〈 1665〉 CHARACTERIZATION OF PLASTIC MATERIALS, COMPONENTS, AND SYSTEMS USED IN THE MANUFACTURING OF PHARMACEUTICAL DRUG PRODUCTS AND BIOPHARMACEUTICAL DRUG SUBSTANCES AND PRODUCTS
USP1665 ( Risk assessment section)
▲〈 1665〉 CHARACTERIZATION OF PLASTIC MATERIALS, COMPONENTS, AND SYSTEMS USED IN THE MANUFACTURING OF PHARMACEUTICAL DRUG PRODUCTS AND BIOPHARMACEUTICAL DRUG SUBSTANCES AND PRODUCTS
1.1 Risk Assessment of Components
Components that have direct contact with a liquid process steam, process intermediate, DS, or DP, and do not have comparators, must be characterized to the extent dictated by their risk profiles whereby a greater risk is associated with a more extensive characterization. This characterization enables selection and may be a critical component of qualification. The risk profile of a component or system, used in a particular circumstance, is established by application of a risk evaluation matrix. Such a matrix is constructed so that it:
- Establishes the appropriate contributors to, or dimensions of, risk
- Provides a means of quantifying the risk, in each of its dimensions
- Links the quantified risk to appropriate characterization strategies
1.1.1 RISK EVALUATION MATRIX
The risk evaluation matrix establishes the relative risk that 1) a plastic component or system will be leached with sufficient tenacity that a process stream contacting the plastic component will contain potentially impactful extractables and 2) that the extractable persists in the process stream and is incorporated in the product output. The matrix then links that risk to a prescribed level of characterization.
1.1.2 DEVELOPMENT AND APPLICATION OF THE RISK EVALUATION MATRIX
In order for a PERL to adversely affect a key drug product quality attribute, two separate actions must occur: 1)
The PERL must be extracted (leached) from a manufacturing component by the process stream under the component’s typical conditions of use, and 2)The PERL must persist in the process stream through the final manufacturing step so that it is incorporated into the finished drug product.
If the contact conditions between a process stream and a manufacturing component are mild, then it is unlikely that PERL extraction will occur. On the other hand, if the contact conditions are harsh, then it is very likely that PERL extraction will occur.
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While the individual details of individual sponsors’ risk evaluation processes may differ, it is proper and reasonable to expect that the processes would be similar in terms of the general concepts applied. To properly address the issue of PERLs, the risk evaluation process must address the following points:
1. The chemical and physical nature of the contacted material or component, establishing the material’s or component’s “propensity to be leached”
2. The chemical nature of the contacting process stream, establishing the process stream’s “leaching power”
3. The conditions of contact, addressing the “driving force” for leaching
4. The ability of upstream process operations to eliminate the PERL from the process stream or to dilute the PERL to such an extent that an adverse effect is unlikely
5. The inherent risk associated with the manufactured drug product, considering such factors as the nature of the manufactured dosage form [for example, inhalation solution (higher risk) versus solid oral (lower risk)], the clinical dosing of the drug product (e.g., daily dose volume), and the duration of the clinical therapy
Regardless of the justified means by which the risk assessment is carried out, the outcome of the risk assessment must be that the risk is defined as low, moderate, or high, consistent with the risk levels illustrated in Figure 1.
1.1.3 LINKING RISK TO CHARACTERIZATION METHODOLOGIES
The various adjusted characterization levels established previously are linked to the following characterization processes:
- Low Risk = partial (baseline) assessment
- Moderate Risk = limited assessment
- High Risk = full assessment (extractables profiling)