BIOPHARMACEUTICAL MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 320

affects product safety, efficacy, and purity, it is referred to as a critical qual-
ity attribute (CQA) [3]. By definition, all specifications are considered to be
CQAs [4].
CQAs should address those aspects of the product that are indicative of prod-
uct safety and efficacy. Historically, CQAs have been synonymous with product
release tests. In recent years, however, health authorities have acknowledged that
not all release tests are necessarily CQAs. Companies have been encouraged
to utilize risk management techniques to analyze products and identify those
attributes that are truly critical to safety and efficacy. While many risk manage-
ment tools may facilitate such analysis, a failure mode and effects (FMEA) type
approach is frequently used. A simple model for identifying CQAs is shown in
Figure 12.1.
In such a model, the severity of harm resulting from a failed attribute and the
likelihood of occurrence of such a failure are used to identify potential CQAs.
The data needed to perform the assessments noted in Figure 12.1 may be drawn
from a variety of sources. Data from preclinical and clinical studies may be used
to assess severity and likelihood of specific compounds. In addition, analysts may
utilize historical information from similar compounds to establish a preliminary
assessment of risk.
Quality attributes are influenced by process parameters. Process parameters
with a high potential to influence CQAs are defined as critical process param-
eters (CPPs) because they have the potential to impact product safety and effi-
cacy. Again, the identification of CPPs can be facilitated using risk management
approaches such as fish bone diagrams and FMEAs. A simple approach to CPP
identification is shown in Figure 12.2.
The analysis is undertaken by first creating a process map that establishes
the process steps, parameters, and target values for the entire manufacturing
operation. While separate process maps may be prepared for individual process
steps as described in this chapter, they should include all phases of the process
having the potential to impact product quality.
Once a process map has been prepared, the individual process parameters
may be evaluated to assess their potential impact on final product quality. The

Assess severity of
excursions beyond
specification limits

Assign criticality to
individual quality
attribute

Identify quality
attributes

Assess risk
acceptability

Assess likelihood
of occurrence of
excursions beyond
specification limits

Figure 12.1 Identification of critical quality attributes.