Day 1 - US Pharmacopeial Convention

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XRF • For true quantitation, appropriate solid standards are needed • Best-suited for larger sample quantities. • Doesn’t work well for light elements Bristol Bristol-Myers Myers Squibb Company Page 8 Proposed Chapter • Applies to drug product • UUnlike lik EMEA Guideline, G id li includes i l d inadvertent i d t t metal t l contamination • Risk-based approach acceptable • Summation or individual element compliance with standard • Proposed chapter provides analytical information Bristol Bristol-Myers Myers Squibb Company
Proposed Chapter • Companion chapter provides limits and elements � Because of specified limits, ICP-OES and ICP-MS provide best options for rapid, accurate, multi-element analysis • Analysts free to use any method they deem appropriate • “Referee” methods available, if analysts do not have method to use � Prior to using one of the compendial procedures, must verify its appropriateness for a given sample and technique – Validation for limit procedures � Control sample—reference material for element of interest at target g concentration � Test sample 1—sample spiked to target concentration in triplicate � Test sample 2—sample spiked to 90% of target concentration in triplicate � RSD NMT 20% (n=6) � Specificity—no false positives or false negatives Bristol Bristol-Myers Myers Squibb Company Page 9 Proposed Chapter (continued) – Validation for quantitative procedures � Accuracy � Control Samples: 50-150% of limit value for element of interest (in triplicate) � Test Samples: samples spiked to 50-150% of limit value for element of interest (in triplicate)—spike recovery 50-150% for mean values � Precision � RSD NMT 20% (n=6) for spiked samples � Intermediate precision: either on different days; OR with different instrumentation; OR with different analysts (RSD NMT 25%) � Specificity � No false positives or false negatives Bristol Bristol-Myers Myers Squibb Company
Page 1 and 2: Impurities, Adulteration, and the C
Page 3 and 4: A Fifteen Year Saga Begins � 1995
Page 5 and 6: Recent Activities � USP published
Page 7 and 8: Design and Scope of Chapters � Li
Page 9 and 10: Impurities and Limits - Current Pan
Page 11 and 12: Some Possible Scenarios Added to th
Page 13 and 14: Results of Team’s Experiments �
Page 15 and 16: Elemental Impurities-Procedures Qu
Page 17 and 18: Stimuli Article: Elemental Impuriti
Page 19 and 20: Acknowledgements Heavy Metals Advis
Page 21 and 22: TOXIC METALS / METALLOIDS REPORTED
Page 23 and 24: Chemical Exposures NHANES III BLOOD
Page 26 and 27: LEAD EXPOSURE IN THE GENERAL U.S. P
Page 28: AMINO ACID COMPOSITIONS KIDNEY PbBP
Page 33 and 34: POTENIAL SIGNIFICANCE OF LEAD LEAD-
Page 35 and 36: Pharmaceutical Applications of Atom
Page 37 and 38: Advantages and Disadvantages of Fla
Page 39 and 40: ICP-MS • Advantages � Very rapi
Page 41: Laser Induced Breakdown Spectroscop
Page 45 and 46: What’s Next? • USP to publish r
Page 47 and 48: Introduction Contents Toxicity of D
Page 49 and 50: Types of Inorganic Impurities 4
Page 51 and 52: Controls on Heavy Metals (HM): USP
Page 53 and 54: Controls on Heavy Metals (HM) & Lea
Page 55 and 56: EEvaluation l ti of f Acceptable A
Page 57 and 58: Dose Levels - NOEL no no-observed o
Page 59 and 60: Reference Dose (RfD) �An estimate
Page 61 and 62: Dose-Response Curves (non-carcinoge
Page 63 and 64: Massachusetts Bay Law Law, Septembe
Page 65 and 66: Lead as impurities in food or drug
Page 67 and 68: Lead in pharmaceutical products and
Page 69 and 70: The Relationship Between Blood Lead
Page 71 and 72: Acute • GI effects - colic, sever
Page 73 and 74: Elemental Mercury Found in mercury
Page 75 and 76: How can Elemental Mercury Enter the
Page 77 and 78: Inorganic Mercury Poisoning • Gas
Page 79: A 27 y.o. male resident of Ramnigar
Page 82 and 83: Itai Itai-Itai Itai or “ouch “o
Page 84 and 85: • NOAEL = 5 µg/kg/day • UF = 1
Page 86 and 87: Proposed Limits (Oral) Elements USP
Page 88 and 89: Proposed Limits (O (Oral) ) Element
Page 90 and 91: Points to consider: What concentrat
Page 93 and 94:
Current and Future Directions and I
Page 95 and 96:
Compendial Challenges for Biologica
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Definition - key elements • What
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Identification and the “Absence o
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Strategy for B&B Product Classes Mo
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Clinical uses of heparin • Treatm
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What was the contamination problem?
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Potential characterization methods
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Orthogonal methods • Orthogonal m
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OSCS contaminated heparin • How d
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Extracted OSCS from 0099‐D01 1 H
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Acknowledgements • Carolyn Swann
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History of adulteration with Diethy
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FDA Request • April 2007: FDA req
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Comments from CDER Office of Compli
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REVISION BULLETTIN IPR Monograph mo
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Tragic Consequences Not If… But W
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• Collaborative Rx-360 Key Princi
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Rx-360.org Shares Technology That C
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To secure the supply chain 11. Firs
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Common sense dictates the use of ta
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There are many new ideas that can b
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To protect the patients you serve,
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Thank you For More Information 31 J
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Introduction Figure 1. Black Cohosh
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An Opportunity • To our knowledge
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Selection of Marker Compounds Sourc
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Region of Cimifugin (not detected)
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Results Marker Compound Actaea Othe
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Discussion (Cont’d) Important con
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Actions by the Regulator in Respons
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Actions by the Regulator in Respons
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Conclusion • By working together
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QUALITY CONTROL ON SAFETY AND EFFIC
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Study on analytical standards of Af
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Analysis of organic residues of mac
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Extractum Flos Lonicerae Siccus 1 2
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Substantial basis research achieve
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The standard characteristics chroma
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Frame of the quality standards stud
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�Extracting way The factors influ
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RRealgar l Cinnabar HPLC-ICP-MS Chr
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Correlation between in vitro and in
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Combating Counterfeiting and Substa
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Good Legislation and Regulation Unr
Page 187 and 188:
The Regulatory Challenge Poor Regis
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Key Findings Nummber of Samples 16
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Addressing the Problem �Regulated
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Advantages of the Minilab � Requi
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Conclusion �Quality is not a luxu
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Day 1 - US Pharmacopeial Convention

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