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22 BioPharm International eBook June 2019 Single-Use Systems Extractables and Leachables The majority of SUS are made from polymeric materials, which are then sealed and sterilized. The pri- mary benefit of this system to the biopharmaceutical industry is that the equipment is already sterile, thus removing the need for clean- ing, sterilization, and validation of the equipment prior to usage. In effect, SUS is a more plug-and-play approach to biologics production. The benefits of SUS do not, how- ever, diminish the potential draw- backs. These include the potential for breakage and the subsequent loss of production material, the high cost of disposal, and the potential for con- tamination through the migration of harmful substances into the drug product (DP). SOURCES OF IMPURITIES IN SUS Impurities can be added at any point in the supply chain, either intentionally or unintentionally. They may be present in the raw materials that constitute the SUS, result from the manufacturing pro- cesses that create the SUS, or form during the aging process of the materials in the SUS. During biopharmaceutical pro- duction, impurities may also be introduced in several ways, includ- ing accumulation during manu- facture, via interaction with the materials in the storage contain- ers, from the environment, during materials processing, introduced with the excipient, or they may result from interaction with the material's surface. Finally, impurities may also form once the DP has been manufac- tured and is in its container clo- sure system. This could be through the aging process of the chemical materials, through the interaction between plastic and DP, or via a chemical reaction taking place in the material's polymeric structure. A pr ima r y task for biolog ics manufacturers is to ensure their suppl iers ad here to a releva nt pharmaceutical quality manage- ment system; they should consider the important quality attributes described in International Council for Harmonization (ICH) Q10 (2). WHAT ARE EXTRACTABLES AND LEACHABLES (E&L)? An extractable is a chemical entity, either organic or inorganic, that can be an extracted substance from the components of a process sys- tem into a solvent under controlled conditions. These would normally be harsher conditions not encoun- tered in the process (e.g., high heat, pressure, or multiple steril- ization cycles). It can also mean strong acids or organic solvents or mixtures from these. The identification of extractables is important because it can lead to the identification of leachables by comparison of the chemical profiles from both. The identification of extractables is important because it can lead to the identification of leachables by comparison of the chemical pro- files from both. Leachables are sub- sets of the extractables. Leachables can end up in the DP, usually at a trace level in relation to the API. Leachables present a problem to the quality of the DP as they may: • Interact with either the API or excipient • Compromise the product's sta- bility (e.g., aggregation, increase in particulates) • Interfere with analytical meth- ods or diagnostic tests • Negatively impact process per- formance (e.g., cell growth, rate of drug release, drug solubility, pH, product yield, etc.) I mpu r it ie s a l s o may p os e a toxicological risk if the leachable substance poses a health risk to the consumer. Finally, they may affect drug efficacy if the leach- able interacts with the API or prod- uct formulation through chemical reaction, thereby altering its stabil- ity and potency. To protect end users, regulators such as FDA and the European Medicines Agency (EMA) require the identification and quantifica- tion of harmful leachable impu- rities that may migrate from the SUS. This must be achieved before the products are offered onto the market. E&L STUDIES Reg u lator s requ i re biopha r ma- ceutical companies to undertake extractables and leachables (E&L) studies. Extractables studies assess the performance of the material i n t he SUS, t hereby deter m i n- ing what substances the patient m ay b e c ome e x p o s e d to du r- ing the taking of the medicine. Leachables studies are performed on the drug product, thereby iden- tif ying the substances to which patients may be exposed. A variet y of analy tical tech- niques are used during E&L stud- ies because no single analytical technique is available to detect all impurities. These can include gas chromatography–mass spec-

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