PROCESS LIFECYCLE VALIDATION - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 201

Step 1: Gather Information (e.g., Process Mapping, Flow Charts, Historical)
Perform process mapping and list all processing steps, operating parameters, and
IPCs.

Step 2: Identify Potential Sources of Harm, Hazards, or Parameters to be Ranked
Identify all potential risk factors, failure modes, hazards, or parameters in the sys-
tem. At this step, it is important not to judge or evaluate the risk but to brainstorm
all potential hazards regardless of severity or frequency of occurrence. Potential
risks for fill/finish operations include patient safety; product degradation and
misbranding; microbial, endotoxin, viral, and chemical contaminations; product
quality and stability; vial integrity; and appearance.

Step 3: Define Scales (Severity, Occurrence, Detection) and Thresholds of the
Ranking Evaluate each risk factor, hazard, or parameter against the predeter-
mined scales and perform the ranking. FMEA or any other RA tool can be used
to determine risk ranking. Severity scales would be the consequences to prod-
uct quality or patient safety if the hazard were to result in harm. What are the
failure modes/hazards and their effects, pathways/sources/controls, and detection
mechanisms? Then, prioritize the risk based on the risk scores.

Step 4: Identify Area that Poses Highest Risk From the risk ranking data identify
steps or areas with highest risk scores using a Pareto analysis (Fig. 8.10). Scores
reflect cumulative risk profile per hazard/risk type to ensure controls are aligned
accordingly. Similarly, ranking can be performed to identify manufacturing steps
with highest risk, or alternatively an RA tool such as HACCP can be used
to identify, rank, monitor, and control the critical points in the manufacturing
process. Note: Critical control points (CCPs) may not be the same as CPPs.

Step 5: Experiment Design and Execution A DoE should be performed to deter-
mine design space and control range for CPPs. For parameters that pose minimum

Sterile bulk freeze and thaw process

4500 120

4000

100

3500

3000 80

2500

Count
% RPN (cumulative)

60

2000

1500 40

1000

20

500

0 0

Product
degradation

Microbial
contamination

Other
contamination

Product
misbranding

Hazard type

Figure 8.10 Pareto chart of hazard analysis for bulk thaw and freeze process.