Biomedical Engineering Reference
In-Depth Information
monitoring with a specification that is equal to or broader than the process
capability or (2) characterization only. If routine monitoring is performed and the
attribute changes over time, the test may also be part of stability assessment.
.
High risk: In the case where the combination of severity and probability results in
high risk, the attribute is considered “critical” and a test for it will be a part of
routinemonitoring. The test may also be part of stability assessment if the attribute
changes over time.
Semiquantitative plots of the criticality determination outcomes such as that shown
in Fig. 4.2 can be used to score low, moderate, or high risk. The location of the “X” on
each plot represents the combination of severity and probability, and this assessment is
based on prior product knowledge, manufacturing experience, and scientific judgment.
Nonclinical and clinical studies that show no adverse impact mitigate the severity and
result in placement of the “X” toward the lower end of the severity scale. A high degree of
process robustness and control or a process capability that is well within the range of prior
product knowledge would mitigate the probability and result in placement of the “X”
toward the lower end of the probability scale. The regions of the plot are colored green
(low risk—noncritical attribute), yellow (moderate risk—key attribute), or red (high
risk—critical attribute) to represent overall risk. The criticality of each attribute
determines the testing plan.
4.1.3 Safety Assessment Strategy for Process-Related Impurities
Process-related impurities can be subdivided into two categories for the purposes of
product quality attribute risk assessment, as shown in Fig. 4.1. Host cell-derived and
bioactive components comprise a category of process-related impurities that undergo
criticality determination in the same manner as performed for product-related substances
and impurities. Examples of this category include host cell DNA, host cell protein,
medium supplements such as protein hydrolysates from plant or microbial sources, or
components such as nucleases or residual protein A from chromatography gels used in
the process to facilitate purification.
Nonbioactive components such as antifoam are considered for their potential safety
risk by evaluating an impurity safety factor (ISF). The ISF is the ratio of the impurity
LD
50
to the maximum amount of an impurity potentially present in the product dose:
ISF
¼
LD
50
level in product dose
where LD
50
is the dose of an impurity that results in lethality in 50% of animals tested,
and the level in product dose refers to the maximum amount of an impurity that could
potentially be present and coadministered in a dose of product. Thus, ISF is a normalized
measure of the relationship between the level of an impurity resulting in a quantifiable
toxic effect and the potential exposure of a patient to impurity in the product. The higher
the ISF, the greater the difference between the toxic effect and the potential product dose
levels for an impurity, indicating therefore a minimized safety risk.
For the calculation of the ISF, the impurity level in a product dose is determined
based on worst-case assumptions. In the absence of an assay to detect impurity, it is
