What are Extractables and Leachables Studies?
Extractables and leachables (E&L) studies are in-depth analytical investigations of the chemical interactions between a pharmaceutical formulation and a drug delivery system, container closure system, or other packaging component. They also extend to assessments of the impact of manufacturing components on drug products. The primary purpose of an E&L investigation is to identify any potential chemicals derived from the interaction of the constituent parts and then to determine the impact to human health and/or drug efficacy that those chemicals pose. This identification is an extractables/leachables profile. Organizations that seek to provide guidance for pharmaceutical E&L studies include the FDA, ICH, BPOG, and USP.
What are Extractables?
Extractables are substances in a manufacturing, packaging, or drug delivery component which can be “pulled out” using stressing conditions such as strong solvents, elevated temperatures, and/or increased surface area. Substances observed in this stage are characterized and identified per FDA guidelines and further evaluated by a toxicologist to determine if the substance is a potential hazard. Common extractables include plasticizers, surfactants, processing aids, degradants, and container closure system materials.
What are Leachables?
Leachables are substances in the manufacturing, packaging, or drug delivery component that leach or “come out” under normal conditions of exposure over the natural lifespan of a product. Sources of leachables are potentially numerous and can include anything from residual manufacturing solvents to ink and adhesives from labels of secondary packaging material. FDA guidelines monitor known extractables and leachables to ensure human exposure levels do not exceed appropriate safety limits.
Two crucial USP chapters include USP <1663> “Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems” and USP <1664> “Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems”. These chapters discuss practical and technical aspects for assessing extractable/leachable risk and designing appropriate experiments to monitor extractables/leachables. You can learn more about these chapters on our USP 1663 and USP 1664 page.
USP <661>, expanded into USP <661.1> “Plastic Materials of Construction” and USP <661.2> “Plastic Packaging Systems for Pharmaceutical use” for delayed implementation, describes the required tests and performance criteria for FDA approval of a plastic packaging system. More information about USP testing of polymeric container closure systems can be found here.
USP <665> (formerly drafted as <661.3>) “Polymeric Components and Systems Used in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products” describes the necessary testing for organic extractables and extractable metals in plastic manufacturing materials and components used in the conversion of raw starting materials into active pharmaceutical ingredients (APIs), biopharmaceutical drug substances (DS), and drug products (DP). This testing encompasses all polymeric materials involved in solution transfer and transport, mixing and reacting, storage, and processing including:
- Tubing and connectors
- Tank liners and mixing bags
- Raw material containers
- Production reagents
- Filters and chromatography columns
The BioPhorum Operations Group (BPOG) has published “Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing” and “Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing.” These documents are gaining traction across the biopharmaceutical and biopharmaceutical supply industries as a “one stop shop” for extractables and leachables testing principles. While not regulatory documents, these protocols have been adapted by many major biopharmaceutical companies. EKG Labs has written extensively on the BPOG documents and their applications.
Extractables and Leachables Studies at EKG Labs
Understanding complex chemical interactions between pharmaceuticals and container closure systems, drug delivery systems, or manufacturing components is critical to designing a proper extractables and leachables program. EKG has years of experience designing and managing large E&L programs. Our experience working with polymer materials and active ingredients uniquely positions us an industry leader in therapeutic product manufacturing and packaging testing. We routinely perform E&L analytical studies with the ultimate goal of submitting data for FDA review and approval. EKG Labs is familiar with guidance from organizations such as the FDA, ICH, BPOG, and USP. Our capabilities include:
- Full scale GMP analytical extractables and leachables programs
- Per USP 1663 and 1664 guidance
- Per BPOG guidance
- USP 661, USP 661.1, USP 661.2, and USP 665 Testing
- Method Development
- Method Validation
- Chemical Characterization
- Impurity Identification
- Elemental Impurities Analysis
Extractables and Leachables Analytical Techniques at EKG Labs
- Chromatographic Characterization – HPLC, LC/MS, GC/MS, GC/FID, GC/TCD, GPC/SEC
- Spectroscopy Characterization – ICP-MS, NMR, MS, PXRD, TF-XRD, UV-Vis, FTIR, Raman
- Extraction Techniques – Soxhlet, Reflux, Immersion, Agitation