McGarvey’s presentation at AAPS PharmSci360 detailed how an operational control strategy can be a key step in accomplishing quality by design, and how a first principles based approach can improve efficacy and efficiency in manufacturing.
The first principles of engineering are foundational propositions and assumptions that cannot be inferred from any other theory.
“First principles are like the rules of the game, the problem with nature is that nature is an infallible referee. When you play football, you can get away with breaking the rules now and again – nature isn’t like that,” explained McGarvey.
When it comes to pharmaceutical manufacturing, McGarvey believes that by understanding the foundations of engineering you first understand how the system works by understanding its buildings blocks.
He said some questions to consider are, “How does the system actually work? What’s important? What is able to determine the behavior of the system that I can then take advantage of that knowledge and make that system operate the way I want it to operate?”
When applying these first principles, the thought process for McGarvey are that if one understands the pieces of the system, one understands the system.
In his keynote he stated, “We [the pharmaceutical industry] are really trying to implement quality by design. It’s relatively new to the pharma industry. The overall purpose is to create, implement, and maintain a process that delivers all that is required reliably from the first day.”
Testing and solving
He further explained that by applying first principles it forces one to slow into thoughtful, reflective and rational thinking, going from specific problems to a generic solution. That generic solution uses the first principles which are infallible.
“I can use first principles to determine if something couldn’t be the root cause, and quickly determine what the root cause is,” he said in his keynote.
To do so, he explained that the first approach to design or re-design is taking a pencil and paper and thinking about the mechanics that are actually going on within the system.
He told us, “If something is happening on the output side, it’s because of something happening on the input side.”
“I took 50 or 60 manufacturing incidents that I’d been involved in or knew about, and traced back the root cause, and basically what it is telling us is that 65% to 75% are in the design,” he elaborated.
Continuous or batch?
Testing that model or remodel should be done through verification and validation, according to McGarvey. “Testing a logical model should be based on the extent we would test a physical model tasked with helping to make the same decisions,” he said in his keynote.
First principles can be applied to either batch or continuous manufacturing. However, to McGarvey, continuous manufacturing is “déjà vu.”
“I would argue this when I did my chemical engineering training back in 1975, all we talked about was continuous. Everything was continuous. That’s because analysis of continuous systems is straightforward,” he told us.
To him there are some advantages to batch process that completely subsume other considerations in manufacturing. The pieces of a batch manufacturing process are disjointed allowing for more efficient problem solving, “If you have a problem with one batch, you don’t have to worry about another batch necessarily.”
However, if a company uses batch or continuous, problem-solving can be done using a method of first principle application.
A broader application
McGarvey mentioned a broader application of first principles and how it can be used in all aspects of pharma beyond manufacturing.
“What we found in practice was, by forcing people to think this way [first principles], it was a way of freeing up thinking. Imagine your brain is full of magnets and they’re all scrambled in different directions, first principles gets your brain orientated,” McGarvey told us.
He is not the only engineer to speak out on the subject of applying this method of thinking. Elon Musk, noted entrepreneur and engineer, gave an interview to the publication Wired in which he mentioned applying the thought process to his own work.