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USP<232> AND ICH Q3D ELEMENTAL IMPURITY STANDARDS FOR X-RAY FLUORESCENCE ANALYSISY. Xiao , M. Zoontjes, T. Soteriou, L. Kempenaers , Malvern Panalytical B.V. Lelyweg 1 (7602 EA), PO Box 13, 7600 AA Almelo, the Netherlands,L. Grimsley , M. Ingham, Malvern Panalytical Nottingham, Tollerton hall, Nottingham, NG12 4GQ, UKe-mail: [email protected]
WHAT IS X-RAY FLUORESCENCE SPECTROMETRY?
IntroductionAfter the recent publication (USP 37-NF 32) of USP chapter <735> X-ray fluorescence (XRF) spectrometry there has been increased interest in this technique in the pharmaceutical industry [1]. One of the key applications of interest is using XRF to determine elemental impurities according to USP<232> and ICH Q3D [2]. Due to this interest and current lack of XRF calibration standards for these elements in the ranges required, it was decided to investigate the possibilities of producing calibration standards for this analysis.
USP<232/233> AND ICH Q3D
• Analytical technique for determining elemental composition.• X-ray tube produces high-energy X-rays.• X-rays interact with and eject inner-shell electrons.• Outer-shell electrons relax into inner shell releasing X-radiation with energy characteristic for the
element.• Detectors determine energy and intensity of emitted radiation.
• USP<232/233> and ICH Q3D are new chapters/guidelines requiring testing and controlling of elemental impurities in drug products.
• Stipulate Permitted Daily Exposures (PDEs) for 24 potential elemental impurities across 3 administration routes (oral, parenteral, and inhalation).
• USP<233> describes analytical procedures for testing and includes options for alternative techniques including XRF.
• Table 1 shows the Oral PDEs for all of the elements in ICHQ3D with the minimum risk assessment elements in bold.
cps/
chan
nel
18.5 19.0 19.5 20.0 20.5keV
Ru KA1 Rh KA1
Rh KB
Pd KA1
Ru KB3
Ag KA1
Ag KA2
21.0 21.5 22.0 22.5 23.0
Ru KA2Pd KA2Rh KA2
Table 1. Oral Permitted Daily Exposures for elemental impurities from ICH Q3D.
SETUP – STANDARDS FOR XRF• Traceable sources of elemental impurities were purchased and used to spike pharmaceutical grade
cellulose.• Most elements required by USP and ICH Q3D are covered in these standards.
Element Class Oral PDE (μg/day) Element Class Oral PDE (μg/day)
Cd 1 5 Rh 2B 100
Pb 1 5 Ru 2B 100
As 1 15 Se 2B 150
Hg 1 30 Ag 2B 150
Co 2A 50 Pt 2B 100
V 2A 100 Li 3 550
Ni 2A 200 Sb 3 1200
Tl 2B 8 Ba 3 1400
Au 2B 100 Mo 3 3000
Pd 2B 100 Cu 3 3000
Ir 2B 100 Sn 3 6000
Os 2B 100 Cr 3 11000
Table 2. Elements and concentration range in XRF standards.
EXTERNAL VALIDATION TESTING• The calibration standards were submitted for external testing by an FDA, and ISO17025 accredited
lab to confirm the expected spiking levels. • A selection of the results are reported in Table 3 for the cellulose standards
Element Weighed conc. (μg/g)
ICP-MS conc. (μg/g) (ave±SD) (n=3)
Element Weighed conc. (μg/g)
ICP-MS conc. (μg/g) (ave±SD) (n=3)
Cd 20 20 ± 0 Rh 50 46 ± 3
Pb 20 20 ± 1 Ru 50 48 ± 3
As 20 20 ± 0 Se 20 20 ± 1
Hg 20 21 ± 0 Pt 50 49 ± 5
Co 50 48 ± 0 Mo 20 18 ± 1
V 100 94 ± 2 Cu 65 65 ± 1
Ni 30 28 ± 1 Cr 1000 943 ± 6
Tl 20 24 ± 1 Sn 320 300 ± 0
Pd 50 45 ± 13 Sb 60 52 ± 6
Ir 50 49 ± 3 Ba 100 97 ± 2
Table 3. External lab testing results
INSTRUMENT CALIBRATION• To test the performance of the standards an energy dispersive XRF spectrometer of
Malvern Panalytical, an Epsilon 4, was calibrated.• 5 grams of sample was prepared as pressed pellets for analysis.• Total measurement time per sample was 65 minutes (can be shortened depending on number of
elements, sample size and accuracy/precision requirements).• LOQ calculated as 10 times the standard deviation on a blank sample.
12As concentration (µg/g)
Inte
nsity
(cps
)
24 36 48 68 72 84 96 12Pb concentration (µg/g)
Inte
nsity
(cps
)
24 36 48 68 72 84 96
Table 4. Calibration results.
METHOD ACCURACY DETERMINATION• To determine accuracy we measured three validation samples, covering together all 20 elements.• Results for all 20 elements are shown in Table 5.
Element Correlation LOQ (μg/g) Element Correlation LOQ (μg/g)
Cd 0.9997 0.7 Rh 0.9998 0.8
Pb 0.9995 0.1 Ru 0.9999 0.8
As 0.9998 0.1 Se 0.9999 0.1
Hg 0.9999 0.1 Pt 0.9999 0.1
Co 0.9998 0.6 Mo 0.9999 0.2
V 0.9998 0.3 Cu 0.9999 0.2
Ni 0.9999 0.3 Cr 0.9999 0.5
Tl 0.9999 0.1 Sb 0.9999 3.7
Pd 0.9999 0.6 Sn 0.9999 4.5
Ir 0.9999 0.2 Ba 0.9979 0.5
Table 5. Recovery results for the validation measurement
ConclusionsThis work shows the development of new pharmaceutical standard reference materials to aid X-ray fluorescence spectrometry users to meet new elemental impurity regulations.
REFERENCES[1] United States Pharmacopeial convention (USP 37-NF 32)[2] ICH Q3D Quality guidelines (http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html)
Element Conc. range (μg/g) Element Conc. Range (μg/g)
Cd 0 - 100 Rh 0 - 200Pb 0 - 100 Ru 0 - 200As 0 - 100 Se 0 - 200Hg 0 - 100 Pt 0 - 200Co 0 - 100 Mo 0 - 400V 0 - 200 Cu 0 - 400Ni 0 - 200 Cr 0 - 500Tl 0 - 200 Sn 0 - 1000Pd 0 - 200 Sb 0 - 300Ir 0 - 200 Ba 0 - 200
Element Given conc. (μg/g)
Results (μg/g) Element Given conc. (μg/g)
Results (μg/g)
Cd 20.1 20.3 Rh 50 50.9
Pb 20 18.4 Ru 50 49.0
As 19.9 20.3 Se 20.1 19.6
Hg 20 19.7 Pt 50 52.0
Co 50 51.2 Mo 20 19.6
V 100 101.7 Cu 65 62.3
Ni 30 29.6 Cr 1000 999.0
Tl 19.9 19.0 Sb 60 62.4
Pd 50 49.7 Sn 320 331.7
Ir 50 51.2 Ba 100 100.7
