Risk-Analysis Tools in Process Validation of Biopharmaceutical Drugs - The authors outline different risk-assessment tools to evaluate the crucial factors and parameters affecting product quality, pot

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Risk-Analysis Tools in Process Validation of Biopharmaceutical Drugs
The authors outline different risk-assessment tools to evaluate the crucial factors and parameters affecting product quality, potential failure points, and the probablity of occurrence for each unit.


BioPharm International
Volume 24, Issue 3, pp. 44-48

FAULT-TREE ANALYSIS


Table 2
FTA is a top-down approach to failure-mode analysis (5). This tool provides a retrospective analysis designed to answer the question, "What caused this failure to happen?" In this approach, one uses Boolean logic (e.g., AND/OR gates) to organize the information in the form of a Fault-Tree Diagram. The failure can be identified, as can the conditions that gave rise to it. These conditions are connected to the main failure with logic-gate operators, which are represented in the form of a Fault-Tree Diagram. For further discussion of FTA, failure mode for production of monoclonal antibodies (mAbs) was assumed. Taking the case of low product titer, a fault tree was created to find the causes of this failure (see Figure 1).

FAILURE-MODE-EFFECT ANALYSIS (FMEA)




FMEA is a bottom-up approach to failure mode analysis. This tool is used to look forward in time. FMEA is designed to answer the question, "What would happen if this failure occurs?" FMEA combines technology with the experience of people to identify potential failure modes of the product or process and enables one to plan for its elimination. Table II shows steps to execute an FMEA. The first two steps are common to all risk-management case studies. Next is to design a 10-point scale to rate severity, occurrence, and detection. Each value of the scale is well defined. This scale makes the design-making process easy, as well as more effective and understandable. Severity (S) is a measure of the consequences of failure. Occurrence (O) is a measure of the frequency of failure. Detection (D) is the ability to recognize the potential failure before the consequences are observed. After these parameters are rated, the process is represented in the form of a block diagram. Further, the risk-priority number (RPN) is calculated by multiplying S, O, and D values (see Eq. 1).


Table 3
RPN is used to access the risk of unit operations, which form the whole process. After determining all the RPNs, the failure mode with highest RPN should be given highest priority for corrective action. For this discussion, production of monoclonal antibodies was considered. Figure 2 shows the process that was considered, and Table I shows the scales of S, O, and D to conclude FMEA analysis. Finally, a FMEA table (see Table III) was generated by taking into consideration points from Table I.


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