elemental impurities; the latest update to usp and ich · 2016-10-10 · risk assessment •...

ELEMENTAL IMPURITIES; THE LATEST UPDATE TO

USP AND ICH

Amir Liba PhDSpectroscopy Team Lead

Trace Metal Analysis in Pharmaceuticals, Why?

• Global Shift to higher consumption of medication/pharmaceutical ingredients• Population increase• Emerging Health Care

• Consumer safety and toxicology• Small molecule therapeutics• Biologics

IMS- 2017 Spending Levels

IMS Health-The Global Use of Medicines: Outlook Through 2017

• Excipients; fillers, colors, flavors, stabilizers• API; source (phyto-, animals, recombinant)• Catalysts; used in API synthesis• Production Equipment; pipes, filters, reactors• Packaging

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Confidentiality Label

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Pharmacopeial Forum Stimuli Vol. 34(6) [Nov.–Dec. 2008]

Precedent Was Set for a Change in Analytical Method

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Timeline for ICH Q3D Replacement Method• Early dialog in Brussels in 2008 • Final Concept Paper on July 2008 • Step 2 completed on June 2013 • Step 4 approval expected on June 2014 and achieved on 12 November 2014,

with a error/corrections released on 16 December 2014• Step 5

EU: Adopted by CHMP, December FDA: Adopted 10 September 2015, issued as Q3D Elemental

Impurities, Guidance for Industry• Implementation New Products June 2016 Existing Products December 2017

Adopted from Eurofin

Timeline for USP<231> Replacement Method1995: 1st Pharmacopeial Forum (PF) “Stimuli to the Revision Process” article (K. Blake)2000: 2nd PF Stimuli article proposed ICP-MS (T. J. Wang)2005: USP heavy metals subcommittee appointed2005: ICP-MS Included in Chinese Pharmacopeia2009: ICP-MS Included in European Pharmacopeia2010: Proposals for USP<232>, <233> and <2232>2012: USP final revision to be published2013: Latest revision published2013: Final Implementation date is postponed2015: USP <232>/<233> becomes official January 1, 20182016: Proposed complete analyte alignment with Q3D

USP Completely aligned with ICH PDEs

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Heavy Metal Chapters – Current and Planned

<2232>

Heavy Metals Limit Test

<233><232>

ElementalImpurities(Limits)

ElementalImpurities

(Procedures)

ElementalImpurities in

Dietary Supplements

Terminology changing:“Heavy Metals” “Elemental Impurities”

Is being replaced with:

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Related method <2232> applies to dietary supplements only

<232> will eventually replace other “metals” General Chapters

<251>

<231>

Lead

<211>Arsenic

<261>Mercury

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ICH Class Element Symbol ICH (ug/day) Oral PDE

USP ug/day) Oral PDE

ICH (ug/day) Parenteral PDE

USP ug/day) Parenteral PDE

ICH (ug/day) Inhalation PDE

USP ug/day) Inhalation PDE

Class 1 Cadmium Cd 5 5 2 2 2 2Lead Pb 5 5 5 5 5 5

Arsenic As 15 15 15 15 2 2Mercury Hg 30 30 3 3 1 1

Class 2A Cobalt Co 50 50 5 5 3 3Vanadium V 100 100 10 10 1 1Nickel Ni 200 200 20 20 5 5

Class 2B Thallium Tl 8 8 8 8 8 8Gold Au 100 100 100 100 1 1

Palladium Pd 100 100 10 10 1 1Iridium Ir 100 100 10 10 1 1Osmium Os 100 100 10 10 1 1Rhodium Rh 100 100 10 10 1 1Ruthenium Ru 100 100 10 10 1 1Selenium Se 150 150 80 80 130 130Silver Ag 150 150 10 10 7 7

