Extractables and Leachables (E&L) Testing for Drug Safety for NDA/ANDA Submissions

Extractables and Leachables (E&L) Testing for Drug Safety NDA ANDA

INTRODUCTION

In modern drug development, Extractables and Leachables Testing for NDA/ANDA plays a critical role in ensuring product safety, purity, and regulatory acceptance. Every packaging component, container-closure system, and manufacturing contact surface can potentially release chemical compounds that affect the drug’s quality or patient health.

At ResolveMass Laboratories Inc., we specialize in comprehensive Extractables and Leachables Testing for NDA/ANDA, delivering submission-ready reports that meet FDA, USP, and ICH expectations. Our mission is to help pharmaceutical innovators and generic manufacturers prove that their products are safe, stable, and compliant.

WHAT ARE EXTRACTABLES AND LEACHABLES?

Extractables are compounds that can be forced out of materials under exaggerated laboratory conditions such as high temperature or aggressive solvents.
Leachables are compounds that actually migrate into the drug product during storage, processing, or shelf life under real-world conditions.

In short:

Extractables = potential risk.
Leachables = actual risk.

Understanding both is vital for robust Extractables and Leachables Testing for NDA/ANDA, as it enables risk assessment, toxicological evaluation, and regulatory justification.

IMPORTANCE OF EXTRACTABLES AND LEACHABLES TESTING FOR NDA/ANDA

Regulatory authorities require manufacturers to assess any possible interaction between the drug and its contact materials. Failing to provide E&L data in an NDA or ANDA submission can delay approvals or trigger information requests.

Key reasons why E&L testing is essential:

Ensures patient safety by preventing harmful impurities.
Protects product stability and efficacy.
Meets FDA and USP requirements for container-closure integrity and material compatibility.
Supports quality by design (QbD) and lifecycle management.
Reduces regulatory risk through submission-ready documentation.

REGULATORY LANDSCAPE FOR Extractables and Leachables Testing for NDA/ANDA

Regulatory agencies worldwide, including the U.S. FDA, emphasize the importance of a risk-based approach for Extractables and Leachables Testing for NDA/ANDA.
The FDA expects sponsors to:

Identify all materials in contact with the drug product.
Conduct controlled extractables and leachables studies.
Justify analytical methods and evaluation thresholds.
Submit structured E&L summary data within the CTD format.

ResolveMass Laboratories aligns every study design with the latest regulatory expectations for NDAs and ANDAs, ensuring smooth review and acceptance.

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PHASES OF EXTRACTABLES AND LEACHABLES TESTING

1. Material Risk Assessment

This phase identifies all materials that come into contact with the drug.

List container-closure components, tubing, stoppers, seals, and processing equipment.
Evaluate risk based on material type, contact duration, and temperature.
Prioritize materials for extractables and leachables evaluation.

2. Controlled Extractables Study

Performed under exaggerated conditions, this study identifies chemical species that could migrate.

Use various solvents and stress conditions.
Generate an extractables profile to represent the “worst-case” scenario.
Determine Analytical Evaluation Threshold (AET) for quantification.
Establish chemical identity, structure, and potential risk.

3. Leachables Study

This study evaluates what actually migrates under real storage or use conditions.

Test finished drug product stored in its final packaging.
Perform time-point sampling and analytical monitoring.
Compare results with extractables data.
Identify unknown leachables and assess safety impact.

4. Toxicological Risk Assessment

If any leachables exceed AET, toxicologists evaluate their safety concern threshold.

Determine safe limits for patient exposure.
Recommend control strategies or material changes if required.

5. Documentation and Submission

ResolveMass provides fully structured reports for NDA/ANDA submissions including:

Detailed tables for extractables and leachables.
Analytical methods and validation data.
AET calculations and justifications.
Summary in CTD format (Modules 2 and 3).

