1. Elemental Impurities– An Update Kahkashan Zaidi, Ph.D. General chapters USP

2. 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

3. Activities--- and USP Stimuli Article in PF 34(5) for public comment (November, 2008) USP published draft revisions for comment in PF 36(1), January, 2010: –Elements and limits chapter –Methodology chapter –Dietary Supplement chapter –Stimuli article with rationales for limits –Stimuli article with responses to comments on PF 34(5) stimuli article Revisions in PF 37(3) Final chapters available on the USP website

4.  Revised to address comments received.  Elements and limits essentially the same as the ICH- Q3D pre-stage 2 proposal.  Available on the USP website. Elemental Impurities – Limits

5. Proposed USP General Chapter Elemental Impurities-Limits

6. Toxicology USP approach to elemental impurity control 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

7. Basics Applies to drug products –Drug substances –Excipients Does not apply to dietary supplements Does not apply to Veterinary products Does not apply to conventional vaccines Speciation is not addressed in this Chapter Procedures are specified in Elemental Impurities – Procedures

8. Elemental Impurities are: Environmental contaminants Catalysts They may be: Naturally occurring Added intentionally Introduced inadvertently –Through interactions with processing equipment –Through non-GMP routes A risk-based control strategy may assure compliance. However, compliance with the limits is required for all drug products at all times.

9. Elemental Impurities-Limits Element OralDaily Dose PDE a (µg/day) a ▪ Parenteral Daily Dose PDE (µg/day) ▪ Inhalational Daily Dose PDE (µg/day) LVP Component Limit (µg/g) Cadmium 5 ▪ 252.51.5 0.05 ▪ 0.25 Lead 10 ▪ 555 0.1 ▪ 0.5 Inorganic arsenic b b 15 ▪ 1.51.5 0.15 Inorganic Mercury b b 151.5 0.15 Iridium 100101.5 1.0 Osmium 100101.5 1.0 Palladium 100101.5 1.0 Platinum 100101.5 1.0 Rhodium 100101.5 1.0 Ruthenium 100101.5 1.0 Chromium 250 ▪ **25 2.5 ▪ * Molybdenum 250 ▪ 10010250 10 2.5 ▪ 1.0 Nickel 250 ▪ 500501.5 2.5 ▪ 5.0 Vanadium 250 ▪ 1001030 2.5 ▪ 1.0 Copper 2500 ▪ 100010070 25 Manganese 2500 25 a PDE = Permissible Daily Exposure based on a 50Kg person. b See Speciation section. * not a safety concern

10. Options to Determine Content 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

11. Proposed USP General Chapter Elemental Contaminants in Dietary Supplements

12. Draft 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 Contaminants in Dietary Supplements Element PDE a (µg/day) Arsenic (inorganic) c c 15 Cadmium5 Lead10 Mercury (total)15 Methylmercury (as Hg) 2 a Permitted Daily Exposure (PDE) is derived from the Provisional Tolerable Weekly Intake (PTWI) that is recommended by the Food and Agriculture Organization of the United Nations and World Health Organization (FAO/WHO) by subtracting the daily exposure (μg/day) to each elemental contaminant from air, food, and drinking water. A body weight of 50 kg and a safety factor are used to calculate the PDE.

14. Proposed USP General Chapter Elemental Impurities – Procedures

15. 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

16. Procedure Validation Requirements Limit Procedure: –Detectability –Precision (For Instrumental Methods) –Specificity

17. Procedure Validation Requirements Quantitative Procedure: –Accuracy –Detectability –Precision Repeatabiltiy Ruggedness –Specificity –LOQ –Range –Linearity

18. Procedure Validation Requirements Defines a procedure acceptance criteria Validation criteria for alternative procedures and Verification criteria for compendial procedures are identical

19. Implementation Chapters and will appear in Second Supplement to USP35 (official Dec 1, 2012). Will be implemented through General Notices with a delayed implementation date of May 1, 2014 All references to USP general chapter Heavy Metals will be removed from the monographs in USP37.

20. Questions?