Guinn noted that Pfizer started a “serious effort” about a year ago to enable flow chemistry to assist in developing its early-phase portfolio. “The driver for doing this is speed to API,” he said.
Of late, there’s been much more interest in flow chemistry, Guinn acknowledged, but “we also know there aren’t many examples of continuous processes going into manufacturing.” One of the keys to changing this is doing more pre-Proof of Concept (i.e., pre-Phase II) flow chemistry work, he said.
One of the traditional bottlenecks in early-phase manufacturing has been the ability to make substantial amounts of API within the time constraints of early clinical work. “We need to make a lot of API, and quickly,” he said. “That’s where the value proposition for flow is.”
Flow chemistry, Guinn said, enables:
- a broader chemical space
- the ability to directly scale medicinal chemistry routes
- improved selectivity and reactivity
- the ability to prepare larger quantities of material with the same hardware (that is, to just run equipment longer).
All of these elements relate to speed to delivery and speak to a clear value proposition, Guinn noted.
He next presented examples of work done, and equipment used, in one of Pfizer’s kilo labs. In one standard reaction, 1-2 kg of product was produced in a day via flow operations, whereas it typically required one week to produce the same amount through batch processes. Guinn also presented examples of some of the modeling being done to support these efforts.
Some of the keys to success of pre-POC flow work, according to Guinn:
- the creation of a dedicated pre-POC flow team (chemistry, engineering, process safety, analytical)
- integration of key skill sets and capabilities
- creation of a Flow Lab for small-scale prep and technology development and assessment
- improving workflows for indentifying “flowable” substrate and for making a rapid flow assessment.
Of course, there are also many opportunities for using flow chemistry post-POC—for example, in isolation and drying—and this work will complement early-phase flow chemistry. Pfizer already has several products (Celebrex and Lyrica are two) that have made use of some flow elements in second-generation manufacturing efforts.
Guinn expects to see more flow chemistry in first-generation product development efforts as well. In order for this to happen, manufacturing teams must overcome many traditional challenges:
- existing batch manufacturing capacity means that there is “not as much pull from manufacturing colleagues for flow processes”
- there is lower API demand for new products, and thus materials cost is not as much of a driver as it has been in the past
- regulatory and operational challenges
- suitable batch synthetic strategies
“Work doing in pre-POC will ultimately have some influence in post-POC,” he said. Regardless, “if we can expand process chemistry [using flow] in the pre-POC space, we will have been successful.”