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Extractables and leachables testing (E&L)
What do we mean by “Extractable and Leachable” ?
In materials science, “extractables and leachables” designates the migration of atoms, ions or molecules in matter whether it be in solids (crystalline or amorphous), liquids or gasses. This phenomenon is irreversible and is therefore a macroscopic concept, referring to notions of chemical concentrations of the different compounds in a material which can change during its use. This natural process designates a diffusion of matter tending to make chemical concentrations of substances homogeneous in any given medium.
Extractables are by definition compounds that can be extracted from a material when in the presence of solvents with variable polarity in extreme conditions. Generally speaking, manufacturers are aware of which types of compounds can be extracted and in ideal cases, provides clients with a list of extractible substances found in a given product. Similarly, leachable substances are compounds capable of migrating from one material to another given the right conditions. Information about extractible substances can be turn out to be useful during tests on specific leachables. However, the correlation between extractables and leachables must be made carefully because leachables are not always found during analysis of extractables. Given that a formulation of a drug can chemically alter known extractables, it is possible to detect leachables that had not shown up during the analysis of extractables. Moreover, matrix effects of the sample, differences in the analytical system, changes in the test method, etc. limit the possibility of drawing direct correlations.
Evaluating a material, its ageing over time, compatibility between different materials (containing polymers, metals or glass) coming into contact with contents (cosmetic or pharmaceutical products, food, medical devices…) constitutes a primary concern for industrialists from the food, cosmetics, pharmaceuticals and Medical Device industries. The impact of a chemical migration (container, packaging, detergent, utensil, implant, equipment…) coming into contact with the product itself (Medical Device, bulk, powder, pills, liquid, the human body…) can be a problem : contamination, non-conformity, complaints, user harm…
The logical question that arises from all this is what are these compounds or substances, and consequently, what are the risks to the patient/client? This are the questions that studies of extractables and leachables must answer. As an example, the FDA published a Guidance for Industry : Container Closure Systems for Packaging Human Drugs and Biologics in 1999 in which it is specified that :
“Packaging must be made of materials that do not release undesirable or hazardous substances to the patient treated with the product.
Accordingly, files should contain extraction tests on the packaging to determine which chemical components or materials are likely to migrate into the product. A toxicity study of these components will need to be conducted.”
In 2005 this text was amended by a European guideline issued by the EMA: Guideline on plastic immediate packaging material which specifies that the purpose of extraction tests is to identify and quantify additives (antioxidants, plasticizers, catalysts, etc.) that can be extracted by contents in contact with its packaging, whether the product is liquid or solid.
Following this in 2006, the Product Quality Research Institute (PQRI) carried out extensive research into inhaled products or products administered nasally.
This research led to certain recommendations : Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Product
These recommendations are now part of FDA standards and referenced across the world in the pharmaceutical industry.
This research mostly covered packaging materials (blister packs, bottles, prefilled syringes, dosing valve, inhalers…) but also elements coming into contact with the product during the manufacturing process (filtration systems, transfer pipes, single use materials…)
The regulated substances can have an effect either on the patient (ex. Carcinogenicity : N-nitrosamines, polyaromatic hydrocarbons…) or on the physicochemical stability of the drug itself.
Given that a specific formulation can have an effect on the type and quantity of leachables, it is the manufacturers’ responsibility to prove that the level of leachable substances does not exceed toxicological constraints. Current guides such as the FDA’s “Container Closure Systems for Packaging Human Drugs and Biologics” and the EMA’s “Guideline on Plastic Immediate Packaging Materials” directives clearly indicate that it is preferred to perform leachable testing on the final formulation.
What are the analysis techniques for extractables and releargables?
- GC-MS, HPLC or UHPLC/MS/MS for detecting, identifying and quantifying organic compounds present in solvents, anti-UV additives, antioxidants, dyes, inks, detergent residues, sterilization residues, polymer residues, … that have been extracted and/or released from the material by a standardized simulant
- UV-Vis spectrophotometry for dosing Chromium VI leached out of metallic alloys
- ICP-AES and ICP-MS particularly adapted for pollutants, inorganic and metallic additives such as heavy metals, mineral or metallic fillers, dyes…
- SEM-EDX microscopy is a quick and reliable tool for diagnosing the state of the surface of a material after an ageing process, the observation of particulates or deposits…
How FILAB supports its customers in the analysis of extractables and leachables
In this context, FILAB has managed to implement extraction and leaching techniques described in standards and guidelines (USP 1663, USP 1664, EN 1186, EN 1388-2, ISO 10993-12…) and in accordance with relevant national or European standards. Moreover, FILAB develops protocols specific to clients’ challenges with the aim of simulating real conditions of contact between a container and its contents to be able to analytically determine their chemical compatibility and to evaluate their level of chemical inertia. Testing chemical inertia consists of demonstrating a containers ability to resist the invasive effects of its contents which are susceptible of extracting and/or leaching chemical compounds.
With extensive experience in implementing these techniques and in developing specific analytical techniques, FILAB can assist you in the context of a study into E&Ls and studies of ageing materials.
The European legislation provides specific guidelines for E&L testing on polymer materials used in medical devices, pharmaceutical products, and other applications.