Platinum Pt 100 100 10 10 1 1Class 3 Lithium Li 550 550 250 250 25 25

Antimony Sb 1200 1200 90 90 20 20Barium Ba 1400 1400 700 700 300 300

Molybdenum Mo 3000 3000 1500 1500 10 10Copper Cu 3000 3000 300 300 30 30Tin Sn 6000 6000 600 600 60 60

Chromium Cr 11000 11000 1100 1100 3 3

Complete Alignment Across 24 Analytes and PDEs Between ICH Q3D and USP <232>

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These chapters apply to• New finished drug products• Drug products containing existing drug substances

• Biologics

• Not in scope• Radiopharmaceuticals• Veterinary drugs• Vaccines• DNA products• Allergenic extracts• Cells, whole blood, cellular blood components, or blood derivatives, including

plasma and plasma derivatives• Gene-based products (gene therapy)• Cells (cell therapy)• Tissue (tissue engineering)• Dialysate solutions not intended for systemic circulation• Total parenteral nutrition (TPNs)• Analytes that are intentionally introduced in the drug for therapeutic benefit• Dietary supplements (USP <2232>)

Analytical Scope

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Risk Assessment

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Risk Assessment• Product risk assessment based on principles of quality risk management is required to assess

elemental impurities• First-hand knowledge of elemental impurities that may be present in the drug

product due to formulations• QbD- Quality by Design; Systematic approach to drug design using science and

risk management to gain better product and process control• PAT- Process Analytical Tech; a system for analysis and control of manufacturing

processes based on measured quality and performance parameters attributed to raw material and in-process material

• The guideline enables targeting of specific elements for controls. It does not require testing of all elements in all materials

• Focus on elemental impurities at risk of exceeding the PDEs• Supplier information (CofA)• Drug formulation process (manufacturing equipment)• Container closure• Testing of final product

• Control threshold of 30% PDE• <30% PDE; no further testing required• >30% PDE; continue testing and remediation providing further controls

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Analytical Procedures• USP <233> ICP-MS and ICP-OES

• Simple calibration to contain a Blank, 0.5J, and 1.5J• Drift Test; 1.5J pre- and post-analysis, NMT 20%

• Two validation parameters• Limit test• Quantitative test

• Speciation is not mandatory unless the levels of As and Hg exceed the PDE

• Sample Prep• Neat• Aqueous• Organic• MW Digestion

Agilent Atomic Spectrometry Portfolio

Agilent 7900 ICP-MS – In a Class by Itself

May 26, 2016

3 Key Benefits of Agilent 7900 ICP-MSFor USP Applications

1) Matrix Tolerance 2) Interference Removal 3) Dynamic Range

Ultra High Matrix Introduction System (UHMI)

Handles tough sample matrices better than any other ICP-MS. Highest total dissolved solids(TDS) capability up to 25%• Reduces sample prep time

and error• Better long-term stability

Octopole Reaction System (ORS4) He Mode

He Mode effectively removes common polyatomic interferences in the samples

• Easy to use - He collision mode only

• Effective for a wide range of sample types

• Accurate measurements

Wider Dynamic Range

11 orders dynamic range: 0.1ppt(DL) to 10,000ppm

• Simplifies method development

• Easy sample prep. • Improves productivity

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Matrix Tolerance

SemiQuant analysis; sample fingerprint

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0

10

20

30

40

50

spike 0% 0.5% 1% 1.5% 2% 5% 10% 25%

Spike Recovery at 0, 0.5, 1, 1.5, 2, 5, 10 and 25% NaCl

75 As [ 25 ppb ] 114 Cd [ 50 ppb ]208 Pb [ 50 ppb ] 201 Hg [ 1 ppb ]

10ppb Spike in 5% HNO3 + 5% HCl + 1% H2SO4 + 1% IPA MatrixConsistent high sensitivity for all isotopes of all elements in He Mode

Good signal for all spike elements in 10ppb spike. Perfect template fit for all elements – ALL isotopes available for quantification / confirmationNo residual interferences and no loss of analyte signal by reaction

