Extractables and Leachables: Why They’re a Critical Part of Your Contamination Control Strategy Under EU GMP Annex 1

When the European Union Good Manufacturing Practice (EU GMP) Annex 1 revision came into force, it reshaped expectations for sterility assurance. While much of the conversation has centered on aseptic processing and barrier technologies, one area that continues to gain attention is extractables and leachables (E&L)—especially in relation to primary packaging components.

Why E&L Risk Is Front and Center

Extractables are chemical substances that can be drawn out of packaging materials under exaggerated conditions, while leachables are those that migrate into the drug product during normal storage and use. Both represent potential contaminants—and under EU GMP Annex 1’s contamination control framework, they cannot be ignored.

Leachables pose a direct risk to patient safety. They can compromise drug stability, introduce toxicological concerns, and even trigger recalls. EU GMP Annex 1 may not provide exhaustive detail on E&L, but it does make clear that risks from product-contact materials must be assessed as part of the Contamination Control Strategy (CCS). Sections 8.132 and 8.136 specifically call out the need to evaluate interactions between products and contact surfaces, including leachables and extractables, and to conduct leachable profile studies for high-risk components.

What EU GMP Annex 1 Really Says—and What It Doesn’t

EU GMP Annex 1 guidance on E&L is limited compared to other areas, focusing primarily on process equipment and single-use systems. However, regulators expect manufacturers to go further. The industry standard approach is to integrate E&L risk assessment into the contamination control framework, supported by references such as USP <1663>, <1664>, and ICH Q3E.

The takeaway? EU GMP Annex 1 sets the expectation, but compliance depends on leveraging broader guidance and best practices.

Why Packaging Is the Biggest Risk

While leachables can originate from many sources—filters, tubing, bioreactor bags as examples —primary packaging components remain the dominant contributor. The reason is simple: contact time. From the moment a drug is filled until it reaches the patient, the product is in continuous contact with its container closure system. That extended exposure amplifies the risk of chemical migration.

This is why extractables data for packaging components is critical. Without it, you cannot design effective leachables studies to ensure compliance. USP <1663> emphasizes that extractables assessments serve two purposes: characterizing packaging materials and identifying potential leachables for stability studies. Both are essential for a robust CCS.

What’s Driving Industry Action?

Drug manufacturers are responding in several ways:

• Early Risk Mapping: Companies are mapping leachable sources across the entire manufacturing process, from upstream operations to fill-finish and storage. This holistic view helps prioritize testing where risk is highest.


• Supplier Collaboration: There’s a growing emphasis on obtaining high-quality extractables data from suppliers. But reliance on supplier data alone is unlikely to be enough as manufacturers may need bespoke studies that are built to purpose. Suppliers can often help with performing these studies on top of providing initial data.


• Standards-Based Testing: USP <1663> and ICH Q3E are forming the backbone of extractables study design. These standards guide conditions, analytical methods, and reporting to ensure data quality.

Key Factors That Influence Leaching

Understanding what drives leaching helps determine the risks from individual components. Three main factors matter most:

1. Drug Solution Chemistry: “Like dissolves like” applies—organic extractables are more likely to migrate into formulations containing surfactants or organic solvents.


2. Component Composition: Materials with primarily nonpolar extractables may pose less risk to aqueous drugs but more to lipid-based formulations.


3. Time and Temperature: Higher temperatures accelerate diffusion, so more will leach over time, increasing leachable levels over shelf life.

Don’t Forget Process Equipment

While packaging dominates leachables risk, process equipment-related leachables (PERLs) also matter. Single-use systems introduce additional complexity, requiring risk assessments for filters, tubing, and bioreactor bags. USP <665> and the extractables study protocol from BioPhorum Operations Group (BPOG) provide frameworks for evaluating these components.

What Good Looks Like

A strong contamination control approach for E&L includes:

• Comprehensive extractables profiles for all packaging components
• Risk-based prioritization of extractables studies for manufacturing components
• Processes designed to reduced leachables within the CCS
• Ongoing review as formulations, suppliers, or processes change

The Regulatory Lens

Inspectors are increasingly asking for documented evidence that E&L risks are understood and monitored. While EU GMP Annex 1 does not prescribe specific tests, regulators expect manufacturers to justify their approach using recognized standards and risk-based principles. Failure to do so can result in observations during inspections.

Bottom line

Understanding extractables and leachables is not just a chemistry exercise—it is a cornerstone of contamination control. By embedding E&L risk management into your CCS, you protect patient safety, strengthen compliance, and reduce the risk of costly surprises.