Establishing Specifications for a Process-Related Impurity
Process-related impurities are impurities that are derived from the manufacturing process.2 These could be extractables and leachables from the media or the additives such as cell culture media components and chromatography
column leachables. Specification setting for many of these process-related impurities is driven by regulatory expectations.
Figure 4 illustrates the clinical and product design spaces for three host cell impurities, namely HCPs, residual DNA, and
endotoxin. It should be noted that HCP and residual DNA data are plotted on the log scale (left axis), whereas the endotoxin
data are plotted on a linear scale (right axis). In comparison to the product quality attributes presented in Figure 3, it
is seen that the product design space is significantly larger than the clinical design space for the host cell impurities.
This is primarily a result of a better understanding of these impurities and their impact on product safety and efficacy,
as well as the demonstrated excess capability of the process to remove these impurities. In addition, prior knowledge from
other products expressed in the same host cell is very applicable for these impurities.
Figure 4. Illustration of clinical and product design spaces for three host cell impurities chosen from Table 1. Host cell
protein (HCP) and residual DNA data are plotted on the log scale (left axis) wheras the endotoxin data are plotted on a linear
scale (right axis).
Setting specifications in the QbD paradigm will involve using product knowledge, process knowledge, prior knowledge, and appropriate
statistical methods to define meaningful specifications. This approach also must include a continuous improvement element,
so that the specifications are revisited and their appropriateness re-examined to reflect changes in process (process improvements,
technology transfer, scale-up, equipment changes), analytical methods (novel techniques), and product knowledge (new clinical
and nonclinical data).
Anurag S. Rathore, PhD, is a biotech CMC consultant and a faculty member at the Indian Institute of Delhi, India, 9650770650, firstname.lastname@example.org
. Rathore is also a member of BioPharm International's editorial advisory board.
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