The guidelines for E&L testing on polymer materials according to European legislation include:
- European Pharmacopoeia (Ph. Eur.) General Chapters 3.1 and 3.2: The Ph. Eur. provides general guidelines for E&L testing of plastic materials and elastomers used in pharmaceutical products and packaging. These chapters outline the general principles for extractables and leachables testing and recommend that manufacturers perform a risk assessment to determine the appropriate testing approach.
- European Medicines Agency (EMA) Guideline on Plastic Immediate Packaging Materials: This EMA guideline provides specific guidelines for E&L testing of plastic materials used in pharmaceutical packaging. The guideline recommends that manufacturers perform a risk assessment to determine the appropriate testing approach and provides specific requirements for extractables and leachables testing based on the intended use and duration of contact between the packaging material and the product.
- ISO 10993-12 and ISO 10993-18: The International Organization for Standardization (ISO) provides guidelines for E&L testing of polymer materials used in medical devices. ISO 10993-12 focuses on sample preparation and reference materials, while ISO 10993-18 outlines the general principles for extractables and leachables testing and recommends that manufacturers perform a risk assessment to determine the appropriate testing approach.
- European Union Regulation on Cosmetic Products (EC) No. 1223/2009: This regulation requires cosmetic companies to conduct extractables and leachables testing on packaging materials and applicators to ensure that they do not introduce any harmful substances into the product.
These guidelines provide general principles and specific requirements for E&L testing of plastic materials and elastomers used in medical devices, pharmaceutical products, and packaging. Manufacturers are recommended to perform a risk assessment to determine the appropriate testing approach.
An extractables and leachables (E&L) testing study typically involves several steps to ensure thorough analysis and accurate results. These steps include:
- Risk assessment: Conduct a risk assessment to identify potential sources of extractables and leachables, taking into consideration the materials used, manufacturing processes, storage conditions, and intended use of the product.
- Study design: Develop a study plan outlining the scope, objectives, and testing strategy for the E&L study. This includes selecting the appropriate extraction methods, analytical techniques, and acceptance criteria based on the risk assessment and regulatory requirements.
- Sample preparation: Collect samples of the materials or products to be tested, ensuring proper handling and storage to prevent contamination. Prepare samples for analysis by applying appropriate extraction methods, such as solvent extraction, accelerated aging, or simulated use conditions, depending on the study objectives.
- Analytical testing: Perform qualitative and quantitative analysis of the extracted samples using various analytical techniques, such as gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), inductively coupled plasma-mass spectrometry (ICP-MS), or other suitable methods, to identify and quantify extractables and leachables.
- Data analysis and interpretation: Analyze the data obtained from the analytical testing to identify and quantify the extractables and leachables present in the samples. Compare the results with established acceptance criteria or toxicological limits to assess the potential risk associated with the detected compounds.
- Toxicological risk assessment: Conduct a toxicological risk assessment to evaluate the potential health risks associated with the identified extractables and leachables. This may involve comparing the concentrations of the detected compounds with established safety thresholds or performing additional toxicological studies if necessary.
- Reporting and documentation: Prepare a comprehensive report detailing the E&L study's findings, including the testing methods, results, data analysis, and toxicological risk assessment. Maintain thorough documentation of the study to ensure traceability and transparency.
- Review and follow-up actions: Review the results of the E&L study and determine if any follow-up actions are required, such as modifying the materials or manufacturing processes, implementing additional quality control measures, or conducting further testing.
By following these steps in an E&L testing study, laboratories can effectively identify and assess the potential risks associated with extractables and leachables in the products, ensuring compliance with regulatory requirements and safeguarding patient safety.
To confirm the accuracy and reliability of an extractables and leachables (E&L) testing study, several quality control measures can be implemented. These measures help ensure that the study is conducted according to established guidelines and industry best practices:
- Method validation: Before starting the E&L study, validate the analytical methods used to identify and quantify extractables and leachables. Method validation should include parameters such as specificity, linearity, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ).
- Use of reference standards: Utilize reference standards when available to confirm the identity and concentration of the detected compounds. Reference standards can help to ensure that the results are accurate and reliable.
- Sample preparation controls: Implement proper controls during sample preparation, such as using blanks, matrix spikes, and duplicate samples. These controls can help to identify any contamination or matrix interference that may affect the accuracy and reliability of the study.
- Instrument calibration and maintenance: Regularly calibrate and maintain the analytical instruments used in the study. This helps to ensure that the instruments are functioning properly and providing accurate and reliable results.
- Analyst training and proficiency: Ensure that the analysts conducting the E&L testing study are well-trained and proficient in the techniques used. This helps to minimize human errors and ensure the accuracy and reliability of the results.
- Data review and quality assurance: Implement a thorough data review process, including quality assurance checks, to identify any inconsistencies or potential errors in the data. This helps to ensure that the data is accurate and reliable before reporting the results.
- Adherence to guidelines and best practices: Conduct the E&L testing study according to established guidelines (such as ISO 10993-18, USP , and Ph. Eur. 3.2) and industry best practices. This ensures that the study is conducted according to the highest quality standards and can be considered reliable.
- Documentation and traceability: Maintain detailed documentation of the E&L testing study, including sample preparation, analytical methods, instrument settings, and data analysis. This helps to ensure traceability and transparency, which are essential for confirming the accuracy and reliability of the study.