ICH Q3E analytical laboratory

The analysis of extractables and leachables is a process for assessing and controlling the migration of chemical substances from packaging or manufacturing materials into a pharmaceutical product. The goal is to ensure that these substances, even at trace levels, do not compromise the safety, quality, or efficacy of the medicine.

• Extractables are compounds that can be extracted from a material under extreme laboratory conditions, using aggressive solvents and high temperatures. Extractables analysis aims to identify the largest possible number of chemical substances that make up a material.

• Leachables are compounds that actually migrate from the material into the finished product under normal use and storage conditions. Leachables are generally a subset of extractables.

ICH Q3E is a guideline that harmonizes regulatory requirements worldwide (Europe, the United States, Japan, etc.) for E&L studies. Its importance is crucial for the pharmaceutical industry because it:

• Ensures patient safety by limiting exposure to contaminants.

• Simplifies the submission process for new medicines by providing a single framework for safety studies.

• Avoids having to repeat analysis for each region of the world.

All finished medicinal products whose primary packaging or manufacturing equipment may release chemical substances. The level of requirement is proportional to the risk: very high for IV injectables, intrathecal, ophthalmic and inhaled products, moderate for topicals and liquid oral dosage forms, and more limited for solid oral dosage forms and aqueous topicals compliant with food-contact regulations. Cell and gene therapy products and combination drug-device products are explicitly included in the scope of ICH Q3E.

ICH Q3E specifies the documentation requirements to be included in registration dossiers (CTD, module 3.2.P.7). The E&L dossier must include:

• The justification for the conditions and methods used in extractables studies (solvents, temperatures, durations, surface-to-volume ratio, analytical methods and their qualification)
• All study reports, with all peaks above the AET identified and quantified (chemical name, structure, CAS number if available, observed level)
• The safety assessment of substances above the AET
• The established and documented E&L correlation
• The control strategy implemented (supplier controls, component acceptance criteria, sampling plan)
• Evidence of the effectiveness of any mitigation measures implemented

Lifecycle management is also covered by ICH Q3E: any change likely to impact the leachables profile — formulation change, component supplier change, manufacturing process change, new dosing regimen, change in patient population — must trigger a documented reassessment.

The AET (Analytical Evaluation Threshold) is the concentration threshold above which extractables and leachables must be identified, quantified, and subjected to toxicological assessment. It is calculated by dividing the SCT (Safety Concern Threshold, a toxicological concern threshold generally set at 1.5 µg/day for organic compounds) by the analytical uncertainty factor (UF), which is itself determined by the qualification of the analytical method. The AET is therefore specific to each study, each product, and each analytical technique.

Not necessarily. ICH Q3E takes a risk-based approach: for low-risk products (solid oral dosage forms, aqueous topicals compliant with food-contact regulations), a streamlined approach based on prior knowledge and extractables data may be sufficient. On the other hand, for injectables, inhaled products, and high-risk dosage forms, a leachables study on the finished product is generally expected. Alternatives (simulated study, abridged dossier) are possible with justification and, where applicable, prior consultation with the regulatory authority.