USING A RISK ASSESSMENT PROCESS TO DETERMINE CRITICALITY OF PRODUCT QUALITY ATTRIBUTES - Quality by Design for Biopharmaceuticals - page 58

assumed that all of the impurity in the process copurifies with the product and no
clearance is achieved by the purification process. Although this is a conservative
assumption and unlikely to occur when orthogonal methods of separation are used in
a purification process, it nevertheless allows calculation of the maximum potential
content in the final product as a worst-case calculation. In the cases where a sufficiently
sensitive assay is available, the actual level of an impurity in the product is determined on
the basis of assay quantitation.
LD 50 values can be found in the literature for many process-related impurities.
Therefore, the LD 50 values represent an available and quantitative indicator of acute
toxicity that provides a useful comparator for assessing the risk posed by process-related
impurity. However, the LD 50 is a relatively imprecisemeasure of toxicity, andLD 50 values
are generally orders of magnitude higher than the levels of process-related impurities.
Anothermeasureof toxicity, theNOAEL(noobservedadverseeffects level), represents the
levelofacompoundshowntobesafeinanimal experiments.NOAELincludesa longer term
andmore comprehensive assessment of organ systemsafety compared to acute lethality by
LD 50 measures. BecauseNOAEL is not readily available formost compounds, it cannot be
routinely employed as a measure of safety. However, when both LD 50 and NOAEL
measures are available, they provide a link between safety and toxicity and are useful
for the assessment of risk. Literature searches have revealed examples of compounds for
which both NOAEL and the LD 50 values are reported, and these examples show that
NOAEL is generallyone to two orders ofmagnitude below theLD 50 values. On the basis of
this rationale,wedesignatedan ISFvalueof1000as representingaconservativeestimateof
safety where values at or above this threshold represent minimal risk.
The risk assessment strategy consists of a series of steps to evaluate impurity in terms
of its risk to product safety. This process is outlined in Fig. 4.3 as a decision tree.
Impurities can be eliminated from further consideration at any step where the safety risk
is determined to be minimal.
Figure 4.3. Representation of process-related impurities safety assessment strategy.