Validation & Compliance: Using Risk Analysis in Process Validation - - BioPharm International


Validation & Compliance: Using Risk Analysis in Process Validation

BioPharm International
Volume 20, Issue 2


Table 3. Process FMEA table for cell culture bioreactor, buffer preparation, and ultrafiltration (UF) installation
Per Q9, risk identification is defined as identifying the hazards. Essentially, identifying the hazards answers the question, "What can go wrong?" This is a brainstorming activity with the team. This activity should generate many known and potential failure modes. The goal is to make this list as exhaustive as possible. Once the team completes the list, the failures are organized into an FMEA worksheet (Table 3). This worksheet will contain all of the information required to complete the analysis. The various failure modes are organized into the sheet according to which part of the process they related to, as outlined in the process flow diagram.

Since identifying all potential failures can be an enormous task when considering an entire manufacturing process, the process map generated during the initiation phase of the risk management process is a valuable tool to generate the logical breaks that organize and focus the brainstorming. In this study, the team generated a list of potential failure modes and the list was organized by the various unit operations identified in a process flow diagram. For this discussion, a subset of the failure modes for the cell culture production bioreactor, ultrafiltration (UF) installation, and buffer preparation were considered (Table 3).


The next step in the risk assessment phase is risk analysis. Risk analysis involves using the actual tool. Per Q9, the qualitative or quantitative estimation of severity or the consequence, and the likelihood and the ability to detect the failure, are determined during the risk analysis. Within the context of the FMEA, the potential effects of the various failure modes are identified and the scales for severity, occurrence, and detection are applied.

For each failure mode, there may be multiple effects. For that reason, the scales are applied to each effect. For example, one of the effects of incorrect buffer composition is that the buffer pH could fall outside operating limits. In this example, a severity value of 7 was assigned, because an excursion outside the operating range for buffer pH would result in an investigation tied to the disposition of a batch of product. The remaining potential effects of failure and the assigned severity, occurrence, and detection values are summarized in Table 3.

Next, the occurrence scale is applied to the failure modes. Referring back to Table 3, the occurrence value for the failure mode, "buffer composition incorrect," is a 4. According to the scale, this potential failure mode is expected to occur between >1% and <10% of the time.

The final scale value to assign is detection. The detection scale is applied to the failure mode or the effect. The detection value assigned to detecting an incorrect buffer composition is 1. Because the current controls can easily identify the failure mode or the effects of this failure mode (pH or conductivity measurements out of range during buffer preparation), the problem would be observed before the buffer were needed in the process.


The final step in the risk assessment is the risk evaluation. The risk evaluation is the gap analysis of the calculated risk relative to the acceptable level of risk (the action threshold). To perform the gap analysis, a risk priority number (RPN) is calculated. The RPN is calculated by multiplying the severity, occurrence, and detection values for each row in the FMEA table.

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