Elemental Impurities Testing
Impurities: Guideline for Elemental Impurities
The ICH Guideline Q3D "Impurities: Guideline for Elemental Impurities" provides an international standard for testing for metals in the member regions, Europe, USA, and Japan.
These guidelines for the determination of heavy metals have been integrated into the American Pharmacopeia (USP/NF) in chapters <232> and <233>. For the European Pharmacopeia (Ph.Eur.), these guidelines appear in chapters 5.20 "Elemental impurities" and 2.4.20 "Determination of elemental impurities."
The previously used visual test from the corresponding pharmacopeias (e.g. USP <231>, Ph.Eur. 2.4.8) has thus been replaced by modern methods using instruments such as the ICP-MS and/or ICP-OES.
In Ph.Eur. 9.3 (published on July 1st 2017) ICH Q3D is now adopted within the chapters "Pharmaceutical preparations" and "Substances for pharmaceutical use".
There is a new paragraph "Elemental impurities" in the chapter "Pharmaceutical preparations":
"For pharmaceutical preparations outside the scope of the general chapter 5.20, manufacturers of these products remain responsible for controlling the levels of elemental impurities using the principles of risk management."
This means that for products outside the scope of ICH Q3D like herbal products etc. the marketing authorization holder (MAH) remains responsible for any possible input of elemental impurities due to production processes, containers or excipients!
The Ph.Eur. monograph "Substances for pharmaceutical use" still excludes herbal drugs, herbal drug preparations and homeopathic mother tinctures from this scope.
This leads to the phenomenon that the MAHs on the contradictory have to establish risk assessments for their products in the end too to fulfill their responsibility!
The GBA Group will gladly help you adapt to fulfill the new requirements by consulting, compilation of risk assessments, as well as analytical tests.
What are the risks associated with elemental impurities?
Elemental impurities can pose serious health risks if present in pharmaceutical products above permitted limits. Even at low concentrations, certain metals can accumulate in the body over time and cause toxic effects.
The ICH Q3D guideline provides a science- and risk-based framework to control these impurities, ensuring patient safety. Compliance with Q3D not only helps meet regulatory requirements but also demonstrates a commitment to high product quality.
The toxic potential depends on the element itself and its bioavailability, which varies by dose and routes of administration. For example, the permitted daily exposure of gold is 300 µg/day for oral administration but only 3 µg/day via inhalation, due to higher absorption by inhalation.
Figure on the right: figure 1: extract from the ICH Q3D guideline
How are these impurities classified?
They are categorized based on the likelihood of their occurrence in production and their toxicity (PDE), from Class 1 (e.g. As, Cd, Hg, Pb) to Class 3 (e.g. Ba, Cu, Li, etc.) and “other elemental impurities” not covered by ICH Q3D.
Class 1: Cd, Pb, As and Hg
The elements that are used only to a limited extent or not used in the production of drug products.Class 2A: Co, V and Ni
Elements have relatively high probability of occurrence in the drug product and thus require risk assessment across all potential sources of elemental impurities and routes of administration.Class 2B: Tl, Au, Pd, Ir, Os, Pf, Ru, Se, Ag and Pt
Elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they may be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients or other components of the drug product.Class 3: Li, Sb, Ba, Mo, Cu, Sn and Cr
The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 µg/day) but may require consideration in the risk assessment for inhalation and parenteral routes. For oral routes of administration, unless these elements are intentionally added, they do not need to be considered during the risk assessment. For parenteral and inhalation products, the potential for inclusion of these elemental impurities should be evaluated during the risk assessment, unless the route specific PDE is above 500 µg/day.Other elemental impurities: e.g. Al, B, Ca, Fe, K, Mg, Mn, Na, W, Zn…
Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guideline. If these elemental impurities are present or included in the drug product they are addressed by other guidelines and/or regional regulations and practices that may be applicable for particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with compromised hepatic function), or quality considerations (e.g., presence of W impurities in therapeutic proteins) for the final drug product.
What are the typical sources of contamination in drug products?
The main sources of elemental impurities are the following:
- Manufacturing equipment
- Drug substances
- Excipients
- Container closure system
Analysis of Heavy Metal Impurites
At GBA Group, we are highly experienced in testing elemental impurities. In 2016, we developed a standardized ICP-MS screening method designed to provide an initial overview of potential elemental impurities in the tested material. This validated method can detect up to 34 different elements and is applicable across a wide range of sample types.
We routinely use microwave digestion to ensure efficient breakdown of even complex matrices, enabling the simultaneous and reliable detection of all relevant metals. The method has been fully validated in a non-product-specific manner and comprehensive validation documentation is available.
Since its implementation, we have continuously refined and adapted this screening approach to meet evolving regulatory requirements. Over the years, we’ve had the privilege of working with numerous clients on evaluation their products, gaining valuable experience together along the way.
Drawing on this expertise, we are pleased to support you in the risk assessment of your drug product.
Guideline
- ICH Q3D Elemental Impurities
Which sample types can be analyzed through in-house screening?
- Drug products
- APIs
- Excipients
Which elemental impurities can be detected through in-house screening?
Class 1
Cd, Pb, As, HgClass 2 A
Co, V and NiClass 2 B
Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag and PtClass 3
Li, Sb, Ba, Mo, Cu, Sn and Crothers
Al, B, Ca, Fe, K, Mg, Mn, Na, W, Zn….
Which instrumentation is used for the analysis?
- Microwave (degistion, as required)
- ICP-MS (The site is equipped with two redundant systems)
What is the status of the method?
non-product-specific validated
What are the advantages of the screening method?
- Up to 34 elements can be determined in parallel in one sequence (same sample preparation). This is a time- and cost-saving approach.
- The threshold of the instrument for the impurities mentioned is very low and very low quantities / concentrations of impurities can be determined. These concentration values are often significantly below the limit required by the ‘ICH Q3D’ guideline.
Typically, the screening is carried out in the first step. If strikingly values are obtained through screening, a product-specific method can be developed and a product-specific validation performed to obtain values where potential matrix effects have been excluded.
These pharmacopoeias refer to the above-mentioned guideline
- US Pharmacopoeia (USP/NF) chapters <232> and <233>
- European Pharmacopoeia (Ph. Eur.) chapters 5.20 "elemental impurities" and 2.4.20 "Determination of elemental impurities "
