Screening of actual pharmaceutical products for Elemental Impurities according to ICH guideline Q3D using XRF

Energy-dispersive X-ray fluorescence spectrometry (EDXRF) is a suitable analytical procedure for screening oral solid drug (OSD) products for Elemental Impurities (EI) according to ICH guideline Q3D. EDXRF represents a cost-efficient, robust and standard-free alternative compared to other methodologies for trace analysis, and therefore utilization of this application should be encouraged.  

This application note demonstrates the capability of EDXRF for EI screening of oral drug products. Method development and validation focused on class 1 (Cd, Pb, As, Hg) and class 2A (Co, V, Ni) elements, as defined by ICH guideline Q3D. To pass successfully the target was set to minimally be able to quantify class 1 elements at 2 ug/g, and for class 2A elements at 10 ug/g. 

Introduction

Energy-dispersive X-ray fluorescence spectrometry (EDXRF) is a suitable analytical procedure for screening oral solid drug (OSD) products for Elemental Impurities (EI) according to ICH guideline Q3D. EDXRF represents a cost-efficient, robust and standard-free alternative compared to other methodologies for trace analysis, and therefore utilization of this application should be encouraged.  

This application note demonstrates the capability of EDXRF for EI screening of oral drug products. Method development and validation focused on class 1 (Cd, Pb, As, Hg) and class 2A (Co, V, Ni) elements, as defined by ICH guideline Q3D. To pass successfully the target was set to minimally be able to quantify class 1 elements at 2 ug/g, and for class 2A elements at 10 ug/g.  

Full details of this study are described in the following publication: B. Sauer et al; J Pharm Biomed Anal; 2020; 179:113005 

Instrumentation 

Measurements were performed using a Malvern Panalytical Epsilon 4 EDXRF spectrometer, equipped with a 15W, 50 kV silver (Ag) anode X-ray tube, 6 software-selectable filters, a high-resolution SDD30 silicon drift detector and a 10 position sample carrousel.  

Sample selection 

Fifteen different end products, representable for a portfolio of more than 400 products of Salutas Pharma GmbH (Novartis), have been selected for validation. These products contain besides an organic part, a variety of metals, with concentration up to a few weight-%. The samples were divided in 2 groups based on the Titanium content.  

Two setup sample sets, spiked with the elements of interest ranging from 1 µg/g to 20 µg/g, were used for method setup and the evaluation of method performance parameters. One sample set was based on a cellulose matrix, while the other Metoprolol succinate (MUT) was chosen as representative of a typical Ti-containing OSD product. MUT encounters common complications with XRF method development: multiple coatings lead to increased sample heterogeneity and Ti content affects the assessment of V, due to a line overlap. 

Sample preparation 

For sample preparation, the tablets were initially crushed using an agate mortar and a Tube Mill control. Limit samples, samples to check the required accuracy to meet the required 2.5 g daily dose, were made by spiking the samples with the required concentration and dry it in an oven at 50ºC. Finally, the selected 15 products were spiked with 2 μg/g Cd, Pb, As, Hg and 10 μg/g V, Ni, Co. The spiking procedure was verified by ICP-MS reference analysis conducted at an external laboratory. 

Five grams of spiked powder was compacted by applying a pressure of 6 tons (hydraulic press) to form a disc shape pressed pellet with a 32 mm diameter.  

Measurement procedure 

For each set, 6 concentrations of sample pellets were prepared in triplicate and both sides of the pellets were measured. The 6 individual values obtained per concentration level were plotted and subjected to linear regression analysis. Four different measurement conditions were used to measure the 7 toxic elements V, Co, Ni, As, Hg, Pb, and Cd (see Table 1). The 7 majors Fe, P, S, Cl, K, Ca & Ti present in the selection of OSD products were simultaneously analyzed. The total measurement time was set at 30 minutes per sample.  

[Figure 1 AN221003-screening-elemental-impuritiex-ICH-XRF.jpg] Figure 1 AN221003-screening-elemental-impuritiex-ICH-XRF.jpg

Figure 1: Recovery and RSD plots for product-specific LOQ validation: Recovery plot for class 1 (A) and class 2A elements (B), RSD plot for class 1 (C) and class 2A elements (D), red dashed line indicates thresholds for method validation

ElementskVuAFilterMediumMeas. time (s)
Ni, As, Hg, Pb50125AgAir600
Cd50300Cu- thickAir900
Co, Fe20240Al- thickAir180
V, S, Cl, K, Ca, Ti12950Al- thinAir120

Table 1. Measurement conditions 

ElementsConcentration range (μg/g)Correlation CoefficientLOQ (μg/g)
Cd0-200.9992.3
Pb0.9990.8
As0.9990.5
Hg0.9991.0
Co0.9981.9
V0.9953.2
Ni0.9981.2

Table 2. Calibration details: LOQ = 10*RSD (1 µg/g spiking level) 

ElementsConcentration range (μg/g)Correlation CoefficientLOQ (μg/g)
Cd0-200.9991.4
Pb0.9990.8
As0.9991.1
Hg----
Co0.9971.0
V0.9808.1
Ni0.9981.7

Table 3. Calibration details: LOQ = 10*RSD (1 µg/g spiking level) 

Validation 

For each OSD product, spiked samples were prepared at concentrations of 2 µg/g and 10 µg/g in triplicate, except for 3 products, which were prepared in duplicate due to sample availability. The concentrations were chosen according to the defined specification limits: 2 ug/g for Cd, Pb, As, Hg and 10 ug/g for V, Ni, Co. In order to compensate for possible sample heterogeneity, both sides of each limit sample were measured, and the calculated mean was used for the assessment of recovery and repeatability. Results are shown in Figure 1.  

The LOQ validation criteria according to Ph. Eur. were met for every product, as shown in the recovery and repeatability plots (Figure 1):  

  • All recovery rates were within 70 % -150 % of the expected values,  
  • RSDs did not exceed 20 %.  

Thus, following this method, element-specific correction algorithms operated reliably and products within the defined matrix range were screened for EI using the EDXRF limit test in compliance with the method validation requirements. 

Conclusion 

This study demonstrates the capability of Epsilon 4 with regards to elemental impurity screening on oral solid dosage drug products within a defined matrix range. The results show that the developed method can be used as a limit test for class 1 and class 2A elements at the defined specification limits of 2 µg/g and 10 µg/g, and is fully compliant with European Pharmacopeia method validation requirements. 

Together with the Epsilon 4 XRF benchtop instrument, Malvern Panalytical can supply a unique cellulose-based calibration method with reference materials, comprising of 20 common elements in pharmaceutical products.  

Acknowledgments 

Malvern Panalytical acknowledges the collaboration with Salutas Pharma GmbH (Novartis) and the combined effort resulting the publication in the Journal of Pharmaceutical and Biomedical Analysis.  

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