More sensitive and selective methodologies have facilitated the identification and quantification of elemental impurities (EIs) in pharmaceuticals and the movement away from the old heavy metal analytical tests to the newer risk-based assessment strategy of ICH Q3D.
Pharmacopeial attention on heavy metal testing increased in the wake of an influential proposal made in USP’s Pharmacopeial Forum in the mid-1990s, and an international effort to develop an improved and harmonized regulatory approach culminated in the adoption of the ICH Q3D guideline on EIs in late 2014.
However, Q3D implementation has been associated with challenges and characterized by a wide diversity of approaches for both new and existing drug products. Some companies have continued to focus on the older heavy metal tests, and the submissions among those that have updated to the new risk-based EI approach have been inconsistent.
A second revision (R2) of the ICH Q3D guideline was developed by ICH’s Quality Expert Working Group (EWG) and endorsed by the ICH Assembly for public comment in September 2020. The revision focused on the establishment of EIs by the dermal route of exposure and also included new exposure limits for silver (via the oral route), gold (oral, parenteral and inhalation routes) and nickel (inhalation route). Q3D(R2) was released for comment by FDA in May 2021, with the Step 4 document posted to the ICH website in April 2022.
The four parts of the following story review the recent ICH Q3D implementation efforts and the support that has come from workshops, research, and guideline and pharmacopeial revisions.
PART I: Role of the PQRI/FDA Workshop in ICH Q3D Implementation Dialogue
Part I provides an overview of the background, scope and content of a watershed November 2020 workshop, cosponsored by the Product Quality Research Institute (PQRI) and FDA, that brought experts and policy makers from industry, health agencies, and pharmacopeias together to assess the Q3D implementation challenges and progress. Included are the workshop discussions on: ● a PQRI survey held prior to the workshop assessing industry experience with regulators ● the Lhasa EI data sharing initiative, and ● the Q3D(R2) draft.
PART II: Regulatory Experience and Perspective in Implementing ICH Q3D
The second part focuses on the regulator experience with Q3D implementation and the industry issues that have been surfacing. Receiving attention are the insights provided at the PQRI workshop by FDA’s Mathew Vera and Sophie Bertilsson from the Swedish Medical Products Agency, who provided a European update. The ensuing Q&A further explored regulatory issues and concerns with Q3D implementation.
PART III: Pharmacopeial Harmonization with ICH Q3D
The third part focuses on pharmacopeial efforts and progress towards harmonization with ICH Q3D. In focus are the updates provided at the pharmacopeia session of the PQRI/FDA workshop by: ● industry consultant Nancy Lewen on USP’s handling of its element-specific chapters ● USP’s Galina Holloway on USP efforts to develop a roadmap to address element-specific tests for EIs in excipient monographs, and ● EDQM’s Ulrich Rose on the EI initiatives in the European Pharmacopeia. Included is a follow up from USP’s Catherine Sheehan at the 2022 IPEC-Americas Excipient World conference on USP’s progress with its element-specific chapters and excipient monographs.
PART IV: Outcomes of PQRI Study on Variability in Elemental Impurity Analysis
Part IV describes the results and conclusions of the second phase of a multi-center, collaborative study commissioned by PQRI to investigate how reliably EIs can be measured in pharmaceuticals. The objective of the study was to provide data-driven insight into the variability and accuracy of various analytical methodologies, as well as an indication of what kind of inter-lab variability exists. Included is a review of the study findings by RTI International’s James Harrington at the 2022 Excipient World Conference.