For the chosen scales in the analysis, the highest possible score would result in an RPN of 1,000 and the lowest possible
score is an RPN of 1. The highest value observed in Table 3 was 280 and the lowest value was 28. The calculated RPNs from
the actual process validation FMEA are plotted in Figure 2. Unit operations that had RPNs greater than or equal to the action
threshold of 30 were included in the scope of the process validation protocol. From Table 3, this included the cell culture
production bioreactor. Although not presented in the FMEA table, all of the primary unit operations for the cell culture and
purification process had RPN scores greater than the action threshold and were included as part of process validation.
Figure 2. The calculated risk priority numbers (RPNs) from the actual process validation failure modes effects analysis.
For unit operations with RPNs below the threshold, a secondary evaluation was performed. From Table 3, the buffer preparation
and UF installation underwent the secondary evaluation. The secondary evaluation may include whether there are procedural
requirements, regulatory commitments, industry expectations, or other requirements that would necessitate the adjustment of
the actual protocol. Of the two unit operations listed, the team agreed that the buffer preparation unit operation should
be included as part of process validation. Buffer preparation operations were added to the scope of process validation activities
based on past regulatory experiences. No such experiences necessitated the inclusion of UF membrane installation. Note that
UF membrane installation or other processes with RPN values below 30 that were not included as part of process validation
are controlled through manufacturing and standard operating procedures. This approach ensures that all operations are appropriately
controlled, and those operations with the greatest potential risk to product quality are controlled and validated.
At this point, the risk assessment phase ends. The risk management process would continue through the steps of risk control,
risk review, and communication. This implies that over the course of the product's lifecycle, the risk assessment is reviewed.
This review includes adjustments to regulatory requirements or to additional information related to the new process.
This case study represents a risk-based approach to evaluating the scope of process validation activities. Through the use
of a process FMEA, an objective assessment of the potential uncertainties and their effect on product quality were evaluated
and organized to make the most optimal decisions. The use of a risk-based approach also provided a consistent method for decision
making which was easily aligned with business goals such as resource allocation and ensuring patient safety. Ultimately, applying
such a risk-based approach to process validation should reduce the number of surprises or minimize their impact through the
consistent use of the tools, proper communication and periodic review. Finally, the risk assessment phase does not replace
the role or importance of the decision-maker. The output of the risk assessment should only support and objectively outline
the tradeoffs and the uncertainties relative to the meeting the goals of the company or the functional area.
Leslie Sidor is director of quality engineering and improvement at Amgen, 303.401.2285, firstname.lastname@example.org
Paul Lewus is a principal validation engineer at Amgen, 303.401.7421, email@example.com
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