The issuance of the FDA's guidance in 2004 advocating a risk-based approach to current good manufacturing practices (cGMPs)
has changed the basic paradigm for quality in the biopharmaceutical industry. This guidance advocates using scientific inquiry
as a foundation for developing quality initiatives that will ensure ongoing product quality. Managing risk in the product
development lifecycle presents the industry with an opportunity to optimize the time, resources, and cost of developing a
drug product. This same opportunity extends to the establishment of our quality argument and all of its related systems.
The challenge in embracing this new approach to quality is shifting from the traditional mindset based on blanket inspection
and testing to one driven by control and monitoring. We must change our approach and quality standards for troubleshooting
and prevention if we are to realize the agency's vision of quality and business synergy. In an industry where the ratio of
quality to operations personnel can reach 3:1, as is often seen in large biopharmaceutical operations, the concept that quality
can operate synergistically with the needs of the business is a radical departure from what we have experienced for the last
With this shift in philosophy by both industry and the regulatory bodies, we find ourselves reinventing our approach and expectations
to fundamental quality activities, such as root cause analysis (RCA). RCA is an approach to problem solving aimed at identifying
the basic drivers or causes for problems or events. The philosophy behind RCA is predicated on the belief that problems are
best solved by attempting to correct or eliminate root causes, as opposed to merely addressing the immediately obvious symptoms.
In investigating a problem or event, there are three basic components we need to understand. We have the symptom, which is
the failure observed against the expected performance; the mechanism that drove the failure; the contributing state or events
that may have supported the failure; and the actual root cause of the failure. Separating these components is the key to an
effective root cause analysis. The relationship among these components is shown in Figure 1.
Figure 1. Relationship among the components of root cause analysis.
By directing corrective measures at root causes, it is hoped that the likelihood of problem recurrence will be minimized.
However, we recognize that complete prevention of recurrence by a single intervention is not always possible. To be effective,
RCA is often a highly iterative process, and is frequently viewed as a tool for continuous improvement.
There is no single approach to RCA: it is an amalgam of different tools, processes, and analyses applied appropriately to
identify the source of the problem or event. Even so, RCA exercises have not always been completely objective. We have all
seen the corrective action and preventative action (CAPA) documents which have been closed, with the recommended root cause
and corrective action being operator retraining. In such cases, the problems invariably reappear later because the corrective
action was off the mark. An effective corrective action based on an effective RCA should eliminate the problem or event from
happening again. In the absence of this reality, the RCA was not effective.
The lack of a disciplined approach to RCA has undermined the effectiveness of CAPA programs and often leads to recurring issues
with products. As a result, the focus of many FDA inspections has been the quality and defensibility of RCAs, which are often
used to close out a CAPA. Nevertheless, the emphasis in the biopharmaceutical industry on moving toward a more process-centric
rather than a product-centric philosophy for quality assurance has laid the groundwork for a more effective RCA exercise.
The emergence of operational excellence initiatives has rekindled interest in structured problem solving techniques such as
Kepner-Tregoe that methodically drive the analysis toward an objectively defensible final conclusion. But the one thing we
have learned as an industry is that there is no magic bullet, no one-size-fits-all solution that we can just buy and implement
to meet this shift in quality philosophy. However, a common framework defines all good investigative processes. This article
describes and illustrates the application of one approach that is very effective in integrating the basic tenets of Quality
by Design and risk management as purported by ICH Q10 as a methodology for an effective RCA.