As an hypothetical example, Figure 1 shows a Pareto Plot of process parameters for the Sakura Tablet case study, which was
last revised in March 2009 by the Japan National Institutes of Health. The figure illustrates the Pareto concept also known
as the 80/20 rule. Many factors in a system are trivial and only a few factors are vital. As a rule of thumb, about 80% of
the problems come from roughly 20% of the factors identified. The plot provides insight into several aspects of risk management.
Figure 1: The Pareto Plot of Risk Priority Number (RPN), where risk=severity * probability * detectability. The RPN informs
the control strategy. As a process improves the probability or detectability changes, and the RPN adjusts accordingly.
First, it can be seen that the factors have been ranked by the magnitude of their risk. As one moves away from the origin,
the effect of subsequent factors decays logarithmically. Some factors clearly cause more risk. "The level of effort... should
be commensurate with the level of risk," according to the ICH Q9 guideline. These vital factors require the greater investment
The second point is that, following a logarithmic distribution, the identification of low risk, noncritical, and improbable
factors extends infinitely while their risk approaches zero. But where do we draw the line between the vital few and the trivial
many? Ultimately, that is a judgment call for negotiation between industry and regulatory authority. However it is a judgment
call to be made by experts backed with an in-depth understanding of the underlying science and a common covenant to work on
what is vital. The Pareto Plot does not provide hard lines of priority but can allow the negotiators to see the magnitude
between what is vital, what is perhaps important, and what is neither.
Risk analysis provides a starting point for continual improvement. It is the best tool we have today for recognizing our imperfect
understanding, prioritizing the work before us, and committing ourselves to the iterative process of improvement. In the pre-Q8,
Q9, and Q10 world, the inability to admit that our understanding was incomplete and that our systems were imperfect meant
a tremendous investment in maintaining a perception to the contrary and generated a culture of mutual distrust. If applied
correctly, the post-Q10 world could enable industry to move beyond a philosophy where every batch of a product is expected
to be a replicate of the validation runs.
Instead, we should set out with the intention to change our processes. We should be able to change them for the better. The
key is to recognize risk assessment as an ongoing process that combines both objective science and subjective judgment to
appropriately prioritize the allocation of resources. As the risk-control strategy is refined, risk is reduced, and new priorities
emerge. Our effort must be applied to the vital few things that matter.
*Note: The ideas in this article were generated during the October 2010 "Integrated Implementation Training Workshops for
ICH Q8, Q9 & Q10," which took place in Bethesda, MD.
Jason J. Orloff is a statistical and engineering consultant at PharmStat, 2000 Dempster Plaza, Evanston, IL 60202, tel. 847.424.1314,