Key Revisions in ICH Draft Guidelines

1. Draft ICH Q3E – Guideline for Extractables and Leachables (E&L)

Background & Purpose

• First harmonized global guideline for E&L, addressing gaps in regulatory expectations that previously caused delays and inconsistencies.

• Aims to protect patient safety and ensure product quality by controlling leachables from packaging, manufacturing systems, and delivery devices.

Scope

• Applies to new drug products, including biologics, ATMPs, and drug–device combinations.

• Covers lifecycle changes (e.g., formulation, packaging, manufacturing) that may alter E&L profiles.

• Focus on organic leachables; elemental leachables refer to ICH Q3D

Key Revisions & Structure

• Risk-Based Framework: Aligns with ICH Q9; integrates pharmaceutical quality and patient safety dimensions.

• Risk Matrix: Considers material properties, route of administration, patient population, and exposure.

• Study Types:

  • Extractables Studies: Semi-quantitative and quantitative.

  • Leachables Studies: Real-time or simulated.

• Analytical Evaluation Threshold (AET): Derived from Safety Concern Threshold (SCT); includes uncertainty factor.

• Safety Assessment: Classifies leachables into toxicological concern categories; includes local toxicity thresholds for ophthalmic, CNS, dermal, and inhalation routes.

• Lifecycle Management: Reassessment required for significant changes or new safety data.

2. Draft ICH M4Q(R2) – Revision of CTD Quality Sections

Background & Purpose

• Overhauls CTD Modules 2 (Quality Overall Summary) and 3 (Quality) to reflect modern science, digitalization, and lifecycle management.

• Addresses inefficiencies in current dossier structures and supports eCTD 4.0 and AI/ML-ready submissions.

Scope

• Applies to chemical, biological, ATMPs, and combination products for initial and lifecycle submissions.

Key Revisions & Structure

• Module 2.3 Restructured:

  • Six subsections, including Overall Development & Control Strategy, Core Quality Information (CQI), and Product Lifecycle Management (PLCM).

  • Requires explicit links between QTPP, CQAs, and control strategy.

• Module 3 Reboot:

  • Adopts DMCS format (Description–Manufacture–Control–Storage) for all components.

  • Enforces structured, machine-readable data for traceability.

• Integration with ICH Q-Series: Embeds Q8–Q14 principles (QbD, risk-based control, analytical lifecycle).

• Digitalization: Mandates structured data for knowledge management and regulatory review efficiency.

• Post-Approval Change Management: Aligns with ICH Q12 using ECs, PACMPs, and PLCM documents.

Impact

• Transforms submissions from static documents to dynamic, data-driven dossiers.

• Requires companies to adopt digital CMC strategies, structured data systems, and robust lifecycle planning.

3. Draft ICH Q1 – Stability Testing of Drug Substances and Drug Products

Background & Purpose

• Consolidates Q1A–Q1F and Q5C into a single, modern guideline.

• Reflects advances in science, risk-based approaches, and lifecycle management.

Scope

• Applies to all molecule types, including biologics and vaccines, across development and post-approval stages.

• Covers marketed products, registration, and lifecycle changes.

Key Revisions & Structure

• 18 Sections + 3 Annexes:

  • Annex 1: Reduced Protocols

  • Annex 2: Stability Modeling (e.g., ASAP, kinetic models)

  • Annex 3: ATMP Stability

• Expanded Topics:

  • In-use stability, short-term excursions, processing hold times, novel excipients/adjuvants.

  • Guidance for continuous manufacturing and combination products.

• Risk-Based Protocol Design: Encourages predictive modeling and science-based flexibility.

• Photostability & Stress Testing: Updated recommendations for forced degradation and confirmatory studies.