ICH Q3E Extractables and Leachables Guidance: Implications for Single‑Use Component Buyers

What does the ICH Q3E guidance cover?

ICH Q3E, published in 2020, provides a harmonised approach for the identification, qualification and control of extractables and leachables (E&L) from pharmaceutical manufacturing equipment, including single‑use (SU) components. The guidance distinguishes between extractables – compounds that can be released under exaggerated conditions – and leachables – compounds that actually migrate into the product under normal use. It outlines a risk‑based workflow that includes:

1. Material characterisation – chemical composition, manufacturing process, and surface treatments.
2. Extractables testing – typically performed with aggressive solvents (e.g., 50 % ethanol, 0.1 M HCl) at elevated temperature (often 50 °C) for a defined period (e.g., 72 h).
3. Leachables assessment – targeted analysis of the product‑contact solution under realistic process conditions.
4. Toxicological evaluation – comparison of detected leachables with established safety thresholds such as the Threshold of Toxicological Concern (TTC).
5. Control strategy – specification limits, supplier qualification, and ongoing monitoring.

The guidance is intended to be compatible with existing standards such as ISO 10993‑1 for biocompatibility and USP <661> for leachables. It does not prescribe specific analytical techniques, but most laboratories employ a combination of LC‑MS, GC‑MS, NMR and HPLC to achieve the required sensitivity (often sub‑ppm levels).

How does ICH Q3E affect the selection of single‑use components?

For buyers, the primary impact of ICH Q3E is the need to incorporate E&L data into the component qualification dossier. Historically, many SU components were qualified solely on material certification and visual inspection. Under Q3E, the following additional criteria become standard:

• Availability of a full extractables report covering at least three representative solvents and a range of temperatures.
• Leachables data generated under the exact process conditions (e.g., buffer composition, pH, contact time). For a typical biopharmaceutical process, this may involve a 30 min contact at 25 °C in a phosphate‑buffered saline (PBS) solution.
• Toxicological justification for any identified leachables, including calculated daily exposure limits and comparison with the TTC (generally 1.5 µg/day for Cramer Class III substances).
• Supplier compliance statements confirming adherence to ISO 13485, GMP, and, where applicable, REACH registration of the raw materials.

The guidance also encourages the use of risk ranking matrices to prioritise components that pose the greatest potential impact on product safety. For example, a component that contacts the drug substance directly for more than 2 h may be classified as high risk, whereas a component used only in a downstream buffer may be low risk.

What data are required from suppliers under ICH Q3E?

Buyers should request a structured package of documentation that typically includes:

| Document | Typical Content | |----------|-----------------| | Extractables Report | List of identified compounds, analytical method details (e.g., LC‑MS parameters), concentration ranges (µg L⁻¹), and solvent/temperature conditions used. | Leachables Report | Results from product‑contact studies, detection limits, and comparison with specification limits. | Toxicology Assessment | Hazard classification (e.g., GHS), TTC comparison, and any required risk mitigation measures. | Certificate of Analysis (CoA) | Batch‑specific data confirming material composition and purity. | Safety Data Sheet (SDS) | Hazard statements, handling precautions, and regulatory classifications. | Supplier Qualification Summary | Evidence of ISO 13485 certification, GMP audit findings, and REACH registration numbers.

If a supplier cannot provide a complete extractables profile, the buyer must decide whether to accept a partial data set (e.g., only one solvent) and, if so, apply additional safety factors. In practice, many large‑scale manufacturers require at least two solvents (water and an organic solvent) to capture both polar and non‑polar extractables.

How can buyers assess compliance and manage risk?

A systematic approach is essential. The following steps are widely adopted in the industry:

1. Define the exposure scenario – Determine the maximum contact time, temperature, and solution composition for each component in the process flow.
2. Map the risk hierarchy – Use a matrix that scores components on contact severity (high, medium, low) and data completeness (full, partial, none).
3. Perform a gap analysis – Compare supplier submissions against the matrix. Any component scoring high on both axes must have a complete E&L dossier before approval.
4. Implement a control strategy – For high‑risk components, set specification limits (e.g., leachable concentration < 0.5 µg mL⁻¹) and require periodic re‑testing, especially after a change in raw‑material source.
5. Document the decision – Record the rationale for acceptance, any mitigation measures (e.g., additional rinsing steps), and the responsible quality‑assurance sign‑off.

Molekula, as a supplier of SU consumables, provides detailed CoAs and, where requested, collaborates on extractables studies. However, the ultimate responsibility for compliance rests with the buyer’s quality and regulatory teams.

What are the practical steps for implementing ICH Q3E in procurement?

To embed the guidance into the procurement workflow, organisations typically:

• Update the supplier questionnaire to include mandatory fields for extractables and leachables data, toxicology justification, and regulatory certifications.
• Train purchasing and quality staff on the fundamentals of E&L science, including interpretation of LC‑MS chromatograms and TTC calculations.
• Integrate E&L review into the supplier audit – Auditors should verify that the supplier’s laboratory follows validated analytical methods and that raw‑material traceability is maintained.
• Create a central repository – Store all E&L reports, CoAs and SDSs in a controlled document‑management system, enabling rapid retrieval during batch release or change‑control activities.
• Review periodically – Re‑evaluate component suitability whenever there is a change in formulation, process temperature, or regulatory expectations (e.g., new REACH restrictions).

By following these steps, buyers can ensure that the adoption of SU technology does not compromise product safety and remains aligned with the ICH Q3E framework.

Frequently asked questions

Q1: Is ICH Q3E mandatory for all single‑use components? A: The guidance is not a legal requirement, but it is widely accepted by regulators (e.g., FDA, EMA) as the standard for E&L assessment. Non‑compliance can lead to regulatory queries during inspections.

Q2: Can I rely on a supplier’s generic extractables data? A: Generic data may be acceptable for low‑risk components, but high‑risk items typically require component‑specific testing under the exact process conditions.

Q3: How often should leachables testing be repeated? A: At a minimum, testing should be repeated when there is a material change (e.g., new polymer batch, altered manufacturing process) or when the component is used in a new product with different exposure parameters.

Q4: What is the role of the TTC in ICH Q3E? A: The Threshold of Toxicological Concern provides a pragmatic exposure limit for chemicals with limited toxicological data. Leachables below the TTC are generally considered acceptable, provided they are identified and quantified.