TABLE: E&L TESTING WORKFLOW OVERVIEW

Stage	Objective	Deliverables
Material Assessment	Identify all contact materials	Material risk summary
Extractables Study	Evaluate potential chemical migration	Extractables profile & AET
Leachables Study	Assess actual migration into drug product	Leachables data report
Toxicological Review	Evaluate safety and exposure limits	Risk evaluation summary
Regulatory Submission	Compile all data into submission format	NDA/ANDA-ready documentation

WHY CHOOSE RESOLVEMASS LABORATORIES INC.

At ResolveMass Laboratories Inc., we bring together science, precision, and regulatory insight to deliver Extractables and Leachables Testing for NDA/ANDA with unmatched accuracy and credibility.

Our Strengths:

Expertise: Decades of combined analytical experience in E&L testing for diverse formulations.
Advanced Instrumentation: LC-HRMS, GC-MS, and ICP-MS for volatile, semi-volatile, and non-volatile compounds.
Regulatory Knowledge: Deep understanding of FDA, ICH, and USP frameworks.
End-to-End Service: From risk assessment to regulatory report generation.
Quality Systems: GLP/GMP-compliant laboratory practices ensuring data integrity and traceability.

ResolveMass is more than a testing lab — it’s your regulatory partner for safe, compliant, and submission-ready outcomes.

BEST PRACTICES FOR NDA/ANDA E&L TESTING

Start E&L evaluation early in development.
Use risk-based study designs focused on product contact materials.
Employ orthogonal analytical techniques.
Validate methods according to ICH guidelines.
Document every step clearly for regulatory review.
Maintain consistency between extractables and leachables datasets.
Include toxicological interpretation for any compound above AET.

These practices ensure the success of Extractables and Leachables Testing for NDA/ANDA and build reviewer confidence in product safety.

COMMON CHALLENGES & SOLUTIONS

Challenge	ResolveMass Approach
Unknown leachables	Employ multi-technique screening and structural elucidation
Low detection sensitivity	Use HRMS and ICP-MS for ultra-trace quantification
Incomplete supplier data	Perform independent material characterization
Delayed submissions	Provide fast turnaround and submission-ready reports
Complex multi-material systems	Design customized multi-matrix E&L strategies

CONCLUSION

In every NDA or ANDA submission, Extractables and Leachables Testing for Drug Safety Submissions is not optional—it’s essential. A comprehensive E&L program proves that packaging and process materials are safe, ensuring drug quality and patient protection.

At ResolveMass Laboratories Inc., we deliver scientifically robust, regulatory-compliant, and submission-ready Extractables and Leachables Testing for NDA/ANDA to support your product approval success.

For tailored study design or quotation, reach out to our experts today.

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TOP 10 FREQUENTLY ASKED QUESTIONS (FAQs)

1. What is the main goal of Extractables and Leachables Testing for NDA/ANDA?

The primary goal of Extractables and Leachables Testing for NDA/ANDA is to ensure patient safety and product quality by identifying and controlling any chemical substances that can migrate from a drug’s packaging, container-closure system, or manufacturing components into the final product.
During the regulatory review of NDAs and ANDAs, agencies such as the U.S. FDA require sponsors to demonstrate that all contact materials are compatible with the drug formulation. Extractables studies identify compounds that could migrate under forced conditions, while leachables studies confirm those that do migrate during storage and use.
At ResolveMass Laboratories Inc., our testing programs aim to eliminate any uncertainty around these interactions, ensuring compliance with FDA expectations and global pharmacopeial standards while safeguarding patient health.

2. When should E&L testing be initiated during drug development?

Extractables and Leachables Testing for NDA/ANDA should ideally begin during the early stages of drug development — specifically, during formulation and packaging design. Initiating E&L studies early helps manufacturers understand potential material risks before finalizing the drug’s container or manufacturing system.
Early testing offers several advantages:
-It supports material selection and compatibility assessment.
-It allows time to mitigate potential migration risks.
-It prevents costly delays during regulatory submission.
ResolveMass Laboratories recommends a staged approach: start with a materials risk assessment, follow with a controlled extractables study, and finally perform leachables testing once the packaging or manufacturing process is finalized. This proactive strategy ensures that E&L data aligns perfectly with NDA or ANDA submission timelines.

