Agilent Technologies, Inc. · NYSE:A
Agilent Technologies — Technical Presentation (December 2010)
65 slides from Agilent Technologies's technical presentation, Dec 8, 2010
Slide 1: New USP <232/233> Elemental Impurity (Metals) Tests
New USP <232/233> Elemental Impurity (Metals) Tests Improved Accuracy and Productivity using Analytical Instrumentations for the Measurement of Heavy Metals in Pharmaceutical Materials USP Webinar Page 1 Dec. 08, 2010
Slide 2: 2010 – Varian Becomes a Part of Agilent
2010 – Varian Becomes a Part of Agilent A Heritage of Innovation: Varian & Agilent USP Webinar Page 2 Dec. 08, 2010
Slide 3: Today's Agilent: Atomic Spectroscopy
Today’s Agilent: Atomic Spectroscopy More choices The addition of the Varian Atomic Absorption (AA) and ICP-OES products to Agilent’s ICP-MS products provides a complete portfolio for routine and research analysis in environmental, food, agriculture, clinical, pharmaceutical, product safety, semicon
Slide 4: Today's Agilent: Atomic Spectroscopy
Today’s Agilent: Atomic Spectroscopy Create the perfect solution ICP-MS ICP-OES AA World’s best, most complete atomic spectroscopy portfolio! USP Webinar Page 4 Dec. 08, 2010
Slide 5: Testing for Metal Impurities in Pharmaceutical Products
Testing for Metal Impurities in Pharmaceutical Products USP Webinar Page 5 Dec. 08, 2010
Slide 6: Trace Metal Analysis in Pharmaceuticals, Why?
Trace Metal Analysis in Pharmaceuticals, Why? The control of impurities has always been a critical issue to the pharmaceutical industry – Catalysts – Raw material (plants, animal proteins, rDNA, etc.) – Excipients (stabilizers, fillers, binders, release agents, flavors, colors, coatings, etc) – Prod
Slide 7: Regulated Pharmaceutical and Clinical Applications
Regulated Pharmaceutical and Clinical Applications Pharmacopeia Testing (API) Natural products (TCM) Metal impurities (Catalysts, Extractables/Leachables) Clinical trials (Metallo-proteins/drugs) Metals Leached from Pharmaceutical Packaging Interaction between formulation and packaging material Stor
Slide 8: Traditional Metals Test for Pharma - USP<231>
Traditional Metals Test for Pharma - USP<231> USP<231> is a limit test for heavy metals in samples It is a qualitative (at best semi-quantitative) test that indicates the content of metallic impurities by colored sulfide precipitate • Elements for which the method can be used are silver, arsenic, bi
Slide 9: USP<231> Sample Preparation
USP<231> Sample Preparation Three different sample preparation techniques can be utilized for USP<231>, depending on the sample type • Each specified in individual monographs. – Method I • Used for samples that are a clear colorless solutions – After addition of a sulfide reagent, the color is compa
Slide 10: Issues with USP<231>
Issues with USP<231> Large sample size required • Sample size for USP<231> is determined by the formula: 2.0/(1000L) L-limit concentration in % USP<231> is a nondiscriminatory test • The sum of all the sulfide-forming analytes are detected Reproducibility • Changes to standards/solutions occurs with
Slide 11: USP<231> Ashing Step Leads to Poor Recovery
USP<231> Ashing Step Leads to Poor Recovery Table showing low recovery for several elements due to high temperature ashing step in USP<231> (600oC ashing leads to almost total loss of volatile analytes such as Hg and Sb). Issues of low recovery are eliminated when ICP (acid digestion) sample prep is
Slide 12: Comparison of USP<231> with ICP-MS
Comparison of USP<231> with ICP-MS Traditional (wet chemical) method for heavy metals testing in pharma materials involves an ashing step and so gives low recoveries for all volatile elements! From: A rapid ICP-MS screen for heavy metals in pharmaceutical compounds; N. Lewen, S. Mathew, M. Schenkenb
