PROCESS LIFECYCLE VALIDATION - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 187

TABLE 8.4 Severity Score and Study Strategy
Severity Score Experimental Strategy

High Multivariate study (DoE)

Medium Univariate study

Low No additional study required

influences important process performance outputs (e.g., titer, step yields or other
key performance indicators), but does not influence product quality is called a
key process parameter (KPP) by many biological firms [16]. Note that KPP could
influence product quality if an extreme deviation in that parameter were to occur.
Given here is an example of a risk-based approach for the identification of CPPs.
It is recommended that if an RA is used, it should follow a defined work pro-
cess (guidelines, expectations, milestones during development), which provides
support and training for conducting appropriate RAs for selecting potential CPPs.

8.7.2.1 New Products For new products, an RA can be incorporated in the
study design to determine whether there is a direct relationship between the pro-
cess parameters and a CQA. Also, the use of pilot, scale-up and manufacturing-
scale data will help determine if there are more CPPs.

8.7.2.2 Existing Products RAs and experimentation may need to be performed
to understand the nature of the change and the impact of process parameters and
material attributes on CQAs in the case of product/process improvement projects
that are in commercial manufacturing (Stage 3), such as:

• improving an existing quality characteristic;
• reducing or eliminating complaint(s);
• resolving an inspection observation;
• instituting a more efficient process (e.g., continuous process);
• instituting a real-time verification or monitoring program; and
• instituting new technologies such as PAT or real-time release testing.

This would include refining the criticality continuum (i.e., complete range of
scoring) in the initial relationships between CQAs and CPPs. On the basis of
an enhanced understanding of these relationships, an initial control strategy can
be designed or redesigned to demonstrate that a product of uniform quality is
produced consistently throughout the manufacturing process.

8.7.2.3 Effect of Processing Steps Some of the steps of drug product man-
ufacturing are notoriously more difficult than others. For example, blending a
powder mixture containing a very low percentage of an active ingredient such