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The Long and Short of USP Guidelines for E&L Testing

Sources of Impurities in Pharmaceutical Products

In the development of a drug product, careful consideration needs to be given to impurities that may originate from manufacturing equipment, process components, and packaging materials. The majority of such impurities are common chemical additives used to improve the physicochemical properties of a wide range of plastic materials. Suppliers and drug manufacturers conduct studies to extract chemical additives from the plastic materials in order to screen and predict those that may leach into a drug product. In this context, the term extractables refers to a profile of extracted compounds observed in studies under harsh conditions. In contrast, the term leachables refers to those impurities that leach from the materials under real-use conditions and may be present in final drug products.

The Importance of USP Guidelines and Packaging Materials

Packaging materials must not interact physically or chemically with a packaged article in a manner that causes its safety, identity, strength, quality, or purity to fail to conform to established requirements. Any plastic material used to construct a Packaging system must meet the applicable requirements of Plastic Materials of Construction 〈661.1〉. All Packaging systems must meet the applicable requirements specified in:

All elastomeric closures must meet the applicable requirements in Elastomeric Closures for Injections 〈381〉. These basic requirements are typically met by manufacturers of packaging materials and components who supply to the pharmaceutical manufacturers.

Container Closure Testing: USP Regulations

The pharmaceutical manufacturers perform additional assessments on their product and container-closure combination. USP <1663> provides the design, justification, and execution of an extractables assessment of pharmaceutical packaging and delivery systems. USP <1664> provides the design, justification, and execution of an assessment of the actual drug product for leachants that may be transferred into the product from contact surfaces of primary container-closure and manufacturing. Need more help understanding USP guidelines? Ask our regulatory experts.

Ensuring Patient Safety and Product Quality: Our Regulatory Perspective

The risk mitigation of extractables and leachables presents significant challenges to regulators and drug manufacturers with respect to the development, as well as the lifecycle management, of drug products. We propose a holistic program, using a science- and risk-based strategy for testing extractables and leachables from primary containers, drug delivery devices, and single-use systems for the manufacture of biotechnology products. The strategy:

  • Adopts the principles and concepts from ICH Q9 and ICH Q8(R2)
  • Is phase-appropriate, progressing from extractables testing for material screening/selection/qualification through leachables testing of final products
  • Is designed primarily to ensure patient safety and product quality of biotechnology products

The holistic program requires robust extraction studies using model solvents, with careful consideration of solvation effect, pH, ionic strength, temperature, and product-contact surface and duration. From a wide variety of process- and product-contact materials, such extraction studies have identified and quantified over 200 organic extractable compounds. The most commonly observed compounds are siloxanes, fatty acid amides, and methacrylates.

Toxicology assessments are conducted on these compounds using risk-based decision analysis. PQRI and ICH guidances (M7) provide structured approaches for generating safety limits based on dose sizes and duration of use. Parenteral permitted daily exposure limits have been derived for the majority of these compounds. Analysis of the derived parenteral permitted daily exposure limits helped to establish action thresholds to target high-risk leachables in drug products on stability until expiry. Action thresholds serve to trigger quality investigations to determine potential product impact. This approach for primary drug containers and delivery devices is also applicable to single-use systems with an understanding of the manufacturing processes of biotechnology products.

In summary, a holistic and scientific approach, based on product/process knowledge that effectively minimizes the risk of leachables to patient safety and product quality, can be justified. If you’re interested in learning more about our holistic scientific approach, contact us.

Additional Resources

The FDA Gets Stricter with E&L Oversight, Can the Industry Keep Up? article in Contract Pharma, featuring Dr. Andrew Kolbert, Avomeen’s CTO, offers valuable insight.

In our years supporting the biopharma industry, we’ve seen some common mistakes made in E&L study design. We’ve outlined what not to do in our blog, Common Pitfalls in Ectractables & Leachables Testing.

Our blog, The Growing Need for Extractables & Leachables Testing of Pharmaceutical Manufacturing Equipment, offers information about FDA oversight and how CROs can help companies navigate the E&L process.

Learn more about FDA’s increasing oversight of E&L testing in pharma in Dr. Kolbert’s article in Tablets & Capsules Magazine.

Learn about our proprietary additives library in our post, Best-In-Class Polymer Additive Library for Identification of Extractables.

Looking for more information about our proprietary polymer additives database? Check out our Development of a Library of Plastic Additives for Identification of Extractables Poster Presentation.



Our expert blogger is Neelam Varshney, Avomeen’s Senior Technical Director of Biopharmaceutical Sciences. She has extensive experience in all CMC aspects of pharmaceutical products, and her expertise ranges from preclinical to post approval regulatory requirements. 

Learn more about Neelam’s expertise and experience.