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Welcome to the USP User Forum

Welcome to the USP User Forum. Istanbul, Turkey January 17, 2013. Elemental Impurities: Recent Changes. <231> Heavy Metals - Background. Introduced in USP VIII (1905) Consists of three procedures, all involving Sulfide precipitation of metals Visual comparison to lead standards

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Welcome to the USP User Forum

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

  2. Elemental Impurities: Recent Changes

  3. <231> 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. <231> Heavy Metals - Issues • Difficulties in reproducibility • Monitor solutions/standards change with time, recovery issues • Difficulties with reagents – safety issues • All procedures generate H2S (USP via thioacetamide reaction with base). H2S more toxic than cyanide • Thioacetamide not allowed in California and several European countries (EP uses Na2S) • 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 <231> (Lewen, N. et al J. Pharm. & Biomed. Anal. 35 (2004) 739-752)

  6. Toxicology • 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

  7. <232>: 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. <232> : Basics • Applies to: • Drug products, but levels in excipients and API’s must be known and reported • Veterinary products, levels 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 <233>

  9. Elemental Impurities <232>

  10. Elemental Impurities <232>

  11. 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

  12. <2232> : Basics • Applies to Dietary Supplements • Dietary Ingredients • Excipients • Does not apply to drug products • Procedures in Elemental Impurities – Procedures <233> 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 <233> • Elemental Impurities - Procedures <233> • Definitions • Compendial Procedures • Procedure 1: ICP-OES • Procedure 2: ICP-MS • Validation • Limit Procedures • Quantitative Procedures • Calculations and Reporting • Comment on Method Verification per <1226>

  14. Key Issues Page on www.usp.org

  15. Implementation and Postponement • Chapters <232> and <233> 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 <231> will be removed from the monographs in USP37, but requirements still apply via General Notices.

  16. Errata from October 1, 2012 for <232> • 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 <233> in the Target Elements Definition

  17. General Chapters <231>, <232> and <233> Kahkashan Zaidi, Ph.D., Senior Scientist kxz@usp.org Contact Information

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