Extractables and Leachables (E&Ls) are a subset of impurities derived from manufacturing systems, container closure systems, drug product delivery systems, and other packaging material that chemically react with drug product components, including Active Pharmaceutical Ingredients (API) and excipients. E&L impurities are commonly found in various complex drug products, including parenterals, ophthalmics, inhalation products, topical formulations, oral liquids, biologics & biosimilars, implantable drug delivery systems, and certain oral solid dosage forms. E&Ls can adversely impact a drug's potency, stability, safety, and/or effectiveness, which makes their analysis critical. Pharmaceutical manufacturers are required by regulatory agencies to demonstrate that any substances that migrate from packaging materials into a drug remain below harmful levels during the product’s expected shelf life.
Safeguarding Drug Safety: The Critical Role of Evaluating Rubber Oligomers in Pharmaceutical Packaging
As biopharmaceutical products continue to evolve in complexity, contamination from packaging materials and ensuring product safety and integrity continue to be a growing concern. For example, FDA's Guidance for Industry on Immunogenicity Assessment for Therapeutic Protein Products flags container closure system leachables as a possible source of rubber oligomers. These compounds potentially enhance immunogenicity and/or toxicity through chemical modification of the drug product or trigger immune adjuvant activity. USP’s new technical guide, “Extractable and Leachable Studies: Importance of evaluating rubber oligomers in drug products,” offers critical insights about oligomer formation, advanced identification methods, and regulatory guidelines.
Rubber Oligomer Technical Guide
Manufacturers are challenged with limited (or general) guidelines, a lack of standardized methods, and quality materials to conduct a comprehensive analysis. Recognizing this challenge and leveraging on expertise in setting standards for packaging components, USP is developing a comprehensive E&L solution comprising of current and upcoming USP General Chapters, Official USP Reference Standards, and Analytical Reference Materials* (ARMs) with supporting technical resources for rubber oligomers, medical device components, manufacturing components, packaging systems and system suitability mixtures.
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USP E&L Reference Standards and Analytical Reference Materials
USP provides Reference Standards and Analytical Reference Materials to analyze E&Ls, of which 18 reference standards are associated with USP-NF General Chapters, including <661.1> Plastic Materials of Construction. The chapter will be official on December 01, 2025; however, USP permits an early adoption of <661.1>.
New Releases: Rubber Oligomer Analytical Reference Materials
Rubber oligomer leachables often arise by interaction of elastomeric materials with drugs or during drug manufacturing. Some of the potential sources are stoppered vials, rubber caps, pre-filled syringes with rubber caps/plungers, rubber liners, and elastomeric components. Just as with other E&Ls, industry is challenged with lack of methods and quality materials for analytical assessment of rubber oligomer leachables. To address this, USP is developing a set of Rubber Oligomer ARMs and w/ a technical guide (above) on GC-MS method to test rubber oligomer leachables.
USP-NF General Chapters
USP-NF General Chapters that present frameworks for the design and execution of testing methodologies to help manufacturers assess drug substances and drug products for the presence of E&Ls, including (note: subscription to USP-NF is required to access the chapters):
- <621> Chromatography
- <671> Containers - Performance Testing
- <1661> Evaluation of Plastic Packaging Systems for Pharmaceutical Use and Their Materials of Construction
- <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems
- <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems
- <1665> Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products
- Upcoming: <661.1> Plastic Materials of Construction (to be official on December 1, 2025)
- Upcoming: <661.2> Plastic Packaging Systems for Pharmaceutical Use (to be official on December 1, 2025)
- Upcoming: <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products (to be official on May 1, 2026)
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USP Education courses
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Related events
- USP Extractables & Leachables Open Forum was held on August 26, 2024
Watch industry, compendial, regulatory and scientific experts discuss the following topics:
- Repeatable Extraction studies
- Ophthalmic drug products
- Liposomes and Microspheres
- Transdermal products
- USP Updates on Extractable and Leachable
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Supporting resources
- Proposals for the Development, Composition, and Routine Use of System Suitability Standard Mixtures in Support of Chromatographic Screening for Organic Extractables and Leachables
- For more information on E&L guidance, visit:
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Questions about USP E&L Solutions?
Contact Analytical Materials Technical Services for inquiries related to USP E&L Products & Resources.
*Analytical Reference Materials (ARM) are released using a process developed by USP’s subject matter experts. The release process is based on internal policies, standard operating procedures, and requirements as defined by USP’s Quality Management System. USP is an ISO 9001:2015 certified facility. ARMs are different from official USP Reference Standards. ARMs are not required for compendial compliance.