Approved USP Chapters on Plastic Components used in Manufacturing

As previously discussed there are currently only a few applicable standards available for plastics used in pharmaceutical equipment engineering. However, this will change now with the new USP general chapters <665> and <1665> which have been previously published for comment in Pharmacopeial Forum (PF) 46(5). They have been finally approved and will become official on May 1, 2022. According to the USP, chapter <665> establishes a baseline for the qualification of plastic components used in the manufacturing of pharmaceutical and biopharmaceutical drugs. Interestingly, USP General Chapter <665> is informational only and not compendially applicable unless otherwise specified by regulators and enforcement bodies.

• Chapter <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products addresses specific points to consider (e.g., process equipment-related leachables (PERLs)) by providing a risk-based approach for characterizing and qualifying plastic components.
  
  
• Information related to the rationale and use of chapter <665> is provided in chapter <1665> Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products.

The testing indicated is applicable to previously unqualified components / systems and may be applied to previously qualified components / systems that have been changed. According to the USP, it is the responsibility of the user to establish and justify how this chapter is implemented to address change control.

Scope of USP general chapter <665>

Pharmaceutical and biopharmaceutical manufacturing systems may be either single-use systems (SUS) or multiple-use systems (MUS), both are in scope of chapter <665>. Active pharmaceutical ingredients (APIs) that are produced by chemical processes and plastic auxiliary items (e.g., scoops, funnels, pipettes, weighing dishes, and beakers) are out of scope. Furthermore, elastomers (e.g., diaphragms, gaskets, and O-rings) are not in the scope of this chapter (USP general chapter <381> Elastomeric Components in Injectable Pharmaceutical Product Packaging/Delivery Systems may be instructive in terms of appropriate tests and specifications).

<665> is applicable solely to those process streams that are either liquids or semisolids. For example, a drug substance (DS) may be stored frozen as a solid. The period of time that the DS is frozen is out of scope (i.e. no risk assessment and testing is required). However, the period of time during which the DS is in a liquid form is within the scope of this chapter.

2-step Approach to component classification

Plastic manufacturing components and systems are qualified as being chemically suited for their intended use if:

• The components or systems have been characterized by the appropriate chemical testing (e.g., extractables profiling)
• The test results have been interpreted in the context of suitability for use (e.g., toxicological assessment)

Matching the risk that PERLs could adversely affect the quality of the drug product (DP) to the required level of testing and assessment is achieved by a 2-step approach, consisting of an initial assessment followed by a risk assessment. The completed initial assessment establishes whether component testing is required. Once the need to perform testing is established, a risk assessment is completed to establish what testing must be performed. Thereafter, testing proceeds as described in <665>.

Risk Assessment

According to the USP, the testing of components is driven by the risk that the component could be unsuited for its intended use based on chemical or biological effects attributed to PERLs. As the risk that the component could be unsuited for use increases, the degree of required testing also increases. The risk assessment is accomplished via a process, which:

• Establishes the appropriate contributors to risk
• Provides a means of quantifying the risk
• Quantifies total risk as a combination of the individual risks
• Links the quantified risk to appropriate characterization strategies

To properly address PERLs, the risk evaluation process must address the following topics:

• Propensity to be leached
• Leaching power
• Driving force for leaching
• Downstream process operations (such as filtration) to either eliminate, remove, or clear the PERL from the process stream or dilute the PERL to the extent that an adverse effect is unlikely
• Risk associated with the manufactured DP, considering such factors as the route of administration, the dosing of the DP (i.e., daily dose volume), and the duration of the therapy (i.e., acute versus chronic)

The outcome of the risk assessment is that the risk is established as either low, moderate, or high. These risk levels define the specific testing required for the components.

For more information about the two new USP general chapters <665> and <1665> access to USP online is required.