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36 Pharmaceutical Technology ® Trends in Manufacturing eBook May 2024 PharmTech.com Qualit y Manufacturing systems used for biopharmaceutical drug substances or drug products can be partially or completely constructed from plastic materials. During the manufacturing process, the drug product and its components could directly come in contact with the plastics and potentially interact with one or more of the manufacturing system's product contact com- ponents. The substances that leach from a product contact manufacturing component could become in- corporated into the process stream. If these leached substances persist in the process stream and continue through the process operations, they could accumu- late in the drug substance or drug product as PERLs (1,2). When present in the drug product, these PERLs can potentially alter the critical quality attributes of the drug product, such as its stability, efficacy, and safety. USP <665>, Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Bio- pharmaceutical Drug Substances and Products, addresses these interactions by providing a risk-based means for chemically characterizing and qualifying plastic components used to manufacture biopharmaceutical drug substances and pharmaceutical and biopharma- ceutical drug products. USP <1665>, Characterization and Qualif ication of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products, communicates the key concepts behind and provides additional information and guidance regarding the applicability and the application of USP <665>. The au- thors discuss a practical approach by which USP <1665> can be applied in a step-by-step manner for the risk assessment, using a case study involving the manufac- turing process for remdesivir injection and single-use technologies (Merck). The testing of a product contact component is driven by the risk that the component may be unsuited for its intended use based on chemical or biological effects attributed to PERLs (1). As such risks increase, the degree of required testing also increases. The risk as- sessment process is accomplished by a risk evaluation matrix that establishes the appropriate contributors to the dimension of risk, provides a quantifying means for the risk in each dimension, quantifies the total risk for each dimension, and links the quantified risk to an appropriate characterization strategy. The risk evaluation matrix evaluates the dimensions that address the risk that a product contact part will be leached by a process stream to the extent that the extractables may be impactful on the final product. As shown in Table I, the dimensions include the dura- tion of product contact, temperature during product contact, chemical composition of the product stream, and the nature of the material with which the product contact component is constructed. The risk evaluation matrix will then evaluate each dimension separately and assign a level of risk based on certain measures relevant to each dimension. The risk evaluation of condition and duration of contact with the process stream addresses the driv- ing force for the leaching. Depending on the dura- tion of contact, the dimension has been divided into short term (<24 hours, Level 1), intermediate (1–7 days, Level 2) and long term (> 7 days, Level 3). The risk evaluation of temperature of the process stream or the component during the contact duration drives the magnitude of leaching. Depending on the temperature during contact time, the dimension has been divided into low (refrigerated, Level 1), intermedi- ate (ambient, Level 2) and high (elevated, Level 3). The risk evaluation of the chemical nature of the con- tacting process stream addresses the process stream's leaching power. The chemical composition of the pro- cess stream in terms of "aqueous", "somewhat organic", and "highly organic" are further discussed in Table II. In case the process stream contains multiple solubi- lizers, such as a protein solution with a surfactant, the process stream is risk-assessed as a compounded risk associated with the individual agents. The risk evaluation of the chemical and physical natures of the contacted component addresses the component's propensity to be leached. The risk di- mension for "the chemical composition of the compo- nent" can be identified as low, intermediate, or high based on the composition or physical properties of the component (2). By composition, the risk dimen- sion can be identified based on the % level of addi- tives in the plastic material. The component is con- TABLE I. Dimensions relevant to risk level (2). Risk dimension Duration of contact Temperature of contact Chemical composition of the process stream Chemical composition of the component Level 1 <24 hours Refrigerated (2 °–8 °C) Aqueous (≤5% organic v/v) pH (pH≥3 and pH≤9) Low risk Level 2 1–7 days Ambient (15 °-25 °C) Somewhat organic (>5% and ≤40%v/v) Intermediate risk Level 3 >7 days Elevated (> 30 ° C) Highly organic (>40%v/v) or pH (pH≥3 and pH>9) High risk