Biomedical Engineering Reference
In-Depth Information
10.2.3 Work Process
The RFT work process consists of following four broad steps:
(1) Risk assessment
(2) Experimental planning
(3) Prioritization
(4) Experimentation
This is a repetitive process usually carried out at various stages of the development,
generally starting prior to the manufacture of ICH lots, prior to process validation lots,
and continues through postlaunch.
The Risk assessment steps consist of first creating a process map and identifying
“focus areas,” followed by identification of quality attributes and how they are measured
for each of the focus areas (FAs), then identifying process parameters using a cause and
effect matrix. The scores from the cause and effect matrix are generally used to prioritize
the parameters and then define the experimental approach.
The remainder of this chapter will be used to illustrate these steps.
10.3 EXAMPLES
10.3.1 Identification of Focus Areas, Process Parameters,
and Quality Attributes
This is the first task in the risk assessment involving creation of a process map and
identification of process parameters and quality attributes.
Identification of Focus Areas (FA).
The drug product manufacturing process
can be viewed as a progression of specific unit operations and defined as a process map.
The specific unit operations can be labeled as focus areas. Typically, drug product
manufacturing begins with compounding, but may require manipulation of the drug
substance (active pharmaceutical ingredient), especially if a biologic is used.
Compounding is directly followed by filtration, filling, and finishing. Additional unit
operations such as component preparation and in-process testing are inherent to drug
product manufacturing. Together, these make up the process map.
Figure 10.3 outlines an example of a process map containing focus areas that may be
identified for a liquid drug product. Many biologics are formulated at the last step of the
downstream purification process. In certain cases, minor dilution steps may remain, but
in general, the process of drug product manufacture primarily involves aseptic fill/finish
operations, (followed by lyophilization in approximately 50% of the products).
In the case considered here, a frozen drug substance requiring further dilution is
used. FA1 is identified as the thaw of the drug substance. Component preparation,
including manufacturing equipment, vials, stoppers, and overseals is identified as FA2.
FA3 is compounding or combining the drug substance with the other excipients required
in the final drug product. In-process testing is usually conducted during the compounding
