The Product Quality Research Institute elemental impurity interlaboratory study: Results and implications for industry

Abstract

Introduction

Pharmaceutical laboratories experienced a paradigm shift in drug product elemental impurity (EI) expectations in International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline Q3D and United States Pharmacopeia (USP) General Chapters <232>/<233>. These guidelines describe a risk-based approach to EI analysis. Few systematic evaluations of interlaboratory performance on EI analysis in pharmaceutics have been conducted following these guidelines. Our goal is to address key technical challenges faced by laboratories during the implementation of these regulations.

Materials and Methods

We organized an interlaboratory study using standardized samples and methodology to assess sample preparation and analysis variability. Participants performed microwave-assisted acid preparation of simulated pharmaceutical products and analyzed Class 1 and 2A EI's by inductively-coupled plasma-mass spectrometry (ICP-MS). Several laboratories performed X-ray Fluorescence spectroscopy (XRF) for comparison.

Results

ICP-MS reproducibility was high both within and between laboratories, except for Hg and V. Exhaustive extraction and total digestion were generally comparable, between 87 and 111 % for As, Cd, Co, and Pb. Total digestion exhibited lower variability than exhaustive extraction. Two types of microwave systems produced comparable results for most elements except Hg and Pb. The summation approach was comparable to direct analysis of tablets except for Hg and Cd, but summation demonstrated greater variability. XRF showed good agreement with ICP-MS and low replicate variability within labs.

Discussion and Conclusions

While the results were generally favorable, they demonstrate that some technical challenges remain to be addressed related to standardizing laboratory practices including interference correction strategies and selection of preparation methods. We discuss implications for method transfer between laboratories.