SILVER SPRING, Md.—The U.S. Food and Drug Administration (FDA) has issued a challenge that scientists and academics are racing to fulfill: to successfully transform batch-based drug manufacturing processes to the more efficient, higher-quality and higher-yield method known as continuous manufacturing (CM). In response to the FDA’s directive, backed by agency grants and DARFA’s deep pockets, researchers are seeking prime candidates for commercialization of a CM success story. A research team at Purdue University’s Center for Cancer Research has reported initial success in the continuous manufacture of lomustine, a cancer drug indicated in the treatment of Hodgkin lymphoma and certain brain cancers.
“There are many factors that must be balanced to achieve an efficient continuous manufacturing process for production of a target drug molecule,” according to Purdue’s David H. Thompson, a professor in Chemistry and a member of the Center for Cancer Research. “Each step must be evaluated in a multistep drug synthesis to determine those transformations that are best done in flow verses those that are best performed in a conventional reactor.”
Traditional batch processing involves adding all of the raw material(s) into the system at the beginning of the process, with the product being discharged all at once some time later, within a closed system—no more ingredients go in, and nothing comes out until the finished product is attained. In CM, material(s) and product are continuously charged into and discharged from the system, respectively, throughout the duration of the process, with outputs from each process step continuously moving to the next step for further processing. Each processing step needs to reliably produce an intermediate material or product with acceptable characteristics, according to a consistent and predictable timeline. Within six months, Thompson’s team developed a method to make lomustine at a rate equivalent to one dose every two hours using continuous manufacture.
“We first examined the steps that had been published for this compound and selected the routes that seemed most direct and efficient. We then used a high-throughput experimentation (HTE) method to identify the set of preferred conditions for the reactions to make lomustine. Next, we used those conditions identified by HTE to optimize the individual reactions in flow. The final step was 'telescoping' the reactions, such that the output from the first reactor was fed into a continuous extractor and then into the second reactor. The lomustine product was collected and then recrystallized in a batch process to produce highly pure lomustine,” details Thompson. “We were successful ... because the pathway was short (two steps) and we were able to balance the needs of the two reactions and integral liquid-liquid separation step.”
The FDA is financially and philosophically committed to advancing CM, as it promises to revolutionize the availability of certain critical treatments. According to an FDA statement issued in February, CM is “a key step towards promoting drug quality and improving the efficiency of pharmaceutical manufacturing. [We are] committed to helping more companies advance these CM platforms, owing to the public health benefits of these more modern approaches. We support the early adopters that are embracing this innovative technology and we look forward to working with other interested companies.”
Starting with just four inexpensive commercially available initial materials, the Purdue team prepared lomustine in just nine minutes using a linear sequence of two chemical reactions performed separately in two telescoped flow reactors, allowing for rapid manufacture of lomustine while avoiding some of the needed steps for batch processing, thereby significantly increasing the purity and yield of the active agent. The ability to reduce production costs has the potential to allow for more agile and cost-effective production of many life-saving medicines. The shared goal for CM is to improve manufacturing flexibility, enhance quality and uniformity, and reduce costs for patients. CM shows particular promise in personalized and regenerative products aimed at very small patient populations, groups too small to warrant large-scale, batch-processed drug development.
The Purdue researchers, the FDA and others working on drug discovery are heartened by CM’s promise, not just with lomustine, but many other potential products. Says Thompson: “One of the most exciting aspects of our combined HTE and continuous synthesis capability is the chance we have to both devote it to the preparation of new lead compounds at Purdue, and democratize the capabilities of the system to other members of the Purdue synthetic chemistry community. Expansion of these tools to a larger set of users will also teach us the strengths and limitations of these tools.”