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PDA J Pharm Sci Technol. 2015 Sep-Oct;69(5):590-619. doi: 10.5731/pdajpst.2015.01073.

Creating a Holistic Extractables and Leachables (E&L) Program for Biotechnology Products.

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Amgen Inc., Thousand Oaks, California, USA and
Amgen Inc., Thousand Oaks, California, USA and.
U.S. Food and Drug Administration (FDA), Washington, DC, USA.


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. A holistic program is proposed, 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). The strategy is phase-appropriate, progressing from extractables testing for material screening/selection/qualification through leachables testing of final products. The strategy 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 were siloxanes, fatty acid amides, and methacrylates. Toxicology assessments were conducted on these compounds using risk-based decision analysis. Parenteral permitted daily exposure limits were derived, as appropriate, 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. The holistic program also evaluates the potential risk for immunogenicity. This approach for primary drug containers and delivery devices is also applicable to single-use systems when justified with a historical knowledge base and understanding of the manufacturing processes of biotechnology products.


In the development of a drug product, careful consideration is 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 purpose of this article is to present a holistic approach that effectively minimizes the risk of leachables to patient safety and product quality.


Action threshold; Biotechnology products; Extractables; Leachables; Safety concern threshold; Single-use systems

[Indexed for MEDLINE]

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