USP 232 & ICH Q3D elemental impurities in drugs

USP 232 & ICH Q3D elemental impurities in drugs

Elemental impurities in pharmaceutical formulations can come from catalysts, formulation ingredients and process vessels. They can interfere with drug efficacy or elicit a direct toxic effect on the patient.

For over 100 years regulators have demanded the testing of heavy metal impurities in pharmaceutical products. Recently, global regulators have issued modern guidelines—such as USP 232 Elemental Impurities & ICH Q3D—for monitoring a range of metal elemental impurities in pharmaceutical materials using inductively coupled plasma (ICP) optical emission spectroscopy (ICP-OES) or mass spectrometry (ICP-MS).

Harmonized pharmaceutical elemental impurity regulations for USP 232 & ICH Q3D

The US Pharmacopeial (USP) Convention proposed three new elemental impurities general chapters in 2010 covering impurity limits, analytical procedures in pharmaceutical products and raw materials, and elemental contaminants in dietary supplements:

  • Chapter <232> Elemental Impurities in Pharmaceutical Products —Limits
  • Chapter <233> Elemental Impurities in Pharmaceutical Products — Procedures
  • Chapter <2232> Elemental Contaminants in Dietary Supplements

These revisions focused on two main areas of work:

  1. Updating the methodology used to test for elemental impurities in drugs and dietary supplements to include procedures that rely on modern analytical technology.
  2. Setting limits for acceptable levels of metal impurities (including, but not limited to, lead, mercury, arsenic, and cadmium) in drugs and dietary supplements.

While no specific event triggered the revision of elemental impurities standards, USP’s scientific experts concluded that these standards should be updated to incorporate modern analytical methods and current health information on these impurities.

An announcement on January 14, 2015 established January 1, 2018 as the new date of applicability for General Chapters <232>, <233> and <2232>. This was intended to align implementation closely with limits and timelines set down by other global pharmaceutical and medical agencies including the ICH Q3D Guidelines for Elemental Impurities. The intention was to provide a buffer period where users could either continue to utilize the existing Chapter <231> approach, or implement the methodology outlined in the new chapters <232>, <233> and <2232>. In the period up to 2018, the USP will be engaging in an ongoing dialogue with the pharmaceutical industry, the FDA, and the ICH to ensure this alignment process goes as smoothly.

A total of twenty four elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt, Li, Sb, Ba, Mo, Cu, Sn, and Cr) are specified with their toxicity limits, defined as maximum permitted daily exposure (PDE) levels in μg/day for the four major drug delivery categories. The PDE limits are shown in the table below.

To meet these low regulated levels, new analytical protocols for measuring elemental impurities using spectroscopic techniques are employed using either:

Permitted daily exposures (PDE) for elemental impurities

Element Cd Pb As Hg Co V Ni Tl Au Pd Ir Os Rh Ru Se Ag Pt Li Sb Ba Mo Cu Sn Cr
Class 1 1 1 1 2A 2A 2A 2B 2B 2B 2B 2B 2B 2B 2B 2B 2B 3 3 3 3 3 3 3
Oral PDE (µg/day) 5 5 15 30 50 100 200 8 100 100 100 100 100 100 150 150 100 550 1200 1400 3000 3000 6000 11000
Parenteral PDE (µg/day) 2 5 15 3 5 10 20 8 100 10 10 10 10 10 80 10 10 250 90 700 1500 300 600 1100
Inhalation PDE (µg/day) 2 5 2 1 3 1 5 8 1 1 1 1 1 1 130 7 1 25 20 300 10 30 60 3

Featured USP 232 & ICH Q3D learning content

Primer

This educational primer from USP, Medicine Maker and Thermo Fisher Scientific is designed to bring you up to speed with the background, tips and tricks needed to set up analysis of elemental impurities in pharmaceuticals, ingredients, nutraceuticals and supplements.

Webinar series

Learn key points to consider when selecting instrumentation for the analysis of trace elements in pharmaceutical samples. On January 1, 2018, USP General Chapters on Elemental impurities <232>, <233>, and <2232> become applicable to drug products and dietary supplements. Join this two-part webinar to get an overview of the possible techniques and technologies for this analysis.

Podcast

The Basics of USP Chapters <232>,
<233>, and <2232>

In this audio podcast, expert Rob Thomas discusses new USP requirements and how they apply to pharmaceutical products and dietary supplements.

Video

The Easiest Route to Compliance in Pharmaceutical Applications

Hear how our solutions enable you to comply with guidelines on elemental impurities in drugs from U.S. Pharmacopeia (USP) and Int. Conference on Harmonisation (ICH).


Elemental impurities literature library

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Type Title Year
Application Brief Single Mode Multi-Elemental Analysis of Traditional Chinese Medicine using the Thermo Scientific iCAP Qc ICP-MS 2016
Application Note Analysis of elemental impurities in drug products using the Thermo Scientific iCAP 7600 ICP-OES Duo 2013
Application Note Analysis of Pharmaceutical Products for their Elemental Impurities with the Thermo Scientific iCAP RQ ICP-MS 2016
Application Note Using cold vapor generation atomic absorption to determine mercury impurities in pharmaceutical products 2016
Application Note Using Graphite Furnace Atomic Absorption to Meet the Requirements of Elemental Impurity Analysis in Pharmaceutical Products for Cadmium and Lead 2016
Blog Mercury in Vaccines: Why are People Getting Mad? 2015
Blog Pharmaceutical USP 232 Chapter Revisions & Harmonization with ICH Q3D 2015
eBook Determining Elemental Impurities in Pharmaceutical Products and Dietary Supplements (Primer - The Medicine Maker) 2015
Infographic Select the Right Technique for Metals Analysis in your Pharma QA/QC Lab 2014
Podcast The Basics of USP Chapters <232>, <233>, and <2232> 2014
Poster Application of an intelligent, on-line sample preparation system for meeting the USP 232, USP 233 and ICH Q3D requirements, using ICP-MS 2015
Presentation Preparing Your Lab for USP Chapters 232 and 233 2016
Product Specifications Thermo Scientific iCE 3000 Series Validator Packages 2016
Product Specifications Thermo Scientific SOLAARsecurity Software 2016
Technical Note Easy and Rapid System Qualification using the iCAP Series Qualification Kit 2013
Technical Note Thermo Scientific Qtegra Intelligent Scientific Data Solution (ISDS) Software for 21 CFR Part 11 Compliant Laboratories 2016
Video The easiest route to compliance in pharmaceutical applications 2015
Webinar Implementation of USP 232 and 323: Which Techniques Should I Consider for Analysis? 2016
Webinar Implementation of USP 232 and ICH Q3D: What is Required and How to Do It 2016
Webinar Learn the Tricks of the Trade to Prepare Your Lab for USP Chapters 232 and 233 2014
Webinar What Does USP Chapter <2232> on Elemental Contaminants in Dietary Supplements Mean for You? 2015
Webinar How to Simplify Your ICP-MS Workflow and Accelerate Productivity 2016

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