Extractables and Leachables (E&Ls) are a subset of impurities derived from manufacturing systems, container closure systems, drug product delivery systems, and other packaging material1 that chemically react with drug product components, including Active Pharmaceutical Ingredients (API) and excipients. When these impurities are transferred under stress conditions, they are called Extractables. When they are transferred under normal conditions, they are called Leachables.
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; however, manufacturers are challenged with limited and general guidelines, and a lack of standardized methods and quality materials to conduct a comprehensive analysis.
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USP Solutions
Recognizing the above challenge and leveraging on expertise in setting standards for packaging components, USP is developing a comprehensive E&L solution comprising of current and upcoming General Chapters and Official Reference Standards, and Analytical Reference Materials* (ARM) with supporting application notes for rubber oligomers, medical device components, manufacturing components, packaging systems and system suitability mixtures.
USP's Rubber Oligomer ARMs
Rubber oligomers 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, screw caps, plastic, and elastomeric components.Rubber oligomer leachables can form carcinogens - for example, halogenated rubber oligomers (C13H23Br / C13H23Cl and C21H39Br / C21H39Cl), which can leach from a rubber stopper and react with small molecule APIs, excipients like glycine, impurities of excipients andprotein/peptides with nucleophilic side chain, leading to potential carcinogens.
Just as with other E&Ls, industry is challenged with lack of methods and quality materials for analytical assessment of rubber oligomer leachables - even more so.
To address this, USP is developing seven rubber oligomer ARMs and an application note on GC-MS method to test rubber oligomer leachables.
Each rubber oligomer ARM from USP will be ready-to-ship and supported with a detailed product information sheet, thus saving manufacturers time and resources, and reducing risk of quality.
Current USP solutions for E&Ls
- 42 USP RS and ARMs to analyze E&Ls, of which 18 RS 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>.
- 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 USP-NF General Chapters
- <661.1> Plastic Materials of Construction (to be official on December 1, 2025)
- <661.2> Plastic Packaging Systems for Pharmaceutical Use (to be official on December 1, 2025)
- <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products (to be official on May 1, 2026)
USP Education courses on E&L (explore here)
- Good Pharmaceutical Packaging - Extractables and Leachables
- Container Closure Integrity Evaluation of Drug Products
- USP Certificate on Impurities
Related events
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Upcoming | USP Open Forum on Extractables & Leachables. Join industry, compendial, regulatory and scientific experts at the USP virtual Open Forum on August 26, 2024, to discuss the current challenges, technical and regulatory considerations for Extractable and Leachable testing of complex drug products.
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USP E&L subject matter experts, Prabhakar Gruddanti and Ravikiran Kaja, conducted a roundtable discussion on System Suitability Standards Proposals from USP for the Analysis of Organic E&Ls. at the Extractables & Leachables Summit on April 19th in Philadelphia, Pa. In addition, Dr. Dennis Jenke, a renowned expert on E&L, presented on USP <665> and <1665>, Extractables from Manufacturing Components: Past, Present and Future(?).
Other Resources
- 1999 The United States - Food and Drug Administration guidance for industry on Container Closure Systems for Packaging Human Drugs and Biologics
- Final concept paper on ICH Q3E Guideline for Extractables and Leachables. The final guidance is expected in November 2025.
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.
1. https://www.pharmaceutical-technology.com/sponsored/extractables-and-leachables-analysis-in-pharmaceutical-quality-control/