Risk-Analysis Tools in Process Validation of Biopharmaceutical Drugs

Published on: 
BioPharm International, BioPharm International-03-01-2011, Volume 24, Issue 3

The authors review risk-assessment tools to evaluate product quality.


Process validation is required by cGMP regulations to ensure that process consistency and the ensuing product conforms to product requirements. A risk-based approach to process validation helps to identify crucial control parameters that affect product quality. The authors outline different risk-assessment tools, such as Failure-Mode-Effect Analysis (FMEA) and Fault-Tree Analysis (FTA) to evaluate the crucial factors and parameters affecting product quality, potential failure points, and the probablity of occurrence for each unit. The authors also review risk assessments performed on different cases from industrial production.

FDA defines process validation as establishing documented evidence to provide a high degree of assurance that the specific process will consistently generate a product that meets predetermined specifications and quality characteristics (1). The International Conference on Harmonization Guideline Q7A defines process validation as "the documented evidence that the process, operated within established parameters, can perform effectively reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes" (2).

These requirements are essential as they ensure the production of a safe product that minimizes the risk to patients. Risk analysis in process validation promises to minimize process risk. Risk-assessment tools help to define the process and identify crucial areas and/or steps in that process, areas of risk and/or hazard, and critical control points (3). Performing risk assessment of scale-up and/or manufacturing process is recommended as well. The entire risk-management team should include experts from multiple disciplines to ask the following questions:

  • What can go wrong in the process?

  • How frequently can it occur?

  • What are the consequences if this process goes wrong?

The information obtained from the risk analysis will only be useful, however, if the input is appropriate. The results from the risk assessment often dictate the number of unit operation steps needed to reduce specific risks to acceptable levels.



Risk management is a team-based approach fostering collaboration from a cross-functional team. Therefore, selection of people in this team is crucial for the success of the exercise. Teams should include individuals skilled in process development, manufacturing, validation, quality control, product characterization, method development, and quality assurance.

Table 1


The various types of risk that pharmaceutical companies confront include patient risk (i.e, safety of drugs), operational risk (i.e., operation safety and process variability), product-quality risk (i.e., endotoxin, viruses, host cell proteins, host cell DNA, protein ligands, refolding agents, and process additives), financial risk (i.e., product loss, reputation, and legal costs), and regulatory risk (i.e., FDA Form 483s, Warning Letters, product recalls, seizures, and legal actions) (3). An appropriate risk analysis can minimize process risk.

The various tools available for risk analysis are fault-tree analysis (FTA), failure-mode-effect analysis (FMEA), Ishikawa diagrams, hazard analysis, and criticalcontrol point (HACCP). In the report, Application of Hazard Analysis and Critical Control Point (HACCP) Methodology to Pharmaceuticals, expert committee members of the World Health Organization discuss FTA and FMEA in detail (4).

Figure 1. A Fault-Tree Analysis for production of mAbs. (Figures courtesy of the authors)


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).

Table 2


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).

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.

Table 3


This is the final step in risk assessment using FMEA. To perform the risk evaluation, an RPN number was calculated as demonstrated in Table III. For the chosen scale of analysis, the maximum RPN is 1000, the minimum is 1. The highest value observed was 280, the lowest was 56. The calculated RPNs are plotted in Figure 3. The action threshold was assumed to be 30 and unit operations having an RPN greater than or equal to 30 were included in the scope of process validation.

Figure 2. A process for production of mAbs considered for FMEA.

Figure 3. Calculated risk priority numbers (RPNs) from the actual process-validation failure mode’s effects.


This article covers the use of risk-based approaches to evaluate the scope of process-validation activities. The use of any particular tool will depend on a company's in-house expertise. The tools described above (i.e., FTA and FMEA) can be used alone or in combination with others. FTA is a top-down approach, whereas FMEA is bottom-up. The use of risk anlaysis also provides a consistent method for evaluating different risks on product quality. Further benefits of using risk-based approaches in process validation are shown in Table IV.

Table 4

Tarun Jain and Ashok Kumar are in the Department of Biotechnology and Environmental Sciences at Thapar University, Patiala-147004, India, tel. +91 9780207803, tarun7777@gmail.com.


1. FDA, Guideline on General Principles of Process Validation (Rockville, MD, May 1987).

2. ICH, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (August 2001).

3. A. Hamid Mollah, Bioprocess Int., 2 (9). 28–34 (2004).

4. WHO, Expert Committee on Specifications for Pharmaceutical Preparations, 37th Report, WHO Technical Report Series 908. World Health Organization, Geneva (2003).

5. J.M. Juran and A.B. Godfrey, Juran's Quality Handbook, 5th edition (McGraw Hill, Columbus, OH, 1999).