What FDA Complete Response Letters Reveal About Extractables & Leachables

Extractables and leachables (E&L) testing has long been a critical—but often underestimated—component of drug development. Recent FDA data make one thing clear: E&L shortcomings are no longer edge cases. They are a recurring, material cause of delayed approvals.

An analysis of 202 FDA Complete Response Letters (CRLs) shows that nearly one in five cited deficiencies related to extractables and leachables. These letters provide rare, unfiltered insight into where development programs most often fall short—and where sponsors can take concrete action to reduce regulatory risk.

This article distills the key lessons from those CRLs and outlines practical strategies for designing E&L programs that stand up to regulatory scrutiny.

What the FDA’s CRLs Are Telling Us

Complete Response Letters are formal notifications issued by the FDA when a drug application cannot be approved in its current form. While each CRL is product-specific, taken together they reveal consistent patterns.

Out of the 202 CRLs reviewed, 37 (approximately 18%) cited E&L-related issues. Digging deeper, a clear concentration of root causes emerged:

• ~60% of E&L-related CRLs were driven by unknown compounds exceeding safety thresholds and/or insufficient toxicological risk assessment.

These findings underscore that E&L failures are rarely about running a study at all—they are about how studies are designed, interpreted, and justified.

The Two Most Common E&L Pitfalls

1. Unknown Compounds Above Safety Thresholds

One of the most frequent CRL findings is the presence of uncharacterized compounds detected above established Safety Concern Thresholds (SCTs). Regulatory expectations are clear: any compound exceeding an SCT must be identified and supported by an appropriate toxicological risk assessment.

SCTs are defined in USP <1663> and <1664> and vary by route of administration. For example:

• Parenteral products: 1.5 µg/day
• OINDP products: 0.15 µg/day (based on exposure to mucosal membranes)

Importantly, when higher SCTs are applied, the sensitization threshold of 5 µg/day must still be considered as a reporting limit, regardless of administration route. Compounds exceeding these limits cannot remain “unknown” in regulatory filings.

In practice, identifying unknowns is far from trivial. Advanced analytical techniques such as high-resolution accurate mass spectrometry (HRAM-MS) and access to extensive spectral libraries are often required. Programs that stop at reporting unidentified peaks instead of fully characterizing them routinely run into regulatory roadblocks.

2. Insufficient Toxicological Risk Assessment

The second major driver of E&L-related CRLs is inadequate toxicological qualification of detected compounds. Quantification alone is not enough.

The ICH Q3E draft guideline outlines a structured, risk-based framework for leachables safety assessment. Within this framework, SCTs are defined as the lower of:

• The Threshold of Toxicological Concern (TTC) for genotoxicity (per ICH M7), or
• The Qualification Threshold (QT) for non-mutagenic compounds

These thresholds depend on both route of administration and duration of exposure, and compounds must be classified according to their mutagenic and carcinogenic potential.

When compound-specific toxicological data are limited—as is often the case—regulators expect scientifically justified approaches such as:

• Read-across from structurally similar surrogate compounds
• Use of in silico or in vitro New Approach Methodologies (NAMs), where appropriate
• Traditional toxicological studies when existing data are insufficient

CRLs frequently cite risk assessments that rely on poorly justified surrogates, misinterpret toxicology data, or incorrectly assume that assessment is unnecessary once compounds are quantified.

Why Do Sponsors Keep Falling Short?

Despite clear regulatory frameworks, E&L deficiencies persist. Experience across multiple programs points to several recurring contributors:

Timing

Many sponsors wait too long to initiate E&L studies. By the time issues surface, container-closure systems and materials are already locked in, making remediation costly and time-consuming.

Over-Reliance on Generic Approaches

Generic testing strategies rarely hold up under scrutiny. Regulators expect E&L programs tailored to the specific materials, formulations, processing conditions, and patient populations of each product.

Gaps in Toxicological Expertise

Interpreting toxicology data, selecting appropriate surrogates, and defining acceptable margins of safety require specialized expertise. These skills are often underestimated—and under-resourced—until a CRL forces the issue.

The consequences are significant. Approval delays following a CRL average 17 months, with estimated costs approaching $1 million per day—a financial and strategic hit few programs can afford.

Strategies to Avoid E&L-Related CRLs

The lessons from recent CRLs point to a clear path forward. Robust E&L programs are not a box-checking exercise; they are a competitive advantage when embedded early and executed rigorously.

Key strategies include:

• Start E&L early: Integrate E&L considerations into formulation and container-closure decisions from the outset.
• Avoid generic templates: Design studies that reflect the specific risk profile of each product.
• Invest in toxicological expertise: Ensure findings are interpreted in a clinically and regulatorily relevant context.
• Leverage experienced partners: Advanced analytical capabilities and proven regulatory experience are essential for characterizing unknowns and defending risk assessments.

Turning Regulatory Insight into Advantage

The FDA’s CRLs provide an unusually transparent view into regulatory expectations for extractables and leachables. Sponsors that act on these insights—by prioritizing early, tailored, and scientifically robust E&L strategies—can significantly reduce approval risk and protect development timelines.

Getting E&L right the first time is no longer optional. It is fundamental to regulatory confidence, patient safety, and successful commercialization.