United States Pharmacopeial

Preparing for USP <665>: What you need to know
United States Pharmacopeial (USP) chapter <665> (Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products) is scheduled for implementation on May 1, 2026.  At that point, compliance will be mandatory. Now is the time for manufacturers and suppliers to start preparing for compliance. 

Scope of materials

USP <665> provides guidance for the evaluation of polymeric materials, particularly those in single-use systems and multi-use systems, used in the manufacture of drug products and substances. The primary concern is that contact of the drug substance (DS), drug product (DP) or materials used in their manufacture with the polymeric components could cause the release of extractables referred to as process equipment-related leachables (PERLs). Accumulation of these compounds during the manufacturing process can adversely impact product quality, efficacy, stability and/or patient safety.

Components and materials within the scope of USP <665> may include:

• Tubing
• Connectors filters
• Containers (e.g., bags and bottles used for mixing or storage)
• Impellers 
• Closures

Potential PERLs include common extractables such as:

• Plasticizers 
• Antioxidants and their degradants
• Pigments
• Lubricants
• Stabilizers
• Slip agents
• Monomers and oligomers
• Residual solvents

Ancillary items (e.g., scoops, funnels, pipettes, graduated cylinders, weighing dishes and beakers) are generally assessed as low risk associated due to limited exposure and are generally considered as out of scope. Similarly, container closure systems and other pharmaceutical packaging are outside the scope of <665>. These systems are covered by the guidance framed in USP <1663> (Assessment of Extractables Associated with Pharmaceutical Packaging & Delivery Systems).

Risk-based approach

USP <665> provides a risk-based approach for assessing the materials and determining the need for extractable/leachable testing. The framework for this evaluation is laid out in this chapter and its complementary chapter USP <1665> (Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products).

Key consideration in the initial assessment includes:

• Location of the component within the process stream
• Type and duration of exposure 
• Equivalency to previously evaluated components

Examination of vendor data is often a critical step in the initial assessment. Equivalency can be evaluated based on:

• Materials of construction, composition and manufacturing process
• Preparation for use (by supplier and end user)
• Functionality and design similarity
• Conditions of use in the manufacturing process
• Use to manufacture of a similar DS or DP with similar composition and clinical usage

An important consideration is that it is the responsibility of the user to document the establishment and justification of the equivalency.

When is testing required?

If comparator equivalence and appropriate justification can be made, then further chemical characterization may not be required. If no comparator equivalence and appropriate justification can be made, the component is subject to a risk assessment. A typical process for this is laid out in USP <1665>: 

• Establish contributors and dimension of risk
• Quantify the risk in each dimension
• Combine the individual risks into a total risk scope
• Link the risk to appropriate testing strategy

The outcomes of the risk assessment include low risk, moderate risk or high risk, which determines the testing required. It is critical to ensure the establishment and justification is accomplished and documented appropriately. 

Testing requirements

Testing may range from:

• Simple tests such as determination of non-volatile residue and ultraviolet absorbance for a single extraction solvent for low-risk components 
• Comprehensive chemical characterization including determination of extracted organic and elemental profiles in a variety of solvents for high-risk components

Common extraction solvents include: 

• Water/ethanol extraction
• Acidic extraction 
• Basic extraction

Alternative extraction solvents may be used if adequately justified for specific applications. Extraction duration ranges from 1 to 21 days based on the type of component and how it is used in the manufacturing process.

Conclusion

USP chapter <665> represents a significant advancement in standardization of procedures used in material evaluation of pharmaceutical products manufactured using plastic-based components and systems. Evaluation of components and systems during the time leading up to the implementation date of May 1, 2026, will position pharmaceutical manufacturers and their suppliers for success under the new requirements. Importantly, compliance should not be viewed as a one-time activity but part of a continuous risk-based approach to establish long-term product safety, regulatory compliance and supply chain robustness.

Working with a trusted partner such as Labcorp can help deliver and maintain successful compliance. 

Recommended edit for clarity:

The primary concern is the potential release of extractables referred to as process equipment-related leachables (PERLs) if polymeric components come into contact with the drug substance, drug product or materials used in their manufacture.