This legitimate question is often asked. It’s also often asked if the design space concept is unique to pharmaceutical and biotech industries. If not pharma, what was the origin of the design space? This search for answers turns up some important lessons, but let’s not get ahead of our story.
A frequently cited reference for Quality by Design (QbD) is the book by Juran (1992) titled, “Juran on Quality by Design.” A review of Juran’s book turns up a lot about the fundamentals of QbD, but there’s no mention of the design space. So what are the origins of the design space?
Our story begins in the 1920s with R. A. Fisher. Fisher founded the field of statistical design of experiments (DOE) while working on agricultural and biological research studies in Rothamstead Experiment station in England. Fisher was frustrated that existing data collected without any structured plan or design did not yield any useful results. He published the first book on the subject (Fisher 1935). DOE is, of course, a critical building block of QbD.
The need Fisher was addressing with DOE was the need to effectively design experiments that produced useful, repeatable results. His work included the demonstration of the value of randomization, replication and blocking, as well as the value of factorial designs that enable one to estimate both the main effects and interactions of variables being studied.
Fast forward some 25 years and we find that in the late 1940s and early 1950s that DOE as a discipline was just gaining acceptance by industry. At the time, there was only one book on the topic, “Industrial Experimentation” by K. A. Brownlee (1949). The need in this case was how to effectively experiment with industrial processes. The big advance, paradigm shift in modern terms, came with the publication of the paper, “On the Experimental Attainment of Optimum Conditions” by Box and Wilson (1951). This paper addressed the problem (the need) of optimization of processes, which led to the idea of an operating window, which in pharma parlance is called the design space. Box and Wilson were working at Imperial Chemical Industries researching how to optimize chemical production processes. Their approach later became known as response surface methodology (RSM).
So how did the design space idea reach pharma? In the late 1960s and early 1970s, Joe Schwartz, a scientist at Merck saw the value of using RSM and process optimization in the development of formulation processes. He continued his research at the University of the Sciences in Philadelphia and educated several graduates on the subject who went to work in the pharma industry.
But the RSM approach didn’t catch on in pharma like it did in the chemical and other process industries. Apparently the process improvement need wasn’t yet identified in pharma. In the early part of this century, however, the FDA saw the need for pharma to improve its processes and developed the idea of QbD as the overarching system to aid the process.
One of the central leaders of the effort at the FDA was Ajaz Hussain, who was aware of Schwartz’s work and deepened his knowledge of the subject by communicating with Schwartz to learn about the approach from the master himself.
And that, friends, is how the design space concept came to be adopted by the pharma and biotech industries today. A nice history lesson indeed, but there is more we can learn from this story. First is the fact that major changes — so-called paradigm shifts — take a long time — sometimes a generation or more before a new idea becomes standard practice. The adoption of a new idea moves forward most rapidly when a major need has been clearly identified and agreed upon, a usable solution has been developed, and clearly and continuously articulated by the adopters.
We also see that few ideas are completely new, but build on the ideas of others. Indeed we stand on the shoulders of giants; in this case, Fisher, Box, Schwartz and Hussain. Clearly QbD, with its design space built on a sound foundation, is worthy of your consideration.