Slide 13: Recognition of the Problems of USP<231>
Recognition of the Problems of USP<231> USP Meeting dated April 2009 • Problem Statement: “We are committed to advancing the current standards (<231>) so that widely agreed upon safe limits for key metal impurities are properly measured, thereby protecting the public health” Clear indication of acce
Slide 14: Goals for USP<231> Replacement
Goals for USP<231> Replacement • Want to set limits for appropriate metal impurities (of known toxicity, that are sufficiently likely to be present) – Limits based on toxicology data, not method capability – Metal species* – Daily dose and budget fraction – Route of administration • Analytical techn
Slide 15: Proposed USP<231> Replacement
Proposed USP<231> Replacement At the same time, USP<231> USP developed a new protocol for dietary supplements USP<232> USP<233> USP<2232> Elemental Impurities Elemental Impurities Elemental Contaminants Limits Procedures in Dietary Supplements USP Webinar Page 15 Dec. 08, 2010
Slide 16: Recent Transformation: <231> to <232>
Recent Transformation: <231> <232> ~100 years July/2010 October/2010 Proposed Date to Take Effect: September, 2013 USP Webinar Page 16 Dec. 08, 2010
Slide 17: Impurities Limits
Impurities Limits - Grouping class I and II under a single table - No change to PDE - Includes Large volume parenterals (LVP > 100 mL) - PDE is now calculated based on the route of exposure USP Webinar Page 17 Dec. 08, 2010
Slide 18: Definitions and Compliance Options
Definitions: - Elemental impurities are defined as catalysts and environmental contaminants which may occur naturally, added intentionally, or introduced inadvertently - “Big Four” analytes must be tested (As, Cd, Hg, Pb) - Speciation is required when the concentrations of Hg and As exceed the limit
Slide 19: Analytical Procedures USP<233>
Analytical Procedures USP<233> • Any and all analytical techniques may be used providing they can meet all the validation requirements • No procedure for speciation is provided, consult USP-NF and published protocols Definitions • Acids to be used should be ultra pure (HNO3, HCl, H2SO4, HF, Aqua Reg
Slide 20: Sample Dissolution
Sample Dissolution •Direct aqueous solutions - Simple solubilization in an aqueous matrix • Direct organic solution - Simple solubilization in an organic matrix •Closed vessel digestion - We recommend addition of 0.5% HCl to stabilize Hg - Dehydrate and predigest 0.5 g sample in 5 mL of strong acid
Slide 21: Analytical Procedures: ICP-MS and ICP-OES
Analytical Procedures: ICP-MS and ICP-OES • Calibration should be acid matrix matched - Blank, 0.5J, and 2J • Rinse with dilute acid • Check instrument drift with the 2J standard solution before and after sample’s analysis. Recovery ±20% • No indication of ISTD • Add Hg stabilizer to diluted stock s
Slide 22: Validation: Accuracy, Precision, Specificity
Validation: Accuracy, Precision, Specificity Limit Procedure: - System suitability must be evaluated prior to any sample analysis (at “J”, accounting for dilution) - “Limit of Detection” - Standard Solution - SRM at the target concentration - Spike 1 - Actual sample spiked with SRM at the target con
Slide 23: Validation - Continued
Validation - Continued Quantitative Procedure: - Accuracy - Standard Solution - 3 replicate SRM solutions containing 50%-150% J of the target analytes - Test Samples - 3 replicate samples under test spiked with SRM at 50%-150% J - Acceptance - 70%-150% spike recovery at each concentration - Precisio
Slide 24: USP<2232>: Dietary Supplements ONLY
