Creating a Holistic Extractables and Leachables (E&L) Program for Biotechnology Products

Area of Science:

• Pharmaceutical Science
• Analytical Chemistry
• Toxicology

Background:

• Extractables and leachables pose significant challenges in drug product development and lifecycle management.
• Impurities can originate from manufacturing equipment, process components, and packaging materials, often being chemical additives from plastics.
• Understanding extractables (under harsh conditions) and leachables (under real-use conditions) is crucial for drug safety.

Purpose of the Study:

• To present a holistic, science- and risk-based strategy for testing extractables and leachables.
• To ensure patient safety and product quality for biotechnology products.
• To minimize the risk of leachables in drug products.

Main Methods:

• Adopting principles from ICH Q9 and ICH Q8(R2) for a phase-appropriate strategy.
• Conducting robust extraction studies with model solvents, considering various factors (solvation, pH, temperature, etc.).
• Identifying and quantifying organic extractable compounds, followed by toxicology assessments and derivation of permitted daily exposure limits.

Main Results:

• Over 200 organic extractable compounds were identified, with siloxanes, fatty acid amides, and methacrylates being most common.
• Parenteral permitted daily exposure limits were derived for most identified compounds.
• Action thresholds were established to target high-risk leachables and trigger quality investigations.

Conclusions:

• The proposed holistic program effectively mitigates risks associated with extractables and leachables.
• The strategy ensures patient safety and maintains product quality for biotechnology products.
• The approach is applicable to primary drug containers, delivery devices, and single-use systems.