Draft Guideline ICH Q3D for Elemental Impurities published!

Recommendation

22/23 February 2024
Munich, Germany

API Regulatory Starting Materials
Definition, Manufacture, Assessment and handling post-approval Changes

The long-awaited "Guideline for Elemental Impurities - Q3D" was published on ICH's website on 5 August 2013. According to the different steps of the ICH process it appeared as a Draft Consensus Guideline and is open for comments (deadline not yet specified).

The document contains 9 chapters and 4 Appendices and outlines the principles of

• Safety assessment (methods used for establishing the PDE for various routes of administration)
• Element classification (assigning the elemental impurities to the classes 1, 2A, 2B, 3 and 4)
• Assessment and control of elemental impurities (taking into accout potential sources of elemental impurites and special considerations for biotechnologically derived products). The principles of quality risk management, described in ICH Q9, should be considered. 
• Speciation (separation of elemental impurities based on oxidation state, complexation state or organic combination)
• Analytical procedures
• Life-cycle management of the control strategy for elemental impurities, and
• Recommendations for submission of elemental impurities control strategy

In the Annexes details are given for

• Establishing exposure limits
• Established PDEs for 24 elemental impurities
• Individual saftey assessments of 20 elemental impurities, and
• Illustrative calculation examples for converting PDEs to concentrations.

The guideline applies to new finished drug products and new drug products containing existing drug substances. Drug products containing proteins, polypeptides (recombinanr or non-recombinant), their derivatives or conjugates are also covered by this guideline.

Drug products used during clinical research stages of development are outside of the scope of the guideline. It does also not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components, crude products of animal or plant origin, dialysate solutions not intended for systemic circulation and drug products containing elements intentionally included for therapeutic benefit. 

The new ICH Q3D Guideline on Elemental Impurities will certaily have a big impact on both the pharmaceutical industry and the API industry in terms of costs and efforts to provide measures to identify, analyse, evaluate and control these kind of impurities. Analytical procedures should be specific for each elemental impurity identified for control during risk assessment. QC lab infrastructure and equipment has to be established unless analyticals are outsourced.

This guideline closes the gap within the collection of already existing impurities guidelines, namely ICH Q3A (impurities in new drug substances), ICH Q3B (impurities in new drug products), ICH Q3C (Guideline for Residual Solvents) and ICH M7 (Genotoxic impurities; draft status; see our news dated 6 March 2013). The delayed publication of this draft guideline has also caused the USP to defer the implementation of General Chapters <232> and <233> on Elemental Impurities in order to coordinate these chapters with the provisions of ICH Q3D (see our news dated 12 June 2013).

The conference session about ICH Q3D on 5 November 2013 in Madrid highlights the key principles of the new Draft Guideline. Experts from industry including a member of ICH's QWP will explain the essential aspects and approaches of determining and controlling metal impurities in drug products. This pre-conference session ideally complements the following 16th APIC/CEFIC European Conference on Active Pharmaceutical Ingredients.

For detailed information please also see the "Guideline for Elemental Impurities - Q3D" itself.