Precautions for E&L (Extractables and Leachables) Analysis and Testing

Considering the differences between small molecule drugs and large molecule drugs can help determine the analytical and testing methods for E&L.

Analyzing extractables and leachables (E&L) is crucial for determining relevant toxicological risks and ensuring the safety of pharmaceutical products. Examining extractables helps identify potential risks of leachable contamination or impacts on the quality of pharmaceutical products. Extractables can be extracted under certain extraction conditions using solvents or can be precipitated at high temperatures without solvents. Extractables may be potential leachables, but not all extractables will leach into the pharmaceutical product.

Potential sources of leachables include primary packaging components, secondary packaging components, intermediate manufacturing components, or APIs. Additionally, some E&L can be introduced during the molding process of components and eventually become leachables, such as release agents or lubricants.

Regulations and Guidelines

To avoid potential safety risks associated with leachables, various regulatory guidelines have been issued. The guidelines contained in Title 21 of the Code of Federal Regulations (CFR) by the FDA emphasize requirements related to drug containers and closures, such as:

• "Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements."

• "Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product. "

• "Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes shall be validated."

Two industry guidance documents published by the Product Quality Research Institute (PQRI), titled "Safe Thresholds and Best Practices for Extractables and Leachables in Oral Inhalation and Nasal Drug Products (4)" and "Safe Thresholds and Best Practices for Extractables and Leachables in Parenteral Drug Products (Intravenous, Subcutaneous, and Intramuscular Injection)," highlight industry-specific details on how E&L assessments should be conducted. The combination of regulatory and industry guidance documents provides a robust guideline for E&L analysis.

Differences between Small Molecule Drugs and Large Molecule Drugs

Leachables can interact with small molecule and large molecule drugs in different ways, and this is a critical factor to consider when testing biologics and small molecule E&L. If small molecule biologics are immunogenic, leachables may interact with proteins in the biologic and trigger an immune response.

The interaction between leachables and small molecule drugs may trigger post-translational modification reactions (such as oxidative phosphorylation, aggregation, or unfolding) in biologics, leading to reduced efficacy of the biopharmaceutical. One of the major concerns in the analysis of leachables in small molecule drugs is their specific toxicity/genotoxicity profile. For biologics, there is also the issue of the ability of leachables to interact with the biologic itself.

Many large molecule biologics are highly sensitive to metal content. Therefore, additional monitoring of metal content may be required. Biopharmaceuticals are sensitive and complex, and extractables or potential leachables that may migrate into the drug product may interact with the biologic, affecting product quality, safety, or stability. Additionally, large molecules have a larger surface area, and interactions can lead to conformational modifications and other interactions that may impact product quality.

Testing for E&L

During E&L studies, key components such as semi-volatile organic compounds, non-volatile organic compounds, volatile organic compounds, and metals can be identified. For extractable studies, exaggerated conditions are typically used to simulate "worst-case scenarios," and the data is used to help determine what further studies are needed to mitigate future risks. Examples of analytical techniques used to detect E&L include gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, and inductively coupled plasma-mass spectrometry. Considering these differences helps determine the appropriate tests for detecting E&L.

The manufacturing of biopharmaceutical disposable products requires rigorous design, with functionality and appearance tailored to their intended use. Following the design phase, rigorous material selection is crucial, which is vital to the biopharmaceutical process and technology. The E&L (Extractables and Leachables) of materials must be taken into account during material selection, as it relates to whether the final product can be used normally. If the manufacturing material affects the progress of the biomanufacturing process, then that material is not suitable. After selecting the appropriate manufacturing materials, the finished products also need to undergo various relevant verifications and risk assessments to ensure that they meet the requirements before they can be normally used in the biopharmaceutical production process.

BioLink possesses a complete manufacturing chain for single-use bioprocessing consumables, meeting various legal and regulatory requirements from material selection to manufacturing. Our product design can be customized according to customer requirements, and after manufacturing, a series of verifications are conducted to ensure the functionality, practicality, and safety of the products (with complete verification qualifications, and all verifications have relevant reports to guarantee the authenticity of the verification results).

BioHub® Single-Use Storage Bag

Product Classification (Applicable to)

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BioHub® Single-Use Storage Bottle

Product Classification:

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Product Classification:

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BioLink has a variety of self-developed single-use consumables, including connectors of various models, clamps, gaskets, storage bottles, single-use storage bags, and single-use cell culture bags, to meet customers' needs for various products.

Reference:

Leon， A. Considerations for Analytical Testing for E&L. BioPharm International 2023 36 （7）.