USP<2232>: Dietary Supplements ONLY Limits based on 10 g max daily intake If total [As] > limit, Inorganic As speciation is required If total [Hg] > 0.2 µg/g, CH3-Hg speciation is required Three options describing analyte limits: • Drug Product Analysis Option - Result= µg/g contaminant (daily
Slide 25: Organo-Metallic Speciation Analysis
Organo-Metallic Speciation Analysis In addition to its common use as a “stand-alone” metals analyser, ICP- MS is eminently suited as a detector for a range of chromatographic separation methods • Capillary Electrophoresis (CE) • Field-flow Fractionation (FFF) • Ion Chromatography (IC) • Liquid Chrom
Slide 26: USP in Federal Law Implementation
USP in Federal Law Implementation • USP does not enforce its own standards • FDA enforces USP standards; compliance focus on manufacturer-approved specs and GMPs • USP standards apply at any time in the life of an article; when tested, must pass to demonstrate compliance • However, USP does not set
Slide 27: USP in Federal Law Implementation (continued)
USP in Federal Law Implementation (continued) • Compliance with USP standards is required at all times. • Frequency of testing and sampling are left to the preferences of first-party (manufacturer), second-party (buyer) and third- party (FDA/regulator) stakeholders, who: “may or may not require addi
Slide 28: Justification for New ICP-MS Method USP<232/233>
Justification for New ICP-MS Method USP<232/233> USP Webinar Page 28 Dec. 08, 2010
Slide 29: ICP-MS has been Incorporated into Pharmacopeias
ICP-MS has been Incorporated into Pharmacopeias European Pharmacopeia (draft 2008) USP Webinar Page 29 Dec. 08, 2010
Slide 30: QC of Traditional Chinese Medicines (TCMs)
QC of Traditional Chinese Medicines (TCMs) Chinese Pharmacopoeia 2005, Appendix IX Agilent Application Notes: • Determination of Toxic Elements in Traditional Chinese Medicine Using Inductively Coupled Plasma Mass Spectrometry, P/N 5989-5591EN • Evaluation of Conventional ICP-MS and ORS-ICP-MS for A
Slide 31: Unmatched Matrix Tolerance and Unparalleled Interference Removal
Unmatched Matrix Tolerance and Unparalleled Interference Removal USP Webinar Page 31 Dec. 08, 2010
Slide 32: Unmatched Matrix Tolerance – HMI Sample Introduction
Unmatched Matrix Tolerance – HMI Sample Introduction • Low-flow (0.15 mL/min typical) • Temperature stabilized (Peltier cooled spray chamber) Now features HMI (High Matrix Introduction) Kit as standard on 7700x model, allowing auto setup of plasma conditions and much higher matrix tolerance USP Webi
Slide 33: Neat Seawater
Neat Seawater 50 ppb spiked signal stability over 150 samples Skimmer after 150 sample introduction Agilent HMI – ultra robust USP Webinar Page 33 Dec. 08, 2010
Slide 34: Removing Polyatomic Interferences in ICP-MS
Removing Polyatomic Interferences in ICP-MS The 7700 Series ORS3 removes interferences using He mode and KED (Kinetic Energy Discrimination) Polyatomic Energy distribution Polyatomic Bias voltage ions of analyte and ions rejects low energy interfering (polyatomic) ions polyatomic ions Analyte with t
Slide 35: Polyatomic Interferences in Complex Matrices
Polyatomic Interferences in Complex Matrices Isotope Principal Interfering Species (mixed matrix) 45 13 Sc C16O2, 12C16O2H, 44CaH, 32S12CH, 32S13C, 33S12C 47 31 Ti P16O, 46CaH, 35Cl12C, 32S14NH, 33S14N Testing the effectiveness of the He collision 49 50 Ti 31 P18O, 48CaH, 35Cl14N, 37Cl12C, 32S16OH,
Slide 36: Polyatomic Interferences in No Gas Mode
Polyatomic Interferences in No Gas Mode Color of spectrum indicates which matrix gave each interfering peak CO2 SO, SOH ClO ArC ClO ArO, CaO SO2, S2, ArN2H, Ar2, Ca2, ArCa, 2E5 SO2H S2O, SO3 cps Unspiked 5% HNO3 + 5% HCl + 1% H2SO4 + 1% IPA Matrix Unspiked Matrix – ALL peaks are due to polyatomic in
Slide 37: Polyatomic Interferences in He Mode