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Agilent 5110 SVDV ICP-OES

Agilent THREE “S” System

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Synchronous Measurement of axial and radial viewed light

Simultaneous Dispersion of all Wavelengths with continuous coverage(167 to 785 nm)– Single Optic with no moving parts

Simultaneous readout of the “Zero Gas Use” CCD continuous wavelength detector

Three “S” Advantages• Ease of Use• Throughput with best accuracy and precision - determinations made

with simultaneous measurements of analyte, background and internal standard

• Reduced Cost of Ownership

Stability of Vertical Torch Agilent 5100 SVDV ICPOESEnhanced Performance

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Agilent 5110 SVDV ICPOES Simplifies Work FlowIntelliQuant

Additional detector read at the end of quantitativeanalysis

Full Spectrum Scan for Rapid Qualitative identification

Semi Quant capability

Simple to use

View Entire SpectrumIntelliQuant Analysis - Details

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View Tabular Results in Intelli-Quant Mode

View approximate concentrations of the elements in a sample on the periodic table

heatmap

View spectrum by wavelength

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Procedure Con’t

Limit Test

• Detectability• Standard Solution; reference sample at the target concentration (1J)• Unspiked Sample• Spike 1 (3X); sample spiked at the target concentration (1J)

- Within 15% of the value obtained for the standard solution• Spike 2 (3X); Spiked at 0.8J

- Intensity is less than that of the standard solution

• Precision (Repeatability)• Sample solution (6X) spiked at 1J

- NMT 20%

• Specificity• Unequivocal assessment of data quality

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Quantitative Test

• Accuracy• Standard Solution containing analyte concentration range between

0.5<J<1.5 of target• Test Sample (3X) spiked at concentration 0.5<J<1.5

- Recovery of 70-150%

• Precision (Repeatability)• Test Sample (6X); actual samples spiked at J

- NMT 20%• Intermediate Precision (Ruggedness)

• Re-analyze the six Precision samples• Different days• Different analyst• Different instrument- NMT 25% of all 12 samples

• Specificity• Unequivocal assessment of data quality

Procedure Con’t

• Agilent range of compliance software includes:- Expandable, server-based software suitable for expanding labs and those with

more than one Agilent ICP-MS (OpenLAB and Data Store)

- Simple, low-cost, PC-based software for a single ICP-MS and ICP-OES (SDA)

- Scalable, expandable, multi-instrument, server-based software (OpenLAB ECM)

Agilent’s 21 CFR Part 11 Solutions– a compliance solution for any size of laboratory

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Agilent’s 21 CFR Part 11 Solutions

OpenLAB ECM• Robust features beyond

requirements of 21 CFR Part 11

• Scalable (multiple instruments, sites and users, server-based)

•Multi-vendor support•Integrated search & retrieve

Best for:Large pharma companies that require a flexible, scalable, site-wide or global compliance solution.

SDA• Meets 21 CFR Part 11• Integrated, free

database• Non-scalable, single

ICP-MS support only• PC-based• Meets compliance

needs for many ICP-MS labs

Best for:Small labs, single instrument, minimum compliance solution needed

OpenLAB DataStore• Exceeds 21 CFR Part

11 requirements• Scalable, two ICP-MS

supported as standard; up to 15 instruments, server-based

• Integrated search & retrieve

• International Language support

Best for:Medium labs, superior security needs, future-proof expandability

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• OsO4; Toxic• NitricOs oxidation• Volatile• High carryover

• Ag• Insoluble in certain Cl concentrations

• Hg• Volatile

• Cd• MoO interferance

Some final thoughts

Agilent Atomic Products are the new Gold Standard for metals testing in pharmaceutical materials.

With the Agilent 7900 ICP-MS and 5110 ICP-OES, labs will be ready for USP<232>/<233> Methods which are replacing USP<231>

May 26, 2016

elemental impurities; the latest update to usp and ich · 2016-10-10 · risk assessment •...

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