Extractables and Leachables for Injectable Drug Products: Building a Risk-Based Primary-Packaging CMC Strategy
Extractables and leachables are not a residual-solvent problem. They are a product-contact materials problem that must be controlled through an integrated assessment of packaging components, manufacturing-system contact materials, analytical capability,…
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Extractables and Leachables for Injectable Drug Products: Building a Risk-Based Primary-Packaging CMC Strategy
Extractables and leachables are not a residual-solvent problem. They are a product-contact materials problem that must be controlled through an integrated assessment of packaging components, manufacturing-system contact materials, analytical capability, toxicological risk, and the actual drug-product exposure profile.
The regulatory architecture has evolved materially. ICH Q3C remains important for residual solvents generated or used in manufacturing, but it is not the primary framework for E&L. In November 2025 FDA published the draft ICH Q3E guideline for Extractables and Leachables. Q3E is explicitly intended to provide a holistic, risk-based framework for assessment and control of E&L and builds on the broader ICH impurity framework. At the same time, USP <1663> and <1664> provide practical frameworks for extractables and leachables assessments, FDA’s container-closure guidance defines the quality expectations for systems used to package human drugs and biologics, EMA maintains requirements for plastic immediate packaging materials, and PQRI work provides an important scientific foundation for risk-based E&L practice.
Start With the Patient and Product Exposure Pathway
For injectable products, the first question is not which solvents to use in an extraction study. It is what materials can contact the formulation from manufacturing through administration, how long that contact lasts, what temperatures and stresses occur, and what the patient exposure could be. Primary containers, elastomeric closures, plungers, syringe barrels, needle shields, transfer tubing, filters, single-use assemblies, storage bags, and device constituents can all contribute organic or elemental species. The risk profile changes with route, dose volume, dosing frequency, formulation composition, pH, surfactant content, protein or lipid content, storage duration, sterilization process, and contact-surface area.
A scientifically defensible E&L strategy therefore begins with a materials-of-construction and contact-pathway map. That map should connect each component to supplier information, material formulation, processing aids, sterilization or irradiation history, product-contact duration, and intended clinical exposure. The objective is to identify where extractables studies are needed, where supplier data may be leveraged, where simulation studies are justified, and where actual drug-product leachables monitoring is required.
USP <1663>: Designing the Extractables Knowledge Base
USP <1663> describes extractables assessment as a framework rather than a universal test recipe. It does not prescribe one extraction condition, one solvent set, one analytical method, or one acceptance criterion for every system. That distinction is important. A high-quality study intentionally challenges the material in ways that reveal compounds that could plausibly migrate under actual or accelerated conditions while avoiding extraction conditions so destructive that they generate a chemically irrelevant profile.
Study design should consider solvent polarity, pH, temperature, time, surface-area-to-volume ratio, sterilization state, and the physical configuration of the component. Analytical coverage commonly requires complementary chromatographic and spectrometric techniques for volatile, semi-volatile, nonvolatile organic, and elemental species. Method sensitivity and reporting thresholds should be scientifically justified against the clinical exposure scenario rather than selected simply because they are instrument defaults.
USP <1664>: Converting Extractables Knowledge Into Drug-Product Leachables Control
USP <1664> shifts the question from what can be extracted from a material to what actually migrates into the drug product over its shelf life. That distinction makes leachables testing inseparable from stability strategy. A leachables program should use the extractables profile to define target analytes and analytical risks, but it must also remain capable of detecting unexpected compounds that appear only in the real formulation or through degradation and interaction mechanisms not reproduced in the extraction study.
The resulting program should connect analytical findings to identification, quantitation, toxicological evaluation, trend assessment, and change control. Where a compound approaches a level of toxicological concern, structure elucidation becomes disproportionately valuable because identification can materially improve the quality of the safety assessment and the ability to establish a specific control strategy.
ICH Q3E Draft: The Emerging Global E&L Architecture
The draft ICH Q3E guideline changes the strategic context because it aims to harmonize E&L assessment and control across pharmaceutical products. Because the November 2025 FDA publication is a draft Level 1 guidance and not for implementation, sponsors should not present Q3E as a finalized legal requirement. But it is highly relevant as a directional framework for development programs being designed now, especially when long stability programs and packaging decisions will mature after Q3E advances through the ICH process.
