Collaborative Studies: XRF Component of Round 1 Study ...pqri.org/wp-content/uploads/2016/11/2-XRF-and-Round-2-Intro... · Instrumental Analysis Variations . INSTRUMENTS . XRF Instrument

Collaborative Studies: XRF Component of Round 1 Study Current Status of PQRI Round 2 Study Donna Seibert on behalf of the Technical/Analytical Challenges Sub-team to the Coalition for Rational Implementation November 9, 2016

X-Ray Fluorescence Analyses of Elemental Impurities: Round 1 Experimental and Results Experimental slides courtesy of Thanh Nguyen

Subject Comments

Objective Follow-on study to compare data generated with XRF to previously generated ICP-MS data for standardized evaluation samples.

Participating Laboratories

Four (4) voluntary XRF groups participated in this round robin testing.

Sample Distribution Raw materials and unknown samples (tablet form) were distributed to all testing labs for analysis.

Sample Preparation Consistency between standards and samples and between labs

Analysis Standardized calibration ranges

Objective and Outline

Preparation of Combined Standard Solutions

Certified Metal ICP Standards 5-100 ppm Combined Standards

(Solutions for Spiking) 5X Concentration from Target Level

Preparation of Solid Matrix for Standards

A blend of the round robin tablet formulation was prepared with the above composition in order to match the native and enhanced tablet matrix

Samples were prepared by grinding the native and enhanced tablets and preparing pellets for analysis

Spike and Mix Standards in Matrix

1 mL volume of 5X standard solution was added to 5 g matrix in disposable acrylic mix vials

Spiked matrix dried overnight in oven at 600C

Clamp vial into mixer/mill and mix for ~5 min

Spex CertiPrep 8000 Mixer/Mill

Preparation of Solid Standards

Pellet Ready for Analysis

Calibration/Analysis of the “ENTIRE” pellet

Transfer “ENTIRE” sample to die assembly

Pressed Pellet

Final Solid Standard Concentration Ranges

Cd (ppm)

Pb (ppm)

As (ppm)

Hg (ppm)

Co (ppm)

V (ppm)

Mo (ppm)

Se (ppm)

0 0 0 0 0 0 0 0

0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25

0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0

Standards were prepared by serial dilution or through randomized concentrations

Calibration Curves

Element Lowest R2 Highest R2

Hg 0.9800 0.9990

Cd 0.9869 0.9986

Pb 0.9904 0.9998

As 0.9918 1.0000

Co 0.9815 0.9992

V 0.9812 0.9999

Mo 0.9958 0.9994

Se 0.9881 0.9999

Instrumental Analysis Variations

INSTRUMENTS XRF Instrument Models • WDXRF - ARL Thermo PERFORM’X • WDXRF – Rigaku Primus II • EDXRF – PANalytical Epsilon 3XLE

Mixer/Mills • Spex 8000 • Retsch PM400

Presses • Angstrom Briquet 445AE-1 • Atlas Autotouch Specac 25T • Atlas Autotouch Specac 40T

VARIABLE PARAMETERS Analysis Atmosphere • Ambient air, He, Vacuum Analysis Time (per analysis) • 10 min – 45 min Size of Pellet • 32-40 mm Pressure of Pellet • 10-25 Ton

XRF Results by laboratory

Native Tablets (ppm) Hg Cd Pb As Co V Mo Se

Lab A (n=3) (0.1) ND ND ND (0.2) ND 0.3 (0.2) Lab B (n=3) ND ND ND ND ND (0.1) 0.5 ND Lab C (n=3) ND (0.1) ND (0.1) (0.1) ND (0.2) ND

Lab D (n=10) (0.2) ND (0.1) ND ND ND (0.0) (0.1) XRF mean (n=12) (0.2) (0.1) (0.1) (0.1) (0.2) 0.3 0.3 (0.2)

Enhanced Tablets (ppm) Hg Cd Pb As Co V Mo Se

Lab A (n=3) (0.2) 0.4 2.5 1.7 0.9 1.6 1.8 0.5 Lab B (n=3) ND 0.3 1.4 1.4 0.4 1.7 2.1 0.3 Lab C (n=3) (0.1) 0.5 1.3 1.1 0.7 1.0 2.1 0.5

Lab D (n=10) 0.6 0.4 2.2 1.6 0.6 1.2 1.6 0.5 XRF mean (n=12) 0.3 0.4 1.8 1.5 0.6 1.5 1.9 0.5

Values in parentheses are below LOQ (0.25 ppm)

XRF Results by laboratory






Lab D (n=10) 0.6 0.4 2.2 1.6 0.6 1.2 1.6 0.5 XRF mean (n=12) 0.3 0.4 1.8 1.5 0.6 1.5 1.9 0.5


XRF Results Compared to ICP/MS Means




ICP/MS mean 0.5 0.0 1.1 0.6 0.2 1.9 0.2 0.2



Lab D (n=10) 0.6 0.4 2.2 1.6 0.6 1.2 1.6 0.5 XRF mean (n=12) 0.3 0.4 1.8 1.5 0.6 1.5 1.9 0.5

ICP/MS mean 0.4 0.4 3.1 1.5 0.7 2.7 1.5 0.6


Arsenic

Tablet Type XRF ICP/MS Open circles denote outliers x indicates point below LOQ (XRF only) Error bars set at 1.5 x Interquartile Range

