Why most extractables & leachables studies fail regulatory review-and how to fix them

Introduction

Extractables and Leachables (E&L) testing has become non-negotiable for pharmaceuticals, biologics, and combination products. Regulatory agencies such as the US FDA, EMA, CDSCO, and WHO increasingly demand robust, risk-based E&L data-not just lab reports.

However, in our experience at SG Pharma Solutions, more than 60 per cent of initial E&L submissions get flagged. The reason? Most projects fail not in the lab, but in study design, regulatory interpretation, and documentation.

This article explores why E&L studies go wrong and how to build a submission-ready package from protocol to final report.

Where most E&L studies fail

1. Copy-Paste Protocols: Many companies use generic protocols copied from past products ignoring differences in formulation pH, contact surface, extractables profile, or intended use.
   
   2. Ignoring Worst-Case Scenarios: Studies often fail to simulate worst-case conditions like high/low pH, light or heat exposure, or extended shelf life.
   
   3. No Justification for Solvent Selection: Using solvents blindly without linking them to product polarity, route of administration, or container material leads to rejection.
   
   4. Misalignment Between Protocol and Lab Output: We’ve seen protocols that call for LC-MS but labs only run GC-MS, missing key leachables.
   
   5. Weak or Missing Toxicological Risk Assessment: Without a TRA, regulators assume the worst. Many Indian companies skip this step.

How to get it right -A practical framework

1. Start with a Risk Assessment: Map out materials, dosage form, route of administration, and expected interactions.
   
   2. Design a Smart Protocol: Use USP <1663>/<1664>, ISO 10993-18, and PQRI guidance. Define simulants, extraction, and detection limits.
   
   3. Coordinate Closely with the Lab: Ensure lab methods match your protocol and regulatory needs.
   
   4. Interpret & Write a Clear Report: Justify decisions, explain methods, and contextualise findings.
   
   5. Include Toxicological Justification: Work with a toxicologist to evaluate and qualify extractables.

Real example: Injectable in a glass vial

We supported a vaccine company using Type I glass vials they assumed were inert. Our E&L study revealed sodium, boron, and aluminum leaching under autoclave stress. Early detection helped them switch stopper formulation and pass the WHO PQ inspection- avoiding ₹5+ crore in delays.

Conclusion

E&L studies aren’t just a checklist. They are a risk-based, regulatory-driven evaluation of product safety. Labs can run the analytics, but only expert design, interpretation, and reporting ensure regulatory approval.

Whether you’re filing a biosimilar, launching a novel device, or validating a closure system, E&L is critical.