The practical implication is to build a program that can survive both today’s expectations and tomorrow’s harmonized framework: risk-based assessment, clear linkage between extractables and leachables, toxicological evaluation, scientifically justified analytical thresholds, traceability to materials and components, and lifecycle control when suppliers, formulations, processes, sterilization methods, or container-closure configurations change.
FDA and EMA Container-Closure Expectations
FDA’s August 2026 draft guidance on Container Closure Systems for Human Drugs and Biological Products provides current guiding principles for evaluating container-closure system quality, including systems that are device constituent parts of combination products. Because it is draft guidance, the article treats it as current regulatory direction rather than a final mandatory standard. For EU submissions, EMA’s guideline on plastic immediate packaging materials remains directly relevant to plastic components in contact with active substances or medicinal products and requires the submitted package to justify suitability of the immediate packaging material.
For injectables, E&L should therefore be integrated with container-closure integrity, compatibility, protection, performance, sterilization, and stability rather than managed as an isolated analytical report. A technically elegant extractables study does not rescue a packaging system whose material selection, integrity, functionality, or product compatibility is poorly justified.
PQRI and the Analytical Evaluation Threshold Concept
PQRI’s E&L work remains influential because it helped operationalize safety-based thinking and the Analytical Evaluation Threshold concept. The AET is best understood as a tool for translating a safety concern level and clinical exposure scenario into an analytical reporting target. It should not be treated as a single universal number applicable to every injectable, every route, or every compound class. Product-specific dose, dosing frequency, analytical uncertainty, compound class, route, and toxicological context matter.
Modern E&L programs also need explicit strategies for high-concern compound classes, including nitrosamines and elemental species where applicable. Supplier composition knowledge is valuable but is not a substitute for a risk assessment grounded in actual materials, processing conditions, and patient exposure.
XGene Injectable E&L CMC Control Architecture
Layer 1 — Product-Contact Risk Map: Map every material contacting the drug product from compounding through administration, including manufacturing-system and packaging components. Rank risk using route, dose, duration, formulation aggressiveness, sterilization, contact area, and supplier/material knowledge.
Layer 2 — Extractables Knowledge Program: Design justified extraction conditions and orthogonal analytical coverage under USP <1663> principles. Characterize known and unknown organic and elemental species and establish traceability to materials and components.
Layer 3 — Leachables Stability Program: Build targeted and non-targeted capability into the stability strategy under USP <1664> principles. Trend identified leachables across shelf life and evaluate newly emerging species rather than relying on a single end-point test.
Layer 4 — Toxicological and Analytical Decision Logic: Translate clinical exposure into scientifically justified analytical thresholds; identify compounds sufficiently to support toxicological assessment; escalate high-concern classes using compound-specific strategies rather than generic thresholds.
Layer 5 — Module 3 and Lifecycle Integration: Integrate E&L with container-closure information, specifications where justified, stability, supplier/change control, comparability, and device/combination-product documentation. The dossier should tell one internally consistent story from material selection to patient exposure.
The commercial value of this architecture is straightforward: XGene can evaluate whether a sponsor’s E&L package is scientifically defensible before the issue becomes an information request, late-stage packaging change, stability surprise, or inspection finding. The highest-value engagement is not running another screening study; it is determining whether the full evidence chain is fit for the product, route, lifecycle stage, and submission strategy.
FDA / ICH Q3E Draft Guideline for Extractables and Leachables, November 2025 — https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q3e-guideline-extractables-and-leachables
USP <1663>, Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems — https://doi.usp.org/USPNF/USPNF_M7126_03_01.html
USP <1664>, Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems — https://doi.usp.org/USPNF/USPNF_M7127_03_01.html
FDA, Draft Container Closure Systems for Human Drugs and Biological Products, August 2026 — https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-human-drugs-and-biological-products
EMA, Guideline on Plastic Immediate Packaging Materials — https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-plastic-immediate-packaging-materials_en.pdf
PQRI, Parenteral and Ophthalmic Drug Product E&L Working Group resources — https://pqri.org/
Re-authored publication body v1.0. Prior ICH Q3C-centered E&L framing removed.