How Leachables and Extractables Testing Supports Regulatory Approval in Biologics

When it comes to biologic drugs, product purity and patient safety are non-negotiable. These complex therapies—often derived from living cells—are incredibly sensitive to contaminants.

That’s why leachables and extractables testing has become a regulatory must for packaging and delivery systems in biologics.

In a highly regulated landscape, failing to assess what might migrate from a container, stopper, or syringe into the product can jeopardize not just patient safety but your entire submission.

If you're navigating regulatory approval for biologics, understanding and implementing leachables and extractables (L&E) testing is essential—not optional.

Quick Overview: Why This Matters

Leachables and Extractables Testing in Biologics: A Snapshot

• Extractables are compounds that can be pulled from packaging materials under aggressive conditions.

• Leachables are compounds that actually migrate into the biologic product under normal use.

• Regulatory agencies like the FDA, EMA, and ICH require robust testing to ensure biologics remain safe, stable, and uncontaminated throughout their shelf life.

• Testing supports pre-approval submissions, ongoing quality control, and post-market surveillance.

Want to dive deeper into the role of L&E testing in regulatory approval? Keep reading.

The Regulatory Role of Leachables and Extractables Testing 1. Meeting Global Regulatory Expectations

L&E testing isn’t just best practice—it’s a regulatory expectation. Major global authorities require it as part of your Chemistry, Manufacturing, and Controls (CMC) submission.

Key guidance documents include:

• FDA Guidance on Container Closure Systems for Packaging Human Drugs and Biologics

• ICH Q3E (Draft) on leachables and extractables

• USP <1663> and <1664> on extractables and leachables evaluations

These frameworks outline what regulators expect in terms of:

• Test design and conditions

• Analytical methods

• Risk assessments

• Reporting and justification of findings

Did You Know?
Even trace levels of a leachable compound can trigger concern if it’s known to be toxic, genotoxic, or capable of altering the biologic’s structure or potency.

2. Protecting Product Quality and Patient Safety

Biologics are highly sensitive to contamination, especially from packaging materials. Uncontrolled leachables can lead to:

• Protein aggregation

• Loss of potency or stability

• Immunogenic responses in patients

• Shelf-life reduction

L&E testing helps you preemptively identify risks and implement design or packaging changes before they impact a clinical trial or market release.

Pro Tip:
Start extractables testing early in development—ideally during container selection—to avoid costly changes later in the pipeline.

3. Enabling a Stronger CMC Package

For your Biologics License Application (BLA) or Marketing Authorisation Application (MAA), regulators require detailed data about how your product interacts with its container.

L&E testing strengthens your submission by:

• Demonstrating a risk-based approach

• Validating container compatibility

• Supporting shelf-life justification

• Providing a scientific rationale for container selection

You’re not just proving your product is effective—you’re proving it’s safe across every possible touchpoint.

Quick Guide: Overcoming Packaging Safety Concerns in Biologics

Let’s say you’re preparing a BLA for a monoclonal antibody. Your team chose a prefilled syringe, but there’s growing concern about silicon oil leachables or interaction with rubber stoppers. Here’s how a proactive L&E strategy solves that.

Common Challenges:

• Are unseen leachables degrading your protein stability?

• Are regulators going to question your container-closure justification?

• Can your delivery system introduce risk during storage?

How to Solve It:

1.     Start with aggressive extractables screening: Use exaggerated conditions to identify all potential risk compounds from primary packaging.

2.     Conduct simulation-based leachables testing: Replicate real-time and accelerated aging to track what compounds actually migrate into your biologic.

3.     Use orthogonal analytical methods: Combine GC-MS, LC-MS, ICP-MS, and FTIR for a thorough and validated analytical approach.

4.     Build a risk assessment matrix: Score each compound based on toxicity, reactivity, and expected exposure to prioritize mitigation.

Why It Works:
This approach gives regulators confidence that your packaging system is safe and well-understood, avoiding delays and demonstrating your product is patient-ready.

Need help setting up your L&E strategy for regulatory approval? Let’s talk.

FAQs What’s the difference between extractables and leachables in simple terms?

• Extractables are what could come out under extreme lab conditions.

• Leachables are what actually migrate into the drug under normal storage or use.
  Both matter—but leachables are more directly tied to patient exposure.

When should I start L&E testing in biologic development?

Early is better. Begin extractables testing during container-closure selection, ideally before Phase 1 trials. Leachables testing becomes critical in Phase 3 when final packaging and stability studies are underway.

What if a leachable is detected in my product?

It depends on the compound. If it’s toxic or affects the product, mitigation may involve switching materials, adding barriers (like coatings), or proving it’s below a safe threshold.

Do regulators require leachables testing for secondary packaging too?

Usually not—primary packaging (in direct contact with the drug) is the focus. Secondary packaging is typically excluded unless it influences product quality.

Conclusion

In the world of biologics, the purity and safety of your product hinges on more than just what’s inside the vial or syringe. The materials that touch your biologic—from stoppers and seals to bags and tubes—must be just as scrutinized.

Leachables and extractables testing is your gateway to regulatory approval. It reassures authorities that your product is stable, your process is sound, and your patients are protected.

By integrating L&E testing early, thoroughly, and intelligently, you’re not just meeting a regulatory box—you’re building trust with regulators and confidence in your product’s future.