Extractables and leachables testing is required whenever a drug product comes into contact with materials that could release chemical compounds, including container closure systems, drug delivery devices, single-use manufacturing equipment, and packaging components. The two study types serve different purposes, require different designs, and are triggered at different points in development.
Key Takeaways
- Extractables vs. leachables — the two study types use different conditions, serve different purposes, and are completed at different points in development.
- The E&L risk assessment comes first — it determines whether a formal extractables study is needed and defines the scope of the leachables program.
- Route of administration sets the regulatory bar — sterile injectables and inhalation products face the most rigorous requirements; lower-risk routes may qualify for a reduced scope.
- BPOG protocol has a defined scope — it applies to single-use bioprocessing equipment; container closure systems and combination products follow different frameworks.
- The threshold of toxicological concern (TTC) anchors the safety evaluation — it provides a default threshold for compounds without established tolerable daily intake values and determines what requires further characterization.
What Separates an Extractables Study from a Leachables Study
Extractables
Extractables are chemical compounds that can be forced out of a material under exaggerated conditions: aggressive solvents, elevated temperature, and extended contact time. The study generates a comprehensive chemical inventory: a worst-case profile of what the material could release under extreme exposure. The conditions are deliberately set beyond real-world use to ensure the data captures the full range of potential migrants before the container or device is finalized.
Leachables
Leachables are compounds that actually migrate into the drug product during normal storage, manufacturing, or patient use. The study conditions reflect the intended product lifecycle: the formulation vehicle, storage temperature, container geometry, and shelf life duration. These are the compounds a patient is exposed to when the product is administered, which is why leachables data feeds directly into product specifications and regulatory submissions.
How the Two Studies Connect
The two studies are connected: extractables data generates a target compound list that the leachables program is designed to monitor. This relationship is a central principle of the PQRI guidance on leachables qualification and shapes how both studies are scoped and sequenced.
When Each Study Is Triggered
Route of Administration Determines the Bar
FDA and ICH guidance consistently apply the most rigorous requirements to products where leachables have direct access to the bloodstream or lungs. In descending order of regulatory scrutiny:
- Inhalation products (MDIs, DPIs, nebulizers)
- Sterile injectables and ophthalmic products
- Oral liquid products in direct container contact
- Oral solid dosage forms (lowest concern for most container interactions)
For inhalation and sterile injectable products, a formal extractables study and a correlated leachables program are expected in any regulatory submission. For lower-risk routes, a documented risk assessment may support a determination that reduced or no testing is warranted.
Container Closure Systems
FDA’s Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics requires safety and compatibility data for all direct-contact materials in any NDA, ANDA, or BLA submission. For sterile products, this typically encompasses the primary container, closure, and any components that contact the formulation during filling or delivery, each characterized individually and as an assembled system.
Drug-Device Combination Products
Combination products — prefilled syringes, autoinjectors, inhaler devices — require E&L evaluation under both pharmaceutical and medical device frameworks. ISO 10993-18 governs chemical characterization of device materials, and the data requirements can overlap with the USP <661> series on plastic packaging. The device component requires extractables characterization; the finished combination product requires a correlated leachables study.
Building a Fit-for-Purpose E&L Risk Assessment
The risk assessment is the document that determines what studies are needed, at what scope, and at what stage. Regulatory agencies expect a written rationale: a defensible justification for the design choices made based on the specific product, materials, and route of administration.
Step 1: Material Inventory and Prior Data Review
Build a complete inventory of every component that contacts the drug product: primary container, closure, delivery device, process equipment, and any secondary materials (adhesives, inks, labels) that could migrate through the primary barrier. For each material, review available extractables data from suppliers or published literature before commissioning new studies. Supplier-generated extractables packages can support a risk assessment, but the quality of those packages varies and may not reflect the solvent conditions relevant to the drug formulation.
Step 2: Exposure Assessment
Quantify patient exposure: daily intake based on dose volume, dosing frequency, and the concentration of potential leachables in the formulation. The threshold of toxicological concern (TTC) framework provides a default safety threshold for compounds without established tolerable daily intake (TDI) values. Compounds above the TTC, or any compound with structural alerts for genotoxicity, require additional toxicological characterization.
