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

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Validation & Compliance: Using Risk Analysis in Process Validation


BioPharm International
Volume 20, Issue 2


Figure 2. The calculated risk priority numbers (RPNs) from the actual process validation failure modes effects analysis.
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.

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.

CONCLUSION

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,
Paul Lewus is a principal validation engineer at Amgen, 303.401.7421,

REFERENCES:

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2. Code of Federal Regulations, Title 21, Food and Drugs. Part 820, Quality System Regulation, 820.75 (a).

3. US Food and Drug Administration. Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach. Final Report. Rockville, MD; 2004 Sept.

4. International Conference on Harmonization. Q9, Quality Risk Management; 2006 June.

5. Vesper JL. Risk assessment and risk management in the pharmaceutical industry clear and simple. Baltimore, MD: Parenteral Drug Association; 2006;74–76.

6. Chan TC. A HACCP framework for risk management in bio/pharmaceutical processes. PDA Letter. 2005 Mar; XLI(3): 1, 14–19.

7. Juran JM, Gruna FM. Quality planning and analysis from product development through use. New York, NY: McGraw-Hill Book Company; 1980; 167–200.

8. McDermott RE, Mikulak RJ, Beauregard MR. The Basics of FMEA. Waitsfield, VT; Resource Engineering, Inc.; 1996.

9. O'Donnell K, Greene A. A risk management solution designed to facilitate risk-based qualification, validation, and change control activities within GMP and pharmaceutical regulatory compliance environments in the EU. Part I, fundamental principles, design criteria, outline of process. J GXP Compl. 2006 July;10 (4):12–25.

10. O'Donnell K, Greene A. A risk management solution designed to facilitate risk-based qualification, validation, and change control activities within GMP and pharmaceutical regulatory compliance environments in the EU. Part II, tool scope, structure, limitation, principle findings, and novel elements. J GXP Compl. 2006 Jul;10(4):27–35.


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