What Is Extractables & Leachables?
An E&L study has two stages. EXTRACTABLES are the full set of substances that can be extracted from the packaging or contact material under exaggerated conditions and show the material's potential. LEACHABLES are the substances that actually migrate into the product under real formulation and real storage conditions. The extractables study is for screening; the leachables study measures the real risk.
Purpose of Extractables & Leachables
The purpose is to show substances migrating into the product from the packaging or manufacturing system are at an acceptable level for patient safety. This assessment is particularly critical for parenteral and inhalation products.
Which Products Is Extractables & Leachables Applied To?
- Injectable products and pre-filled syringes
- Inhalation products
- Single-use manufacturing systems
- Eye drops and sterile solutions
- Medical device-drug combinations
In Which Sectors Is Extractables & Leachables Used?
Standards Related to Extractables & Leachables
- USP <1663> (assessment of extractables)
- USP <1664> (assessment of leachables)
- TS EN ISO 10993-18 (chemical characterization of medical devices)
- TS EN ISO 10993-17 (establishment of allowable limits for leachable substances)
- Ph. Eur. 3.1 and 3.2 series (packaging materials)
Extractables & Leachables Conditions
- Extraction
- Under exaggerated conditions, with solvents of different polarity
- Leachable
- In the real product formulation and real storage conditions, over the shelf life
- Screening
- Untargeted and targeted screening by GC-MS, LC-MS/HRMS and ICP-MS
- Threshold
- The analytical evaluation threshold is set based on the toxicological assessment
Equipment for Extractables & Leachables
- GC-MS and GC-MS/MS
- LC-HRMS (high-resolution mass spectrometry)
- ICP-MS
- Extraction and conditioning systems
- Sample concentration equipment
Sample Requirements for Extractables & Leachables
- Packaging or contact material specimens
- Specimens filled with the real product for the leachables study
- Material composition and supplier information must be provided
- Storage condition and shelf life must be provided
Duration of Extractables & Leachables
The extractables study can be completed within a few weeks. The leachables study is tied to the stability programme and runs for the product's shelf life.
Extractables & Leachables Procedure
- 1Material composition and contact conditions are assessed.
- 2Extraction conditions and solvents are determined.
- 3Exaggerated extraction is applied.
- 4Untargeted screening is performed by GC-MS, LC-HRMS and ICP-MS.
- 5Detected substances are identified and quantified.
- 6The leachables study is run with the real product over the shelf life.
Extractables & Leachables Acceptance Criteria
The acceptance criterion is that detected substances stay below the safe exposure levels set by the toxicological assessment. There is no fixed numerical limit: the threshold is calculated based on the product's route of administration, daily dose and treatment duration.
Evaluation of Results
Extractables results do not substitute for leachables results: a substance that appears under exaggerated conditions may never leach in the real product, or conversely, formulation components can increase leaching. Unidentified peaks are a separate risk item and are treated with the worst-case assumption in the toxicological assessment.
Extractables & Leachables Report
- Material and product identification, contact conditions
- Extraction conditions and solvents
- Screening methods and detection thresholds
- Substances detected, their identification confidence and amounts
- Toxicological assessment and safety margin
Accreditation
EUROLAB holds internationally recognised accreditation obtained from accreditation bodies party to the IAF and ILAC multilateral recognition arrangements, under ISO/IEC 17025 for laboratory testing, ISO/IEC 17020 for inspection and surveillance, and ISO/IEC 17021-1 and ISO/IEC 17065 for system and product certification. This chain ensures the reports and certificates issued are accepted worldwide.
Whether this test can be offered within accredited scope depends on your product and the standard applied; since accreditation is method-based, the scope is confirmed in writing at the quotation stage.
Scope and authorisationsRelated Regulations
- 2001/83/EC Directive on Medicinal Products for Human Use
- (EU) 2017/745 Medical Device Regulation
- GMP Guide (EudraLex Volume 4)
Pharmaceutical Analysis — What Does This Testing Field Cover?
