Table II: Values considered key operating parameters to product, process, and design performance.
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One possible justification for determining CPPs is given in the following example. To normalize and standardize the effect
size, the percent of tolerance for two-sided specification limits and the percent of design margin for one-sided limits were
used to evaluate the effect size of a factor and or interaction. Values of <10% were not considered practically significant.
Values of 11–19% were considered to be key operating parameters and values >20% were considered to be CPPs critical to product,
process and design performance, as shown in Table II. Although thresholds for criticality are somewhat arbitrary, they have been set relative to the design-space explored and
as a percentage of the CQA attribute and therefore should have product performance relevance.
Application of CPPs for control.
CPP selection typically comes from several sources, including risk assessments, scientific knowledge, and characterization
and optimization studies. Once all CPPs have been identified, the next step is to determine practical application of them
for process control. Typical considerations include: ease of use and/or ease of adjustment; safety and other risk factors;
on-line or in-line measurement; and off-line or near-line measurement. Just knowing that a factor is critical and knowing
the relative effect size of the factor to the product specifications and CQAs is a great start but it is not sufficient. Care
needs to be exercised to make sure the CPP factors can be used in a safe and effective way to consistently adjust process
parameters to their intended targets. Linking statistical process control (SPC) and process analytical technology (PAT) methods
to the sensitivities identified during CPP selection is a big plus and ties the adjustment method together with process monitoring
and control methods (5).
Thomas A. Little, PhD, is president of Thomas A. Little Consulting, 12401 N Wildflower Lane, Highland, UT 84003, tel. 925.285.1847, drlittle@dr-tom.com
References
1. ICH, Q8 (R2) Pharmaceutical Development (2009).
2. ICH, Q9 Quality Risk Management (2006).
3. ICH, Q10 Pharmaceutical Quality System (2009).
4. ICH, Q11 Development and Manufacture of Drug Substances, Step 4 document (2012).
5. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (2004).
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