The bioprocess industry has experienced rapid transformation through the adoption of single-use components (SUC) such as polymeric bags, tubing, filters, and fittings. These technologies enhance process flexibility, reduce cleaning validation efforts, and minimize cross-contamination risks. However, they also introduce new challenges to understanding the full impact of using plastic materials.

To help address these challenges, the United States Pharmacopeia (USP) introduced General Chapter <665> “Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products”. The chapter provides a harmonized, risk-based framework for qualifying polymeric process components and ensuring the safety of biopharmaceutical manufacturing systems.

USP <665> covers polymeric process contact materials used throughout drug substance and drug product manufacturing. Examples include:

• Tubing, connectors, manifolds, and bags
• Filter housings and membranes
• Single-use bioreactors and mixing systems
• Chromatography column housings

USP <665> introduces the term “process equipment-related leachables (PERLs)” or substances that can migrate from process equipment into process streams. Extractables are chemicals released under exaggerated conditions; leachables are found under actual process conditions. Both are evaluated to ensure they do not compromise product quality. A key principle of USP <665> is its risk-based approach. The level of testing required depends on:

• Contact type (direct vs. indirect)
• Duration of contact
• Process temperature and pH
• Solvent characteristics
• Sterilization methods

This approach prevents unnecessary testing while focusing resources on components with the highest potential risk.

USP <665> is complemented by USP <1665>, which provides detailed analytical expectations. Required studies include:

• Extraction testing under defined conditions established via risk-based analysis
• Analytical characterization of volatile, semi-volatile, and non-volatile organics as well as inorganic species
• Toxicological evaluation based on risk context and Analytical Evaluation Threshold (AET)

It must be noted that USP <665> studies chemical migrants, and this does not replace but rather is complementary to biocompatibility testing. Together, they provide a complete picture of material-process compatibility.

USP <665> is a compendial chapter rather than the voluntary guidance of the BPOG protocol. While the BPOG protocol was utilized to provide insights into L&E historically, there are marked differences:

Aspect	BPOG Protocol	USP <665>
Solvents	Water, 50% ethanol, 1 N NaOH, 1 N HCl, isopropanol	Polar & non-polar solvents; conditions defined in <1665>
Temperature & Duration	40 °C & 121 °C, up to 70 days cumulative	40 °C for 21 days (risk-based)
Data Requirements	Full mass balance, TOC, LC/MS, GC/MS, ICP-MS	Similar suite, but risk-based selection
Thresholds	Fixed surface-area normalized threshold (e.g., 0.1 µg/cm²)	Analytical Evaluation Threshold (AET) determined by risk

Both frameworks emphasize risk-based qualification, but USP <665> formally defines equivalent pathways allowing manufacturers to leverage existing data from similar components, an advantage for reducing redundant testing and costs. Manufacturers who already follow the BPOG protocol will find much of their existing data transferable to USP <665> compliance. However, gap analyses may reveal differences in solvent selection, extraction conditions, and documentation requirements.

USP <665> was approved in 2024 and becomes mandatory on May 1, 2026. Early review is encouraged to allow sufficient time for supplier qualification, data generation, and regulatory alignment. By providing a standardized testing framework, USP <665> helps to align expectations between component manufacturers and end users, facilitating vendor qualification and supply chain robustness. This alignment is especially critical in multiproduct biologics facilities that rely on validated, consistent SUS components.

References:

Preparing for USP : What you need to know | Labcorp

Ensuring Drug Product Safety Compliance Strategies Under USP 665 and 1665 | Pharmaceutical Engineering

Single-Use Systems: The Future of Biopharmaceutical Processing – Medical Design Briefs

USP <665>, USP<1665> or BPOG Extractables and Leachables for Bioprocessing Single-Use Systems

Application of the Risk Evaluation Matrix as per USP <665> and <1665> for Evaluation of Leachables Risk from Single-Use Components Used in Biomanufacturing | BioPharm International