Polyatomic Interferences in He Mode Color of spectrum indicates which matrix gave each interfering peak 2E5 cps Unspiked 5% HNO3 + 5% HCl + 1% H2SO4 + 1% IPA Matrix ALL polyatomic interferences are removed in He Mode (same cell conditions) ALL polyatomic interferences are removed in He Mode Is sensi
Slide 38: Matrix Mix with Spike (10ppb) in He Mode
Matrix Mix with Spike (10ppb) in He Mode Consistent sensitivity and perfect template match for all elements 2E5 cps 10ppb Spike in 5% HNO3 + 5% HCl + 1% H2SO4 + 1% IPA Matrix Consistent high sensitivity for all isotopes of all elements in He Mode Good signal for all spike elements in 10 ppb spike. P
Slide 39: Unique Screening Capability of 7700 with He Mode
Unique Screening Capability of 7700 with He Mode The 7700 with ORS3 operates effectively in helium mode, allowing all common matrix interferences (even unknown ones) to be removed from ALL analytes at the same time (no cell gas mode switching needed). This provides a unique semiquant screening capab
Slide 40: Pharmaceutical Sample Analysis using ICP-MS
Pharmaceutical Sample Analysis using ICP-MS USP Webinar Page 40 Dec. 08, 2010
Slide 41: Gelatin Capsules
Gelatin Capsules In-sample spike levels Units Component Gel Caps Limit levels 0.5J J 1.5J 75 As [He] µg/g 1.5 0.91 PPM As, Hg 0.75 1.5 2.25 111 Cd [NG] µg/g 0.5 0.011 Cd 0.25 0.5 0.75 208 Pb [NG] µg/g 1 0.088 Pb 0.5 1 1.5 201 Hg [NG] µg/g 1.5 0.039 Cr-V 5 10 15 52 Cr [He] µg/g 25 0.13 Os-Ir 1.25 2.5
Slide 42: 7700x ICP-MS Calibrations for the Big Four
7700x ICP-MS Calibrations for the “Big Four” 75As 111Cd 201Hg 208Pb USP Webinar Page 42 Dec. 08, 2010
Slide 43: Gelatin Capsules 0.5 J Spike Recovery
Gelatin Capsules 0.5 J Spike Recovery 120 100 80 % Recovery 60 GelCap 0.5J 40 GelCap 0.5J 20 GelCap 0.5J 0 Analyte 120 100 80 % Recovery 60 GelCap 0.5J 40 GelCap 0.5J 20 GelCap 0.5J 0 Analyte USP Webinar Page 43 Dec. 08, 2010
Slide 44: Gelatin Capsules 1.0 J Spike Recovery
Gelatin Capsules 1.0 J Spike Recovery 120 100 80 GelCap 1.0J % Recovery 60 GelCap 1.0J 40 GelCap 1.0J 20 GelCap 1.0J 0 GelCap 1.0J GelCap 1.0J Analyte 120 100 80 GelCap 1.0J % Recovery 60 GelCap 1.0J 40 GelCap 1.0J 20 GelCap 1.0J 0 GelCap 1.0J GelCap 1.0J Analyte USP Webinar Page 44 Dec. 08, 2010
Slide 45: Gelatin Capsules 1.5 J Spike Recovery
Gelatin Capsules 1.5 J Spike Recovery 120 100 80 % Recovery 60 GelCap 1.5J 40 GelCap 1.5J 20 GelCap 1.5J 0 Analyte 120 100 80 % Recovery 60 GelCap 1.5J 40 GelCap 1.5J 20 GelCap 1.5J 0 Analyte USP Webinar Page 45 Dec. 08, 2010
Slide 46: Amoxicillin (API)
Amoxicillin (API) Average (n=3) Limit µg/day Pass/Fail µg/g µg/day Arsenic 0.075 0.075 15 Pass Mercury 0.009 0.009 15 Pass Lead 0.031 0.031 10 Pass Cadmium 0.002 0.002 5 Pass Avg (n=3) µg/g µg/day Limit (µg/day) Pass/Fail Chromium 0.194 0.194 250 Pass Copper 0.032 0.032 2500 Pass Manganese 0.014 0.0
Slide 47: Amoxicillin Spike Recoveries
Amoxicillin Spike Recoveries Arsenic Mercury Lead Cadmium Chromium Copper Manganese Molybdenum Specification (J) 25 250 250 25 1.5 1.5 1 0.5 (µg/g) “J” = 10 “J” = 10 “J” = 10 “J” = 10 Avg. %Rec 81 102 105 98 97 100 103 96 0.5J (n=3) RSD = 0.86 RSD = 2.8 RSD = 0.57 RSD = 0.82 RSD = 0.52 RSD = 0.20 RS
Slide 48: Pharmaceutical Sample Analysis using ICP-OES
Pharmaceutical Sample Analysis using ICP-OES USP Webinar Page 48 Dec. 08, 2010
Slide 49: Agilent ICP-OES
Agilent ICP-OES The world's most productive high performance simultaneous ICP-OES • Continuous wavelength coverage provides extended dynamic range and reduced interferences, giving you maximum confidence in your results • Robust plasma ensures reliable and reproducible results—even with the most com
Slide 50: Instrumentation