3. What analytical techniques are used in E&L testing?

A comprehensive Extractables and Leachables Testing for NDA/ANDA program employs a wide range of analytical techniques to detect volatile, semi-volatile, non-volatile, and elemental impurities.
Commonly used instrumentation includes:
–GC-MS (Gas Chromatography–Mass Spectrometry): For volatile and semi-volatile organic compounds.
–LC-HRMS (Liquid Chromatography–High Resolution Mass Spectrometry): For non-volatile and polar compounds.
–ICP-MS / ICP-OES (Inductively Coupled Plasma–Mass Spectrometry/Optical Emission Spectrometry): For inorganic or elemental impurities.
–FT-IR, UV-Vis, and NMR: For structural elucidation of unknowns.
At ResolveMass Laboratories, we apply orthogonal analytical platforms and validated protocols to ensure complete chemical coverage and accurate quantification at trace levels — meeting or exceeding the Analytical Evaluation Threshold (AET) required for regulatory acceptance.

4. How is the Analytical Evaluation Threshold (AET) determined?

The Analytical Evaluation Threshold (AET) is the critical concentration limit above which any leachable must be identified and evaluated for toxicological risk. Determining the correct AET is a cornerstone of Extractables and Leachables Testing for NDA/ANDA.
It is calculated using parameters such as:
–Maximum Daily Dose (MDD) of the drug product.
–Safety Concern Threshold (SCT) depending on the route of administration (oral, parenteral, inhalation, etc.).
–Uncertainty factors to account for analytical limitations.
For example, products with higher patient exposure (e.g., injectable formulations) require a lower AET due to increased risk. ResolveMass Laboratories provides customized AET calculations that align with product dosage, patient exposure, and regulatory guidance, ensuring complete justification in NDA/ANDA documentation.

5. What materials are typically tested in E&L studies?

Extractables and Leachables Testing for NDA/ANDA covers all materials that may directly or indirectly contact the drug product. These include:
-Primary packaging systems such as vials, bottles, ampoules, syringes, and caps.
-Container-closure components like rubber stoppers, gaskets, and seals.
-Process contact materials such as filters, tubing, gaskets, connectors, and mixing vessels.
-Secondary packaging or delivery devices, if there is potential for leaching.
Each material is evaluated based on its composition, surface area, duration of contact, and exposure conditions. ResolveMass Laboratories conducts complete material mapping to ensure that every potential source of extractables and leachables is covered, leaving no compliance gaps during NDA or ANDA submission.

6. How does E&L testing differ for NDAs and ANDAs?

Although the core principles of E&L testing are the same, the scope and depth can vary between New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs).

For NDAs, E&L testing is typically comprehensive because it supports a new formulation or packaging system. The studies must generate complete extractables and leachables profiles, establish AET, and perform toxicological risk assessments.

For ANDAs, the goal is to demonstrate equivalence to the reference listed drug (RLD). Therefore, E&L testing focuses on comparative analysis — ensuring that extractables and leachables from the generic product’s container-closure system do not present higher risk than the RLD.

ResolveMass Laboratories offers both full-scope and bridging-style E&L studies designed specifically to meet the unique regulatory expectations of NDA and ANDA pathways.

Reference

Jenke, D. R. (2013). Extractables and leachables considerations for pre-filled syringes and injection devices. PDA Journal of Pharmaceutical Science and Technology, 67(5), 430–445. https://doi.org/10.5731/pdajpst.2013.00905

Norwood, D. L., & Stults, C. L. M. (2015). A practical approach to extractables and leachables in pharmaceutical packaging and drug delivery systems. Journal of Pharmaceutical Sciences, 104(2), 388–396. https://doi.org/10.1002/jps.24224

About the Author

Priyal Darji

Priyal Darji, B.Pharm, is an experienced professional in analytical chemistry and pharmaceutical formulation development. She has extensive hands-on expertise in method development, impurity profiling, characterization studies, polymer chemistry for novel drug delivery formulations, contributing to research and development projects within the pharmaceutical sector. Her work focuses on bridging analytical precision with innovative formulation science.