Since the publication of ICH Q9: Quality Risk Management in 2005 (1), there has been much written about the application of risk management to the production process, product development and validation (2–5). Relatively little has been published about its application to some of production’s supporting processes that comprise an important part of the pharmaceutical quality system (PQS). Annex 2 of ICH Q9 outlines the application of Quality Risk Management (QRM) to some of these supporting processes—change management/ change control, quality defects, auditing/ inspection, documentation, training, calibration/preventive maintenance and periodic review. The use of QRM should result in more effective and more efficient processes.
In 2008, the U.S. FDA’s Kimberly Trautman said, “A whole host of us still think of risk management as an FMEA…we can’t live with that,” adding, “We have to integrate that [risk management] more fully for our whole quality system” (6). In fact, ICH Q9 flat out states that, “QRM should be integrated into existing operations” (1). The real benefits from QRM arise when it is embedded in all processes, routine activities and the culture of the company. It is a way of thinking. The way to start achieving this goal lies in redesigning processes and their accompanying procedures to contain risk analysis as a formal and integral part of the process.
To illustrate the impact of embedding QRM in a company’s culture, consider the following example involving change control. The risk analysis takes into account the severity, consequences if a failure occurs, and probability or uncertainty of failure.
Change Control and QRM
The purpose of this risk analysis is to ensure that changes to critical process parameters do not adversely affect the process and, therefore, product quality. The process itself facilitates change—which is vital to continuous improvement. The seven specific process steps are outlined in Figure 1.
Figure 1 Change Control
There are three risk assessments required for this process, shown by Steps 2, 3 and 4. In Step 2, the originator of the change conducts a risk analysis as well as a cost/benefit analysis. What is the risk that the change will adversely affect the effectiveness and/or efficiency of the process? What is the cost of implementing the change versus its benefit to the manufacturing process? The originator’s supervisor repeats the analysis in Step 3. The most important risk analysis, performed by a member of QA, occurs in Step 4. The quality of this analysis depends on several factors:
- Competency of the QA professional
- The quality of the information supplied by the originator; this information should be supplied in a standard format to facilitate its review and understanding and to assure that it is complete
- Knowledge Management, meaning the originator and the QA professional have all the organizational knowledge available pertinent to the process affected by the change; it should be clear what are the critical material attributes (CMAs), the critical process parameters (CPPs) and the critical quality attributes (CQAs) of the product, and this information should be available for the production process, analytical methods, equipment, facilities and critical systems like air and water
- Both the originator and the QA professional should be able to talk to experts in other areas, such as engineering, production, regulatory affairs, quality control, etc.
For Step 5 (low risk changes), the QA professional gives the originator permission to implement the change. There is nothing more to be done. Of course, all is documented in a standard format. For Step 7 (high risk changes), there is the typical team review. The reviewers usually involve QA, QC, production, engineering, regulatory affairs, validation and others if needed. For Step 6 (selective review), the QA professional requires review by one or two experts before making a decision. Typically, one would expect that 75–80% of the changes are low risk, 15–20% medium risk and 10–15% high risk.
For training, the inductive method is recommended. This involves taking the last 100 changes and placing them into three categories—high, medium and low risk—under the auspices of a multidisciplinary team, i.e., 75% in low, 15% in medium and 10% in high. This usually involves some discussion and time. It works best if the team members have been thoroughly trained in risk thinking. After this sorting, the team looks at the three categories and describes what all the low risk changes have in common, and similarly for the medium and high risks. This can lead to a description of high, medium and low risk that can be expressed in a procedure. For training new users, the 100 concrete examples along with the procedure are used. The example of change control is only one example of the application of risk analysis to supporting, nonproduction or nonvalidation processes. Risk analysis can, and should be, applied to all processes. Risk analysis is invaluable in deciding how many checks, signatures and reviews are necessary. It is also particularly useful in setting up sampling plans for environmental monitoring, and materials sampling.
The real benefits of QRM come when risk analysis becomes part of our routine thinking and approach and when it is embedded in the design of all processes. It focuses limited resources, both capital and human, on the most frequent and severe issues, mitigating risk to the lowest possible level given the resources available.
Note: This article originally appeared in the PDA Letter, a publication produced by the Parenteral Drug Association. July 7, 2016
- ICH Q9: Quality Risk Management
- Ahmed, R., et al. PDA Technical Report No. 44. Bethesda: PDA, 2008.
- Ramnarine, E., et al. PDA Technical Report No. 54. Bethesda: PDA, 2012.
- Haddad, G., et al. PDA Technical Report No. 54-2. Bethesda: PDA, 2013.
- Harclerode, W. et al. PDA Technical Report No. 54-3. Bethesda: PDA, 2013.
- “FDA Device Center’s Trautman On Quality System Lessons And Goals.” International Pharmaceutical Quality, Jan./Feb. 2008
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