Instrumentation Agilent 720-ES Simultaneous CCD ICP-OES • Axial configuration • VistaChip custom-designed and patented CCD detector • Continuous wavelength coverage from 167 to 785 nm • High efficiency 40 MHz RF generator • Cooled-Cone Interface (CCI) displaces cooler tail of plasma • Increases line
Slide 51: Agilent 720-ES ICP-OES
Agilent 720-ES ICP-OES - Computer-optimized echelle optical and detector design • Thermostatted to 35oC for stability and fast start-up • All wavelengths captured in one reading • Fewer optical components • High light throughput • Excellent signal-to-noise • Thermostatted to -35oC for low noise • Ad
Slide 52: Long Term Stability: % Recovery of CCV
Long Term Stability Continuing Calibration Verification (CCV) Ag 328.068 Al 237.312 120 As 188.980 Ba 585.367 110 Be 313.042 Ca 315.887 % Recovery of CCV Cd 214.439 100 Co 228.615 Cr 267.716 Cu 324.754 90 Fe 238.204 K 769.897 Mg 285.213 80 Mn 257.610 Na 568.821 Ni 231.604 70 Pb 220.353 Sb 217.582 Se
Slide 53: Specificity
Specificity The procedure must be able to unequivocally assess each Target Element in the presence of components that may be expected to be present, including other Target Elements and matrix components. Intensity As 193.696 Intensity Cd 214.439 331 600 100 µg/L Pt 100 µg/L Pt 300 500 5 µg/L Cd 250
Slide 54: FACT - Multicomponent Spectral Fitting
FACT - Multicomponent Spectral Fitting European Pharmacopeia 6.0 2.2.57. Inductively coupled plasma-atomic emission spectrometry Describes the advantage of spectral fitting USP Webinar Page 54 Dec. 08, 2010
Slide 55: FACT - Multicomponent Spectral Fitting
FACT - Multicomponent Spectral Fitting • Information about position and intensities of potential interferences is displayed during method development • FACT modelling can be performed and saved before or after sample measurement. It improves the resolution mathematically beyond the practical and the
Slide 56: Impurity Limits
Impurity Limits Element Component Adjusted for 50x Prep Dilution Limit (µg/g) Limit (µg/g) J .5J J 1.5J As 1.5 0.015 0.03 0.045 Cd 0.5 0.005 0.01 0.015 Pb 1 0.01 0.02 0.03 Hg 1.5 0.015 0.03 0.045 Cr 25 0.25 0.5 0.75 Cu 250 2.5 5 7.5 Mn 250 2.5 5 7.5 Mo 25 0.25 0.5 0.75 Ni 25 0.25 0.5 0.75 Pd 10 0.1
Slide 57: Control Sample Data
Control Sample Data USP Webinar Page 57 Dec. 08, 2010
Slide 58: Amoxicillin Sample Spikes
Amoxicillin Sample Spikes USP Webinar Page 58 Dec. 08, 2010
Slide 59: Amoxicillin Repeatability
Amoxicillin Repeatability Element % RSD As 3.73 Cd 0.77 Cr 0.69 Cu 0.48 Hg 1.07 Ir 0.43 Mn 0.44 Mo 0.47 Ni 0.43 Os 0.96 Pb 2.15 Pd 0.50 Pt 0.40 Rh 0.58 Ru 0.34 V 0.43 USP Webinar Page 59 Dec. 08, 2010
Slide 60: Sodium Bicarbonate Sample Spikes
Sodium Bicarbonate Sample Spikes USP Webinar Page 60 Dec. 08, 2010
Slide 61: Sodium Bicarbonate Repeatability
Sodium Bicarbonate Repeatability Element % RSD As 5.99 Cd 2.96 Cr 0.97 Cu 1.34 Hg 1.40 Ir 1.17 Mn 1.00 Mo 0.95 Ni 0.99 Os 1.19 Pb 8.32 Pd 1.39 Pt 1.18 Rh 0.95 Ru 1.24 V 1.01 USP Webinar Page 61 Dec. 08, 2010
Slide 62: Results Confirmation Capability
Results Confirmation Capability USP Webinar Page 62 Dec. 08, 2010
Slide 63: ICP-MS/OES Compliance with 21 CFR Part 11
ICP-MS/OES Compliance with 21 CFR Part 11 Agilent’s complete solution for Compliance ensures: • Data security – Secure central storage of data Full support of all – User access limited to authorized individuals requirements mandated by 21 CFR Part 11 • Data integrity in closed system – Automatic dat
Slide 64: ICP-MS and ICP-OES are the new Gold Standard for metals testing
ICP-MS and ICP-OES are the new Gold Standard for metals testing in pharmaceutical materials. USP Webinar Page 64 Dec. 08, 2010
Slide 65: Thank You / Questions?
&j y “7, f- se a ; r "Lig \ I" : pe * THANK YOU QUESTIONS?
Agilent Technologies — Technical Presentation (December 2010) on 6ix