ICH Q3D Guideline on Elemental Impurities: key principles

Presented by Dr Landolfi to the online event: Impurity Profiling Live Virtual Conference held on November 26-27, 2020, and organized by CPhl Conferences

Topics of her presentation were:

  • Understanding and analyzing guideline and its scope
  • Guideline philosophy and intent
  • Advancements in the guidance – New Appendix
  • Case study

Q3D guidance is a quality guideline focused on elemental impurities (EIs). It establishes Permitted Daily Exposures (PDE) levels for the most common  Elements (24) that can contaminate drug products in particular for the oral, parenteral, and inhalation routes of administration.

The guideline provides information on the toxicological properties of concerned elements grading them with regards to their hazardous in 4 classes. It gives information on the risk assessment procedures providing PDE for each of them and reports information on quality procedures and related control measures in DPs

The Q3D(R2) Maintenance EWG is currently undertaking maintenance of the Guideline to develop PDE levels for cutaneous and transdermal products.

In establishing cutaneous and transcutaneous limits, the role of skin is paramount.

The skin is an environmental barrier and a complex organ that has many functions, including prevention of water loss, temperature regulation, it is a sense organ and protects the body from external aggression limiting the penetration of exogenous materials,

It has metabolic functions as well. These properties, or at least some of them, have been considered in defining the dermal PDEs.

The stratum corneum serves as a highly effective barrier, especially to hydrophobic compounds and charged molecules,  such as metal ions.

A compromised basal cell layer could facilitate direct entry of EIs into the dermis and its associated blood vessels, potentially increasing systemic absorption.

Therefore, the generic PDE for the cutaneous route should not be applied to drug products intended to treat skin with substantial disruption of the basal cell layer of the epidermis For these cases, the parenteral PDE is generally an appropriate starting point

Small cuts, needle pricks, skin abrasions and other quick healing daily skin injuries are not associated with substantial basal cell layer disruption of the epidermis, so the total amount of drug product which can potentially come into contact with the dermis is therefore considered negligible.

Dermal PDEs for daily, chronic application to the skin are determined considering local and systemic toxicities where sensitization was deemed the most relevant effect. Since most of elements do not penetrate skin, a generic conservative 1% dermal absorption for most of them, other than arsenic (As) and thallium (Tl), is considered






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Article Issued by Carla Landolfi

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