Cadmium


Lead


Mercury


Cobalt


Molybdenum


Selenium


Vanadium


Conclusions

• Results generally comparable to ICP-MS • Bias from background levels in materials used to

make standards ▫ Apparent in Pb and V results ▫ Standard additions in calibration setup could

correct for this bias • When sample is not limited, XRF offers quick

and economical analysis ▫ Once calibration is established, only check

standards need to be analyzed

Acknowledgements

Company Contributors

Rigaku Thanh Nyugen, Glenn Williams

PANalytical Andrew Fussell

Dow Corning Tom Case, Jason Sturm

RTI Andrea McWilliams, Frank Weber, James Harrington

Perrigo Josh Foote, Tanya Davis

PQRI Sponsored Study Concept Elemental Impurities in Pharmaceuticals Second Round Experimental Outline

Slides courtesy of James Harrington

Project Objectives

• Address some of the key technical challenges faced by industry in preparation for compliance to ICH Q3D and USP <232>/<233>

• Provide a data-driven way to discuss technical aspects and expected variation of ICP-MS analysis of elemental impurities

• More specific objectives: ▫ Inter-laboratory data comparison for standardized samples ▫ Inter-laboratory evaluation of effectiveness of microwave digestion ▫ Comparison of acid leach/extraction techniques to total metal extraction ▫ Examination of the correlation (good or bad) between the analysis of

individual components (summation) vs. the formulated tablet analysis ▫ Comparison of ICP-MS and alternative techniques (ICP-OES and XRF)

• PQRI Sponsorship allows wider participation

• Study administrator—RTI International

Second Round Design Improvements & Best Practices

General • Consistency among alternative techniques and digestion methods to

ensure adequate data for comparison • ICP-OES (14) and XRF (6) analysis considered proactively • Raw materials distributed widely for summation approach comparison

Uniform Sample Preparation • Specify parameters such as sample size, sampling technique, acid

mixtures, and digestion temperature/pressure • Document type of digestion vessels and microwave model used

Uniform Analysis • Define procedures around LOQs, calibration, and data reporting • Document interference management (reaction/collision gases,

correction equations, etc.) and internal standards

Evaluation Samples & Analysis

Second Round Improvements—

Evaluation Samples

• Liquid sample to assess instrumental variation

• Evaluation samples with higher EI levels overall

• Multiple powdered or tableted evaluation samples targeting different levels

• EI source from pharma materials wherever possible

Powdered or tableted material at three concentrations and liquid sample are aliquoted and shipped to each participating laboratory.

Samples extracted in triplicate using the uniform method. Alternate extraction methods may be used if available in

addition to the uniform method.

Uniform method sample extracts/liquid

sample must be analyzed by ICP-MS.

Optional alternate method sample

extracts are analyzed by ICP-MS.

Replicate results and average/SD reported by extraction method and analysis method. Total samples for ICP-MS analysis are 12, alternative

digestion and analysis techniques will be in addition to basic results.Minimum samples: 12, maximum: 36.

Uniform method sample extracts, liquid may be analyzed by ICP-OES or other

instrument.

Samples extracted in triplicate using the uniform

acid leaching method.

Samples extracted by acid leaching method must be analyzed by

ICP-MS.

Results for replicates and average/SD are reported. Total samples for acid leach analysis

are 12.

Formulation Challenges

• Ideal solid formulation is tableted ▫ To preserve homogeneity

• Pharmaceutical materials that contain significant, known levels have been elusive ▫ Few materials contain significant As & Hg

• Combination of materials must have ▫ Favorable mixing & flow properties ▫ Compressibility

• Current path for solid formulations ▫ Tablets similar to the first round tablets ▫ Include small amounts of XRF standards ▫ Three levels of elemental impurities

Second Round Recruiting

• Distributed participant questionnaire for analytical laboratories in early August.

• Response as of 11/01/16: ▫ 28 laboratories submitted forms + 1 verbal commitment

Pharma manufacturers: 15 laboratories Contract/CRO: 9 laboratories Instrument manufacturers: 2 laboratories Government: 2 laboratories

1 lab

11 labs

17 labs

Next steps:

• Finalize formulations • Produce tablets and liquid sample

▫ Partnering with Liverpool John Moore’s University

• Uniform method and acid leach method development ▫ To be developed with finalized tablets prior to distribution

• Still seeking participant laboratories! ▫ Can accommodate up to 50 labs

Acknowledgements

• James Harrington, RTI • Frank Weber, RTI • Phil Riby, Liverpool John Moore’s University • Dave Schoneker, Colorcon • PQRI • TAC Team members • All participating labs

Detail Slides

Second Round Participating Laboratories

• J.M. Huber • Chemical Solutions • LGC, Ltd • MSD Oss • AstraZeneca (x2) • Colorcon • Dow Corning • Eurofins Frontier Global Sciences • ELS, Ltd • PANalytical • Pfizer (x2) • Evonik • Perrigo

• Rigaku • Ineos Oxide • Perkin Elmer Health Sciences • Reading Scientific Service, Ltd • Solvias AG • Health and Safety Laboratory, UK • Procter and Gamble • SGS Life Science Services • RTI International • USP India (verbal) • Vertex Pharmaceuticals • AbbVie • GlaxoSmithKline • Intertek Pharmaceutical Services

Second Round Equipment

• Available equipment ▫ ICP-MS: 23 laboratories ▫ ICP-OES: 14 laboratories ▫ XRF: 6 laboratories ▫ Microwave digestion: 21 laboratories ▫ Alternative digestion: 11 laboratories

• Raw Materials analysis interest ▫ 20 laboratories

• Acid Leaching interest ▫ 10 laboratories

• HF digestion available ▫ 14 laboratories

Documents

Collaborative Studies: XRF Component of Round 1 Study ...pqri.org/wp-content/uploads/2016/11/2-XRF-and-Round-2-Intro... · Instrumental Analysis Variations . INSTRUMENTS . XRF Instrument