Step 3: Study Scope Determination
Based on the material inventory and exposure assessment, document which materials require formal extractables studies, which solvents and conditions apply, whether BPOG protocol is appropriate, and when leachables monitoring must begin. This output is the study scope rationale — a written record that supports regulatory review and anchors any future change assessment.
BPOG Protocol: Scope and Limitations
The BioPhorum Operations Group (BPOG) protocol provides a standardized extraction scheme for single-use bioprocessing equipment — bioreactor bags, tubing assemblies, filter housings, and connectors used in biologics manufacturing. It specifies six extraction solvents at defined temperatures and contact times, generating a comprehensive chemical profile for comparison across suppliers and reducing duplicative testing for commonly used components.
Applying BPOG Correctly
Container closure systems, drug delivery devices, and combination products require study designs governed by FDA guidance, ICH Q2, ISO 10993, and USP monographs — not BPOG. Applying BPOG methodology outside its intended scope creates a study-design mismatch that regulatory reviewers can challenge. The risk assessment should specify which framework governs each material and document the rationale.
Analytical Methods Used in E&L Studies
No single technique covers the full chemical space of potential extractables. Extractable and leachable testing in pharmaceutical analysis typically requires a combination of platforms, each suited to a different compound class:
- GC-MS and GC-MS/MS — volatile and semi-volatile compounds, including residual solvents, antioxidants, and plasticizers
- LC-MS/MS — polar and ionic compounds, including degradation products, UV stabilizers, and oligomers
- ICP-MS — elemental impurities, including metals that may leach from elastomers, adhesives, or pigments; required for compliance with ICH Q3D and USP <232>/<233>
- Ion chromatography (IC) — inorganic anions and cations not covered by ICP-MS
Method selection and detection limits are documented in the study protocol, with limits of quantitation set below the applicable reporting threshold.
When to Start: Integrating E&L Work Into the Development Timeline
The two studies have different triggers and different regulatory deliverables — sequencing them correctly is as important as the study design itself.
- Extractables — formulation development. Extractables studies on primary container and device components can begin before the container is finalized. Completing this work early means the data can inform material selection — if a compound with a genotoxic structural alert appears in the extractables profile, substituting the material is far less disruptive at this stage than after an IND has been filed.
- Leachables — stability and registration. Leachables monitoring begins once the formulation, container, and storage conditions are defined, typically at the start of formal stability studies. For inhalation products, leachables qualification may be required to support a clinical trial application at earlier stages. Leachables data is expected in the drug product specification as part of any NDA, BLA, or MAA filing.
E&L Testing: Common Questions
What is the difference between an extractables study and a leachables study?
An extractables study profiles compounds that can be forced from a material under exaggerated solvent and temperature conditions. A leachables study measures compounds that actually migrate into the drug product under real storage and use conditions.
Is E&L testing required for all pharmaceutical products?
Not at the same scope. Sterile injectables and inhalation products require formal extractables and leachables programs. For lower-risk routes such as oral solids, a documented risk assessment may support a determination that reduced or no testing is warranted.
When should an E&L risk assessment be initiated?
During formulation development, before primary container and device components are finalized. Completing extractables work early allows the data to inform material selection before those decisions become difficult or costly to reverse.
Does BPOG protocol apply to container closure systems?
No. BPOG was developed for single-use bioprocessing equipment. Container closure systems require study designs under FDA container closure guidance, USP compendial standards, and ICH guidelines.
What happens to an approved E&L package when the container changes?
Any change to the container, closure, or device component that could alter the leachables profile triggers a reassessment. FDA post-approval change guidance and ICH Q12 address what constitutes a reportable change — a documented, traceable risk assessment makes that determination significantly more straightforward.
Work with a Laboratory That Understands E&L From Risk Assessment to Regulatory Submission
BA Sciences is a full-service cGMP contract testing laboratory with demonstrated expertise in extractables and leachables testing for drug products, medical device combination products, container closure systems, and single-use bioprocessing equipment. Our team supports the full E&L workflow — risk assessments, BPOG-protocol and custom extractables studies, leachables monitoring, and regulatory submissions support — using ICP-MS, GC-MS/MS, LC-MS/MS, and other platforms as required.
Ready to discuss your E&L program? Request a quote or contact us to speak with a member of our team.
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