The section below describes the field that the Extractables & Leachables test belongs to; the conditions and acceptance criteria of this particular test are given in the sections above. The scope specific to your product is confirmed in writing at the quotation stage.
Pharmaceutical analysis determines the identity, purity, quantity and behaviour of an active substance and of the finished product. What sets this family apart is that the methods are largely defined in PHARMACOPOEIAS: the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP) give both the method and the acceptance framework together.
The binding nature of the pharmacopoeial method shapes how the field works. In other sectors a laboratory can choose a suitable method, whereas here the method in the monograph governs; if an alternative method is to be used, its equivalence must be demonstrated. This is what makes results comparable worldwide.
Analyses are carried out in several groups. Identity and assay (HPLC, UV, titration) show what the product is and how much active substance it contains. The impurity profile and residual solvents look for unwanted compounds arising from the manufacturing process. Elemental impurities address metals originating from catalysts and equipment. Dissolution and disintegration behaviour is the most important in vitro indicator of how the drug will be released in the body.
The DISSOLUTION TEST is one of the most critical measurements in the field. It is not enough for a tablet to contain the right amount of active substance; that substance must dissolve at a suitable rate. The dissolution profile is used to assess the effect of formulation changes on bioavailability and holds a central place in generic drug licensing.
METHOD VALIDATION is a mandatory step in this family. If a pharmacopoeial method is used, it is verified that the method works properly under that laboratory's conditions. If an in-house method has been developed, it is validated against parameters such as linearity, precision, accuracy, specificity, limits of detection and quantification, and robustness. A result produced with an unvalidated method cannot be used in a licence dossier.
Stability studies determine shelf life and are the longest-running work in the field. The product is held under defined temperature and humidity conditions, analysed at set intervals, and the results become the basis of the shelf life and storage condition claims. Accelerated conditions give preliminary information but real-time data is what counts.
The microbiological side is a separate body of work: microbial enumeration, testing for specified microorganisms, sterility testing for sterile products and the bacterial endotoxin test. For sterile products, packaging integrity and sterilisation validation also come into play.
Data integrity has moved to the centre of inspections in recent years. It is not enough for the result to be correct; the raw data must be traceable, unalterable and auditable. Validation of electronic record systems has therefore become an inseparable part of analysis.
Method groups in this field
Identity and assay
HPLC, UPLC, UV-Vis spectrophotometry, titration, identity confirmation by FTIR.
Impurities and residues
Related impurities, degradation products, residual solvents (GC headspace), nitrosamine screening.
Elemental impurities
Determination of elemental impurities by ICP-MS and ICP-OES and the associated risk assessment.
Physicochemical
Dissolution and disintegration, hardness, friability, uniformity of dosage units, water content (Karl Fischer), particle size.
Microbiological
Microbial enumeration, specified microorganisms, sterility, bacterial endotoxin, preservative efficacy.
Stability
Real-time and accelerated stability studies; photostability and in-use stability.
Commonly confused in this field
- The pharmacopoeial method is binding; an alternative method may be used only by demonstrating its equivalence.
- A result produced without method validation cannot be used in a licence dossier.
- Accelerated stability does not replace real-time data; shelf life is supported by real-time results.
- The dissolution profile is sensitive to apparatus type, agitation rate and medium; the conditions must be complete in the report.
- A shortcoming in data integrity produces a non-conformity in an inspection even when the result is correct.
- A change of formulation or supplier requires analytical comparison and, where necessary, a new stability study.
Which decisions these results support
- The licence dossier and batch release
- Determining shelf life and storage conditions
- Method transfer and method validation
- Incoming raw material acceptance control from suppliers
- Assessing the effect of a formulation change on bioequivalence
Related Tests
Frequently Asked Questions About Extractables & Leachables
Is the supplier's E&L report sufficient?
It can be a starting point for extractables data but is not sufficient. Leachables risk depends on the formulation and storage condition, so the assessment must be carried out with your product.
What happens if an unidentified peak is found?
It is assessed with the worst-case assumption: the unknown substance is compared against the strictest toxicological threshold. If it exceeds the threshold, a structure elucidation study is required, which is a separate and lengthy undertaking.