adequate time to rule on three appeals related to the chapters. A planned General Notices proposal will appear in PF 39(1) in January 2013, which if approved, will make the two chapters applicable to all monographed articles as of May 1, 2014. All references to USP general chapter Heavy Metals will be removed from the monographs in USP37, but requirements still apply via General Notices.

16. Errata from October 1, 2012 for Limits in Table 1 (Elemental Impurities for Drug Products) for Molybdenum: Inhalation Daily Dose = 10 µg/day (not 250) Limits in Table 2 (Default Concentration Limits for Drug Substances and Excipients): –Ruthenium and Vanadium limits for oral, parenteral and inhalational products were incorrectly increased by factor of 10 –Molybdenum inhalation limit incorrectly increased by a factor of 25 Last line under Analytical Testing: “when testing is done…minimally include As, Cd, Pb (not Pd) and Hg in the Target Element evaluation.” –Same errata for in the Target Elements Definition

17. Contact Information General Chapters, and Kahkashan Zaidi, Ph.D., Senior Scientist kxz@usp.org