In a conversation at CPHI Barcelona last week, Paul Quigley, principal research fellow of drug substance at Quotient Sciences, explained how the contract development and manufacturing organization (CDMO) is embracing this innovation and how regulators are adapting to its potential.
To enter the market, drug developers must develop ways to manufacture the API – the drug substance forming the active part of the finished product. The manufacturing process also must meet critical quality assurance guidelines set by regulators, known as Good Manufacturing Practices (GMP).
APIs have traditionally been manufactured via a method known as batch production. This can require hundreds of tonnes of raw materials and it often takes months to complete the manufacturing process. Another major drawback of this process is that it can be difficult to carry out safely and sustainably when using hazardous reagents at high temperatures and pressures.
To address this obstacle, Quotient Sciences is one of a growing wave of companies exploring an alternative approach known as flow technology, or continuous flow manufacturing. Using this method, reagents are mixed continuously in pipes and require much lower volumes of hazardous reagents than in batch processes. According to Quigley, this could cut waste in the manufacturing process and make it safer, quicker, and cheaper.
“Flow [technology] has been around for centuries,” he said, adding that the process is often used to manufacture industrial chemicals in bulk using catalysts. But its impact in the pharmaceutical industry is only starting to grow, and the World Economic Forum included it in its top 10 emerging technologies in 2021.
Flow technology benefits for CDMO customers
Established in 1990, Quotient has hundreds of clients, with the majority being biotech and big pharma companies. The CDMO’s Translational Pharmaceutics platform is designed to streamline drug development by handling drug substance, drug product, and clinical testing activities all in one organization.
As biotech companies face tight funding conditions in the current markets, Quigley explained that Quotient’s drug development acceleration platform is in higher demand than ever. “All the time, every biotech needs rapidity. The most important thing for most biotechs is time,” he said. When biotech companies raise money, “it's a cash burn to get to that key clinical milestone faster,” he added.
Flow technology is one of many innovations that Quotient is deploying to speed up the production of drug substances. In a project with the US National Institute of Health (NIH), the firm was tasked to innovate on the batch manufacturing process of a drug candidate, which was producing low yields and high impurities. Quotient overhauled the manufacture of the drug substance by using ethanol as a solvent and implementing a continuous flow process.
“It radically simplified it,” noted Quigley. “It was much easier; we were able to do three stages in one with much higher purity, much higher reaction, faster delivery, and we were able to take months out of the delivery for the client.”
Using flow technology also opens up the manufacturing process to other innovations. Quotient is also exploring the use of methods such as electrosynthesis and photochemistry to make API manufacturing more efficient – advances that are difficult with batch processes due to the huge volumes involved.
“Try to shine a light in a batch process; it only permeates to a small depth,” said Quigley. “You can have high intensity light in flow [technology] because it permeates all the way. It doesn't take a rocket scientist to think that flow is a really good option.”
Challenges and regulations
While continuous flow manufacturing has big promise for the pharmaceutical industry, there are still hurdles to overcome when scaling it up to GMP standards. Additionally, manufacturers still need to isolate the final materials from the continuous flow process once it is done, which often requires returning it to a batch process.
“That element of continuous production is still in its infancy,” said Quigley. “We aspire to come up with technical solutions that can do the isolation on a continuous basis. We're not there yet as an industry.”
Another consideration is that manufacturers considering a switch to continuous flow manufacturing need to carefully consider regulatory compliance in addition to process validation and data management. Nonetheless, regulators are evolving their guidelines to keep up with rapidly advancing flow technology in the pharmaceutical industry.
“With flow technology, some of the regulators took a while to respond, but they have responded,” said Quigley. He added that the U.S. Food and Drug Administration (FDA) is one of the most pragmatic regulators with regards to the technology and that European agencies are catching up.
The next generation of drug substance manufacturing
As technology marches on in the biopharma space, Quigley sees demand changing from customers. For example, larger molecules are becoming established, leading to requests for the development of antibody-drug conjugates (ADCs) and proteolysis targeting chimeras (PROTACs). Additionally, customers are clamoring to make their products more economical and less damaging to the environment.
To meet shifting demands, Quotient sees continuous flow manufacturing playing a key part in future drug substance manufacturing. Additionally, the company is partnering with experts across the industry to harness novel technologies such as synthetic biology.
“There is an ongoing race for new drug delivery technologies,” commented Quigley. “We continue to invest on the technology side for drug delivery.”